Vol 19.2 Dementia.2013

Continuum: Lifelong Learning in Neurology—Dementia, Volume 19, Issue 2, April 2013
Issue Overview
Dementia, April 2013;19(2)
Continuum: Lifelong Learning in Neurology® is designed to help practicing neurologists stay
abreast of advances in the field while simultaneously developing lifelong self-directed learning
skills.
Learning Objectives
Upon completion of the Continuum: Lifelong Learning in Neurology Dementia issue,
participants will be able to:
► Recognize the key features for the diagnosis of Alzheimer disease, vascular dementia, and
frontotemporal dementia
► Apply the newly proposed criteria for the diagnosis of Alzheimer disease
► Identify the appropriate use of CSF and imaging biomarkers in clinical dementia diagnosis
► Use appropriate pharmacologic and nonpharmacologic approaches for the management of
patients with dementia
► Summarize the latest research advances in the diagnosis and treatment of dementia
► Recognize the diagnostic and treatment challenges of dementia in the oldest old
Core Competencies
The Continuum Dementia issue covers the following core competencies:
► Patient Care
► Medical Knowledge
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

► Practice-Based Learning and Improvement
► Interpersonal and Communication Skills
► Professionalism
► Systems-Based Practice
Disclosures
CONTRIBUTORS
Claudia Kawas, MD, Guest Editor

Professor of Neurology and Neurobiology & Behavior, University of California, Irvine, Irvine,
California
*Dr Kawas serves on the data monitoring committees for Eli Lilly and Company and Quintiles Inc, and receives a
research grant from Avid Radiopharmacuticals.
†Dr Kawas reports no disclosure.
Ammar A. Alobaidy, MD
Behavioral Neurology Fellow, University of Toronto, Toronto, Canada; Senior Specialist in
Neurology, Sultan Qaboos University Hospital, Sultan Qaboos University, Muscat, Oman
*Dr Alobaidy reports no disclosure.
†Dr Alobaidy discusses the use of medications for the treatment of behavioral and psychiatric symptoms of
dementia, none of which carry indications from the US Food and Drug Administration. The text cites reviews of
clinical trials in frontotemporal degeneration as applicable, as well as case reports, but clinicians are urged to
specify that any such use of medications should be openly discussed with patients and substitute decision makers as
off-label prescriptions.
Virginia D. Buckles, PhD

Research Professor of Neurology and Executive Director of The Charles F. and Joanne Knight
Alzheimer’s Disease Research Center, Washington University School of Medicine, St Louis,
Missouri
*†Dr Buckles reports no disclosure.
Szófia S. Bullain, MD
Clinical Instructor and Geriatric Neurology Fellow, Department of Neurology, University of
California, Irvine, Irvine, California
*Dr Bullain has received a travel scholarship from the Orange County Chapter of the Alzheimer’s Association to
attend an international conference and receives grant support and other salary support from the National Institute
on Aging.
†Dr Bullain reports no disclosure.
Anna D. Burke, MD
Geriatric Psychiatrist and Dementia Specialist, Banner Alzheimer’s Institute, Phoenix, Arizona
*Dr Burke reports no disclosure.

†Dr Burke discusses the unlabeled use of atypical antipsychotics, antidepressants, and anticonvulsants for the
treatment of agitation in dementia.
Tiffany Chow, MD
Associate Professor of Neurology and Geriatric Psychiatry, University of Toronto, Toronto,
Canada; Senior Scientist, Baycrest Rotman Research Institute, Centre for Addiction and Mental
Health, University of Toronto, Toronto, Canada
*Dr Chow has served as an independent medical examiner and medicolegal consultant to Lesser & Associates.
†Dr Chow discusses the use of medications for the treatment of behavioral and psychiatric symptoms of dementia,
none of which carry indications from the US Food and Drug Administration. The text cites reviews of clinical trials
in frontotemporal degeneration as applicable, as well as case reports, but clinicians are urged to specify that any
such use of medications should be openly discussed with patients and substitute decision makers as off-label
prescriptions.
Giovani Coppola, MD
Assistant Professor, Departments of Psychiatry and Neurology, Semel Institute for Neuroscience
and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles,
Los Angeles, California
*Dr Coppola receives or anticipates receiving grants, personal compensation, or other support from the Dr. Miriam
and Sheldon G. Adelson Medical Research Foundation, John Douglas French Alzheimer’s Association Foundation,
Muscular Dystrophy Association, NIH, Takeda Pharmaceutical Company Limited, and Tau Consortium.
†Dr Coppola reports no disclosure.
María M. Corrada, ScM, ScD

Associate Adjunct Professor of Neurology, University of California, Irvine, Irvine, California
*Dr Corrada receives research support from the Alzheimer’s Association and the National Institute on Aging.
†Dr Corrada reports no disclosure.
Douglas Galasko, MBBCh

Professor, Department of Neurosciences, University of California, San Diego, San Diego,
California; Chief, Neurology Service, VA Medical Center, San Diego, California
*Dr Galasko serves as a consultant for Elan Corporation and serves on the data and safety monitoring boards of
Elan Corporation and Janssen Pharmaceuticals, Inc. Dr Galasko serves as an editor-in-chief of Alzheimer’s
Research and Therapy.
†Dr Galasko reports no disclosure.
Philip B. Gorelick, MD, MPH, FAAN

Medical Director, Hauenstein Neuroscience Center, Saint Mary’s Health Care, Grand Rapids,
Michigan; Professor, Department of Translational Science and Molecular Medicine, Michigan
State University College of Human Medicine, Grand Rapids, Michigan
*Dr Gorelick has received personal compensation for activities with AstraZeneca/Quinteles; BrainsGate; Dendreon
Corporation; Daiichi Sanko Co, Ltd; F. Hoffmann-La Roche Ltd/PAREXEL International Corporation; Forest
Laboratories, Inc/Watermark Medical; and Takeda Pharmaceutical Company Limited. Dr Gorelick’s employer
receives compensation for Dr Gorelick’s research work from Lundbeck and for Dr Gorelick’s service on the
speakers’ bureau of Boehringer Ingelheim.
†Dr Gorelick discusses the unlabeled use of treatment of cardiovascular risk factors in the prevention of cognitive
impairment and the unlabeled use of cholinesterase inhibitors for the treatment of vascular cognitive impairment.
Geri R. Hall, PhD, ARNP, GCNS, FAAN

Advanced Practice Nurse, Banner Alzheimer’s Institute, Phoenix, Arizona
*Dr Hall has served as an expert witness for a legal case regarding a resident care facility.

†Dr Hall reports no disclosure.
John Hart Jr, MD

Professor, University of Texas at Dallas, Dallas, Texas; Medical Science Director, University of
Texas at Dallas Center for Brain Health, Dallas, Texas; Professor of Neurology and Psychiatry at
the University of Texas Southwestern Medical Center, Dallas, Texas
*Dr Hart has served on the speakers bureau for Forest Laboratories, Inc, and as a medicolegal consultant.
†Dr Hart reports no disclosure.
Tina Hoang, MSPH

Staff Research Associate, Northern California Institute for Research and Education, San
Francisco VA Medical Center, San Francisco, California
*†Ms Hoang reports no disclosure.
Keith A. Johnson, MD
Associate Professor of Radiology, Harvard Medical School, Boston, Massachusetts
*Dr Johnson serves as a consultant for Avid Radiopharmaceuticals, Bayer AG, Elan Corporation/Janssen
Pharmaceuticals, Inc, GE Health Care, and Pfizer Inc. Dr Johnson has received honoraria and payment of travel
expenses from Pfizer Inc; serves as an associate editor for the Journal of Neuroimaging; receives book royalties
from Lippincott Williams & Wilkins; and receives research support from Alzheimer’s Association, Avid
Pharmaceuticals, Bristol-Myers Squibb Company, Janssen Alzheimer Immunotherapy, NIH, and Pfizer Inc.
†Dr Johnson discusses the unlabeled potential future use of amyloid imaging in preclinical and prodromal stages of
Alzheimer disease.
Oscar Lopez, MD
Director, University of Pittsburgh Alzheimer’s Disease Research Center, Professor of Neurology
and Psychiatry, Chief, Behavioral and Cognitive Neurology Division, University of Pittsburgh,
Pittsburgh, Pennsylvania
*Dr Lopez serves as a consultant for Lundbeck, Mertz, Lilly, and Baxter.
†Dr Lopez reports no disclosure.
Marc R. Nuwer, MD, PhD, FAAN

Chief of Clinical Neurophysiology, Hospital Department Head of Clinical Neurophysiology and
Neurology, Brain Research Institute, University of California, Los Angeles, Los Angeles,
California
*Dr Nuwer serves as a medical reviewer for SleepMed.
†Dr Nuwer reports no disclosure.
David Nyenhuis, PhD, ABPP

Director of Neuropsychology, Hauenstein Neuroscience Center, Saint Mary’s Health Care,
Grand Rapids, Michigan; Associate Professor, Department of Translational Science and
Molecular Medicine, Michigan State University College of Human Medicine, Grand Rapids,
Michigan
*†Dr Nyenhuis reports no disclosure.
Aimee L. Pierce, MD
Assistant Clinical Professor, University of California, Irvine School of Medicine,
Irvine, California
*Dr Pierce has received personal compensation for survey participation from LeadPhysician.

†Dr Pierce discusses the unlabeled use of donepezil, galantamine, and rivastigmine for
the treatment of mild cognitive impairment, and the unlabeled use of quetiapine for the
treatment of dementia-related psychosis.
Laura B. Powers, MD, FAAN

Dr Powers is retired from private practice.
*Dr Powers serves as ICD-9-CM Advisor for the Coding Subcommittee of the AAN Medical Economics and
Management Committee and serves in an editorial capacity for Neurology: Clinical Practice.
†Dr Powers reports no disclosure.
John M. Ringman, MD, MS

Associate Clinical Professor, Mary S. Easton Center for Alzheimer’s Disease Research at
UCLA, University of California, Los Angeles, Los Angeles, California
*Dr Ringman serves as a consultant for Avanir Pharmaceuticals, Inc; Phloronol, Inc; Takeda Pharmaceutical
Company Limited; and StemCells, Inc. Dr Ringman serves as site investigator for clinical trials sponsored by
Alzheimer’s Disease Cooperative Study, Bristol-Myers Squibb Company, Elan Corporation; Genentech, Inc;
Janssen Alzheimer Immunotherapy; Medivation, Inc; and Pfizer Inc.
†Dr Ringman reports no disclosure.
Lon S. Schneider, MD, MS

Professor of Psychiatry, Neurology, and Gerontology, Keck School of Medicine, University of
Southern California, Los Angeles, California
*Dr Schneider has served on the scientific advisory boards of or has consulted for AC Immune; Accera, Inc; Allon
Therapeutics, Inc; AstraZeneca; Baxter; Biogen Idec; Biotie Therapies; California Department of Justice; Elan
Corporation; Eli Lilly Corporation; EnVivo Pharmaceuticals; Hoffmann-La Roche, Inc; Janssen Pharmaceuticals,
Inc; Johnson & Johnson Services, Inc; Lundbeck, Merck & Co, Inc; Phloronol, Inc; Piramal Life Sciences; Takeda
Pharmaceutical Company Limited; TauRx Ltd; Toyama Chemical Company, Ltd; and Zinfandel Pharmaceuticals,
Inc. Dr Schneider and the University of Southern California have received research support from Baxter; Eli Lilly
Corporation; Genentech, Inc; and TauRx Therapeutics. Dr Schneider has received grants from the NIH and the
State of California.
†Dr Schneider discusses the unlabeled use of donepezil, galantamine, rivastigmine, and memantine. Information on
drugs is provided for general purposes only and not relied on for prescribing. Before prescribing any of the drugs
discussed, the physician should be knowledgeable about the full prescribing information that can be obtained from
the manufacturers.
B. Joy Snider, MD, PhD

Associate Professor of Neurology, Washington University, St Louis, Missouri
*Dr Snider receives research support from Eli Lilly and Company for a clinical drug trial and anticipates serving as
a site principal investigator and coinvestigator on such trials in the future.
†Dr Snider reports no disclosure.
Reisa A. Sperling, MD
Professor of Neurology, Harvard Medical School, Boston, Massachusetts; Director, Center for
Alzheimer Research and Treatment, Brigham and Women’s Hospital, Massachusetts General
Hospital, Boston, Massachusetts
*Dr Sperling serves as a consultant for Bayer AG; Biogen Idec; Bristol-Myers Squibb Company; Eisai Co, Ltd;
Janssen Pharmaceuticals, Inc; Eli Lilly and Company; Merck & Co, Inc; Neurophage Pharmaceuticals; Pfizer Inc;
Hoffman-La Roche Inc; and Satori Pharmaceuticals. Dr Sperling receives research support from Alzheimer’s
Association, American Health Assistance Foundation, Bristol-Myers Squibb Company, Fidelity Foundation,
Massachusetts Alzheimer’s Disease Research Center, and National Institute on Aging.
†Dr Sperling discusses the unlabeled potential future use of amyloid imaging in preclinical and prodromal stages of
Alzheimer disease.

Pierre N. Tariot, MD
Director, Codirector Alzheimer’s Prevention Initiative, Banner Alzheimer’s Institute, Phoenix,
Arizona; Research Professor of Psychiatry, University of Arizona College of Medicine, Phoenix,
Arizona
*Dr Tariot has served as a consultant for Abbott Laboratories; AC Immune; Adamas Pharmaceuticals, Inc;
Allergan, Inc; AstraZeneca; Avanir Pharmaceuticals, Inc; Avid Radiopharmaceuticals; Boehringer Ingelheim;
Bristol-Myers Squibb Company; Eisai Co, Ltd; Elan Corporation; Eli Lilly and Company; Genentech, Inc;
GlaxoSmithKline; MedAvante, Inc; Medivation, Inc; Merck & Co, Inc; Novartis AG; Otsuka Pharmaceutical Co,
Ltd; Pfizer Inc; Sanofi-Aventis; Toyama Pharmaceutical Association; and Worldwide Clinical Trials, Inc. Dr Tariot
holds stock options in Adamas Pharmaceuticals, Inc, recently forfeited options in MedAvante, Inc, and is a
contributor to a patent titled “Biomarkers of Alzheimer’s Disease.” Dr Tariot receives research support from
Abbott Laboratories; Alzheimer’s Association; Arizona Department of Health Services, AstraZeneca; Avid
Radiopharmaceuticals; Bristol-Myers Squibb Company; Elan Corporation; Eli Lilly and Company; Genentech, Inc;
GlaxoSmithKline; Medivation, Inc; Merck & Co, Inc; National Institute on Aging; National Institute of Mental
Health; Pfizer Inc; and Toyama Pharmaceutical Association.
†Dr Tariot discusses the unlabeled use of cholinesterase inhibitors and memantine for people with dementia, as well
as the unlabeled use of antipsychotics, antidepressants, and anticonvulsants. Information on drugs is provided for
general purposes only and not relied on for prescribing. Before prescribing any of the drugs discussed, the
physician should be knowledgeable about the full prescribing information that can be obtained from the
manufacturers.
Jack W. Tsao, MD, DPhil, FAAN

Professor of Neurology, Uniformed Services University of the Health Sciences, Bethesda,
Maryland
*Dr Tsao holds stock in Illumina and Biogen.
†Dr Tsao describes preliminary findings with genetic testing.
Kyle B. Womack, MD
Assistant Professor of Neurology and Neurotherapeutics and Psychiatry, University of Texas
Southwestern Medical Center, Dallas, Texas
*Dr Womack has received research support from Allon Therapeutics, Inc, and Bayer AG.
†Dr Womack reports no disclosure.
Kristine Yaffe, MD
Roy and Marie Scola Endowed Chair in Psychiatry; Professor of Psychiatry, Neurology, and
Epidemiology, University of California, San Francisco, San Francisco, California
*Dr Yaffe serves on the data and safety monitoring boards for the National Institute on Aging and Takeda
Pharmaceutical Company Limited; and receives grant support from the NIH, Alzheimer’s Association, American
Health Assistance Foundation, the California Department of Public Health, and the US Department of Defense.
†Dr Yaffe reports no disclosure.
MULTIPLE-CHOICE QUESTION WRITERS
Douglas J. Gelb, MD, PhD, FAAN

Professor of Neurology, University of Michigan, Ann Arbor, Michigan
*†Dr Gelb reports no disclosure.
D. Joanne Lynn, MD, FAAN

Associate Dean for Student Life and Clinical Professor, Department of Neurology, The Ohio
State University College of Medicine, Columbus, Ohio

*Dr Lynn holds stock or stock options greater than 5% of the company or more than $10,000 in value in Bristol-
Myers Squibb Company and Hospira, Inc. Dr Lynn receives research support from Acorda Therapeutics; Allergan,
Inc; Novartis AG; EMG Serono, Inc/Pfizer Inc; and Mt Sinai Medical Center.
†Dr Lynn reports no disclosure.
*Relationship Disclosure
†Unlabeled Use of Products/Investigational Use Disclosure
Methods of Participation and Instructions for Use
Continuum: Lifelong Learning in Neurology® is designed to help practicing neurologists stay
abreast of advances in the field while simultaneously developing lifelong self-directed learning
skills. In Continuum, the process of absorbing, integrating, and applying the material presented is
as important as, if not more important than, the material itself.
The goals of Continuum include disseminating up-to-date information to the practicing
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encouraging critical thinking; and, in the final analysis, strengthening and improving patient
care.
Each Continuum issue is prepared by distinguished faculty who are acknowledged leaders in
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pretest, multiple-choice questions with preferred responses, and a patient management problem.
For detailed instructions regarding Continuum CME and self-assessment activities, visit
aan.com/continuum/cme.
The review articles emphasize clinical issues emerging in the field in recent years. Case reports
and vignettes are used liberally, as are tables and illustrations. Video material relating to the
issue topic accompanies issues when applicable.

The text can be reviewed and digested most effectively by establishing a regular schedule of
study in the office or at home, either alone or in an interactive group. If subscribers use such
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can be met.

LIFELONG LEARNING IN NEUROLOGY ®
Dementia
Volume 19 Number 2 April 2013
CONTRIBUTORS
Claudia Kawas, MD, Guest Editor
Professor of Neurology and Neurobiology & Behavior, University of California,
Irvine, Irvine, California
*Dr Kawas serves on the data monitoring committees for Eli Lilly and Company and Quintiles
Inc, and receives a research grant from Avid Radiopharmacuticals.
†Dr Kawas reports no disclosure.
Ammar A. Alobaidy, MD
Behavioral Neurology Fellow, University of Toronto, Toronto, Canada; Senior
Specialist in Neurology, Sultan Qaboos University Hospital, Sultan Qaboos
University, Muscat, Oman
*Dr Alobaidy reports no disclosure.
†Dr Alobaidy discusses the use of medications for the treatment of behavioral and
psychiatric symptoms of dementia, none of which carry indications from the US Food and
Drug Administration. The text cites reviews of clinical trials in frontotemporal degeneration
as applicable, as well as case reports, but clinicians are urged to specify that any such use of
medications should be openly discussed with patients and substitute decision makers as
Virginia D. Buckles, PhD

Research Professor of Neurology and Executive Director of
The Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington
University School of Medicine, St Louis, Missouri
*†Dr Buckles reports no disclosure.
Szófia S. Bullain, MD
Clinical Instructor and Geriatric Neurology Fellow, Department of Neurology,
University of California, Irvine, Irvine, California
*Dr Bullain has received a travel scholarship from the Orange County Chapter of the
Alzheimer’s Association to attend an international conference and receives grant support
and other salary support from the National Institute on Aging.
†Dr Bullain reports no disclosure.
Continuum (Minneap Minn) 2013;19(2) www.aan.com/continuum

CONTRIBUTORS continued
Anna D. Burke, MD
Geriatric Psychiatrist and Dementia Specialist, Banner Alzheimer’s Institute,
Phoenix, Arizona
*Dr Burke reports no disclosure.
†Dr Burke discusses the unlabeled use of atypical antipsychotics, antidepressants, and
anticonvulsants for the treatment of agitation in dementia.
Tiffany Chow, MD
Associate Professor of Neurology and Geriatric Psychiatry, University of Toronto,
Toronto, Canada; Senior Scientist, Baycrest Rotman Research Institute, Centre for
Addiction and Mental Health, University of Toronto, Toronto, Canada
*Dr Chow has served as an independent medical examiner and medicolegal consultant to Lesser
& Associates.
†Dr Chow discusses the use of medications for the treatment of behavioral and psychiatric
symptoms of dementia, none of which carry indications from the US Food and Drug
Administration. The text cites reviews of clinical trials in frontotemporal degeneration as
applicable, as well as case reports, but clinicians are urged to specify that any such use of
medications should be openly discussed with patients and substitute decision makers as
Giovani Coppola, MD
Assistant Professor, Departments of Psychiatry and Neurology, Semel Institute for
Neuroscience and Human Behavior, David Geffen School of Medicine, University of
California, Los Angeles, Los Angeles, California
*Dr Coppola receives or anticipates receiving grants, personal compensation, or other support
from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, John Douglas French
Alzheimer’s Association Foundation, Muscular Dystrophy Association, NIH, Takeda
Pharmaceutical Company Limited, and Tau Consortium.
†Dr Coppola reports no disclosure.
María M. Corrada, ScM, ScD

Associate Adjunct Professor of Neurology, University of California, Irvine,
Irvine, California
*Dr Corrada receives research support from the Alzheimer’s Association and the National
Institute on Aging.
†Dr Corrada reports no disclosure.

Professor, Department of Neurosciences, University of California,
San Diego, San Diego, California; Chief, Neurology Service, VA Medical Center,
San Diego, California
*Dr Galasko serves as a consultant for Elan Corporation and serves on the data and safety
monitoring boards of Elan Corporation and Janssen Pharmaceuticals, Inc. Dr Galasko serves as
an editor-in-chief of Alzheimer’s Research and Therapy.
†Dr Galasko reports no disclosure.
www.aan.com/continuum April 2013

Philip B. Gorelick, MD, MPH, FAAN
Medical Director, Hauenstein Neuroscience Center, Saint Mary’s Health Care,
Grand Rapids, Michigan; Professor, Department of Translational Science and
Molecular Medicine, Michigan State University College of Human Medicine,
Grand Rapids, Michigan
*Dr Gorelick has received personal compensation for activities with AstraZeneca/Quinteles;
BrainsGate; Dendreon Corporation; Daiichi Sanko Co, Ltd; F. Hoffmann-La Roche
Ltd/PAREXEL International Corporation; Forest Laboratories, Inc/Watermark Medical;
and Takeda Pharmaceutical Company Limited. Dr Gorelick’s employer receives compensation
for Dr Gorelick’s research work from Lundbeck and for Dr Gorelick’s service on the speakers’
bureau of Boehringer Ingelheim.
†Dr Gorelick discusses the unlabeled use of treatment of cardiovascular risk factors in the
prevention of cognitive impairment and the unlabeled use of cholinesterase inhibitors for
the treatment of vascular cognitive impairment.
Geri R. Hall, PhD, ARNP, GCNS, FAAN

Advanced Practice Nurse, Banner Alzheimer’s Institute, Phoenix, Arizona
*Dr Hall has served as an expert witness for a legal case regarding a resident care facility.
†Dr Hall reports no disclosure.
John Hart Jr, MD

Professor, University of Texas at Dallas, Dallas, Texas; Medical Science Director,
University of Texas at Dallas Center for Brain Health, Dallas, Texas; Professor of
Neurology and Psychiatry at the University of Texas Southwestern Medical
Center, Dallas, Texas
*Dr Hart has served on the speakers bureau for Forest Laboratories, Inc, and as a
medicolegal consultant.
†Dr Hart reports no disclosure.
Tina Hoang, MSPH

Staff Research Associate, Northern California Institute for Research and
Education, San Francisco VA Medical Center, San Francisco, California
*†Ms Hoang reports no disclosure.

Keith A. Johnson, MD
Associate Professor of Radiology, Harvard Medical School, Boston,
Massachusetts
*Dr Johnson serves as a consultant for Avid Radiopharmaceuticals, Bayer AG, Elan
Corporation/Janssen Pharmaceuticals, Inc, GE Health Care, and Pfizer Inc. Dr Johnson has
received honoraria and payment of travel expenses from Pfizer Inc; serves as an associate
editor for the Journal of Neuroimaging; receives book royalties from Lippincott Williams &
Wilkins; and receives research support from Alzheimer’s Association, Avid Pharmaceuticals,
Bristol-Myers Squibb Company, Janssen Alzheimer Immunotherapy, NIH, and Pfizer Inc.
†Dr Johnson discusses the unlabeled potential future use of amyloid imaging in preclinical
and prodromal stages of Alzheimer disease.
Oscar Lopez, MD
Director, University of Pittsburgh Alzheimer’s Disease Research Center,
Professor of Neurology and Psychiatry, Chief, Behavioral and Cognitive
Neurology Division, University of Pittsburgh, Pittsburgh, Pennsylvania
*Dr Lopez serves as a consultant for Lundbeck, Mertz, Lilly, and Baxter.
†Dr Lopez reports no disclosure.

Chief of Clinical Neurophysiology, Hospital Department Head of Clinical
Neurophysiology and Neurology, Brain Research Institute, University of
California, Los Angeles, Los Angeles, California
*Dr Nuwer serves as a medical reviewer for SleepMed.
†Dr Nuwer reports no disclosure.
David Nyenhuis, PhD, ABPP

Director of Neuropsychology, Hauenstein Neuroscience Center, Saint Mary’s
Health Care, Grand Rapids, Michigan; Associate Professor, Department of
Translational Science and Molecular Medicine, Michigan State University
College of Human Medicine, Grand Rapids, Michigan
*†Dr Nyenhuis reports no disclosure.
Aimee L. Pierce, MD
Assistant Clinical Professor, University of California, Irvine School of Medicine,
Irvine, California
*Dr Pierce has received personal compensation for survey participation from LeadPhysician.
†Dr Pierce discusses the unlabeled use of donepezil, galantamine, and rivastigmine for
the treatment of mild cognitive impairment, and the unlabeled use of quetiapine for the
treatment of dementia-related psychosis.

Laura B. Powers, MD, FAAN
Dr Powers is retired from private practice.
*Dr Powers serves as ICD-9-CM Advisor for the Coding Subcommittee of the AAN Medical
Economics and Management Committee and serves in an editorial capacity for Neurology:
Clinical Practice.
†Dr Powers reports no disclosure.
John M. Ringman, MD, MS

Associate Clinical Professor, Mary S. Easton Center for Alzheimer’s Disease
Research at UCLA, University of California, Los Angeles, Los Angeles, California
*Dr Ringman serves as a consultant for Avanir Pharmaceuticals, Inc; Phloronol, Inc; Takeda
Pharmaceutical Company Limited; and StemCells, Inc. Dr Ringman serves as site investigator
for clinical trials sponsored by Alzheimer’s Disease Cooperative Study, Bristol-Myers Squibb
Company, Elan Corporation; Genentech, Inc; Janssen Alzheimer Immunotherapy;
Medivation, Inc; and Pfizer Inc.
†Dr Ringman reports no disclosure.

Professor of Psychiatry, Neurology, and Gerontology, Keck School of Medicine,
University of Southern California, Los Angeles, California
*Dr Schneider has served on the scientific advisory boards of or has consulted for AC
Immune; Accera, Inc; Allon Therapeutics, Inc; AstraZeneca; Baxter; Biogen Idec; Biotie
Therapies; California Department of Justice; Elan Corporation; Eli Lilly Corporation; EnVivo
Pharmaceuticals; Hoffmann-La Roche, Inc; Janssen Pharmaceuticals, Inc; Johnson & Johnson
Services, Inc; Lundbeck, Merck & Co, Inc; Phloronol, Inc; Piramal Life Sciences; Takeda
Pharmaceutical Company Limited; TauRx Ltd; Toyama Chemical Company, Ltd; and
Zinfandel Pharmaceuticals, Inc. Dr Schneider and the University of Southern California have
received research support from Baxter; Eli Lilly Corporation; Genentech, Inc; and TauRx
Therapeutics. Dr Schneider has received grants from the NIH and the State of California.
†Dr Schneider discusses the unlabeled use of donepezil, galantamine, rivastigmine, and
memantine. Information on drugs is provided for general purposes only and not relied on for
prescribing. Before prescribing any of the drugs discussed, the physician should be
knowledgeable about the full prescribing information that can be obtained from
the manufacturers.
B. Joy Snider, MD, PhD

Associate Professor of Neurology, Washington University, St Louis, Missouri
*Dr Snider receives research support from Eli Lilly and Company for a clinical drug trial and
anticipates serving as a site principal investigator and coinvestigator on such trials in
the future.
†Dr Snider reports no disclosure.

Reisa A. Sperling, MD
Professor of Neurology, Harvard Medical School, Boston, Massachusetts;
Director, Center for Alzheimer Research and Treatment, Brigham and Women’s
Hospital, Massachusetts General Hospital, Boston, Massachusetts
*Dr Sperling serves as a consultant for Bayer AG; Biogen Idec; Bristol-Myers Squibb
Company; Eisai Co, Ltd; Janssen Pharmaceuticals, Inc; Eli Lilly and Company; Merck & Co, Inc;
Neurophage Pharmaceuticals; Pfizer Inc; Hoffman-La Roche Inc; and Satori Pharmaceuticals.
Dr Sperling receives research support from Alzheimer’s Association, American Health
Assistance Foundation, Bristol-Myers Squibb Company, Fidelity Foundation, Massachusetts
Alzheimer’s Disease Research Center, and National Institute on Aging.
†Dr Sperling discusses the unlabeled potential future use of amyloid imaging in preclinical and
prodromal stages of Alzheimer disease.
Director, Codirector Alzheimer’s Prevention Initiative, Banner Alzheimer’s
Institute, Phoenix, Arizona; Research Professor of Psychiatry, University of
Arizona College of Medicine, Phoenix, Arizona
*Dr Tariot has served as a consultant for Abbott Laboratories; AC Immune; Adamas
Pharmaceuticals, Inc; Allergan, Inc; AstraZeneca; Avanir Pharmaceuticals, Inc; Avid
Radiopharmaceuticals; Boehringer Ingelheim; Bristol-Myers Squibb Company; Eisai Co, Ltd;
Elan Corporation; Eli Lilly and Company; Genentech, Inc; GlaxoSmithKline; MedAvante, Inc;
Medivation, Inc; Merck & Co, Inc; Novartis AG; Otsuka Pharmaceutical Co, Ltd; Pfizer Inc;
Sanofi-Aventis; Toyama Pharmaceutical Association; and Worldwide Clinical Trials, Inc.
Dr Tariot holds stock options in Adamas Pharmaceuticals, Inc, recently forfeited options in
MedAvante, Inc, and is a contributor to a patent titled “Biomarkers of Alzheimer’s Disease.”
Dr Tariot receives research support from Abbott Laboratories; Alzheimer’s Association;
Arizona Department of Health Services, AstraZeneca; Avid Radiopharmaceuticals;
Bristol-Myers Squibb Company; Elan Corporation; Eli Lilly and Company; Genentech, Inc;
GlaxoSmithKline; Medivation, Inc; Merck & Co, Inc; National Institute on Aging; National
Institute of Mental Health; Pfizer Inc; and Toyama Pharmaceutical Association.
†Dr Tariot discusses the unlabeled use of cholinesterase inhibitors and memantine for people
with dementia, as well as the unlabeled use of antipsychotics, antidepressants, and
anticonvulsants. Information on drugs is provided for general purposes only and not relied
on for prescribing. Before prescribing any of the drugs discussed, the physician should be
knowledgeable about the full prescribing information that can be obtained from
the manufacturers.

Professor of Neurology, Uniformed Services University of the Health Sciences,
Bethesda, Maryland
*Dr Tsao holds stock in Illumina and Biogen.
†Dr Tsao describes preliminary findings with genetic testing.

Kyle B. Womack, MD
Assistant Professor of Neurology and Neurotherapeutics and Psychiatry,
University of Texas Southwestern Medical Center, Dallas, Texas
*Dr Womack has received research support from Allon Therapeutics, Inc, and Bayer AG.
†Dr Womack reports no disclosure.
Kristine Yaffe, MD
Roy and Marie Scola Endowed Chair in Psychiatry; Professor of Psychiatry,
Neurology, and Epidemiology, University of California, San Francisco,
San Francisco, California
*Dr Yaffe serves on the data and safety monitoring boards for the National Institute on
Aging and Takeda Pharmaceutical Company Limited; and receives grant support from the
NIH, Alzheimer’s Association, American Health Assistance Foundation, the California
Department of Public Health, and the US Department of Defense.
†Dr Yaffe reports no disclosure.

Douglas J. Gelb, MD, PhD, FAAN
Professor of Neurology, University of Michigan, Ann Arbor, Michigan
* †Dr Gelb reports no disclosure.
D. Joanne Lynn, MD, FAAN

Associate Dean for Student Life and Clinical Professor, Department of
Neurology, The Ohio State University College of Medicine, Columbus, Ohio
*Dr Lynn holds stock or stock options greater than 5% of the company or more than $10,000
in value in Bristol-Myers Squibb Company and Hospira, Inc. Dr Lynn receives research
support from Acorda Therapeutics; Allergan, Inc; Novartis AG; EMG Serono, Inc/Pfizer Inc;
and Mt Sinai Medical Center.
†Dr Lynn reports no disclosure.

Volume 19 ■ Number 2 ■ April 2013

www.aan.com/continuum
Dementia
Guest Editor: Claudia Kawas, MD
Editor’s Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .323
REVIEW ARTICLES
Biomarkers of Alzheimer Disease: Current and Future Applications
to Diagnostic Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .325
Reisa Sperling, MD; Keith Johnson, MD
Alzheimer Disease Pharmacologic Treatment and Treatment Research . . . . . .339

New Genes and New Insights from Old Genes: Update on

Alzheimer Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .358
John M. Ringman, MD, MS; Giovanni Coppola, MD
Nonpharmacologic Treatment and Prevention Strategies for Dementia . . . .372

Kristine Yaffe, MD; Tina Hoang, MSPH
The Clinical Problem of Neuropsychiatric Signs and Symptoms

in Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .382
Anna Burke, MD; Geri Hall, PhD, ARNP, GCNS, FAAN; Pierre N. Tariot, MD
The Diagnostic Evaluation of a Patient With Dementia . . . . . . . . . . . . . . . . . . .397

Mild Cognitive Impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .411

Oscar L. Lopez, MD
Understanding and Treating Vascular Cognitive Impairment . . . . . . . . . . . . .425

Philip B. Gorelick, MD, MPH, FAAN; David Nyenhuis, PhD, ABPP
Incorporating New Diagnostic Schemas, Genetics, and Proteinopathy

into the Evaluation of Frontotemporal Degeneration . . . . . . . . . . . . . . . . . . . .438
Tiffany W. Chow, MD; Ammar A. Alobaidy, MD
Dementia in the Oldest Old . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .457

Szófia S. Bullain, MD; María M. Corrada, ScM, ScD
Volume 19 ■ Number 2 www.aan.com/continuum 0000

313

ETHICAL PERSPECTIVES
“Will I Get Alzheimer Disease?” When Cognitively Normal Patients
Ask to be Tested for Alzheimer Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .470
B. Joy Snider, MD, PhD; Virginia D. Buckles, PhD
PRACTICE ISSUES
Genetic Testing for Early-Onset Alzheimer Disease . . . . . . . . . . . . . . . . . . . . . .475
Coding for Behavioral Neurology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .480

John Hart Jr, MD; Kyle B. Womack, MD; Laura B. Powers, MD, FAAN;
SELF-ASSESSMENT AND CME

Learning Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .315
Instructions for Completing the Self-Assessment Pretest and Tally Sheet . . . . . .317
Self-Assessment Pretest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .319
Instructions for Completing CME and Tally Sheet . . . . . . . . . . . . . . . . . . . . . . . .491
Multiple-Choice Questions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .493
Multiple-Choice Questions—Preferred Responses . . . . . . . . . . . . . . . . . . . . . . .503
Patient Management Problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .519
Patient Management Problem—Preferred Responses . . . . . . . . . . . . . . . . . . . .525
Aimee Pierce, MD
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .538
List of Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Back Cover
314 www.aan.com/continuum April 2013

Learning Objectives
Upon completion of the Continuum: Lifelong Learning in Neurology
Dementia issue, participants will be able to:
Recognize the key features for the diagnosis of Alzheimer disease, vascular
▲
dementia, and frontotemporal dementia

Apply the newly proposed criteria for the diagnosis of Alzheimer disease
▲
Identify the appropriate use of CSF and imaging biomarkers in clinical

▲
dementia diagnosis
Use appropriate pharmacologic and nonpharmacologic approaches for the
▲
management of patients with dementia

Summarize the latest research advances in the diagnosis and treatment of dementia
▲
Recognize the diagnostic and treatment challenges of dementia in the oldest old
▲
Core Competencies
The Dementia issue covers the following core competencies:
Patient Care
▲
Medical Knowledge
▲
Practice-Based Learning and Improvement

▲
Interpersonal and Communication Skills

▲
Professionalism
▲
Systems-Based Practice
▲
1

SELF-ASSESSMENT

INSTRUCTIONS FOR THE Dementia
SELF-ASSESSMENT PRETEST
To earn American Board of Psychiatry and Volume 19 ■ Number 2 ■ april 2013
Neurology (ABPN) Maintenance of Certification
(MOC) self-assessment participation credit for this Tally Sheet
issue of , complete the Self-Assessment
Pretest in one of three ways: SELF-ASSESSMENT PRETEST RESPONSES
1. Go to www.aan.com/continuum/cme and complete After completing this tally sheet, please enter your
the test online (available to subscribers only), or
answers online at
2. Read through the questions in the issue and www.aan.com/continuum/cme.
mark your answers on the adjacent tally sheet
before entering them online at 1. a b c d e 14. a b c d e
www.aan.com/continuum/cme, or
3. Request a faxable paper scorecard if you do not
2. a b c d e 15. a b c d e
have computer access or you are a nonsubscriber
who has purchased a single issue (send an email to
ContinuumCME@aan.com); however, we encourage 3. a b c d e 16. a b c d e
all subscribers to use the online system.
Once you have completed the Self-Assessment 4. a b c d e 17. a b c d e
Pretest, use your results as a guide as you read the
issue. To obtain self-assessment CME credits, you
must complete the post-reading Multiple-Choice 5. a b c d e 18. a b c d e
Questions at the end of the issue, along with an
issue evaluation. No self-assessment credit will 6. a b c d e 19. a b c d e
be awarded for completing the Self-Assessment
Pretest alone.
7. a b c d e 20. a b c d e
Upon completion of the Self-Assessment Pretest and
post-reading Multiple-Choice Questions, participants
may earn up to 12 AMA PRA Category 1 CreditsTM 8. a b c d e 21. a b c d e
toward ABPN MOC self-assessment (part 2).
Self-assessment credits earned will appear on AAN
member CME transcripts within 2 business days 9. a b c d e 22. a b c d e
and may be viewed at www.aan.com/education/
certificate. AAN nonmember subscribers may request 10. a b c d e 23. a b c d e
a transcript of credits earned by contacting AAN
Member Services at memberservices@aan.com or
(800) 879-1960. 11. a b c d e 24. a b c d e
AMA PRA Category 1 Credits not designated for
self-assessment may be obtained by completing 12. a b c d e 25. a b c d e
only the 40 post-reading Multiple-Choice Questions
(up to 10) and/or the Patient Management Problem 13. a b c d e
(up to 2) found at the end of the issue.
Participants have up to 3 years from the date of
publication to earn CME credits. No CME will be
awarded for the Dementia issue after April 30, 2016.
The ABPN has reviewed Continuum: Lifelong

Learning in Neurology and has approved this
product as part of a comprehensive lifelong
learning and self-assessment program, which is
mandated by the American Board of Medical
Specialties (ABMS) as a necessary component of
maintenance of certiﬁcation.

Continuum (Minneap Minn) 2013;19(2) www.aan.com/continuum 317

Self-Assessment
Self-Assessment Pretest 5. Which of the following diseases is most likely to present with a
clinical syndrome resembling behavioral variant frontotemporal
dementia (bvFTD)?
A. dementia with Lewy bodies
The Self-Assessment Pretest is designed to B. Huntington disease
help neurologists meet the American Board of Psychiatry C. late-onset Alzheimer disease
and Neurology (ABPN) self-assessment and lifelong learn- D. posterior cortical atrophy
ing component (part 2) for Maintenance of Certification E. progressive supranuclear palsy
(MOC). To obtain self-assessment CME credits, complete
the Self-Assessment Pretest (25 questions) before reading 6. A 78-year-old man with a clinical dementia syndrome consistent
this issue. Pretest results are intended to help you focus your with early-stage Alzheimer disease undergoes amyloid posi-
tron emission tomography (PET) imaging. Which of the
learning by identifying your current knowledge gaps with
following areas would most likely show amyloid positivity
regard to the topic. After submitting your pretest responses, early in his disease?
study the entire issue using your pretest results as a guide to
direct your learning. Then complete the 40 Multiple-Choice A. caudate nucleus and connections
B. lingual cortex
Questions at the end of the issue. Upon completion of both
C. precuneus
the Self-Assessment Pretest and the D. rostral anterior cingulate
Multiple-Choice Questions, you may earn up to 12 AMA E. superior temporal gyrus
PRA Category 1 Creditsi toward self-assessment.
AMA PRA Category 1 Credits for may 7. Which of the following is the most common site of pathology
be obtained by completing only the 40 Multiple-Choice in patients with vascular cognitive impairment?
Questions, but these credits will not qualify for self- A. frontal cortex
assessment without completion of the Self-Assessment B. hippocampus
Pretest. C. parietal cortex
D. subcortex
E. tentorium cerebri
8. A 95-year-old woman develops dementia. As part of a clinical

1. Mutation of which of the following genes is the most common research study, she agrees to allow postmortem examination
cause of familial Alzheimer disease? of her brain. Which of the following neuropathologic diagnoses
A. amyloid precursor protein (APP) is more likely to be seen in this patient with dementia compared
B. clusterin (CLU) to younger elderly patients with dementia?
C. presenilin 1 (PSEN1) A. corticobasal degeneration
D. presenilin 2 (PSEN2) B. dementia with insufficient pathology
E. translocase of outer mitochondrial membrane 40 homolog C. dementia with Lewy bodies
(TOMM40) D. frontotemporal dementia
E. large vessel infarcts
2. Which of the following symptoms would be most suggestive
of a significant memory disorder as opposed to normal aging? 9. Which of the following statements most accurately character-
A. difficulty with multitasking izes the relative efficacy of donepezil, galantamine, rivastigmine,
B. forgetting to pay bills and memantine for moderate Alzheimer disease?
C. misplacing keys or the television remote control A. donepezil is more effective than the other three
D. occasional difficulty retrieving acquaintances’ names medications
E. taking longer to complete complex tasks B. galantamine is more effective than the other three
medications
3. Maintenance of cognitive function later in life correlates best C. memantine is more effective than the other three
with high levels of which of the following? medications
A. alcohol use D. none of these medications has been proven to be more
B. physical activity effective than the other three
C. social inactivity E. rivastigmine is more effective than the other three
D. sleep disturbances medications
E. tobacco use
4. Which of the following cognitive functions is usually most

impaired early in the course of Alzheimer disease?
A. episodic memory
B. executive function
C. procedural memory
D. semantic memory
E. visuospatial function
Continuum (Minneap Minn) 2013;19(2):319–321 www.aan.com/continuum 319

Self-Assessment
10. A 63-year-old postal service employee has been referred for a 16. In a 70-year-old patient with hypertension, hyperlipidemia,
medical evaluation because after 18 years of exemplary job diabetes, an ongoing history of tobacco use, and a history of
performance, she has been making ‘‘silly mistakes’’ over the past stroke, the evidence is strongest that which of the following
year, and the problem is getting progressively worse. She reduces the risk of vascular cognitive impairment?
reports feeling ‘‘like I’m forgetting how to read.’’ On examination, A. blood pressure control
she has normal visual acuity and full visual fields, but she is B. moderation of alcohol intake
unable to explain what is happening in the ‘‘cookie theft’’ C. smoking cessation
picture, focusing on just one small area at a time and failing to D. statin use
connect the isolated components. Her neurologic examination E. weight control
is otherwise normal. Which of the following is the most likely
diagnosis? 17. Which of the following adverse effects occurs most commonly in
A. dementia with Lewy bodies patients taking higher doses of cholinesterase inhibitors for
B. frontotemporal dementia Alzheimer disease?
C. normal aging A. anhidrosis
D. normal pressure hydrocephalus B. anorexia
E. posterior cortical atrophy C. cardiac arrhythmia
D. chorea
11. Familial behavioral variant frontotemporal dementia (bvFTD) E. constipation
is most commonly due to mutations in which of the
following? 18. Alzheimer disease is associated with a decrease in CSF
A. chromosome 9 open reading frame 72 (C9ORF72) concentration of which of the following substances?
B. the gene for amyloid precursor protein (APP) A. albumin
C. the gene for microtubule-associated protein tau (MAPT) B. amyloid-" 1-42
D. the gene for presenilin 2 C. oligomeric amyloid
E. the gene for progranulin D. phosphorylated tau
E. tau
12. Which of the following is the approximate annual rate of
progression from mild cognitive impairment to Alzheimer 19. A 76-year-old man with moderate dementia has been doing
disease? relatively well at home with the devoted care of his wife. They
A. 2% have established a routine with stimulating but not overwhelm-
B. 6% ing activities, such as sorting through family pictures, talking
C. 12% about past travels, and playing simple children’s games. His
D. 24% daughter comes from out of town and challenges him to do the
E. 32% crossword puzzle in the Sunday paper. He attempts a few words
with her help but soon becomes agitated, shouts out some
13. Which type of dementia is most likely to be associated with unpleasant words, and then goes to his bedroom and refuses to
amyloid negativity on an amyloid positron emission tomog- come out. Which of the following triggers in this situation most
raphy (PET) image? contributed to this patient’s escalation of neuropsychiatric signs?
A. Alzheimer dementia A. change of environment
B. frontotemporal lobar degeneration B. delirium
C. Lewy body dementia C. excessive demand to achieve activity beyond limitations
D. mild cognitive impairment D. fatigue
E. mixed Alzheimer and vascular dementia E. misleading stimulus
14. Clinical efficacy, safety, and tolerability in patients with 20. Which of the following symptoms is most pathognomonic for
Alzheimer disease have been most clearly established for a the semantic variant of primary progressive aphasia?
drug (or drugs) in which of the following categories? A. agrammatism
A. amyloid-" antibodies B. impaired comprehension of single words
B. gamma secretase inhibitors C. impaired prosody
C. ginkgolides D. impaired repetition of sentences
D. nicotinic receptor agonists E. impaired repetition of single words
E. N-methyl-D-aspartate (NMDA) receptor antagonists
21. Which of the following levels of blood pressure is associated
15. Compared to the Montreal Cognitive Assessment, the Mini- with the lowest risk of dementia in the oldest old?
Mental State Examination has which of the following A. high blood pressure
advantages? B. low blood pressure
A. assesses a broader set of cognitive domains C. low or normal blood pressure
B. costs less D. normal blood pressure
C. is available in more languages E. there is no association of dementia with any blood pressure
D. is more sensitive for mild dementia level in this age group
E. is shorter

Self-Assessment
22. According to the National Institute on Aging and Alzheimer’s 24. Utilization of comprehensive evidence-based caregiver training
Association Criteria, which of the following clinical character- programs such as the Progressively Lowered Stress Threshold
istics place a patient at ‘‘intermediate likelihood’’ (rather than has been shown to result in significant declines in which of the
‘‘high likelihood’’ or ‘‘unlikely’’) that his or her mild cognitive following?
impairment (MCI) syndrome is caused by Alzheimer disease? A. aspiration
A. absence of core clinical symptoms of MCI B. cognitive decline
B. presence of a systemic disorder that may cause cognitive C. late day confusion
deficits D. memory
C. presence of core clinical symptoms of MCI and a single E. weight loss
positive biomarker for either amyloid or neuronal damage
D. presence of core clinical symptoms of MCI, but neither 25. A gene in which mutations have been demonstrated to cause
amyloid nor neuronal damage markers are positive frontotemporal dementia and a rare variant has been
E. presence of core clinical symptoms of MCI, positive amyloid associated with both Alzheimer disease and frontotemporal
ligand scan, and positive CSF markers for neuronal damage dementia in a large epidemiologic study codes for which of the
following proteins?
23. High blood pressure in midlife is associated with an increased A. clusterin
risk of which of the following dementing conditions, in which B. complement receptor 1
group of subjects? C. microtubule-associated protein tau (MAPT)
A. Alzheimer disease in men but not in women, vascular D. PICALM, a component in clathrin-mediated endocytosis
dementia in both men and women E. triggering receptor expressed on myeloid cells 2 (TREM2)
B. both Alzheimer disease and vascular dementia, in both
men and women
C. both Alzheimer disease and vascular dementia, in men but
not in women
D. vascular dementia in both men and women, no increased
risk of Alzheimer disease
E. vascular dementia in men but not in women, no increased
risk of Alzheimer disease

Editor’s Preface
* 2013, American Academy
Making Sense of the of Neurology.
Newest Information on
the Dementias
In probably no other disor- article, Drs John Ringman
der within neurology are the and Giovanni Coppola in-
concepts of disease onset, form us nongeneticists
pathogenesis, and diagnosis about the genetic aspects
evolving more rapidly than of Alzheimer disease, in-
in the dementiasValbeit cluding the rare gene
without a concomitant sig- mutations that cause
nificant advancement in autosomal dominant
preventive or treatment forms of the disease; the
optionsVyet. In this issue common variations (poly-
of , Guest morphisms) of the apoli-
Editor Claudia Kawas, MD, poprotein E gene that
has assembled an expert fac- have a differential effect
ulty to elucidate the current on Alzheimer disease
state of the art in the demen- In this issue of susceptibility; and the
tias and to help us provide a , Guest role of these genetic
rational, informed, and con- Editor Claudia Kawas, studiesVor lack thereofV
temporary approach to the in clinical practice. Dr
clinical diagnosis, manage-
MD, has assembled Kristine Yaffee and Tina
ment, and counseling of our an expert faculty Hoang then review the
patients with these disorders. to help us provide evidence that certain car-
This issue begins with a a rational, informed, diovascular, dietary, and
discussion by Drs Reisa lifestyle factors might rep-
Sperling and Keith Johnson
and contemporary resent modifiable risk
on the CSF and imaging approach to the factors for the develop-
biomarkers for Alzheimer clinical diagnosis, ment of dementia. Next,
disease. Whether these management, and Drs Anna Burke, Geri
biomarkers are ready, Hall, and Pierre Tariot
near-ready, or not-ready for
counseling of our tackle the neuropsychiat-
prime time (daily clinical patients with ric (behavioral) aspects
practice), these authors in- dementia. of dementia, providing
form us about both the practical advice in regard
potential usefulness and the current to both nonpharmacologic strategies
pitfalls of these new and evolving tests. and pharmacologic interventions (rec-
Next, Dr Lon Schneider discusses the ognizing the US Food and Drug Ad-
pharmacologic treatment of Alzheimer ministration warning on both typical
disease; within this extremely practical and atypical antipsychotics) of these
review (including specifics of dosing distressingVfor both patients and their
and listing of common side effects) is a caregiversVsymptoms.
frank and realistic analysis of the limita- In his review, Dr Douglas Galasko
tions of our current therapies. In the next provides us with an expert’s practical

Editor’s Preface
approach to the history, examination, Dr Jack Tsao provides a practical analysis

and diagnostic assessment of the pa- of the issues to consider in regard to
tient presenting with dementia, which Alzheimer disease genetic counseling,
we can emulate in our practices. Dr testing, and disclosure, and Drs John
Oscar Lopez then discusses mild cog- Hart, Kyle Womack, Laura Powers, and
nitive impairment (MCI), including the Marc Nuwer thoroughly review the
history and continuing evolution of this coding aspects relevant to dementia.
diagnostic concept, underscoring its Like all issues, there
clinical heterogeneity and the impor- are ample opportunities for CME. Reading
tance of recognizing the potential role the material, answering the Multiple-
of coexisting illnesses in the manifesta- Choice Questions that were crafted by
tion of the clinical syndrome. Next, Drs Drs Joanne Lynne and Douglas Gelb, and
Philip Gorelick and David Nyenhuis reviewing the explanatory discussions will
provide a state-of-the-art discussion assess and enhance your knowledge of
and review of vascular cognitive im- the material, and you will be able to earn
pairment, from the evolution of the up to 10 AMA PRA Category 1 CME
nomenclature to the diagnostic, man- Creditsi. An alternative opportunity also
agement, and preventive strategies for now allows you to obtain up to 12 AMA
this important cause or contributor to PRA Category 1 CME Credits specifically
cognitive impairment. Next, Drs Tiffany approved by the American Board of Psy-
Chow and Ammar Alobaidy present a chiatry and Neurology (ABPN) for self-
comprehensive yet extremely accessible assessment by simply completing and
review of frontotemporal degeneration submitting the Self-Assessment Pretest
and its behavioral and primary progres- before reading the material and com-
sive aphasia variants, including an ap- pleting the postreading Multiple-Choice
proach to the clinical recognition and Questions. The Patient Management
diagnosis of these syndromes, an expo- Problem, written by Dr Aimee Pierce,
sition of the nomenclature and clinical follows the case of a 64-year-old man
distinctions between the aphasia vari- from his earliest cognitive symptoms to
ants, and an explanation of the rapidly severe dementia. By following his case
evolving knowledge regarding the un- and answering multiple-choice ques-
derlying proteinopathies and genetic tions corresponding to important diag-
aspects of these syndromes. Their re- nostic, prognostic, therapeutic, and
view is grounded by a discussion of counseling decision points along his
clinical management and support for course (reinforcing many of the issues
affected patients and their families. Fi- addressed in the previous articles) you
nally, Drs Szófia Bullain and Marı́a will have the opportunity to earn up to 2
Corrada discuss dementia in the oldest AMA PRA Category 1 CME Credits.
old and the unique diagnostic and I thank Dr Kawas and her expert
etiopathologic features of dementia in team of authors who have created a
this fastest-growing segment of the issue providing us with
population. such clear and up-to-date information that
In this issue’s Ethical Perspectives sec- we can use at the bedside to inform our
tion, Drs B. Joy Snider and Virginia Buckles individual approaches to the diagnosis,
analyze the ethical issues involved in a management, and counseling of our
theoretical case of a cognitively normal patientsVand their familiesVaffected
patient requesting amyloid imaging be- by dementia.
cause of her concern for Alzheimer dis- VSteven L. Lewis, MD, FAAN
ease. In the Practice Issues section, Editor-in-Chief

Review Article
Biomarkers of
Address correspondence to
Dr Reisa Sperling, Brigham
and Women’s Hospital,
Memory Disorders Unit,
Alzheimer Disease: 221 Longwood Ave,

Boston, MA 02115,
reisa@rics.bwh.harvard.edu.
Current and Future Relationship Disclosure:

Dr Sperling serves as a
consultant for Bayer AG;
Applications to Biogen Idec; Bristol-Myers

Squibb Company; Eisai Co,
Ltd; Janssen Pharmaceuticals,
Inc; Eli Lilly and Company;
Diagnostic Criteria Merck & Co, Inc; Neurophage

Pharmaceuticals; Pfizer Inc;
Hoffman-La Roche Inc; and
Reisa Sperling, MD; Keith Johnson, MD Satori Pharmaceuticals.
Dr Sperling receives research
support from Alzheimer’s
Association, American Health
ABSTRACT Assistance Foundation,
Bristol-Myers Squibb Company,
Purpose of Review: This article reviews recent advances in imaging and fluid Fidelity Foundation,
biomarkers for Alzheimer disease (AD) and their application to newly proposed Massachusetts Alzheimer’s
diagnostic criteria across the continuum of AD. Disease Research Center, and
National Institute on Aging.
Recent Findings: There have been remarkable developments in neuroimaging Dr Johnson serves as a
markers for AD over the past decade, most notably the advent of positron emission consultant for Avid
tomography (PET) amyloid imaging using radiotracers that label fibrillar forms Radiopharmaceuticals, Bayer
AG, Elan Corporation/Janssen
of amyloid-" (A"). Similarly, new research in CSF markers suggests CSF levels of Pharmaceuticals, Inc, GE
A"1j42 and phosphorylated tau may be useful in the early diagnosis of AD and Health Care, and Pfizer Inc.
prediction of cognitive decline. The National Institute on Aging and the Alzheimer’s Dr Johnson has received
honoraria and payment of
Association recently convened three workgroups to develop joint recommendations travel expenses from Pfizer
for new diagnostic guidelines across the spectrum of AD. These recommendations Inc; serves as an associate
incorporate biomarkers and propose updated criteria for the previously recognized editor for the Journal of
Neuroimaging; receives book
stage of AD dementia, the evolving definition of mild cognitive impairment, and a royalties from Lippincott
newly proposed concept of stages of preclinical AD. Williams & Wilkins; and
Summary: Recent advances in AD biomarkers have increased the ability to detect receives research support
from Alzheimer’s Association,
evidence of early AD pathology in vivo. These biomarkers have been incorporated Avid Pharmaceuticals,
into new diagnostic recommendations, but a number of challenges remain for the Bristol-Myers Squibb Company,
biomarkers to become widely applied in clinical practice. Janssen Alzheimer
Immunotherapy, NIH,
and Pfizer Inc.
Continuum (Minneap Minn) 2013;19(2):325–338. Unlabeled Use of Products/
Investigational Use
Disclosure: Drs Sperling
and Johnson discuss the
Diagnostic criteria for Alzheimer dis- across several stages of disease. This unlabeled potential future
use of amyloid imaging in
ease (AD) were first proposed more review will cover new developments preclinical and prodromal
than a quarter of a century ago.1 The in AD biomarkers and the application stages of Alzheimer disease.
original criteria served the neurologic of these biomarkers to the proposed of Neurology.
field well, both for diagnosis in clinical criteria for the spectrum of AD.
practice and for inclusion of appropri-
ate populations into clinical research; BIOMARKERS
over the past few years, however, it The quest for accurate and useful in
has become evident that the diagnos- vivo biomarkers for AD has evolved
tic criteria should be revisited and rapidly over the past decade, with
updated to reflect recent advances in advances in CSF markers and multiple
biomarker research and the recogni- types of neuroimaging. Biomarkers for
tion that AD represents a continuum AD can be categorized in many ways,

Alzheimer Disease Biomarkers and Diagnostic Criteria
KEY POINTS
h Biomarkers are but in terms of the new diagnostic CSF A" could precede evidence of A"
conceptualized into two criteria, the biomarkers were concep- deposition in PET amyloid imaging,
broad categories: (1) tualized into two broad categories: (1) but this may reflect the thresholds for
markers of amyloid-" markers of amyloid-" (A") accumula- positivity that are utilized in PET
accumulation and tion and (2) markers of neuronal in- studies. It is also important to note
(2) markers of jury or neurodegeneration. that both CSF and PET amyloid imag-
neuronal injury or ing markers are thought to reflect
neurodegeneration. Markers of Amyloid-ß amyloid accumulation primarily into
h Paradoxically, Alzheimer Accumulation fibrillar forms and may not reveal
disease is associated Markers of A" accumulation currently other forms of A", such as smaller
with a decrease in CSF include CSF assays of A"1Y42 and posi- soluble speciesVso-called oligomeric
amyloid-"1Y42 that is tron emission tomography (PET) amyloid species of A"Vthat some researchers
generally thought to imaging. Paradoxically, AD is associated believe represent the toxic forms of
represent evidence with a decrease in CSF A"1Y42 that is A". There is intense, ongoing research
that amyloid-" is
generally thought to represent evidence to develop stable assays for oligomeric
polymerizing and
that A" is polymerizing and depositing A"; however, these assays have not been
depositing as fibrillar
plaques. PET imaging
in the brain as fibrillar plaques. PET im- validated in clinical studies to date.
of amyloid-" utilizes aging of A" utilizes derivatives of histo- The ability to detect A" deposits
derivatives of pathologic stains, such as thioflavins, during life with PET imaging has
histopathologic stains, that bind to fibrillar forms of A". transformed clinical AD research, per-
such as thioflavins, that In general, CSF and PET markers of mitting direct visualization of one of
bind to fibrillar forms of A" accumulation have yielded similar the defining neuropathologic features
amyloid-". findings. CSF assays have been avail- of AD. Recent studies suggest that
h Recent studies suggest able for 20 years, and therefore more amyloid PET is likely equivalent to
that amyloid PET is longitudinal data are available, but the demonstration of amyloid plaque pa-
likely equivalent to more recent advent of PET amyloid thology at autopsy.3 A" deposits con-
demonstration of imaging has facilitated larger multicen- tain a characteristic pattern of protein
amyloid plaque ter studies. The majority of studies pub- structure known as beta-sheet, and
pathology at autopsy. lished to date have utilized carbon-11 numerous PET ligands have been
h A negative amyloid PET (11C)Ybased Pittsburgh Compound B developed that bind specifically to this
study signifies few or no (PiB) imaging. Recently, however, several type of structure and permit either
amyloid deposits and tracers using fluorine-18 (18F)Vincluding visual or quantitative assessment of
indicates that the 18F-flutemetamol, 18F-florbetaben, and amyloid positivity. A negative amyloid
likelihood of cognitive 18F-florbetapirVhave been developed. PET study thus signifies few or no
impairment due to
Florbetapir was recently approved by amyloid deposits and indicates that
Alzheimer disease
the US Food and Drug Administration the likelihood of cognitive impairment
is low.
(FDA) for detection of amyloid as a due to AD is low. In contrast, a
h The most important diagnostic aid in evaluating causes of positive amyloid PET has been shown
concept to recognize in
dementia, and it is likely that additional to correspond to moderately to se-
considering the high
approvals will follow. At this point, it has verely elevated levels of A" deposits
image-to-pathology
correlation is that
not been determined whether insur- (Figure 1-1). The most important
amyloid positivity does ance, in particular Medicare, will cover concept to recognize in considering
not reliably distinguish PET amyloid imaging as part of the di- the high image-to-pathology correla-
clinical diagnoses. agnostic workup. tion is that amyloid positivity does not
The few studies combining CSF and reliably distinguish clinical diagnoses,
PET markers of A" published to date so that neurologically normal people
suggest a fairly tight correlation be- as well as those with mild cognitive im-
tween these two markers.2 There is pairment (MCI), AD dementia, and other
some suggestion that decreases in neurodegenerative diseases including

FIGURE 1-1 Carbon-11 Pittsburgh Compound B positron emission tomography (PET) amyloid
images show two transaxial slice levels in six older individuals, with age and
Mini-Mental State Examination (MMSE) score listed at the bottom. Regions of red
and yellow indicate high Pittsburgh Compound B retention, indicating presence of fibrillar
amyloid deposition. From left to right: a 75-year-old clinically normal woman who is amyloid
negative; a 76-year-old clinically normal man with evidence of amyloid deposition in parietal
and temporal cortices; a 74-year-old woman with amnestic mild cognitive impairment (aMCI)
and an MMSE of 25 who is amyloid negative; a 77-year-old man with aMCI and an MMSE
of 27 demonstrating amyloid deposition in frontal, temporal, and parietal cortices; and an
81-year-old woman with mild Alzheimer disease dementia with an MMSE of 25 who
demonstrates evidence of amyloid deposition in frontal, temporal, and parietal cortices.
Lewy body dementia can all be ‘‘amy- plex cognitive processes. The compo-
loid positive.’’ In other words, positiv- nents of the default network include
ity on amyloid markers alone does not precuneus, posterior cingulate, in-
establish a diagnosis of AD dementia ferior parietal, lateral temporal, and
and must be considered in a full clinical superior frontal cortices, which are
context. particularly vulnerable to amyloid
The amyloid-positive PET brain im- deposition.4Y6 The earliest and most
ages have for the first time permitted heavily affected brain regions are the
a detailed view of the specific anatomy middle frontal gyri (part of the cogni-
of amyloid accumulation during life. tive control network) and parietal/
The exploration of this anatomy coin- precuneus/posterior cingulate re-
cided with important developments in gions, thought to be key nodes of the
functional imaging, which converged default-mode network. The anatomy is
over the past decade to focus on highly stereotyped, but substantial var-
highly interconnected brain regions iability has been observed in early
organized into large-scale cortical net- phases of amyloid accumulation regard-
works, in particular a set of functioning the specific regions involved and
ally connected brain regions known as the bilateral symmetry of involvement
the default network, which has been over time. Typically, by the time a per-
implicated in memory and other com- son manifests objectively measurable

KEY POINT
h Increased levels of CSF cognitive impairment, amyloid PET is established and documented impair-
tau and phosphorylated strongly positive in these regions, and ment (Case 1-1), particularly in youn-
tau have also been eventually, as has been noted in the ger patients for whom a more certain
demonstrated to predict neuropathologic literature, even pri- pathologic basis for their diagnosis
progression to dementia mary cortices become involved at the could guide management. The under-
in subjects with mild end stages of AD dementia. lying pathology of frontotemporal lo-
cognitive impairment The majority of data available on bar degeneration (FTLD), for example,
and are already elevated amyloid PET comes from the 11C is not thought to involve A", and a
in clinically normal agent PiB.7 Because of the short small but growing body of evidence
mutation carriers in physical half-life of 11C-PiB (20 mi- confirms amyloid negativity in autopsy-
autosomal dominant
nutes), it is rapidly being replaced in confirmed FTLD.12 For disorders in
familial Alzheimer
most clinical settings and for multi- which the histopathology is heteroge-
disease.
center studies by amyloid-binding li- neous (such as posterior cortical atrophy,
gands labelled with 18F, which has a progressive aphasia, and corticobasal
110-minute half-life.3,8,9 The rates of syndrome) and for Lewy body demen-
amyloid positivity reported for amy- tia, amyloid PET may not provide de-
loid PET according to traditional clin- finitive diagnostic utility (Case 1-2).
ical classifications are approximately as
follows: for clinically diagnosed AD Markers of Neuronal Injury or
dementia, 90% positive; for MCI, ap- Neurodegeneration
proximately 60% positive; and for Researchers are pursuing multiple bio-
cognitively intact older people, ap- markers of neuronal injury or
proximately 30% to 40% positive, neurodegeneration, which might be
depending on the age cohort. Similar further subcategorized as (1) molecu-
proportions have been reported using lar markers of neuronal injury, (2)
CSF biomarkers of A".10 In longitudi- imaging markers of synaptic dysfunc-
nal clinical follow-up of patients with tion, and (3) imaging markers of
MCI with baseline amyloid PET, ap- neuronal loss and atrophy. CSF phos-
proximately half were positive on phorylated tau (P-tau) 181 and total
amyloid imaging (versus only 10% of tau measures are thought to reflect
patients who were negative for MCI) neuronal injury and neuronal death,
convert to a clinical diagnosis of AD respectively. The combination of ele-
dementia over the course of 1 to 3 vated CSF P-tau with low CSF A"1Y42
years.11 Of particular interest is the is thought to indicate a biomarker
substantial fraction of apparently signature of AD (Case 1-3). Al-
healthy elderly with normal cognition though hyperphosphorylation of tau
who are amyloid positive, whose con- is thought to be a key contributor to
dition is termed preclinical AD on the intraneuronal neurofibrillary-tangle
hypothesis that the presence of amy- formation, it is not clear whether CSF
loid puts them at higher risk for tau measures fully reflect the burden
developing AD dementia. The precise of tangle pathology and whether these
level of increased risk is being actively markers will remain dynamic at later
evaluated in research settings. stages of AD. Increased levels of CSF
The clinical utility of amyloid PET in tau and P-tau have also been demon-
dementia care is likewise a topic of strated to predict progression to de-
investigation about which data are mentia in subjects with MCI14 and are
only now being gathered and evaluat- already elevated in clinically normal
ed. Substantial clinical value may lie in mutation carriers in autosomal domi-
differential diagnosis of patients with nant familial AD.15

Case 1-1
A 74-year-old, right-handed professor of linguistics was referred for a
second opinion regarding progressive cognitive decline. The patient and
his wife reported changes in cognition dating back approximately 2 years,
when he had increased difficulty in giving lectures without consulting his
notes. He also described word-finding difficulty and occasional problems
with getting lost while driving in familiar places. There was no report of
behavioral changes except that he seemed a bit more withdrawn in social
situations, which they attributed to decreased confidence in his conversational
abilities. He had been diagnosed with Alzheimer disease by another
academic neurologist approximately 6 months ago and was started on a
cholinesterase inhibitor. The patient and his wife wanted another opinion
because they felt he was continuing to worsen, and they were interested in
enrolling in an antiamyloid antibody trial.
On examination, he was alert and oriented except for day of the week.
He demonstrated mild inattention with months of the year backward and
on serial 7’s. He encoded five words, had four of the five at 30 seconds
without distraction, and recalled two of the five after 5 minutes. He
correctly recognized one additional word on multiple-choice testing. His
speech was fluent but he had several pauses for word-finding, and his
vocabulary was less rich than might have been expected for a person of his
background. His repetition and basic grammatical comprehension were
intact, but his clock drawing was impaired, with particular difficulty in
placing the hands on a clock to indicate 11:10. He scored 24 in the
Mini-Mental State Examination and 1.0 on the Clinical Dementia Rating
Scale. The remainder of his neurologic examination was otherwise
unremarkable except for mild saccadic intrusions.
Both he and his wife were anxious to get him enrolled in research
studies, particularly clinical trials for potential disease-modifying therapies.
He underwent MRI and positron emission tomography (PET) amyloid
imaging as part of a research protocol. The MRI revealed mild atrophy in
both frontal and parietal cortices, with relatively intact medial temporal
lobe structures. The PET amyloid imaging was negative on visual inspection
and by quantitative threshold. Because this patient was strongly considering
enrolling in an antibody trial, the PET amyloid imaging results were felt to
be clinically relevant. The PET findings were discussed with the patient and
his wife, since it was felt that the negative amyloid result made the diagnosis
of Alzheimer disease less likely. Other neurodegenerative diseases,
including frontotemporal lobar degeneration, were also discussed.
A few weeks later, the patient’s wife called to say that his niece (his
brother’s daughter, who was living in another country) had been diagnosed
with Pick disease, but no imaging or genetic testing was available. At the
family’s request, genetic testing was performed on the patient and revealed
a progranulin mutation, confirming a diagnosis of frontotemporal lobar
degeneration. The patient was taken off cholinesterase inhibitors and was
started on a serotonin-selective reuptake inhibitor and memantine (also used
for treatment in frontotemporal dementia by some neurologists).
Comment. This case illustrates the potential utility of a negative PET
amyloid imaging study in a patient with dementia. The negative PET scan
substantially decreased the likelihood that this patient’s clinical syndrome
was due to Alzheimer disease, prompting further diagnostic workup.

KEY POINT
h The characteristic
pattern of
Case 1-2
A 76-year-old man was evaluated for memory loss and a gait disorder with
fluorodeoxyglucose
the onset associated with a fall approximately 4 years ago. He reported
abnormalities associated
a false belief about the presence of a nonexistent family member living in
with Alzheimer
the house. His Mini-Mental State Examination score was 25/30, and his
disease is bilateral
neuropsychological evaluation was notable for mild episodic memory
temporoparietal
difficulties. A fluorodeoxyglucose positron emission tomography (PET) scan
hypometabolism.
showed bilateral temporoparietal associated with left frontal hypometabolism,
consistent with Alzheimer disease (AD). A neurologist noted parkinsonism and
began treatment with dopaminergic medication, which was thought to be
ineffective; the neurologist then made a diagnosis of Lewy body dementia.
His motor function, memory, and delusions worsened. Two years later, he
underwent amyloid PET with Pittsburgh Compound B (PiB), which revealed
a pattern of marked positivity in widespread cortical regions. He died of
complications from a traumatic subdural hematoma; an autopsy revealed
Lewy body dementia with marked congophilic angiopathy, and a positive
correlation between amyloid-" levels and regional PiB retention.13
Comment. This case illustrates that a positive PET amyloid imaging may
be associated with cerebral amyloid angiopathy and Lewy body dementia
and therefore is not specific to a clinical diagnosis of AD dementia.
Several imaging markers are avail- markers, FDG does not indicate clear
able that are presumed to reflect spatial patterns that distinguish be-
synaptic dysfunction. The most widely tween normal aging and MCI or AD.16
studied is 18F-fluorodeoxyglucose As with these other modalities, the
(FDG)-PET, which has been used observed heterogeneity in FDG patterns
since the 1980s. FDG-PET measures of metabolism may be due to individual
glucose metabolism in the brain and is differences (particularly in cognitive re-
thought to reflect synaptic activity. The serve)17 or to comorbid conditions of
characteristic pattern of FDG abnormal- aging such as vascular disease, as well as
ities associated with AD is bilateral to idiosyncratic factors. While FDG
temporoparietal hypometabolism, al- hypometabolism does seem to be some-
though frontal hypometabolism has what more sensitive than structural
also been reported in later stages of imaging biomarkers for monitoring cog-
AD. Single-photon emission computed nitive transition from preclinical to
tomography (SPECT) imaging has established AD,18 it is still unknown
shown a very similar pattern of func- which variable is best associated with
tional abnormality but is not widely used the cognitive symptoms and how it
now because of the increased availability could be translated into clinical use.
of PET imaging with superior resolution. The availability of FDG-PET has in-
FDG-PET is a widely available tech- creased dramatically over the past de-
nology that may aid clinicians in making cade and the standardization of methods
a correct diagnosis, particularly when has improved substantially; however,
deciding whether early stages of cogni- costs of PET technology remain high,
tive impairment are due to AD pathol- and cost effectiveness in dementia diag-
ogy or FTLD. However, further work is nosis has been difficult to demonstrate.
needed to determine the diagnostic Functional MRI (fMRI) is a less devel-
value of FDG when assessing preclinical oped method for assessing synaptic
stages of AD. Like other imaging bio- function but has the potential advantage

Case 1-3
A 54-year-old, left-handed businesswoman was referred by her primary
care physician for evaluation of her cognitive and behavioral changes. The
patient’s husband and daughter reported that they had begun to notice
the changes 3 years ago, with her decreased interest in hobbies and
exercise, and increased difficulty preparing complicated meals. She had
initially been diagnosed with depression and anxiety but continued to
decline on antidepressants. Over the past year, she had gotten lost twice
while driving, and her husband had taken over paying most of the bills.
The patient also described intermittent episodes of bilateral paresthesia
involving her arms and legs, and sometimes her face. She was in otherwise
excellent health and took no medications. Her mother had developed
dementia late in life (ie, early eighties) but had not had an autopsy.
On examination, the patient was alert but disoriented to the date. She
could not give any details of recent current events. She had marked
difficulty with attention and even simple calculations. On memory testing,
she encoded three words but recalled only one of the three at 5 minutes.
She recognized two out of three on multiple-choice but also picked one
false answer. Her speech was fluent, but she had mild naming difficulty
for body parts and low-frequency items. Her affect was not depressed, but
she described being ‘‘petrified’’ that she was losing her mind. Her Mini-Mental
State Examination score was 25. The remainder of her neurologic
examination was only significant for mild symmetric hyperreflexia.
Her MRI revealed mild hippocampal atrophy for her age, slight atrophy
in left greater than right temporal and parietal cortices, and no evidence
of white matter lesions. She had a previous spine MRI to work up the
paresthesia, which was read as normal.
Her husband was particularly anxious to have more diagnostic workup
done because some of the family members and other physicians still
thought the symptoms were psychiatric or possibly related to Lyme
disease, although her serum titers were negative for both immunoglobulin
G and immunoglobulin M. She underwent a lumbar puncture, which
revealed no white blood cells, a slightly elevated protein level of 64 mg/dL,
low CSF amyloid-", and elevated phosphorylated tau on a commercial CSF
assay, thought to be consistent with a diagnosis of Alzheimer disease.
Comment. This case illustrates the potential utility of CSF markers in
aiding diagnosis in young patients and those who may present with
unusual clinical symptoms.
of not requiring any contrast agent or Functional connectivity MRI (fc-MRI)

radiation exposure. Functional MRI can studies have demonstrated similar pat-
assess brain function during cognitive terns of dysfunction as those reported
tasks, which typically requires special in FDG-PET, preferentially affecting the
stimulus equipment, or during the connectivity in a network of cortical
resting state, sometimes referred to as regions known as the default-mode
‘‘task-free’’ fMRI using blood oxygen network (defined above).4 Another
levelYdependent (BOLD) imaging. In MRI technique for assessing brain
task-free fMRI, the correlation between function and blood flow is arterial spin
activity within intrinsic networks or labeling MRI (ASL-MRI), which is also
‘‘functional connectivity’’ is assessed. noninvasive and has demonstrated

KEY POINTS
h Convergent studies similar patterns of abnormalities to re- likely to be more difficult to detect
suggest that atrophy gional FDG hypometabolism.19 Both subtle atrophy in early AD with visual
begins years before the fc-MRI and ASL-MRI have yet to be inspection, as would be available in
diagnosis of dementia. validated in multicenter studies but may most clinical situations. MRI may also
h Atrophy is not specific prove useful in assessing therapeutic be useful for ruling out other relatively
to Alzheimer disease. response in clinical trials. less common but potentially treatable
Structural imaging (particularly volu- causes of dementia and cognitive im-
h Amyloid might be
metric MRI) has been extensively doc- pairment, including cerebrovascular
necessary but not
sufficient to result in
umented in AD. Progressive cerebral disease and neoplasm. Also, it is impor-
Alzheimer disease atrophy is a characteristic feature of tant to note that atrophy is not specific
dementia. neurodegeneration that can be as- to AD. Indeed, hippocampal volume
sessed with structural imaging, in par- loss is seen in normal aging as well as in
ticular with volumetric MRI. AD is hippocampal sclerosis and other neu-
characterized by an insidious onset rodegenerative diseases that can mimic
and inexorable progression of atrophy AD. Nevertheless, the combination of
in the medial temporal lobe structures volumetric MRI and molecular markers
(including the hippocampus and ento- of AD may prove valuable in improving
rhinal cortex) and by cortical thinning, both diagnostic accuracy and prediction
particularly in heteromodal cortices of future clinical course.
including the posterior cingulate,
precuneus, lateral parietal, temporal, Models of Biomarker Trajectories
and frontal regions.20,21 Patients with in Alzheimer Disease
AD with atypical clinical presentations Accumulating data from multiple bio-
tend to demonstrate patterns of atro- marker and imaging modalitiesV
phy concordant with their deficits, such acquired by the Alzheimer’s Disease
as visual variants demonstrating poste- Neuroimaging Initiative (ADNI); the
rior cortical atrophy and those with Australian Imaging, Biomarkers and
prominent language deficits demon- Lifestyle (AIBL) study; and several
strating left temporal atrophy. other longitudinal cohort studies at
Convergent studies suggest that leading academic centersVfacilitated
atrophy begins years before the diag- the development of hypothetical
nosis of dementia. Even in very mildly models of the temporal course of
impaired individuals (ie, those with these biomarkers across the spectrum
Mini-Mental State Examination scores of AD.18 These models proposed a
greater than 24), the volumes of specific sequence of biomarker abnor-
medial temporal lobe structures are malities that began before any evi-
reduced by 15% to 30%.22,23 This is dence of clinical symptoms, and a
consonant with autopsy studies series of sigmoid curves to characterize
suggesting that patients with MCI have the temporal dynamics of these bio-
already lost 50% of neurons in the markers (Figure 1-2).27 These models
perforant pathway.24 Several studies postulated that markers of amyloid
have also demonstrated evidence of accumulation typically become abnor-
atrophy in amyloid-positive, clinically mal first but, importantly, suggested
normal older individuals, in a pattern that amyloid might be necessary but
similar to that observed in MCI and not sufficient to result in AD dementia.
AD.25,26 It should be noted that the These models also acknowledged
majority of these research studies some gaps in understanding and data
employ computer software to calcu- that did not fully fit these models,
late quantitative measurements. It is including evidence of early synaptic

FIGURE 1-2 Hypothetical model of dynamic biomarkers of Alzheimer disease. Biomarkers:
Amyloid-" (A") as identified by CSF A"42 assay or positron emission tomography
(PET) amyloid imaging (red); synaptic dysfunction evidenced by fluorodeoxyglucose
PET or functional MRI (orange), with a dashed line to indicate that synaptic dysfunction may be
detectable in carriers of the *E4 allele of the APOE gene prior to detectable amyloid-" deposition;
neuronal injury evidenced by CSF tau or phosphorylated tau (green); volumetric MRI (blue).
Biomarkers change from normal to maximally abnormal (y axis) as a function of disease stage
(x axis). The temporal trajectories of two key clinical indicators used to stage the disease, cognition
(purple) and clinical function (maroon), are also illustrated.
Adapted from Jack CR Jr, et al, Lancet Neurol.18 B 2010, with permission from Elsevier. www.sciencedirect.com/science/
article/pii/S1474442209702996.
Reprinted from Sperling RA, et al, Alzheimers Dement.27 B 2011 The Alzheimer’s Association. All rights reserved.
www.alzheimersanddementia.com/article/S1552-5260(11)00099-9/fulltext.
dysfunction present in some genetic at- led by Dubois put forth the concept
risk groups that might precede evidence of a prodromal stage of AD, which
of amyloid accumulation. It is also suggested that amnestic MCI plus evi-
important to acknowledge that demo- dence of positive AD biomarkers might
graphic factors might influence the be considered very mild AD. In 2010,
temporal trajectory of these hypothetical the National Institute on Aging and the
curves, including age, genetics, socio- Alzheimer’s Association (NIA-AA)
economic factors such as education, and established three working groups to
other indicators of cognitive reserve. develop new criteria for AD. Each
group was asked to focus on one of
NEW DIAGNOSTIC CRITERIA the three phases of AD: (1) the pre-
Largely informed by the advances in symptomatic or preclinical phase, (2)
biomarker research discussed above the symptomatic predementia phase,
and by increasing recognition of early often referred to as MCI, and (3) the
stages of clinical impairment, a number dementia phase. The working groups
of expert groups have worked over the were international in composition and
past decade to develop new diagnostic included people with a range of exper-
criteria. Petersen and colleagues28 be- tise, including neurologists, psychia-
gan to define and validate criteria for trists, neuropsychologists, radiologists,
MCI. An international group of experts epidemiologists, and biostatisticians

KEY POINTS
h The most common from both academia and the pharma- neuropsychological testing. The most
presentation of ceutical industry. The groups were common presentation of AD dementia
Alzheimer disease asked to review the literature and is the amnestic form, which involves
dementia is the develop consensus on new diagnostic impairment of episodic memory (ie,
amnestic form, which criteria that could be used by clinicians the ability to learn and retain new in-
involves impairment in and researchers. There was also a small formation). However, some patients
episodic memory (ie, the workgroup charged with harmonizing have initial involvement of other cog-
ability to learn and the discussion of biomarkers across the nitive domains, such as language or
retain new information). three workgroups, which helped to visuospatial or executive functioning.
However, some patients develop a common diagnostic frame- The term mild cognitive impairment
have initial involvement
work across the continuum. applies to patients who have some evi-
of other cognitive
The NIA-AA workgroups that dealt dence of cognitive impairment but have
domains, such as
language or visuospatial
with the symptomatic phases of AD not progressed to dementia. The core
or executive functioning. (ie, MCI and dementia) developed clinical criteria in the NIA-AA criteria30
sets of core clinical diagnostic criteria are similar to those listed for AD de-
h Alzheimer disease is
that were intended to serve as a guide mentia but differ in the degree of
increasingly recognized
as a continuum.
for a wide range of clinicians con- functional impairment. These criteria
fronted with the typical patient pre- include (1) concern regarding a change
senting for evaluation of cognitive in cognition, which may be identified
decline. In these groups, biomarkers by the patient, an informant, or a clini-
were considered to be a potential cian; (2) impairment in one or more
adjunct to diagnosis, primarily for cognitive domains that is greater than
research purposes, that would serve one would expect for the patient’s age or
to increase the certainty of the etiolo- educational background and may be
gy of the clinical diagnosis. The NIA- confirmed with neuropsychological test-
AA workgroup on preclinical AD and ing; and (3) preservation of indepen-
the international workgroup led by dence in functional activities. There may
Dubois took a slightly different ap- be some mild problems with more com-
proach, using biomarker criteria to bet- plex activities, but those with MCI main-
ter identify patients who were on the tain their independence in daily life,
early AD trajectory for research studies. requiring only minimal assistance. The
degree of decline in cognition and func-
Clinical Criteria for Alzheimer tion is not yet consistent with dementia.
Dementia and Mild Cognitive It is important to note that AD is
Impairment Due to increasingly recognized as a continuum.
Alzheimer Disease There are no exact transition points that
The clinical criteria for AD dementia in define when a patient has progressed
the NIA-AA criteria are similar to the from the MCI phase to the dementia
National Institute of Neurological and phase (nor from the preclinical phase to
Communicative Disorders and Stroke MCI). These transitions are typically a
and the Alzheimer’s Disease and Re- matter of clinical judgment, relying on
lated Disorders Association (NINCDS- multiple pieces of information, and the
ADRDA) criteria from 1984. The core division into discrete stages may be
clinical criteria for AD dementia29 in- somewhat arbitrary.
clude an insidious onset over months Although the focus of these work-
to years with a clear-cut history of groups was on diagnostic criteria for
progression of cognitive decline, usu- AD, it is important to acknowledge that
ally obtained from an informant. Cog- there are causes of MCI and dementia
nitive decline can be affirmed by other than AD pathology. It is necessary

to consider other systemic and brain stage of preclinical AD may be charac-
diseases that can alter cognitive function, terized by evidence of cognitive or
such as vascular disease, other neurode- behavioral change from the patient’s
generative diseases, and neuropsychiatric baseline status or poor performance on
diseases, including depression. AD is less challenging cognitive tests. After much
likely to be the underlying cause of debate, the term preclinical was se-
impairment when there are atypical lected, as opposed to presymptomatic,
symptoms or a clinical course suggestive to recognize that patients may demon-
of vascular disease, frontotemporal de- strate very subtle changes in cognition
mentia, or Lewy body dementia. Biomark- and behavior that can precede MCI by
ers may play an important role in the several years but would not typically be
differential diagnosis of AD as the un- brought to a clinician’s attention. The rec-
derlying etiology of clinical impairment. ommendations for the study of preclinical
AD were intended purely for research
Research Criteria for Preclinical purposes, since they do not have any
Alzheimer Disease clinical utility at the present time.
The most controversial aspect of the
NIA-AA criteria was the proposal to Impact of Biomarkers on
recognize a new presymptomatic or Diagnostic Criteria
preclinical stage of AD.27 This stage As mentioned above, the NIA-AA work-
was conceptualized to represent the groups conceptualized biomarkers as
‘‘silent’’ phase of AD when the path- falling into two major categories: (1) bio-
ophysiologic process has begun in the markers that reflect the accumulation of
brain but there is not yet clear evidence the A" peptideVeither CSF A"1Y42 or
of clinical impairment. The preclinical PET amyloid imaging, and (2) biomark-
phase of the disease is primarily defined ers of neuronal injury, which include
by changes in biomarkers, but the last CSF tau, FDG-PET, and volumetric MRI.
a,b
TABLE 1-1 Dementia and Mild Cognitive Impairment Criteria Incorporating Biomarkers
Biomarker Probability Neuronal Injury (CSF Tau,

of Alzheimer Disease Fluorodeoxyglucose
Diagnostic Category Etiology Aß (PET or CSF) PET, Structural MRI)
Alzheimer disease (AD) High likelihood Positive Positive
dementia/mild cognitive
impairment (MCI) due to AD
Dementia/MCIVIntermediate Intermediate Positive Untested
likelihood Untested Positive
Dementia and MCIV Uninformative Untested/ Untested/conflicting/

biomarkers uninformative conflicting/ ambiguous
ambiguous
Dementia and MCIVunlikely Lowest Negative Negative
due to AD
A" = amyloid-"; PET = positron emission tomography; CSF = cerebrospinal fluid; MRI = magnetic resonance imaging.
a
Modified from McKhann GM, et al, Alzheimers Dement.29 B 2011 The Alzheimer’s Association. All rights reserved.
b
Modified from Albert MS, et al, Alzheimers Dement.30 B 2011 The Alzheimer’s Association. All rights reserved.
www.alzheimersanddementia.com/article/S1552-5260(11)00104-X/fulltext.

For the diagnostic criteria pertaining INCORPORATING BIOMARKERS

to the symptomatic phases of disease, a INTO CLINICAL PRACTICE
set of algorithms were proposed by When the NIA-AA criteria for MCI and
which biomarkers from the two catego- AD dementia were developed, it was
ries mentioned above could be exam- noted that biomarkers were deemed
ined individually (because often only to be primarily for research use. PET
one biomarker test is available) or in amyloid imaging was not yet clinically
combination, to enhance the certainty available, but one 18F PET agent has
that the underlying etiology of the since been FDA approved. Several
symptoms is AD (Table 1-1). It was important issues about incorporating
also recognized that biomarkers might biomarkers into clinical practice were
be useful to estimate the likelihood of also raised in these guidelinesVin
progression to the next stage of the particular, the need for standardiza-
disease (eg, from MCI to dementia). tion across centers. Although work has
In the preclinical research criteria, a begun in standardizing CSF assays,
staging framework based on bio- PET imaging, and volumetric MRI mea-
markers was proposed to characterize surements, there are not yet well-
patients at increasing risk of progres- validated, established normative values
sion toward MCI and dementia. Stage 1 and calibration metrics for any of the
is characterized as asymptomatic cere- biomarkers. Additional work is re-
bral amyloidosis; stage 2 is amyloidosis quired to make these biomarkers more
plus neurodegeneration; and stage 3 easily interpretable to physicians in a
is amyloidosis, neurodegeneration, and variety of clinical settings.
evidence of very subtle change in cog-
nition or behavior but is not sufficient SUMMARY AND FUTURE
to be diagnosed with MCI. Table 1-2 DIRECTIONS
summarizes the categorization of bio- The field of AD has seen many
markers across the stages of preclini- advances in diagnosis and biomarker
cal AD. development over the past decade.
a
TABLE 1-2 Staging Categories for Preclinical Alzheimer Disease Research
Markers of Neuronal
Markers of Injury (CSF, Tau, Subtle Cognitive
Aß Accumulation Fluorodeoxyglucose or Behavioral
Stage Description (PET or CSF) PET, MRI) Change
1 Asymptomatic Positive Negative Negative
cerebral amyloidosis
2 Asymptomatic Positive Positive Negative
amyloidosis +
neuronal injury
3 Amyloidosis + Positive Positive Positive
neuronal
injury + subtle
cognitive decline
A" = amyloid-"; PET = positron emission tomography; CSF = cerebrospinal fluid; MRI = magnetic resonance imaging.
a
Modified from Sperling RA, et al, Alzheimers Dement.27 B 2011 The Alzheimer’s Association. All rights reserved.

Hopefully these biomarkers will serve healthy controls: a multicentre phase 2
diagnostic study. Lancet Neurol 2011;10(5):
to improve understanding of the path- 424Y435.
ophysiologic processes of AD during
9. Vandenberghe R, Van Laere K, Ivanoiu A,
life and to elucidate the link between et al. 18F-flutemetamol amyloid imaging
the pathology and clinical manifesta- in Alzheimer disease and mild cognitive
tions of this terrible disease. Much impairment: a phase 2 trial. Ann Neurol
2010;68(3):319Y329.
work remains to be done to standardize
currently available biomarkers to enable 10. Fagan AM, Roe CM, Xiong C, et al.
Cerebrospinal fluid tau/beta-amyloid(42)
optimal use in the clinical setting, to ratio as a prediction of cognitive decline in
develop more sensitive and specific nondemented older adults. Arch Neurol
biomarkers for early diagnosis, to track 2007;64(3):343Y349.
progression, and to monitor response 11. Klunk WE. Amyloid imaging as a biomarker
to future disease-modifying therapy. for cerebral ß-amyloidosis and risk prediction
for Alzheimer dementia. Neurobiol Aging
2011;32(suppl 1):S20YS36.
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Review Article
Alzheimer Disease
Dr Lon S. Schneider, Keck
School of Medicine ,University
of Southern California, 1540
Pharmacologic Alcazar St, CHP-216, Los

Angeles, CA 90033,
lschneid@usc.edu.
Treatment and Relationship Disclosure:

Dr Schneider has served on
the scientific advisory boards
Treatment Research of or has consulted for AC

Immune; Accera, Inc;
Allon Therapeutics, Inc;
AstraZeneca; Baxter;
Lon S. Schneider, MD, MS Biogen Idec; Biotie Therapies;
California Department of
Justice; Elan Corporation;
Eli Lilly Corporation;
ABSTRACT EnVivo Pharmaceuticals;
Purpose of Review: This article reviews marketed pharmacologic treatments Hoffmann-La Roche, Inc;
Janssen Pharmaceuticals, Inc;
for Alzheimer disease as well as their efficacy, effectiveness, adverse effects, and Johnson & Johnson Services,
issues involved in their use, including duration of treatment, adverse events, and Inc; Lundbeck, Merck & Co,
controversies. Current experimental drug development, including challenges Inc; Phloronol, Inc; Piramal
Life Sciences; Takeda
to developing successful drugs for Alzheimer disease, are also reviewed and Pharmaceutical Company
assessed. Limited; TauRx Ltd; Toyama
Recent Findings: Cholinesterase inhibitors and memantine are the available Chemical Company, Ltd; and
Zinfandel Pharmaceuticals, Inc.
pharmacologic treatment options. They show limited clinical effects over the Dr Schneider and the
shorter term for some patients, mild to moderate cholinergic adverse effects in University of Southern
a minority of patients, and potentially underappreciated toxicity over the longer California have received
research support from Baxter;
term. No subsequent experimental drug in development has been successful Eli Lilly Corporation;
thus far; there has not been a new drug marketed for Alzheimer disease since Genentech, Inc; and TauRx
2003. Therapeutics. Dr Schneider
has received grants from the
Summary: Cholinesterase inhibitors and memantine are marketed for the NIH and the State of California.
treatment of Alzheimer disease. Drug development programs aimed at new Unlabeled Use of
targets, including the amyloid-" cascade, have been unsuccessful thus far despite Products/Investigational
Use Disclosure:
their designs to detect very small or minimal clinical effects from the experimental Dr Schneider discusses the
drugs. Marked advances in preclinical science nevertheless support a basis for unlabeled use of donepezil,
considerable optimism that effective interventions will be found soon. galantamine, rivastigmine, and
memantine. Information on
drugs is provided for general
Continuum (Minneap Minn) 2013;19(2):339–357. purposes only and not relied
on for prescribing. Before
prescribing any of the drugs
discussed, the physician should
be knowledgeable about the
full prescribing information
CURRENT MEDICATIONS The Cholinergic Hypothesis and that can be obtained from
the manufacturers.
APPROVED BY THE US FOOD Cholinesterase Inhibitors
AND DRUG ADMINISTRATION The use of cholinesterase inhibitors for of Neurology.
The cholinesterase inhibitors tacrine, Alzheimer disease is based on the cho-
donepezil, rivastigmine, and galan- linergic hypothesis of memory impair-
tamine were approved by the US Food ment.1,2 The hypothesis implies that
and Drug Administration (FDA) for cholinergic deficits are responsible for
marketing in the United States for the cognitive and behavioral changes in
treatment of Alzheimer disease in 1993, patients with dementia and age-related
1996, 2000, and 2001, respectively. memory impairment and, further, that
Memantine was approved by the FDA pharmacologic augmentation of central
in 2003 for the indication of moderately cholinergic function will improve cogni-
severe to severe Alzheimer disease. tive function. The cholinergic hypothesis

Alzheimer Disease Pharmacologic Treatment
KEY POINTS
h The cholinergic hypothesis is supported by observations of marked severely impaired and nursing home pa-
of memory impairment decline of the cholinergic corticobasal tients, as reviewed in a Cochrane re-
implies that cholinergic projections, loss of cholinergic cell bod- view.5 One nonYindustry-sponsored,
deficits are responsible for ies in the nucleus basalis, and reduced randomized, placebo-controlled trial fol-
cognitive and behavioral choline acetyltransferase activity, which lowed patients over several years and
changes in patients with is needed for acetylcholine synthesis. reported modest cognitive effects over
dementia and age-related Further support for the hypothesis in- 2 years but no significant effects on loss
memory impairment, cludes correlations between the above of function, nursing home placement,
and that augmentation cholinergic deficits and neuritic, amyloid-" or health economic measures.6
of central cholinergic (A") peptideYcontaining plaques and de- Pharmacokinetics and drug inter-
function will improve
cline in cognitive test performance. actions. Oral bioavailability approaches
cognitive function.
Historically, the targeted cholinergic 100%, with peak concentration occur-
h Historically, the targeted treatment approaches have included ring in 3 to 4 hours (Tmax). It is both
cholinergic treatment (1) using acetylcholine precursors with metabolized extensively in the liver
approaches have
the expectation that more acetylcholine and excreted unchanged in the urine.
included using
will be produced; (2) using direct cho- Donepezil has a long elimination half-
(1) acetylcholine
precursors; (2) direct
linergic agonists to mimic and replace life of 70 hours, and steady state occurs
cholinergic agonists; the effects of acetylcholine; and (3) us- in approximately 2 weeks. A 23-mg
and (3) cholinesterase ing cholinesterase inhibitors to inhibit extended-release formulation has been
inhibitors. the enzyme-induced metabolism of in- marketed, indicated for patients with
trasynaptic acetylcholine. The first two moderate to severe Alzheimer disease
approaches, using several different who have been maintained on 10 mg/d
drugs, have shown no significant or and who might benefit from an in-
meaningful clinical effects.3 In addition, creased dose. This formulation’s Tmax
barriers to the successful development is approximately 8 hours, with peak
of muscarinic agonists include the plasma concentrations about twice as
difficulty in finding a drug with clear M1 high compared to the 10 mg/d dose.
subtype agonismVnot affecting other Rivastigmine. Rivastigmine is a pseu-
muscarinic receptor subtypesVand doirreversible cholinesterase inhibitor
with few adverse effects.4 that is selective for acetylcholinesterase
Tacrine. Tacrine is very rarelyVif at and butyrylcholinesterase. In the two
allVused and is not actively marketed published trials showing efficacy, doses
as it requires administration 4 times were titrated weekly over 7 weeks to
per day, a complicated four-step dose one of two dosage ranges, 1 mg/d to
titration, and is associated with re- 4 mg/d or 6 mg/d to 12 mg/d, and
versible direct hepatotoxicity requiring dose decreases were not permitted,
regular monitoring of serum transami- possibly contributing to less tolerability
nases. It is historically important as the and seemingly more side effects.7,8
first drug approved for Alzheimer dis- A transdermal patch formulation has
ease, setting the roadmap for Alzheimer been marketed based on a placebo-
drug development, but will not be controlled study comparing a 17.4-mg
discussed further. patch, 9.5-mg patch, and 6 mg of orally
Donepezil. Donepezil is a long- administered rivastigmine twice per day
acting reversible acetylcholinesterase in- in 1195 patients with moderately severe
hibitor. Two phase 3 clinical trials Alzheimer disease (ie, Mini-Mental State
showed evidence of efficacy for FDA Examination [MMSE] scores of 10 to 20)
approval. Additional randomized clinical over 6 months. All formulations showed
trials were completed and include trials efficacy, but fewer adverse events oc-
of 6 and 12 months’ duration and in curred with the patch formulations.9

KEY POINTS
Pharmacokinetics and drug inter- excreted in the urine. Galantamine does h The most common
actions. Rivastigmine has little protein not inhibit CYP 2D6 or 3A4 and has adverse events due to
binding and is well absorbed. Although little effect on the metabolism of other cholinesterase inhibitors
the elimination half-life is less than 2 drugs; however, inhibitors of CYP 2D6 include nausea,
hours, enzyme inhibition lasts about 9 or 3A4, such as paroxetine and ketoco- diarrhea, vomiting,
hours. The drug is not metabolized by nazole, respectively, may decrease clear- anorexia, and weight
the liver. It is slowly hydrolyzed and ance and increase the bioavailability and loss. Muscle cramps are
then excreted by the kidneys. The phar- plasma levels of galantamine. Some common with donepezil.
macokinetics of the transdermal patch other CYP 2D6 inhibitors include ami- h Early cholinergic effects
shows maximum concentration in 8 to triptyline, fluoxetine, and quinidine. are frequently related to
16 hours and a 3-hour elimination half- Adverse effects of cholinesterase the initial dosing and
life after the patch is removed. Its inhibitors. The most common adverse titration of the
extrahepatic metabolism makes it un- events due to cholinesterase inhibitors medications.
likely to have significant pharmacoki- are cholinergically mediated and in-
netic interactions. clude nausea, diarrhea, vomiting, an-
Galantamine. Galantamine is a rever- orexia, and weight loss (Table 2-1).
sible competitive acetylcholinesterase Muscle cramps are common with do-
inhibitor with relatively less butyryl- nepezil. Early cholinergic effects are fre-
cholinesterase inhibition compared to quently related to the initial dosing and
rivastigmine. Competitive inhibitors po- titration of the medications. Reducing
tentially are less active in brain areas the dose temporarily and retitrating
that have remaining high acetylcho- may reduce the reemergence of acute
line levels and more active in other cholinergic adverse events. Many pa-
areas. Galantamine also functions as an tients tend to become tolerant to the
allosteric modulator of nicotinic recep- adverse events. Weight loss, fatigue,
tors, possibly enhancing cholinergic and anorexia may occur over time and
transmission by presynaptic nicotinic be tolerated by patients and family and,
stimulation. hence, may not be recognized as
Efficacy of galantamine has been adverse events induced by cholinester-
demonstrated at doses of 8 mg twice a ase inhibitors. Few trials have directly
day and 16 mg twice a day, with fewer compared cholinesterase inhibitors with
adverse effects at the lower dose, in at respect to adverse events.3 More ad-
least four randomized trials of 3 and 6 verse events are observed, however,
months’ duration. A Cochrane review with 23 mg/d donepezil than with 10
concluded that galantamine shows con- mg/d of donepezil in a direct compar-
sistent positive effects of 3 to 6 months’ ison, with many patients experiencing
durationVwith no additional improve- nausea and vomiting,11 and fewer ad-
ment with doses over 16 mg/dVand verse events are seen with transdermal
that the frequency of gastrointestinal rivastigmine compared to orally ad-
adverse events is similar to other cholin- ministered rivastigmine.
esterase inhibitors.10 Anorexia varies in incidence from
Pharmacokinetics and drug inter- 8% to 25% at higher doses of cholines-
actions. Galantamine is well absorbed terase inhibitors compared with 3% to
with approximately 90% bioavailability. 10% in patients on placebo and may be
Peak concentrations occur in approxi- dose related. Similarly, the proportion
mately 1 hour. The half-life of the com- of patients with weight loss in clinical
pound is approximately 7 hours. A trials (ie, losing greater than 7% of
sustained-release form is also available. their weight) ranges from 10% to
It is metabolized by the liver and 24% in patients taking higher doses

a
TABLE 2-1 Maintenance Dosages and Adverse Events of Marketed Cholinesterase Inhibitors
Adverse Events as
Maintenance Reported in Clinical Trials
Drugb Dosage (% Versus Placebo)c,d Comments
Donepezil 5Y10 mg/d Nausea, diarrhea, insomnia, 10 mg/d may be somewhat more
vomiting, muscle cramps, fatigue, efficacious than 5 mg/d in some trials
anorexia, dizziness, abdominal pain,
myasthenia, rhinitis, weight loss,
anxiety, syncope (2% versus 1%)
Donepezil 23 mg/d About twice the rate of adverse For use only in patients with
23 mg, sustained events associated with continuing moderate to severe Alzheimer
release 10 mg/d disease who have been maintained
on 10 mg/d for 93 months
Rivastigmine oral 3 mg, 4.5 mg, or Nausea, vomiting, anorexia, Effective dosage range 3Y6 mg twice
6 mg twice dizziness, abdominal pain, diarrhea, daily
daily malaise, fatigue, asthenia, headache,
May be taken with food
sweating, weight loss, somnolence,
syncope (3% versus 2%); rarely,
severe vomiting with esophageal
rupture
Rivastigmine 4.6, 9.5, or 13.3 Adverse events as above but tend Transdermal application avoids first
transdermal patch mg per 24 h, to be less frequent and severe pass hepatic metabolic effect
transdermal
Better tolerated than oral
Galantamine 8 mg or 12 mg Nausea, vomiting, diarrhea, Effective dosage range is 16Y24 mg/d
twice daily anorexia, weight loss, abdominal
pain, dizziness, tremor, syncope
(2% versus 1%)
Galantamine 16 mg/d or Same as galantamine Effective dosage range is 16Y24 mg/d
extended release 24 mg/d
a
Modified with permission from Schneider LS, Lippincott Williams & Wilkins.3
b
Tacrine is very rarely used currently, if at all, and is not included here.
c
Methods for obtaining and reporting adverse events vary among trials, making it difficult to determine relative rates of adverse events
across drugs.
d
Cholinergic adverse events generally occur early in the course and are related to initiating or increasing medication, and tend to be mild
and self-limited. With cholinergic adverse events medications should be temporarily stopped and restarted at lowest doses.
KEY POINT compared to 2% to 10% of patients monary disease and asthma; urinary
h Anorexia varies in incidence treated with placebo. outflow obstruction; and risk of sei-
from 8% to 25% at higher General precautions, listed in the zures. Bradycardia may lead to syncope,
doses of cholinesterase
prescribing information for the drugs, falls, and injury. Finally, cholinesterase
inhibitors compared with
should be considered when using cho- inhibitors may prolong the effects of
3% to 10% in patients on
placebo and may be dose
linesterase inhibitors. These include in- succinylcholine-type muscle relaxants.
related. The proportion of creased gastric acid secretion; increased
patients with weight loss in risk for gastrointestinal bleeding, espe- Long-Term Safety of
clinical trials ranges from cially in patients concurrently using anti- Cholinesterase Inhibitors
10% to 24% in patients inflammatories; sinus bradycardia, espe- The long-term safety of cholinesterase
taking higher doses cially in patients with sick sinus and inhibitors has not been systematically
compared to 2% to 10% other supraventricular conduction de- studied. An analysis of Canadian med-
of placebo-treated patients. lays; exacerbation of obstructive pul- ical and prescription records, however,

KEY POINTS
indicated that patients on cholinester- with donepezil have demonstrated effi- h An analysis of Canadian
ase inhibitors (mainly donepezil) were cacy for patients with severe Alzheimer medical and prescription
hospitalized for syncope nearly twice as disease. Despite differences in mecha- records showed that
often as people with dementia who did nism of action and dosing levels, no patients on cholinesterase
not receive these drugs. Moreover, they evidence exists for efficacy differences inhibitors were hospitalized
showed a 69% increased risk for brady- between the three cholinesterase inhib- for syncope nearly twice
cardia, a 49% increased risk for having a itors. The relevant clinical question, how- as often as people with
pacemaker implanted, and an 18% in- ever, is to what degree these consistent dementia who did not
creased risk for hip fractures.12 The but modest effects translate into mean- receive these drugs.
absolute incidence of these events is ingful clinical improvement. h Despite differences in
about 2% of treated patients per year, In a Cochrane review,13 the drugs are mechanism of action
implying that one patient will be hos- associated with an overall mean 2.4 points and dosing levels, no
pitalized for syncope for every 50 to effect (range 1.1 to 3.9) over placebo on evidence exists for efficacy
100 patients treated for 1 year. the Alzheimer Disease Assessment differences between the
three cholinesterase
ScaleVCognitive Subscale (ADAS-Cog)
Effectiveness of Cholinesterase inhibitors. In a Cochrane
over 6 months, and absolute mean
review, the drugs are
Inhibitors improvement over baseline with treat- associated with an
Most investigations of drugs that dem- ment ranges from worsening or no overall mean 2.4 points
onstrate efficacy for Alzheimer disease change to improvement of about 1.9 effect over placebo on
have been done in 3- or 6-month trials ADAS-Cog points (Figure 2-1). This the Alzheimer Disease
in patients with mild to moderate Alz- difference represents 10% or less change Assessment ScaleV
heimer disease. In addition, studies on the ADAS-Cog, which is within the Cognitive Subscale.
FIGURE 2-1 Cholinesterase inhibitors, optimum dose versus placebo. The figure shows the mean drug-placebo difference
on the ADAS-Cog from several clinical trials along with 95% confidence interval widths displayed as
horizontal lines. The overall mean effect is j2.37 points with 95% confidence intervals of j2.73 to j2.03.
ADAS-Cog = Alzheimer Disease Assessment ScaleVCognitive Subscale; ITT-LOCF = intention to treat last observation carried
forward; ChEI = cholinesterase inhibitors; SD = standard deviation; IV, Fixed = inverse variance, fixed effect; CI = confidence
interval; Chi2 = Chi squared; df = degrees of freedom; Z = Z score.
13
Reprinted with permission from Birks J, Cochrane Database Syst Rev. B 2006, John Wiley & Sons, Inc. onlinelibrary.wiley.com/doi/10.1002/
14651858.CD005593/abstract.

KEY POINT
h A 23-mg extended- bounds of the scale’s test-retest error. 6 months.11 A significant 2.2 mean
release formulation of Although clearly some patients improved drug-placebo difference on the SIB
donepezil is intended to substantially with cholinesterase inhibi- was not supported by efficacy on the
be used after a patient tors, some also worsened to a greater clinician’s global assessments, and
has been treated with extent than those treated with placebo. dropouts were substantially greater
10 mg/d for at least Withdrawals due to adverse events, par- with the higher dose compared to
3 months and when the ticularly gastrointestinal adverse effects, continuing the 10 mg dose, 30% versus
clinician is uncertain were higher for all three cholinesterase 18%. A post hoc analysis indicated that
whether the patient is inhibitors compared with placebo. Intol- the more severe patients showed a
benefiting from the erability may have more to do with initial somewhat greater 3.1 effect on the SIB
10-mg dose.
titration than with longer-term treat- and significance on the global assess-
ment, at least with respect to nausea ment of 0.09 points on a scale from 1 to
and vomiting. 7. The 23-mg formulation was approved
Because of the design of the trials for marketing by the FDA despite
and the modest therapeutic effect, it is recommendations for nonapproval by
difficult to identify individual treatment two FDA officers. A citizen watchdog
responders, especially those who may group has expressed concern about the
be benefiting by a couple of points. added risks of the higher dose and has
Overall, the use of cholinesterase in- sued the FDA for its removal. As
hibitors involves balancing the modest donepezil is now generically manu-
expectations for benefit with the poten- factured, the branded 23-mg extended-
tial for adverse effects due to the drugs, release formulation sells at a premium
and considerable clinical judgment. over the generics and is heavily pro-
moted. Clinicians should be cautious,
Cholinesterase Inhibitors for however, not to use 20 mg of generic
Severe Alzheimer Disease donepezil in place of the 23-mg branded
Donepezil is the only cholinesterase dose, as the formulations are different.
inhibitor specifically labeled for patients
with severe Alzheimer disease (ie, with Dosage and Use of
MMSE scores of 10 or less). The efficacy Cholinesterase Inhibitors
evidence is based on three 6-month, Donepezil is started at 5 mg/d and can
randomized, placebo-controlled clinical be increased to 10 mg/d after 4 weeks.
trials.4 Effects were modest, on the or- Both 5 mg/d and 10 mg/d are effective
der of several points on the Severe Im- doses, but the 10-mg/d dose is some-
pairment Battery (SIB), a scale ranging what more so when the dosing groups
from 100 to 0.14 In addition, the 23-mg are directly compared. The sustained-
extended-release formulation of done- release 23-mg/d donepezil formulation
pezil is intended to be used in more is indicated for moderate to severe
moderate to severe cases after a patient Alzheimer disease but only for patients
has been treated with 10 mg/d for at who have been treated with 10 mg/d for
least 3 months and when the clinician at least 3 months.
is uncertain whether the patient is The starting dose of rivastigmine is
benefiting from the 10-mg dose. In 1.5 mg twice a day with meals, increased
the only clinical trial to document its to 3 mg twice per day after 2 weeks. Sub-
efficacy, 1467 patients with Alzheimer sequent increases to 4.5 mg and 6 mg
disease with MMSE scores from 20 to twice a day are determined by tolerability
0 who had been treated with donepezil and can be considered after 2 weeks of
10 mg/d were randomized to 23 mg/d treatment. Higher daily doses are associ-
or to continue their 10 mg/d dose for ated with better efficacy than are lower

KEY POINTS
doses. The transdermal patch is started at ment and progression to Alzheimer h Cholinesterase inhibitors
4.6 mg (5 cm2) per day and increased to disease. The two galantamine trials, are not indicated for
one 9.5-mg (10 cm2) patch per day after when combined, were particularly mild cognitive impairment,
4 weeks, if tolerated. A 13.3-mg (15 cm2) concerning for an excess in deaths yet their use may be
patch was recently approved, allowing associated with the drug. In some trials, common practice.
for a further increase after 4 weeks at nominally significant drug-placebo dif- Clinical trials of
the 9.5-mg dose. The maintenance doses ferences on the ADAS-Cog were ob- cholinesterase inhibitors
are 4.6 mg/d, 9.5 mg/d, or 13.3 mg/d. served at earlier time points during the in MCI were not positive
Initial dosing for galantamine is 4 mg first year. The effects were not sus- on their primary
twice a day, raised to 8 mg twice a day tained, however, and appeared more outcomes and showed
an excess in adverse
after 4 weeks. The dose can be raised to evident in the patients with more se-
events.
12 mg twice a day after another 4 weeks vere cognitive impairment and in
if patients are tolerating the medication APOE*E4 carriers. h Memantine was approved
but do not appear to be benefiting from by the US Food and Drug
MEMANTINE Administration in late
it. The initial dose of the extended-
2003 for moderate to
release formulation is 8 mg/d, raised to Memantine was approved by the FDA
severe Alzheimer
16 mg/d after 4 weeks, and can be in late 2003 for moderate to severe disease. The basis for
increased to 24 mg/d based on tolera- Alzheimer disease. It is characterized approval was positive
bility and benefit. With all cholinester- as a moderate-affinity, uncompetitive outcomes on two
ase inhibitors, raising the dose too soon N-methyl-D-aspartate (NMDA) receptor 6-month-long
increases risks for cholinergic adverse antagonist; a rationale for its use is that placebo-controlled
events. it may protect against overstimulation clinical trials. In one trial
of NMDA receptors that may occur cholinesterase inhibitors
Cholinesterase Inhibitors for in Alzheimer disease as well as con- were not allowed, and in
Mild Cognitive Impairment sequent glutamate- and calcium- another, patients had
Cholinesterase inhibitors are not indi- mediated neurotoxicity. been taking donepezil
for at least 6 months
cated for mild cognitive impairment The basis for approval was positive
(over 2 years on
(MCI), yet their use may be common outcomes on two 6-month-long placebo-
average). A third trial
practice, and nearly half of patients so controlled clinical trials. In one trial did not show significant
diagnosed in the Alzheimer’s Disease cholinesterase inhibitors were not al- effects.
Neuroimaging Initiative (ADNI) were lowed,21 and in the other trial, all pa-
receiving them.15 The several random- tients had been taking donepezil for at
ized, placebo-controlled trials of cholin- least 6 months (over 2 years on aver-
esterase inhibitors for MCI used the age) before being randomized to
typical doses for Alzheimer disease, memantine or placebo.22 A third mod-
tended to be long-term (from 2 to 4 erate to severe Alzheimer disease trial
years), and the onset of Alzheimer did not show significant effects for
dementia as main end points. Never- memantine, however.23
theless, the two 2-year galantamine The trials were similar to the design of
trials,16 one 4-year rivastigmine trial,17 cholinesterase inhibitors trials but in-
and one over-3-year donepezil trial18 cluded only patients with MMSE scores
were not positive on their primary out- less than 15Vhence the moderate to
comes and showed an excess in ad- severe Alzheimer disease indicationV
verse events (summarized in at least whereas mild to moderate Alzheimer
three systematic reviews10,19,20). Uncer- disease trials are usually operationalized
tainty regarding definitions of MCI limit as MMSE 10 to 26, and for memantine as
inferences that can be drawn from the 10 to 22.
outcomes of these trials as there were The SIB, a global assessment, and an
broad variations in cognitive impair- activities of daily living (ADLs) inventory

KEY POINTS
h Only one of three trials were primary outcome measures. The an open-channel NMDA receptor antag-
of memantine in mild to SIB is used as the cognitive outcome onist that does not have apparent phar-
moderate Alzheimer measure instead of the ADAS-Cog be- macologic activity until higher glutamate
disease showed significant cause the patients are too severely im- levels trigger the receptor and cause the
improvement on the paired to perform on the latter. Although ion channel to open. It is speculated that
Alzheimer Disease the outcomes are different, the standard- the drug then enters the channel, block-
Assessment ScaleV ized statistical magnitudes of benefit from ing it and preventing calcium influx,
Cognitive Subscale and memantine in two of the three moderate depolarization, and hyperactivation of
global assessment. to severe Alzheimer disease trials is the neuron. Memantine could be viewed
Memantine has not similar to modest effect sizes seen in as a modulator of glutamatergic activity.
been approved by the
cholinesterase inhibitors trials with pa- As this hypothesized mechanism is
US Food and Drug
tients with mild to moderate Alzheimer apparently neuroprotective, it is not
Administration for
patients with mild
disease. clear what exactly is involved in
Alzheimer disease. It is important to note that only one memantine’s short-term and symptom-
of three trials of memantine in mild to atic effect in 6-month trials. Memantine
h A Cochrane review
moderate Alzheimer disease that were may have effects on long-term potentia-
concluded that
memantine had a small
of similar design to cholinesterase tion that may correlate with a short-term
beneficial effect in inhibitor trials showed statistically sig- effect on memory.29,30
moderate to severe nificant improvement on the ADAS-Cog The above is speculative, however,
Alzheimer disease and and global assessment.24 Two others did and potential long-term efficacy has not
was well tolerated. not show significant drug-placebo been tested in the long-term and large
h Adverse events with differences,25Y27 and in pooled analyses clinical trials that would be required.
memantine are did not show efficacy for mild
infrequent but can Alzheimer disease.28 Hence, memantine Pharmacokinetics
include headache, has not been approved by the FDA for Memantine is well absorbed, not affected
dizziness, confusion, patients with mild Alzheimer disease.28 by food; bioavailability approaches 100%,
somnolence, and A once-per-day 28-mg sustained- and it is widely distributed throughout
infrequent hallucinations. release formulation was approved by the body. Plasma protein binding is
In clinical trials, the the FDA in 2010 but has not yet been about 45%; the time to maximum
frequency of marketed. The basis for FDA approval plasma concentration is between 3 to
gastrointestinal
was a 6-month, placebo-controlled, Alz- 7 hours and elimination half-life is 60 to
symptoms is less than
heimer disease trial involving 677 pa- 80 hours. Memantine undergoes mini-
placebo; diarrhea
occurred half as often.
tients with MMSE scores between 3 and mal hepatic metabolism, and it is mostly
12 (completed in 2010 but unpub- excreted unchanged in the urine.
lished), in which there were statistically
significant effects favoring sustained- Adverse Effects
release memantine on the SIB and global Adverse events are infrequent but
assessment but not on ADLs. Reported can include headache, dizziness, con-
adverse events were similar to placebo. fusion, somnolence, and infrequent
Controlled clinical trials of me- hallucinations. In clinical trials, the
mantine are summarized in a Cochrane frequency of gastrointestinal symptoms
review that concluded that memantine is less than placebo, and, for example,
had a small beneficial effect in moderate diarrhea occurred half as often.
to severe Alzheimer disease and was The actions of memantine may re-
well tolerated.27 duce the cholinergic effects of donepezil
(although this has not been formally
Mechanism of Action studied). There appear to be no adverse
The therapeutic mechanism of action of drug interactions with cholinesterase
memantine is unknown, but it may act as inhibitors.

KEY POINTS
Dosage and Use periods. Cognitive effects are consid- h Extracts from leaves of
Per prescribing information, memantine ered to last up to 3 months. Several the Ginkgo biloba, or
is started at 5 mg/d for 1 week and then 6-month placebo-controlled trials in pa- maidenhair, tree are
increased weekly by 5 mg/d until 10 mg tients with Alzheimer disease showed widely sold in the
twice daily is reached. The reason for equivocal outcomes.35 United States as food
this titration regimenVconsidering Extracts from leaves of the G biloba, supplements for which
memantine’s long half-life and high or maidenhair, tree are widely sold in health claims are not
degree of tolerabilityVis because it the United States as food supplements permitted. A specific
for which health claims are not permit- standardized extract,
was used in the trials that supported
ted and most insurance plans will not EGb 761, is approved
its marketing approval, and other regi-
by the formularies of
mens have not been tested. reimburse.36 A specific standardized
Germany and France.
In clinical practice, memantine is extract, EGb 761 (ie, standardized to
a certain level of flavonoids and h G biloba extract is also
either prescribed alone or added to a
ginkgolides), is approved by the formu- used as a memory
cholinesterase inhibitor, often after the
enhancer in people
latter has been used for a time. Some laries in some countries, most notably
without Alzheimer
clinicians, however, start memantine Germany and France.
disease; however,
along with or very soon after a cholines- Rationales for G biloba extract as clinical trials in older and
terase inhibitor, an off-label use. Its an Alzheimer disease treatment are younger adults who
duration of effectiveness is not known that in preclinical models the flavonoids do not have cognitive
beyond the 6-month length of the clin- and ginkgolides are antioxidants, ap- impairment show mixed
ical trials; however, it tends to be pre- pear neuroprotective, may inhibit results at best.
scribed for indefinite periods. Some A"42-induced neuron death, enhance h A Cochrane review that
open-label observations from clinic co- neurogenesis, and inhibit A" aggrega- included 35 clinical trials
horts have suggested that therapy with a tion. None of these properties has reported inconsistent
cholinesterase inhibitor and memantine been demonstrated in humans. evidence that G biloba
together may ameliorate the course of G biloba extract is also used as a had clinically significant
Alzheimer disease,31,32 while observa- memory enhancer in people without benefits for dementia or
tions from clinical trial extensions and Alzheimer disease; however, clinical cognitive impairment.
ADNI suggest that any effects may wane trials in older and younger adults who
over 6 to 12 months of treatment.15,33,34 do not have cognitive impairment
The practical issue of how long to show mixed results at best.36
treat is particularly challenging in pa- A Cochrane systematic review that
tients with severe dementia and poor included 35 clinical trials reported in-
quality of life, especially when the clin- consistent evidence that G biloba had
ician is uncertain as to whether or not clinically significant benefits for demen-
an individual patient is benefiting. tia or cognitive impairment.37 One FDA
regulatoryYquality 6-month trial in mild
CEREBROLYSIN AND GINKGO to moderate Alzheimer disease was
BILOBA conducted in the United States with
Cerebrolysin and Ginkgo biloba stan- the expectation for gaining FDA ap-
dardized extract are mentioned because proval but failed to demonstrate ef-
they are licensed or on medication for- ficacy.38 A 6-month trial conducted at
mularies of many countries (not the British primary care sites also failed to
United States). Cerebrolysin is a peptide show efficacy.39
and amino acid preparation from por- The controversies about EGb 761
cine brain that may have neurotrophic include its promotion in the United
actions in preclinical models. It is States for Alzheimer disease and a tepid
administered intravenously or intramus- endorsement from the German Insti-
cularly 5 days a week for 4-week tute for Quality and Efficiency in Health

KEY POINTS
h A medical food is a food Care that it might improve ADLs, show combination of compounds including
formulated for the cognitive benefit, and improve be- uridine, choline, omega-3 fatty acids,
dietary management havioral symptoms, but only in demen- phospholipids, B vitamins, and antioxi-
of an illness that has tia patients with ‘‘psychopathologic’’ dants.46 The rationale is that the com-
distinctive nutritional symptoms, conclusions, however, that bination enhances dendritic spine
requirements, and is relied on only two studies conducted in growth, synapse formation, and neuro-
intended to be used Eastern Europe.40 transmitter precursors, ultimately im-
under medical G biloba EGb 761 extract is also proving cognitive function. Thus far,
supervision. notable because three prevention trials results of a 12-week, placebo-controlled
h A formulation of to delay the onset of Alzheimer disease trial in 225 patients with Alzheimer
medium-chain or MCI41Y43 did not yield significant disease were not significant on most
triglycerides is marketed results. Two trials included 3069 and outcomes; and the primary outcome, a
as a medical food for 2854 nonimpaired or MCI patients neuropsychological memory composite
Alzheimer disease in the followed over 5 years. In sum, little, if score, from a 24-week trial with 259
United States. Another
any, evidence exists for G biloba ex- patients with mild Alzheimer disease,
medical food, marketed
tract either improving symptoms or showed a statistical trend in favor of the
in late 2012 in Europe
and Brazil, is a
preventing Alzheimer disease. formulation. No increase in adverse
combination of events over placebo was reported in
compounds including
MEDICAL FOODS the later trial.
uridine, choline, A medical food is a food formulated for
omega-3 fatty acids, the dietary management of an illness that CONTROVERSIES ON THE
phospholipids, has distinctive nutritional requirements, EFFECTIVENESS OF CURRENT
B vitamins, and and is intended to be used under medical TREATMENTS
antioxidants, intended supervision.44 Thus physicians may Considerable controversy surrounds
to enhance synaptic write prescriptions for medical foods. the use of currently available drugs for
function and A formulation of medium-chain tri- treating Alzheimer disease, involving
neurotransmitters,
glycerides is marketed as a medical food not only the limited efficacy and adverse
presumably improving
for Alzheimer disease. The rationale for effects but also the desperation and
cognitive function.
Controlled trials of
this formulation proposes that unmet needs of many patients and their
these two medical foods Alzheimer disease may result in part families, as well as the frustration of
have not been positive. from mitochondria dysfunction and im- clinicians. This controversy is played
paired glucose metabolism; therefore, out between two positions: either that
enriching a diet with a food that is the drugs are effective and should be
converted to ketones that would pre- considered the standard of care for Alz-
sumably enhance electron transport in heimer disease, or that they are in-
mitochondria would be therapeutic.45 A effective and not worthwhile in terms
randomized, placebo-controlled, 12- of cost and adversity. Hence, the over-
week trial in Alzheimer disease showed arching controversy is whether or not
an improvement in cognitive function their use yields clinically meaningful
after 6 weeks that was lost at 12 weeks; or therapeutically useful outcomes,
another trial in MCI was also negative. and for whom. As examples, the Agency
The main adverse events reported by for Healthcare Research and Quality
the manufacturer are gastrointestinal (AHRQ) stated that ‘‘treatment of de-
symptoms; cautions include risk for mentia with cholinesterase inhibitors
ketoacidosis in patients at risk, includ- and memantine can result in statistically
ing those with alcohol abuse history significant but clinically marginal im-
and poorly controlled diabetes. provement in measures of cognition
Another medical food, marketed in and global assessment of dementia.’’47
late 2012 in Europe and Brazil, is a The United Kingdom’s National Institute

for Health and Clinical Excellence
(NICE) and a health assessment group
initially concluded in 2006 that the
cholinesterase inhibitors can delay cog-
nitive impairment for 6 months,48 but
that they are not cost-effective.49 Addi-
tional concerns raised included the fact
that the real impact of treatment is
difficult to assess because of the limited
methodologic quality of the trials, a lack
of generalizability, the fact that patients
with medical comorbidities were not
included in the trials, and that the mean
scores are difficult to interpret.48 NICE
is less restrictive, however, in their
revised opinion.
Pharmaceutical advertising cam-
paigns, some of which have resulted in
FDA warnings for overstating efficacy, FIGURE 2-2 Comparison of the identical effect of
donepezil from a clinical trial compared to
have contributed to the perception of placebo, with standard deviation (SD) bars
effectiveness that influences both phy- (left) reflecting the distribution of outcomes and standard
sicians and caregivers.50,51 error of the mean (SEM) limits (right) reflecting the precision of
the outcomes. The narrow standard error bar indicates the
relatively high precision and strong statistically significant
Efficacy Versus Effectiveness drug-placebo estimate of the difference. The SD limits show
how, despite the statistical significance, substantial overlap
The issue of efficacy versus effectiveness occurs in outcomes between patients treated with donepezil
of cholinesterase inhibitors is illustrated and patients treated with placebo, such that very few
individuals can be seen to benefit on ADAS-Cog scores. Even
and discussed in Figure 2-2.52 Despite the patients who improve to the greatest extent (eg, those
trends showing clear statistical signifi- outside the 1 SD limit) are still in the moderately severe
dementia range.
cance, it can be seen that there is
substantial overlap in outcomes be- ADAS-Cog = Alzheimer Disease Assessment ScaleVCognitive
tween drug and placebo patients. Even Subscale; AD = Alzheimer disease.
the patients who improve to the greatest Reprinted from Lindner MD, et al, Academic Press.52 B 2008, with
extent on the ADAS-Cog are still in the permission from Elsevier.
moderately severe dementia range. This

illustrates the meaning of the ‘‘small’’ or
‘‘modest’’ cognitive effects of cholines- Duration of Treatment KEY POINT
terase inhibitors and makes inferences Placebo-controlled clinical trials with h It is difficult to identify
the individual patient
about this effect, indicating improved marketed cholinesterase inhibitors gen-
who benefits from
health outcomes, difficult. erally have lasted 6 months, with a few cholinesterase inhibitors
It is difficult to identify the individual exceptions lasting up to 12 months or or memantine because
patient who benefits from cholinester- longer. Inferences are made that if the outcome measures
ase inhibitors or memantine because the the drugs are effective over this period and mean changes on
outcome measures and mean changes then they will continue to be beneficial scale scores do not
on scale scores do not identify re- far longer, perhaps indefinitely. Over identify responders.
sponders. Further, most trials have not the long term, however, as patients
taken caregiver views into account, inevitably worsen, it becomes even
although one that did shows that impor- more difficult to determine whether
tant aspects of the treatment response any given individual is benefiting from
are missed by current measures.53 the drugs.

KEY POINTS
h Discontinuation of In some 3-month-long and 6-month- stopped after a fixed period of 12 weeks
cholinesterase inhibitors long trials, after medication has been and patients were then randomized to
has been associated discontinued patients on average return continuing drug or to placebo58 as well
with worsening of to the cognitive level of the patients con- as when patients were discontinued
cognition and confusion temporaneously treated with placebo from some 6-month trials. Yet worsen-
in some patients in within 6 weeks. Such findings are taken ing of behavior and confusion do not
trials. Yet worsening of to indicate that the drugs have overall appear common when the drugs are
behavior and confusion symptomatic effects and that continuous stopped in clinical practice, as is fre-
do not appear common use is required to maintain benefits. quently done. In clinical practice only
when the drugs are Some observational studies using 19% to 23% of patients continued to
stopped in clinical
clinic databases or open-label exten- take donepezil or rivastigmine for more
practice. In clinical
sions of clinical trials suggest that than 1 year, and about one-third dis-
practice, 19% to 23%
of patients continued
patients who continue cholinesterase continued the drugs within 2 months.59
to take donepezil or inhibitors over at least 1 year have a Tapering and withdrawal of done-
rivastigmine for more delay in nursing-home placement com- pezil after maintenance treatment for an
than 1 year, and about pared to those who cannot tolerate or average of 2 to 3 years was formally
one-third discontinued do not take them, and that the addition tested in a randomized controlled trial
the drugs within of memantine could further contribute of severely impaired patients with
2 months. to the delay.31,32,54,55 These observa- Alzheimer disease; continuing donepezil
h In a withdrawal trial tions, however, are not controlled was compared with discontinuing it,
after maintenance and are subject to the potential bias and, simultaneously, starting memantine
treatment with that patients who experience a less- was compared with not starting it.60
donepezil for 2 to progressive course continue their Over the 1-year follow-up period, con-
3 years in severely medications, while patients who are tinuing donepezil was associated with
impaired patients with destined to progress more quickly do better cognitive scores and ADLs, and
Alzheimer disease, not continue, resulting in apparent adding memantine when donepezil
continuing donepezil
therapeutic effects that are illusory. was discontinued was better than not
was associated with
Moreover, comparisons are made be- adding it. Many patients, however, dis-
better cognitive scores
and activities of daily
tween cohorts from time periods both continued donepezil without difficulty;
living. Many patients before and after the ready availability of notably, only half of the patients who
discontinued donepezil the cholinesterase inhibitors.56 These were assigned to continue donepezil
without difficulty, and observational studies, however, con- actually continued treatment beyond
only half of the patients trast with the long-term controlled trials the 1-year follow-up, suggesting that
assigned to continue in MCI and with observations from the many patients perceived that continu-
donepezil actually ADNI15 and Australian Imaging Bio- ing donepezil, at least under double-
continued treatment markers and Lifestyle datasets,57 where blinded conditions, was not effective.
beyond the 1-year the use of cholinesterase inhibitors Thus, the outcomes support decisions
follow-up. Thus, the over the long term is associated with either to continue medication or to
outcomes support
faster decline. Thus, duration of treat- taper and discontinue it when physicians
decisions either to
ment remains an unresolved issue. are uncertain of continuing benefit.61
continue medication or
to taper and discontinue
This trial also did not support the typi-
Effects from Withdrawal of cal use for memantine as an add-on to
it when physicians are
uncertain of continuing
Cholinesterase Inhibitors or donepezil, showing that the add-on was
benefit. Memantine not better than continuing donepezil
Discontinuation of cholinesterase inhib- alone, a finding that adds to the con-
itors has been associated with worsen- troversy of whether the drugs taken
ing of cognition and confusion in some together are better than either alone. It
patients. This effect was evident in a is generally good practice to taper these
clinical trial in which donepezil was medications before discontinuing, even

KEY POINTS
though both donepezil and memantine acerbating restlessness, agitation, or h Only three of 14 trials
have long terminal half-lives. sleeplessness. showed significant
effects for cholinesterase
Effectiveness for Treatment of OVERVIEW OF ALZHEIMER inhibitors improving
Disruptive Behaviors DISEASE DRUGS IN DEVELOPMENT behavior; none of these
The evidence base for advocating cho- Not for the want of trying over the past effects was large. Trivial
linesterase inhibitors and memantine 2 decades, and despite substantial prog- effects were reported
for treating disruptive behaviors in Alz- ress in understanding pathogenetic in the more mildly
heimer disease consists of post hoc processes associated with Alzheimer cognitively impaired
analyses of individual items on behavior disease, no new practical treatments patients, but no effect
was reported in the
rating scales from randomized trials. In a have been developed. A 2008 estimate
more severely impaired.
summary analysis of 14 cholinesterase identified 172 experimental drugs for
inhibitor trials that assessed effects on Alzheimer disease that had been in h Regulatory criteria for
behavior in post hoc analyses, only phase 1 to phase 3 development, half marketing symptomatic
and disease-modifying
three showed significant effects for of which had already failed by that time,
therapies require
improving behavior62; none of these ef- and nearly all of those have now been
demonstrating
fects was large.13 Another meta-analysis discontinued.52 This enormously high improvements in
reported significant but trivial effects failure rate is due almost entirely to ef- cognition and activities
on behavior in the more mildly cogni- ficacy and safety issues. of daily living, overall
tively impaired patients, but no effect in The phenotypic heterogeneity and improvements
the more severely impaired.63 The fact pleomorphic expression of the illness compared to placebo,
that patients were not chosen for hav- implies that many potential therapeutic and adequate safety.
ing behavior problems and their symp- targets may exist. The many drugs
tom ratings were rather low at baseline under development can be grouped
limits reasonable inferences about clin- into approaches directed at A" and
ical efficacy. tau proteins; at neurotrophic, neuro-
One randomized placebo-controlled protective, and anti-inflammatory mecha-
trial prospectively assessed donepezil’s nisms; and at various neuroreceptors.
efficacy for improving behavior in pa- The dominant target areas currently
tients who had clinically important agita- are drugs targeting A", neuronal nico-
tion and did not find an effect for tinic receptors, and 5-HT subtype
donepezil over placebo, which itself had receptors.
a moderate effect.64 Of considerable
importance was that donepezil did im- Regulatory Requirements
prove cognitive function in this trial, Regulatory criteria for marketing symp-
suggesting that the effects on cognition tomatic and disease-modifying therapies
do not necessarily affect behavior. A require demonstrating improvements
similarly designed randomized con- in cognition and ADLs, overall improve-
trolled trial, but with memantine, did ments compared to placebo, and ade-
not demonstrate its efficacy at improving quate safety.66 For drug development
behavior, either.65 programs, pharmaceutical companies
As many patients with disruptive plan fairly standard protocols, usually
behaviors are treated with both cholin- including patients with mild or mild to
esterase inhibitors and memantine, the moderate Alzheimer disease and using
opportunities to use the drugs specifi- standard outcome measures (such as the
cally to treat agitation and disruptive ADAS-Cog),67 standard ADLs, and global
behavior are limited, however. Finally, change and severity scales, regardless
a clinician would want to be sure that of whether efficacy is being tested over
the cholinesterase inhibitor is not ex- the short or long term.

KEY POINTS
h The gist of the amyloid Cholinesterase inhibitors, memantine, targets, none has had significant clinical
cascade hypothesis and small molecules that are considered effects. In 2011 and 2012, two negative
is that amyloid-" to have symptomatic effects are tested trials of +-secretase inhibitors, sema-
deposition drives tau over 6 months. Drugs in development gacestat and avagacestat, and several
phosphorylation, tangle that are considered as modifiers of negative trials of monoclonal antibodies,
formation, and neuron illness progression have been tested bapineuzumab and solanezumab were
death. generally in more mildly impaired pa- reported. Other A" antibodies, A" vac-
h There are several tients and over 18 months. cines, +-secretase modulators, and "-
amyloid-"Ytargeted secretase inhibitors continue to be
experimental The Amyloid Cascade Hypothesis tested, as well as methods to modify or
approaches, including The amyloid cascade hypothesis is the enhance the function of apolipoprotein
modulation of most-researched conceptual framework E4 to increase brain clearance of A".71
amyloid-" production, for Alzheimer disease, and it markedly There are now several clinical examples
inhibition of amyloid-" influences drug development.68 The demonstrating that reducing A" in the
aggregation,
gist of the amyloid cascade hypothesis brain is possible but that decreasing
enhancement of
is that A" deposition drives tau phos- production or reducing fibrils or plaques
amyloid-" degradation,
and use of passive and
phorylation and tangle formation and is not clearly associated with clinical
active immunization to neuron death.69 The pathologic and improvement and could be associated
raise antibodies that clinical expression of Alzheimer disease with harm in some circumstances.72Y76
target and remove results from the increased production
amyloid-". and/or impaired clearance of various A" Tau in Alzheimer Disease and
peptides produced by variations in the Anti-Tau Approaches to Therapy
processing of the neuronal membrane The neurofibrillary tangles that define
protein amyloid precursor protein and are characteristic of Alzheimer dis-
(APP) and that one or several forms of ease correlate with the clinical severity
A" drive pathogenesis.68,70 Although of dementia.77 The tangles represent
A"40 is the most prevalent A" peptide, the aggregation and accumulation of
A"42 and perhaps others have greater hyperphosphorylated forms of the
propensity to aggregate into oligomers, microtubule-associated protein tau.
fibrils, and amyloid-containing deposits Microtubule-bound soluble tau supports
that are thought to be toxic. Amyloid axonal transport. Hyperphosphorylation
plaques, protofibrils, oligomeric and of tau might disrupt microtubules and
monomeric forms of A" may each be axonal transport and lead to the forma-
responsible for the pathogenic expres- tion of soluble tau aggregates and insol-
sion of the illness. For example, A" uble paired helical filaments, and could
oligomers may show synaptic toxicity contribute to neurodegeneration.
effects, and plaque-derived A" fibrils may A current hypothesis is that Alz-
be proinflammatory and neurotoxic. heimer pathology starts as pretangles in
proximal axons of the noradrenergic
Anti-Amyloid Approaches locus ceruleus that spreads by neuron-
There are several A"-targeted experi- to-neuron and trans-synaptic transport
mental approaches, including modula- of tau aggregates to the entorhinal
tion of A" production, inhibition of A" cortex, hippocampus, and neocortex.78
aggregation, enhancement of A" degra- This prionlike, protein-templating cross-
dation, and use of passive and active neuronal propagation hypothesis sug-
immunization to raise antibodies that gests several interventions aimed at tau
target and remove A". Unfortunately, and also small-molecule interventions
although several drugs have been dem- targeted toward midbrain monoaminer-
onstrated to be active at their intended gic systems.

KEY POINTS
Anti-tau therapeutic strategies. The neurogenesis effects, and reduction of h The range of anti-tau
range of therapeutic approaches under A"42. therapeutic approaches
development include inhibiting tau ki- under development
nases; enhancing phosphatase activity CHALLENGES OF DEVELOPING include inhibiting tau
in an effort to enhance microtubule sta- EFFECTIVE TREATMENTS FOR kinases; enhancing
bility; blocking or inhibiting tau hyper- ALZHEIMER DISEASE phosphatase activity in
phosphorylation, tau aggregates, and The considerable challenges to devel- an effort to enhance
filament formation; and enhancing oping effective treatments for Alzheimer microtubule stability;
clearance of aggregates with drugs or disease include the uncertainty and lack blocking or inhibiting
antibodies. A few of these approaches of validated drug and molecular targets tau hyperphosphorylation,
tau aggregates, and
have progressed from preclinical to and the ability to conduct efficient clin-
filament formation; and
phase 2 clinical trials.79,80 ical development programs. Estab-
enhancing clearance of
Tau pathology is not specific to lishing validated drug targets requires aggregates with drugs
Alzheimer disease, however, and occurs greater understanding of the patho- or antibodies.
in several other disorders, including genic processes leading to illness. For
h Challenges to developing
frontotemporal dementia, corticobasal example, the amyloid cascade may be
effective treatments for
degeneration, and progressive supra- well understood and potential drugs Alzheimer disease include
nuclear palsy; any ‘‘anti-tau’’ approach targeting various components are ap- the uncertainty and lack
could be considered for any of the parent. Yet it is possible that no inter- of validated drug and
tauopathies. vention in this area will demonstrate molecular targets and
efficacy because the amyloid cascadeV the ability to conduct
Other Approaches and Small as strongly associated with Alzheimer efficient clinical
Molecules pathology as it isVmay still not be a development programs.
Most of the ‘‘small molecules’’ ap- relevant therapeutic target. Establishing validated
proaches target neurotransmitter Barriers to developing successful drug targets requires
receptors. They include nicotinic neu- drugs for Alzheimer disease include greater understanding
of the pathogenic
ronal receptor agonists or modulators, current translational models from ani-
processes leading to
drugs that are active at serotonin (5- mal to man (ie, efficacy in mice does
illness.
hydroxytryptophan subtype receptors), not predict efficacy in humans), the
histamine (H3 subtype receptor) antag- various clinical presentations of the
onists, metabolic enhancers, phospho- illness, and the numerous potential
diesterase type 4 (PDE 4) enzyme pathologic targets for new drugs. It is
inhibitors, +-aminobutyric acid A recep- possible that newer approaches to
tor modulators, monoamine oxidase prevention trials, earlier interventions,
type B enzyme inhibitors, and group interventions aimed at particular clinical
2 metabotropic glutamate receptor in- and biological subtypes of Alzheimer
hibitors. Some of these drugs have ef- disease, and smaller phase 2a trials to
fects on A" generation or secretase gain early signals of potential efficacy
activity in preclinical models. For ex- may be helpful. Although there are
ample, alpha-7 neuronal nicotinic mod- many explanations for the failures in
ulators may enhance cholinergic trials, the most likely are that the
function and alter A". H3 antagonists experimental drugs do not work.
may act on H 3 presynaptic auto-
receptors to increase cholinergic and SUMMARY
monoaminergic neurotransmitter re- The currently marketed medications for
lease and are associated with enhanced Alzheimer disease are the cholinesterase
cognitive function in preclinical models. inhibitors and memantine. Vitamins,
Group 2 metabotropic glutamate inhib- food supplements, and G biloba ex-
itors might combine cognitive effects, tract have not been shown to be

effective. No pharmacologic approaches randomised double-blind trial. Lancet 2004;

363(9427):2105Y2115.
have been demonstrated to prevent
or delay onset of MCI or Alzheimer 7. Corey-Bloom J, Anand R, Veach J. A
randomized trial evaluating the efficacy and
dementia. safety of ENA 713 (rivastigmine tartrate), a
New drug development has mainly new acetylcholinesterase inhibitor, in
targeted the amyloid hypothesis and patients with mild to moderately severe
Alzheimer’s disease. Int J Geriatr
thus far has been unsuccessful. Other Psychopharmacol 1998;1:55Y65.
experimental approaches for which
8. Rosler M, Anand R, Cicin-Sain A, et al.
there are some indications for efficacy Efficacy and safety of rivastigmine in
in early-phase development include patients with Alzheimer’s disease: international
small molecules that are active at nico- randomised controlled trial. BMJ 1999;
318(7184):633Y638.
tinic and serotoninergic receptor sub-
sites. Several approaches to targeting 9. Winblad B, Grossberg G, Frölich L, et al.
IDEAL: a 6-month, double-blind,
tau protein are gaining momentum. placebo-controlled study of the first skin
As there are many potential and no patch for Alzheimer disease. Neurology
validated drug targets for Alzheimer dis- 2007;69(4 suppl 1):S14YS22.
ease, experimental drug development 10. Loy C, Schneider L. Galantamine for
faces numerous challenges. Finally, drug Alzheimer’s disease and mild cognitive
development will be influenced by impairment. Cochrane Database Syst Rev
2006;(1):CD001747.
somewhat different diagnostic criteria
for AD and for prodromal AD than used 11. Gill SS, Anderson GM, Fischer HD, et al.
Syncope and its consequences in patients
in the past; the use of diagnostic, with dementia receiving cholinesterase
prognostic, and predictive biomarkers; inhibitors: a population-based cohort study.
and the potential to make pharmaco- Arch Intern Med 2009;169(9):867Y873.
logic interventions before the onset of 12. Farlow MR, Salloway S, Tariot PN, et al.
cognitive symptoms. Both substantial Effectiveness and tolerability of high-dose
(23 mg/d) versus standard-dose (10 mg/d)
hope and challenges lie ahead. donepezil in moderate to severe Alzheimer’s
disease: a 24-week, randomized, double-blind
study. Clin Ther 2010;32(7):1234Y1251.
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Review Article
New Genes and New

Dr John M. Ringman, Easton
Center for Alzheimer’s
Disease Research at UCLA,
10911 Weyburn Ave., #200,
Los Angeles, CA 90095Y7226
jringman@mednet.ucla.edu.
Insights from Old
Relationship Disclosure:
Dr Ringman serves as a
consultant for Avanir
Genes: Update on
Pharmaceuticals, Inc;
Phloronol, Inc; Takeda
Pharmaceutical Company
Limited; and StemCells, Inc.
Alzheimer Disease
Dr Ringman serves as site John M. Ringman, MD, MS; Giovanni Coppola, MD
investigator for clinical trials
sponsored by Alzheimer’s
Disease Cooperative Study,
Bristol-Myers Squibb Company, ABSTRACT
Elan Corporation; Genentech, Purpose of Review: This article discusses the current status of knowledge regarding
Inc; Janssen Alzheimer
Immunotherapy; Medivation, the genetic basis of Alzheimer disease (AD) with a focus on clinically relevant aspects.
Inc; and Pfizer Inc. Dr Coppola Recent Findings: The genetic architecture of AD is complex, as it includes multiple
receives or anticipates susceptibility genes and likely nongenetic factors. Rare but highly penetrant autosomal
receiving grants, personal
compensation, or other dominant mutations explain a small minority of the cases but have allowed
support from the NIH, the John tremendous advances in understanding disease pathogenesis. The identification of a
Douglas French Alzheimer’s strong genetic risk factor, APOE, reshaped the field and introduced the notion of
Foundation, the Muscular
Dystrophy Association, genetic risk for AD. More recently, large-scale genome-wide association studies are
Takeda Pharmaceutical adding to the picture a number of common variants with very small effect sizes.
Company Limited, the Adelson Large-scale resequencing studies are expected to identify additional risk factors, in-
Medical Research Foundation,
and the Tau Consortium. cluding rare susceptibility variants and structural variation.
Unlabeled Use of Summary: Genetic assessment is currently of limited utility in clinical practice because
Products/Investigational of the low frequency (Mendelian mutations) or small effect size (common risk factors)
Use Disclosure:
Drs Ringman and Coppola
of the currently known susceptibility genes. However, genetic studies are identifying
report no disclosures. with confidence a number of novel risk genes, and this will further our understanding
* 2013, American Academy of disease biology and possibly the identification of therapeutic targets.
of Neurology.
Continuum (Minneap Minn) 2013;19(2):358–371.
INTRODUCTION Mendelian fashion are rare (accounting

The clinical and pathologic entity for approximately 1% of cases), genetic
known as Alzheimer disease (AD)1 is factors are likely to play an important
the most common cause of dementia, role in all forms of the disease. Over
a problem that, considering increasing the last 20 years tremendous advances
longevity, is growing in its public have been made in genetic and informa-
health implications.2 Late-onset AD, tion technology, such that novel ap-
the most common form of the illness proaches (including genome-wide
(typically defined as onset after 65 years association studies and whole-genome
of age), is rarely caused by mutations sequencing) have joined more tradition-
transmitted in Mendelian fashion, and al mapping methods, such as familial
yet its heritabilityVbroadly defined as genetic linkage studies and candidate
the proportion of disease vulnerability gene case-control studies, as powerful
due to heritable genetic factorsVhas means to identify genetic variants associ-
been estimated to be somewhere be- ated with common diseases such as late-
tween 58% and 79%.3 Therefore, al- onset AD. Studying large populations
though cases of AD inherited in a with these sensitive techniques has

KEY POINTS
allowed the identification of several new the Volga-German AD kindred to a h Although cases of
genes consistently associated with AD gene on chromosome 1 that was Alzheimer disease
risk. However, the overall magnitude of highly homologous to PSEN1 and was inherited in a Mendelian
the risk conferred by each of these is ultimately dubbed PSEN2. It was sub- fashion are rare
small, and therefore the clinical rele- sequently recognized that the patho- (accounting for
vance of these findings is as yet genic alterations of these genes all approximately 1% of
undefined. Nonetheless, study of the contribute to the increased absolute cases), genetic factors
pathways through which these genes or relative production of the 42-ami- are likely to play an
contribute to AD pathology is an avenue no-acidYlength cleavage product important role in all
toward the identification of potential of APP11 (the A"42 version of the forms of the disease.
therapeutic targets. Because significant amyloid-" [A"] peptide), which is a h Studying large
progress in developing treatments for major constituent of the plaques that populations with
AD has been lacking, such new ap- characterize the illness. Further in vivo sensitive techniques
proaches are of critical importance. and in vitro work served to support has allowed the
identification of several
This review will discuss progress in this ‘‘amyloid cascade hypothesis’’ of
new genes consistently
understanding of the genetic under- AD etiology (recently reviewed by
associated with
pinnings of AD, clinical relevance Benilova and colleagues).12 Simply Alzheimer disease risk.
where applicable, and how this knowl- put, it is speculated that increased However, the overall
edge is guiding future research into production or decreased elimination magnitude of the risk
treatments for and prevention of AD. of the A" peptide is the trigger initiat- conferred by each of
ing a series of events ultimately leading these is small, and
FAMILIAL ALZHEIMER DISEASE: to the pathology and clinical manifes- therefore the clinical
MENDELIAN FORMS tations of the various forms of AD. relevance of these
The observation of the familial occur- Further genetic evidence supporting findings is as yet
rence of AD dates back almost to Alois this hypothesis is that subjects with undefined. Nonetheless,
Alzheimer’s initial description of the Down syndrome (who have three study of the pathways
through which these
disease, before dementia of late onset copies of chromosome 21),13 mosai-
genes contribute to
was understood to have a similar cism for trisomy 21,14 or duplications
Alzheimer disease
underlying pathology. However, the of the APP gene15 can all develop AD pathology is an
genes underlying these rare forms of pathology. Although this predominant avenue toward the
the illness remained elusive until the hypothesis has led to important in- identification of
early 1990s, when cloning and linkage sights into the pathologic cascade lead- potential therapeutic
studies allowed for the identification ing to AD, this knowledge has yet to targets.
of three genes that cause this fully translate into meaningful interven-
penetrant, early-onset, autosomal tions. Indeed, it may be possible to
dominant form of the disease: amyloid clear the deposited fibrillar forms of A"
precursor protein (APP), presenilin 1 without significantly influencing clini-
(PSEN1), and presenilin 2 (PSEN2). cal disease.16
Mutations in the APP gene were Although substantive disease-modifying
identified first,4 4 years after the interventions do not yet exist, these ad-
amyloid precursor protein was discov- vances have enabled definitive diagno-
ered to be the major component of sis of familial AD and therefore can have
senile plaques5 and cerebral blood significant effects on patients and their
vessel amyloid6 and mapped to chro- families in terms of understanding
mosome 21.7Y9 In 1995, young-onset the illness, its inheritance, and its
familial AD was linked to chromosome prognosis. Furthermore, this progress
14 in some families, and subsequently allows for the possibility of presymp-
the PSEN1 gene was cloned.10 Around tomatic testing in unaffected at-risk
the same time, linkage was made in subjects. Therefore, clinicians should

Genetics in Alzheimer Disease
KEY POINT
h Although substantive have a thorough understanding of from the recent discovery of a variant
disease-modifying the phenotypes and of testing that is near the "-secretase cleavage site
interventions do not yet available. (A673T) in APP that is associated with
exist, these advances decreased production of A" and a
have enabled definitive Amyloid Precursor Protein decreased risk for late-onset AD.22
diagnosis of familial Mutations in the APP gene encoding This supports the assertion that phar-
Alzheimer disease and for amyloid precursor protein were macologic inhibition of "-secretase
therefore can have the first mutations identified to cause activity is a promising direction to pur-
significant effects on familial AD and are currently the sue in developing therapies to treat or
patients and their second most common cause of famil- prevent AD.
families in terms of
ial AD. Twenty-four mutations have
understanding the Presenilin 1
been reported that are thought be
illness, its inheritance,
and its prognosis.
pathogenic (www.molgen.ua.ac.be/ PSEN1 mutations are the most com-
Furthermore, this ADMutations), are concentrated near mon cause of familial AD; 197 variants
progress allows for the the N-terminal (the "-secretase cleavage have been preliminarily associated with
possibility of site) and C-terminal (the +-secretase familial AD (www.molgen.ua.ac.be/
presymptomatic testing cleavage site) ends of the A" portion ADMutations). Of these, a few lack
in unaffected at-risk of APP, and affect the amount of A" confirmation, or there are reasons to
subjects. Therefore, produced by cells. The V717I substi- suspect pathogenicity, such that 185
clinicians should have a tution in APP, occurring near the are currently thought confidently to
thorough understanding +-secretase site, was the first described cause familial AD. The majority of
of the phenotypes and familial AD mutation4 and appears to these are missense mutations causing
of testing that is
have arisen independently in white, amino acid substitutions in the coding
available.
Japanese,17 and Mexican18 populations. region of the gene, although a few
In addition, several APP variants associ- consist of insertions or deletions of
ated with familial AD have been de- portions of the protein. The Presenilin
scribed that occur within the A" 1 protein (PS1) was identified to be the
sequence. In vitro studies of some of catalytic site of the +-secretase complex
these mutations indicate that the mu- that cleaves the APP protein to produce
tant protein resulting from such alter- A" fragments.23 By causing conforma-
ations self-assembles more efficiently, tional changes in PS1,24 the majority of
which is hypothesized to ultimately pathogenic PSEN1 mutations cause an
result in more rapid aggregation in the increased absolute or relative produc-
brain. The nature of the amyloid pa- tion of A"42,25 and it is thought that
thology can differ in people with these this is the mechanism through which
mutations, such that plaque morpholo- they cause AD.
gy can be distinctive19 with excessive Although many of the 185 PSEN1
deposition.20 Such pathology some- mutations are described in single fam-
times results in cerebral infarcts or ilies, a few have been reported repeat-
hemorrhages that can be a major edly and appear to represent founder
aspect of the clinical presentation.20,21 effects. The E280A substitution, found
More recently, duplications of the APP in subjects from Colombia, represents
locus have also been identified in the largest group of families and has
familial AD associated with cerebral been well characterized by investigators
amyloid angiopathy (CAA),15 confirm- there.26 The G206A substitution was
ing that these mutations cause familial described in Caribbean Hispanics,
AD through a ‘‘gene dose’’ effect in mostly originating from Puerto Rico.27
increasing A" production. Further sup- Another mutation (A431E) that has
port for the amyloid hypothesis comes been repeatedly identified in people

KEY POINTS
whose family roots originate in the founder effect mutation (N141I). Peo- h The existence of
state of Jalisco in Mexico also appears ple with PSEN2 mutations have a these groups of
to represent a founder effect.28 The mean age of onset of 54 years, with a familialYAlzheimer
existence of these groups of familial-AD range from 39 to 75 years of age in disease families of
families of specific ethnic and geo- one series.35 Among people with the specific ethnic and
graphic origins indicates that inquiring N141I mutation, seizures were present geographic origins
about patients’ ancestral origins can in 31%. Because the pathogenicity of indicates that inquiring
be informative. identified variants in PSEN2 is not about patients’
PSEN1 mutations tend to cause the always clear, caution needs to be ex- ancestral origins can
youngest age of symptom onset ercised when interpreting results of be informative.
(44Y46 years of age in one series).29 such testing with patients and their h In a retrospective chart
However, unusual rare cases of onset families (Case 3-1). review comparing
as young as the twenties30 and a family clinical features
with a mean age of onset as late as age Insights into Late-Onset between 32 patients
Alzheimer Disease Derived with familial Alzheimer
76 (bearing the A79V substitution)
from Familial Alzheimer Disease disease due to PSEN1
have been described.31 PSEN1 mutation
mutations and
carriers are more likely to have the As described above, the discovery that 81 patients with
atypical features that sometimes accom- the pathogenic mutations in familial nonfamilial early-onset
pany familial AD, including spastic AD genes affect the catabolism of APP, Alzheimer disease,
paraparesis,32 early myoclonus, and sei- causing the increased absolute or rela- those with PSEN1
zures.33 In a retrospective chart review tive production of the amyloidogenic mutations tended to be
comparing clinical features between 32 form of the A" peptide, fueled the younger (42 versus 56
patients with familial AD due to PSEN1 amyloid cascade hypothesis of AD. years of age at onset),
mutations and 81 patients with non- Although increased production of more likely to have
familial early-onset AD, those with these forms of A" has not been con- memory complaints as
PSEN1 mutations tended to be younger sistently demonstrated in late-onset the presenting feature
(84% versus 58%, with
(42 versus 56 years of age at onset), AD, it is thought that a decreased abil-
nonfamilial cases
more likely to have memory complaints ity to eliminate A" may lead to its oligo-
frequently presenting
as the presenting feature (84% versus merization, toxicity, and ultimately with visuospatial and
58%, with nonfamilial cases frequently cerebral deposition in this more com- language deficits)
presenting with visuospatial and lan- mon form of the disease. and more likely to
guage deficits), and more likely to Unlike late-onset AD, in which the experience significant
experience significant headaches, my- ability to predict the future develop- headaches, myoclonus,
oclonus, gait abnormalities, and pseu- ment of disease is imperfect, the study gait abnormalities, and
dobulbar affect.34 The presence of of asymptomatic people carrying fa- pseudobulbar affect.
such features in a young-onset case of milial AD mutations, who are essen- The presence of
AD when the family history is un- tially certain to develop the illness, such features in a
available should prompt the clinician allows biochemical, imaging, behav- young-onset case of
Alzheimer disease when
to consider genetic testing. ioral, and cognitive changes occurring
the family history is
very early in the disease course to be
unavailable should
Presenilin 2 identified.37 Many reports of relatively prompt the clinician to
Mutations in the PSEN2 gene are small series of such subjects have consider genetic testing.
rarest and tend to have the oldest provided important insights, with
and most variable age of onset.29 Of studies of the Colombian kindred
21 variants in PSEN2 described on carrying the E280A PSEN1 mutation
www.molgen.ua.ac.be/ADMutations, being the largest. Studies of this popula-
possibly only eight,35 or at most 13, tion have documented the course of
are thought to be pathogenic for AD. cognitive decline38 and, more recently,
This includes a large Volga-German have provided insight into the course

KEY POINTS
h Because the
pathogenicity of
Case 3-1
A cognitively intact 38-year-old woman presented with concerns that she was
identified variants in
going to develop familial Alzheimer disease (AD) because a genetic test had
PSEN2 (and other
come back positive for a PSEN2 mutation. Further inquiry into the patient’s
familial Alzheimer
family history revealed that her father had developed AD symptoms in
disease genes) is not
his mid-sixties and died of the disease at age 74; his mother and father were
always clear, caution
not known to have had dementia, although one of his three siblings had
needs to be exercised
dementia thought to represent AD, with onset of symptoms in his early
when interpreting
seventies. The patient’s mother was still alive and well at age 71.
results of genetic testing
Review of the commercial test results showed a S130L substitution in
with patients and their
PSEN2 that had been previously reported to be associated with AD.
families.
However, review of the reported cases showed an association in individual
h Trials to prevent familial patients, including some with late onset, and segregation with the
Alzheimer disease disease within a family had not been demonstrated. In addition, in vitro
by administering studies of this variant indicated it did not increase the amount of
experimental amyloid-" 42 (A"42) or the ratio of A"42 to A"40 produced.36 On the AD
medications to and frontotemporal dementia (FTD) mutation database website
asymptomatic mutation (www.molgen.ua.ac.be/ADMutations), it was listed as ‘‘pathogenicity
carriers are in unclear.’’ This information was conveyed to the patient, who was relieved
development and to find out she was unlikely to develop AD of young onset.
should commence Comment. This case illustrates many points. First, when autosomal
in 2013. dominant AD of young onset is suspected, it is preferable to perform
genetic testing on a related affected person to know whether there is
something that can be tested for before performing presymptomatic
testing. In this case it may well have revealed that her affected father
did not carry this variant. Also, not all reported variants are pathogenic,
and it can take some knowledge of the field and research to interpret the
results of a given test. The history in this family does not make a strong
case for young-onset autosomal dominant disease. Finally, presymptomatic
patients should always undergo genetic counseling before testing, in
part to prepare them for the possibility of an inconclusive result.
of biomarker changes.39,40 In addition, brain areas, and cerebral atrophy on

a separate international consortium of MRI occur in a fairly predictable
sites has been established to increase manner.41 This knowledge increases
the number of people at risk for familial our understanding of the disease
AD mutations that might be studied process and establishes the character-
(the Dominantly Inherited Alzheimer istics of biomarkers that can be used
Network, or DIAN, NIH U01 AG016570). as surrogate outcome measures in pre-
Collectively, these efforts have convention trials. Indeed, with the recent
firmed that these mutations lead to failure of promising antiamyloid ap-
increased levels of A"42 measurable in proaches to treat late-onset AD in large
plasma and CSF. They have also sug- Phase III trials, there is increasing
gested a sequence of biomarker changes attention toward prevention of the dis-
in which decrement of A"42 in the CSF, ease. Trials to prevent familial AD by
cerebral deposition of fibrillar amyloid administering experimental medica-
detectable with nuclear imaging, in- tions to asymptomatic mutation carriers
creased levels of tau in the CSF, de- are in development and should com-
creased cerebral metabolism in certain mence in 2013.

KEY POINTS
APOLIPOPROTEIN E amount of A" accumulation differed in h In humans, APOE is
ApoE is a protein involved in lipid mice transgenic for human ApoE in an highly polymorphic; the
transport that acts as a scaffold in isoform-specific way, such that it was APOE*E3 allele is the
high-density lipoprotein (HDL) parti- greater in *E4 mice than in *E3, where most common, followed
cles and is highly expressed in the it was in turn greater than in *E2 mice. by the *E4 allele,
liver and in the CNS, where it is made In vitro studies suggest that ApoE, which is in turn more
by astrocytes and microglia. In addi- particularly the *E4 form, promotes common than the *E2
tion to transporting lipids, it also has a fibrillogenesis of A".49 Lipidation of allele. The *E3, *E4,
role in the transportation of forms of particles containing ApoE may be and *E2 alleles, which
A" including A"42. In humans, the required for amyloid clearance, as differ in only one or two
amino acids, have been
gene for ApoE (APOE) is highly poly- mice devoid of the ATP binding cas-
reproducibly shown to
morphic; the APOE*E3 allele is the sette 1 (ABCA1), which lipidates ApoE,
have differential effects
most common, followed by the *E4 show increased amyloid deposition,50 on risk of late-onset
allele, which is in turn more common and overexpression of ABCA1 reduces Alzheimer disease, with
than the *E2 allele. The *E3, *E4, and amyloid deposition.51 Microdialysis ex- *E4 conferring a greater
*E2 alleles, which differ in only one or periments in transgenic mice suggest risk than *E3, which in
two amino acids, have been reproduc- that ApoE isoforms differentially influ- turn confers a higher
ibly shown to have differential effects ence A" clearance such that *E4 clears risk than the *E2 allele,
on risk of late-onset AD, with *E4 A" more slowly than does *E3 or with odds ratios
conferring a greater risk than *E3, *E2.52 There is therefore ample conver- between approximately
which in turn confers a higher risk gent evidence for ApoE as a potential 4 for heterozygous and
than the *E2 allele, with odds ratios therapeutic target for disease-modifying approximately 15 for
homozygous carriers of
between approximately 4 for hetero- interventions in AD. Multiple ways of
the *E4 allele.
zygous and approximately 15 for ho- influencing the A" clearance through
mozygous carriers of the *E4 allele.42 the ApoE pathway have been sug- h There is ample
Multiple mechanisms through gested, including ApoE mimetics53 and convergent evidence for
ApoE as a potential
which the different ApoE forms may stimulation of its production with per-
therapeutic target for
mediate the differential risk for AD oxisome proliferator-activated receptor-
disease-modifying
have been identified (reviewed by Kim gamma (PPAR+) agonists54 and the liver interventions in
and colleagues43 and Verghese and X receptor (LXR) agonist bexarotene.55 Alzheimer disease.
colleagues44), including differential ef- The prevalence of the *E4 allele in
fects on A" transport and deposition. the population varies depending on
Human pathologic studies show a ethnicity but is typically in the range of
positive correlation between *E4 allele 15% to 20%. Among people with AD,
dose and amyloid45 and neuritic plaque the prevalence is around 50%, again
density46 at autopsy. Studies in cogni- depending on the specific population
tively normal individuals have demon- being studied. The increased risk con-
strated that carriers of the APOE*E4 ferred by the *E4 allele is generally
allele have higher amyloid binding on thought to be a three- to fourfold
imaging and lower A"42 levels in CSF increase, and the lifetime risk of devel-
(suggestive of its deposition in the oping AD in someone with this poly-
brain) than do noncarriers.47 morphism is 50% among those who
Work in transgenic mice has begun live to be 80 years of age. Having two
to elucidate the mechanistic role for copies of APOE*E4 increases the risk
ApoE in amyloid transport and depo- of a younger age of AD onset and
sition. Amyloid deposition in mice makes the development of AD by age
with human APP mutations was di- 80 highly probable.56 It must be re-
minished when crossed with ApoE membered, however, that most of
‘‘knockout’’ mice.48 Furthermore, the these studies have been performed in

KEY POINT
h The prevalence of the white subjects; it appears that the risk so far found that, among the highly
*E4 allele in the for AD conferred by the *E4 allele in educated and engaged participants,
population varies Latino populations is lower.57 Al- the risk of adverse sequelae in the
depending on ethnicity though judicial use of APOE testing in short term was not significantly in-
but is typically in the young-onset cases can be informative creased,58 but long-term retention of
range of 15% to 20%. (Case 3-2), presymptomatic suscep- specific lifetime risk information was
Among people with tibility testing is not typically recom- low. Studies such as this will help
Alzheimer disease, the mended (see guidelines below) because guide medicine as it becomes increas-
prevalence is around of the poor predictive value, variability ingly personalized, largely because of
50%, again depending in risk conferred across ethnic groups, our increasing understanding of the
on the specific
and lack of definitive treatment options. genetic underpinnings of illness.
population being
However, in light of the increasing A recent study proposed that a
studied. The increased
risk conferred by the
research interest in preventing AD and repeat polymorphism within the neigh-
*E4 allele is generally the possible differential response to boring TOMM40 gene explains part of
thought to be a future AD treatments depending on the risk traditionally attributed to the
three- to fourfold APOE genotype, investigators have APOE locus.59,60 Independent studies
increase, and the begun to look at the effects of reveal- could not detect this effect after cor-
lifetime risk of ing the APOE genotype to asymptom- recting for APOE genotype,61,62 so this
developing Alzheimer atic patients in controlled settings, association remains controversial.
disease in someone with most notably in the Risk Evaluation
this polymorphism is and Education for Alzheimer’s Disease VARIATION IN FAMILIAL
50% among those (REVEAL) study. In this study, subjects ALZHEIMER DISEASE GENES IN
who live to be 80 years LATE-ONSET ALZHEIMER DISEASE
potentially interested in knowing their
of age.
genetic status are randomized to either Late-onset AD also has a familial
receive this information or not, and tendency that may or may not have
various longitudinal assessments of an autosomal dominant pattern of
their psychological reactions and un- inheritance. In such cases, competing
derstanding are made. This study has mortality, in which people destined to
Case 3-2
The 40-year-old son of a 63-year-old man diagnosed with Alzheimer disease
(AD) presented because of concern regarding his own risk for developing
AD. His mother had AD at age 80, and his father’s brother had it at age 70.
Because of the patient’s concern for developing the same problem, he
had his father tested for PSEN1, APP, and PSEN2 mutations by another
doctor; all were negative. Despite this, he was still concerned that he would
develop the same disease his father had and was seeking further help.
After discussing the implications of the various possible results, APOE
testing was sent on the affected father by his treating physician, as a result
of which he was found to be an *E4/*E4 homozygote. This provided an
explanation for the relatively young onset of disease in the patient’s
father. Although the patient now knew he was at increased risk for
developing AD, he was relieved to know that it was not autosomal
dominantly inherited disease of young onset.
Comment. This case illustrates how judicial use of APOE testing can relieve
anxiety but should be done only with oversight from a knowledgeable
clinician rather than in a direct-to-consumer fashion. (See Guidelines for
Genetic Testing in Alzheimer Disease).

KEY POINT
develop AD die of other causes before correction for population stratifica- h Although hundreds of
manifesting the illness, can be one tion) have allowed the identification genes have been
factor making the inheritance pattern of robust and replicable genetic risk implicated or studied at
difficult to interpret. In light of the factors for AD. Most of these suscep- some point over the
continuity in phenotype between fa- tibility genes have been identified past 20 years in
milial AD and late-onset AD, it is of through large, collaborative genome- relationship with
interest if alterations in the genes for wide association studies, which con- Alzheimer disease, only
familial AD also contribute to the risk sist of the assessment of hundreds of recent, large-scale
of late-onset AD. Unbiased genome- thousands of SNPs in a large number studies and rigorous
wide association studies typically fail of cases and controls.65 Most often, a statistical analyses
(including correction for
to show a relationship between famil- replication series is studied to validate
population stratification)
ial AD genes and risk of late-onset AD, the results.
have allowed the
including a recent study that looked at Four recent large collaborative identification of robust
single-nucleotide polymorphisms genome-wide association studies and and replicable genetic
(SNPs) from 3,940 cases and 13,373 one meta-analysis identified or con- risk factors for
controls.63 A study was recently per- firmed three novel genes or loci in Alzheimer disease.
formed31 in which the APP, PSEN1, 2009 (CLU, CR1, PICALM),66,67 and six
and PSEN2 genes were sequenced in in 2011 (ABCA7, MS4A6A/MS4A4E,
patients affected by late-onset AD, and EPHA1, CD33, CD2AP, BIN1).68Y70
the frequency of variants compared Clusterin (CLU), a ubiquitously ex-
between affected individuals from pressed chaperone protein, is involved
families in whom four or more mem- in transport, aggregation, and clearance
bers were affected and controls. Using of A", and is present in A" deposits.71
this more sensitive approach, an in- Complement receptor 1 (CR1) is a re-
creased frequency of variants in these ceptor for the complement C3b pro-
genes was observed versus in controls tein, an inflammatory marker of AD,
and in reference databases. This in- and possibly protective against A"-
cluded the A79V PSEN1 mutation induced neurotoxicity. Interestingly,
described above in which the age of the genetic susceptibility at this locus
onset is late, illustrating that continu- is probably linked to a copy-number
ity between familial AD and late-onset polymorphism.72 PICALM (phosphati-
AD can occur. dylinositol binding clathrin assembly
protein) is a key component of
OTHER RISK FACTORS FOR clathrin-mediated endocytosis and is
ALZHEIMER DISEASE thought to be involved in A" clearance,
Common Variants possibly via endothelial cells.73 Less is
As with other complex diseases, fam- known about the more recently iden-
ilies with familial AD and a Mendelian tified genes, but they have been linked
inheritance are a minority and explain to the same broad pathways of innate
only a small fraction of the estimated immunity (CD33, EPHA1, MS4A), A" pro-
overall heritability. Although hundreds duction and clearance (BIN1), lipid
of genes have been implicated or metabolism (ABCA7), and intracellular
studied at some point over the past transport (CD2AP).
20 years in relationship with AD (for a A possibly unifying hypothesis for
catalog of candidate gene association Mendelian rare variants and common
studies, please refer to the AlzGene risk genes could involve increased A"
online database www.alzgene.org),64 production in Mendelian forms of the
only recent, large-scale studies and disease, and impaired clearance (pos-
rigorous statistical analyses (including sibly caused by a myriad of genetic

variants) in the late-onset, complex microglia. Although the sequence var-

forms.74 Population attributable fraction iants identified are rare, the identifica-
(the proportion of estimated genetic tion of a novel gene will most likely
contribution explained) is approx- generate new insights in the disease
imately 28% for APOE and less than pathogenesis. Additional possible
10% for all other risk factors identi- sources of susceptibility variants have
fied;68,75 therefore, these 10 AD-associ- not been studied extensively in AD.
ated variants (APOE and the additional These include de novo variants, copy-
nine named above) explain approxi- number variation,81 structural varia-
mately 20% of the total variation of tion, and mosaicism.
risk and approximately 33% of the Because of the small effect size (for
risk attributable to genetic effects,76 common variants) and low frequency
which suggests that numerous other (for rare variants), the advances in
factors of similar effect size wait to be genetics still have very limited clinical
identified. utility. Even in diseases in which
hundreds of loci have been identified,
Rare Variants such as inflammatory bowel disease,
Whether the genetic contribution to AD the predictive value for individual pa-
and other common complex diseases tients is still low.82,83 The main, more
comes from common or rare variants attainable outcome of large-scale ge-
(or a combination) is a major issue in netic studies is to identify loci related to
complex disease genetics.77 Technical disease susceptibility and thus gain
advances in sequencing now allow the insight into the biology of the disease,
sequencing of a large number of genes with the identification of genes and
(or even the whole genome) in a large pathways involved in disease patho-
number of samples and will allow for genesis, and possibly novel thera-
the elucidation of the contribution of peutic targets. The use of genetic
rare variation to the genetic architec- assessment in clinical practice to guide
ture of complex disease. treatment and predict outcome will
Initial studies are beginning to probably be possible at some point in
identify and confirm the role of rare the future, but our current knowledge is
variation in AD susceptibility. A rare still far from having an impact on
coding variant (A152T) in the gene clinical practice.
encoding for the microtubule-associ-
ated protein tau (MAPT), in which Guidelines for Genetic Testing
other mutations cause FTD, has been in Alzheimer Disease
associated with the risk of both AD The most recent guidelines for genetic
and FTD in a study involving more testing in AD were published in 2011
than 15,000 subjects.78 The above-men- and represented a consensus from the
tioned rare variant in APP (A673T) has National Society of Genetic Counselors
been identified in an Icelandic cohort and the American College of Medical
and has a protective role.22 Finally, Genetics.84 Because the genetics of AD
two recent reports indicated that rare are complex, our current understand-
variants in the triggering receptor ing is incomplete, and interventions
expressed on myeloid cells 2 (TREM2) proven to definitively prevent AD are
gene increase the risk for AD.79,80 lacking, genetic testing for AD should
TREM2 is an innate immune receptor typically only be performed in consul-
expressed on the cell membrane of a tation with a genetic counselor or other
subset of myeloid cells, including person versed in the genetics of AD.

KEY POINTS
Briefly, the guidelines can be sum- evaluations to better define their status h Ten Alzheimer diseaseY
marized as follows: (1) a comprehen- and ability to comprehend and cope associated variants
sive family history should be obtained with results. explain approximately
to reveal the likelihood, considering In the consensus statement from the 20% of the total
competing causes of death, of a family National Society of Genetics Counselors variation of risk and
history of AD or other causes of demen- and the American College of Medical approximately 33% of
tia; (2) patients should be fully informed Genetics, it was recognized that these the risk attributable to
regarding the limits of the understand- guidelines were based on the current genetic effects.
ing of the genetics of AD and of the state of this rapidly changing field; that h Because of the small
ability to treat or prevent it; (3) testing in any individual case, clinical judg- effect size (for common
for AD in the pediatric population is not ment might supersede these recom- variants) and low
recommended; and (4) revealing test- mendations; and that ethics committee frequency (for rare
ing for risk-susceptibility genes such consultation is recommended in chal- variants), the advances
as APOE is not widely recommended lenging situations. The reader is re- in genetics still have very
limited clinical utility.
except in the context of fully informed ferred to the full article for details.84
patients and families, as in research With increasing understanding of the
studies. As such, direct-to-consumer genetics of ADVand, hopefully, im-
APOE testing is not advised. With provements in our ability to prevent
regard to testing for APP, PSEN1, or and treat itVthese guidelines will no
PSEN2 mutations in symptomatic pa- doubt be subject to change.
tients, (1) such testing should be
offered in the context of a family history SUMMARY
of autosomal dominant inheritance in
In the last 30 years there have been
which one or more cases are of early
substantial advances in understanding
onset, or in young-onset cases with
of the genetic basis of AD, although
unknown family history (eg, adoption);
genetic assessment is currently of limited
(2) scientific literature and mutation
utility in clinical practice because of the
databases such as the AD and FTD
low frequency (Mendelian mutations) or
mutation database (www.molgen.ua.
small effect size (common risk factors)
ac.be/ADMutations) should be con-
of the currently known susceptibility
sulted to help understand the like-
genes. However, genetic studies are
lihood of pathogenicity of a given
identifying with confidence a number
mutation before revealing the result
of novel risk genes that will improve
to patients and family members. Re-
understanding of disease biology and
garding the implications for asymp-
possibly the identification of therapeu-
tomatic people, (1) asymptomatic
tic targets.
first-degree relatives should be in-
formed of the 50% likelihood of in-
heriting the mutation and disease in the ACKNOWLEDGMENTS
case of a pathogenic mutation being The authors were supported by PHS
identified in an affected patient; (2) K08 AG-22228, Alzheimer’s Disease
testing for asymptomatic at-risk subjects Research Center Grant P50 AG-16570,
should be performed in accordance with and the Easton Consortium for
the International Huntington Associa- Alzheimer’s Disease Drug Discovery
tion and World Federation of Neuro- and Biomarker Development. The au-
logy Research Group on Huntington’s thors would also like to thank Dr Lars
Chorea Guidelines; and (3) people Bertram for providing the most up-
thought to be asymptomatic should dated susceptibility-gene classification
undergo cognitive and psychological from AlzGene (www.alzgene.org).

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Review Article
Nonpharmacologic
Dr Kristine Yaffe, MD,
University of California,
San Francisco, 4150 Clement
Street, Box 181, San Francisco,
CA 94121,
kristine.yaffe@ucsf.edu.
Treatment and
Dr Yaffe serves on the data
and safety monitoring boards
Prevention Strategies
for the National Institute
on Aging and Takeda
Limited; and receives grant
for Dementia
support from the NIH, Kristine Yaffe, MD; Tina Hoang, MSPH
Alzheimer’s Association,
American Health Assistance
Foundation, the California
Department of Public Health, ABSTRACT
and the US Department of Purpose of Review: Epidemiologic studies can provide critical evidence to inform
Defense. Ms Hoang reports
no disclosure. the timing and duration of nonpharmacologic interventions. Although more studies
Unlabeled Use of Products/ are needed to further determine long-term efficacy, the evidence supporting mod-
Investigational Use ifiable risk factors for prevention is compelling, and prevention strategies that in-
Disclosure:
Dr Yaffe and Ms Hoang report
corporate multidomain nonpharmacologic factors may have the most impact.
no disclosures. Recent Findings: Epidemiologic studies have identified a number of promising
* 2013, American Academy nonpharmacologic factors that have the potential to lower the risk of developing
of Neurology. dementia.
Summary: Potential modifiable strategies for dementia prevention include cardiovas-
cular risk factors; lifestyle risk factors such as physical, cognitive, and social activity as
well as nutrition, smoking, and alcohol use; and sleep quality. Results of randomized
controlled trials for the treatment of cardiovascular risk factors have not been
consistent, while interventions that increase physical, cognitive, and social activity
have demonstrated protective effects for dementia risk. Trials of single-nutrient dietary
supplementation have also been conflicting, but focus on multinutrient supplemen-
tation shows promise. Observational data also indicate that sleep quality may be a
modifiable risk factor for dementia prevention.
INTRODUCTION randomized controlled trials. In addi-

Evidence from epidemiologic studies tion, epidemiologic studies of these
has been crucial in identifying several modifiable risk factors can help facilitate
potential modifiable risk factors for de- the transition from observational data
mentia. Although new disease-modifying to effective prevention. This review sum-
drugs are currently under investigation, marizes the major nonpharmacologic
recent pharmacologic trials have not risk factors with potential effects on
been very successful. It may still be years dementia prevention.
before an effective drug is available for
prevention of Alzheimer disease (AD). CARDIOVASCULAR RISK FACTORS
Although a consensus report from the A number of cardiovascular risk fac-
NIH determined that the body of proof tors have demonstrated a strong rela-
for modifiable risk factors is not yet tionship with cognitive decline and
conclusive,1 nonpharmacologic strate- dementia, including hyperlipidemia,
gies may be promising alternatives, with hypertension, obesity, and diabetes.2
several already under investigation in These findings are strengthened by

KEY POINTS
studies investigating the association risk due to effects on cerebral blood h Cardiovascular risk
between metabolic syndrome (a con- flow.7 Evidence from blood pressure factors (including
stellation of cardiovascular risk factors) treatment trials (such as Action in Di- hyperlipidemia,
and cognitive function.3 In epidemio- abetes and Vascular Disease: Preterax hypertension, obesity,
logic studies, midlife vascular risk fac- and Diamicron MR Controlled Evalua- and diabetes) are
tors have been consistently associated tion [ADVANCE], Hypertension in the associated with
with risk of late-life dementia,2 but Very Elderly Trial cognitive function increased risk of
the association of late-life vascular risk assessment [HYVET-COG], and the dementia.
factors with dementia is less well Study on Cognition and Prognosis in h Results of previous
established.4 the Elderly [SCOPE]) varies; some tri- treatment trials for
Data from observational cohort als demonstrate a benefit, and others hyperlipidemia and
studies indicate that high cholesterol report no effects, which may be a re- hypertension have been
levels can increase a patient’s risk of sult of differences between classes of mixed, but additional
dementia, and both neuropathologic drugs used for hypertension therapy.8 randomized controlled
trials are needed to
and observational studies of patients To further understand the effects of
understand the
on statin therapies correspond with blood pressure treatment, the ongoing
potential impact for
these findings.5 High cholesterol may Systolic Blood Pressure Intervention dementia prevention.
increase the production and aggrega- Trial (SPRINT) will monitor the course
tion of amyloid-" by increasing en- of cognitive decline with intensive blood
zyme activation in the amyloidogenic pressure control.9
pathway and by interfering with the The association between obesity
peptide’s interactions with the cell and increased risk of dementia might
membrane, but few studies have dis- be related to obesity’s role as a marker
tinguished between the effects of spe- of vascular and inflammatory damage,
cific lipids such as high-density or low- since adipose tissues also secrete in-
density lipoproteins.5,6 Efforts to trans- flammatory proteins such as leptin,
late these findings into preventive which may affect neurodegeneration.10
interventions remain unsuccessful, as Similar to hypertension, obesity in late
randomized controlled trials have not life may not have the same association
shown any benefits from statin therapy; as midlife obesity with risk of develop-
however, the lack of positive results ing dementia.11 While few studies have
could be related to issues of blood-brain focused solely on weight loss for de-
barrier permeability as well as timing of mentia prevention, a meta-analysis of
therapy.6 In addition, although the weight loss trials reported benefits for
data are limited, the US Food and attention and executive function pri-
Drug Administration has recently mod- marily in obese subgroups; however,
ified drug safety labeling to inform long-term randomized controlled trials
health care providers and consumers are needed to determine the effective-
of reports that some patients may ex- ness of such interventions.12
perience memory loss or cognitive im- The commonly observed diabetes-
pairment while on statin therapies. associated increase in the risk of de-
As with hypercholesterolemia, high mentia could be the result of several
blood pressure in midlife, approxi- pathways, including disruption of insulin
mately ages 40 to 60, has also been signaling necessary for brain function,
associated with increased risk of vas- increased accumulation of advanced
cular dementia and AD. An increasing glycation end products, and interference
number of studies also indicate that with amyloid-" clearance.13 The role of
hypotension in late life, roughly age glycemic control is still uncertain but
60 and older, may increase dementia may have a U-shaped association with

Nonpharmacologic Treatment and Prevention
KEY POINT
h Epidemiologic studies cognitive impairment. Studies have life, and physical function; however, the
indicate that physical demonstrated associations with both benefits for cognitive function are still
activity may delay hyperglycemia and hypoglycemia.14 unclear.21
cognitive decline, and Preliminary treatment trials with intra-
evidence from early nasal insulin have been encouraging, Cognitive and Social Activity
randomized controlled and studies have reported positive effects The protective effects of cognitive
trials supports these for cognition in patients with cognitive activity have given rise to the concept
findings. impairment.15 of cognitive reserve, in which factors
such as education can serve as a buffer
LIFESTYLE RISK FACTORS against the effects of neuropathologic
Physical Activity damage associated with dementia.
Observational studies suggest a strong High levels of education have been
association between physical activity consistently associated with decreased
and maintenance of cognitive func- risk of dementia, and older adults with
tion. Physical activity may reduce risk dementia who have more education
of dementia by increasing oxygen sat- tend to have higher levels of plaque
uration and neurogenesis as well as accumulation than older adults with
decreasing vascular risk factors, inflam- less education but similar progression
mation, and depressive symptoms.16 A of symptoms.22 In a study of older
meta-analysis of prospective studies in adults, the effect of plasma amyloid-"
nondemented older adults found that on cognitive decline was attenuated
high, moderate, and low levels of physi- by cognitive reserve (defined as a high
cal activity were all protective against level of education or literacy),23 and
cognitive decline compared to no phys- neuropathologic studies indicate that
ical activity.17 In support of these cognitive activity may increase neuro-
findings, imaging studies also suggest nal density and cortical thickness,
that physical activity is associated with which modifies or compensates for
beneficial effects on brain structure.18 the effects of cerebrovascular dis-
Generally, higher levels of physical ease.24 In evaluations of cognitive
activity have been more protective in engagement (ie, participation in activ-
cohort studies; however, in one prospec- ities such as games, puzzles, or read-
tive study of older women, sustained ing), increased cognitive activity was
strenuous physical activity before men- also associated with lower risk of cog-
opause was negatively associated with nitive decline and dementia.25 In addi-
cognitive function in late life.19 tion, a small study of older adults
Evidence from randomized con- found that cognitive activity in early
trolled trials indicates that both aero- and midlife was associated with lower
bic exercise and resistance training levels of amyloid-" deposition,26 and
can delay cognitive decline. 20 Al- cohort studies indicate that frequent
though these findings are still prelim- cognitive activity can compensate for
inary, physical activity interventions in the effects associated with low level of
older adults have reported benefits for education.27
executive function, processing speed, Randomized controlled trials in both
delayed memory, and attention; pa- healthy and impaired adults indicate
tients with mild cognitive impairment that cognitive training can be beneficial,
have shown particularly positive ef- and suggest that interventions targeting
fects.20 In patients with dementia, multiple domains are better than those
physical activity interventions have im- focused on a single domain; however,
proved depressive symptoms, quality of the effects on dementia risk are still not

KEY POINT
confirmed.28 A recent Cochrane review perception of receiving more in re- h Interventions that
suggests that cognitive interventions, lationships than given, was more im- increase a patient’s
particularly those that involve cognitive portant for cognitive function than the cognitive and social
stimulation, can benefit cognitive func- number of ties and social interactions.32 activity may have the
tion in dementia patients, although potential to serve as
evidence for other outcomes (includ- Diet and Nutrition a buffer against the
ing improvements in quality of life and The biological and epidemiologic evi- neuropathologic
well-being) was more uncertain.29 dence to support the role of nutrient damage associated
As with cognitive activity, higher intake in dementia risk is robust. Al- with dementia.
levels of social engagement and social though few studies have investigated
networks have also been associated the lifelong effects of diet on dementia
with lower cognitive decline and re- risk, early-life nutrition has been shown
duced risk of dementia in observational to affect academic and cognitive perfor-
studies.30 The benefits of social en- mance,35 and studies in late life have
gagement may be linked to the mech- investigated the effects of a variety of
anisms of cognitive reserve. Social specific nutrients, including B vitamins
activities can increase cognitive stimu- (essential for DNA metabolism, includ-
lation as well as enhance social support ing homocysteine methylation), antiox-
and influence. However, reverse cau- idants (protective against oxidative
sality may also be an underlying factor damage and amyloid-" toxicity), and
for this association. As dementia pro- fatty acids (necessary for neural mem-
gresses, patients may be less able to brane integrity with possible protective
engage in social activity.31 Neverthe- effects against oxidative damage).36
less, several long-term prospective While many studies have demonstrated
studies with follow-up times of over a strong associations between deficien-
decade have also demonstrated similar cies for these nutrients and cognitive
protective relationships between social function, the findings from most ran-
engagement and risk of dementia in domized controlled trials of single-
both mid- and late-life.32 Evidence nutrient supplements have not been
from some trials suggests that in- positive. For example, trials of folic acid
creased engagement in social activity supplementation in older adults with-
can reduce the risk of cognitive decline out dementia ranging from 1 month to
and dementia. A group-based interven- 3 years did not show significant benefits
tion to increase social engagement in for cognitive function.37 A similar line of
lonely older adults led to improvement evidence has emerged for antioxidants,
in their Alzheimer Disease Assessment in which supplementation with vitamins
ScaleVCognitive Subscale (ADAS-Cog) E and C has not been consistently
scores after 3 months.33 Similarly, a protective.36 Large randomized con-
social-interaction intervention improved trolled trials have demonstrated that
cognitive function in Chinese elders, Gingko biloba use is not effective,38,39
although the results were not as signif- and trials for fatty acids in older adults
icant as those for physical activity.34 The have shown few benefits40; however, a
amount and duration of social engage- meta-analysis of fatty acid trials by
ment required to lower dementia risk is individual cognitive domain outcomes
undetermined, but an observational suggests that there may be improve-
study of social network characteristics ment on specific domains, including
in older adults indicates that the quality immediate recall and processing
of social engagement, defined as sat- speed in nondemented patients with
isfaction with social engagement and cognitive impairment.41

KEY POINTS
h Nutrient deficits have Several factors may contribute to the nicotine may have short-term benefits
been associated with lack of efficacy in these trials. Most early to cognition, cigarette smoking in-
increased risk of studies did not assess nutrient deficien- creases inflammation and oxidative
dementia. Single-nutrient cies, and there may be threshold bene- stress,47 and neuroimaging studies
supplementation trials fits for nutrient supplementation. In indicate that smoking may negatively
have not consistently addition, a single-nutrient effect at the affect both macrostructures and
demonstrated benefits, individual level may be too small to microstructures of the brain.48,49 Meta-
but results from capture with pilot trials. Furthermore, analysis of prospective studies indi-
multinutrient trials while observational studies often evalu- cates that, compared to nonsmokers,
are promising. ate the effects of individual nutrients, current smokers had higher rates of
h Smoking is associated the standard diet includes a wide range cognitive decline as well as increased
with increased risk of of nutrients that could have both syn- risk of dementia, while former smokers
dementia, whereas ergistic and antagonistic interactions. did not have an increased risk of de-
moderate alcohol use Dementia prevention through dietary mentia when compared to nonsmokers
may have a protective
intervention may be more effective if (Case 4-1).47 Although few smoking-
effect.
multinutrient deficiencies are addressed. cessation trials focus on benefits for
In a cohort of older adults, the Mediter- cognitive function, a recent study of
ranean diet (which is high in antioxidants older adults enrolled in a smoking-
and omega-3 fatty acids) was associated cessation intervention revealed that par-
with lower risk of mild cognitive impair- ticipants who were able to quit smoking
ment and AD,42 and analysis of other experienced less cognitive decline than
healthy dietary patterns has shown unsuccessful quitters after 2 years; how-
similar protective associations with cog- ever, the two groups did not differ in
nitive function.43 This is also supported brain imaging outcomes.50
by preliminary cross-sectional data inves- In contrast to smoking, moderate
tigating dietary patterns’ relation to total alcohol consumption may lower de-
cerebral brain volume and to white mentia risk. Studies have reported
matter hyperintensity volumes.44 To that there may be a J-shaped curve in
date, a small number of multinutrient risk, in which moderate alcohol use is
trials have been conducted; in healthy protective compared to nondrinking,
older adults, the effects of multivita- but higher levels of alcohol consump-
min supplementation were mixed,45 tion are associated with increased risk
but preliminary multinutrient and of dementia. Meta-analysis of epidemi-
medical food interventions that have ologic studies found that moderate
included vitamins, minerals, and fatty alcohol use was associated with de-
acids for patients with dementia have creased risk of AD and any dementia.51
reported a delay in cognitive decline Proposed pathways may be related to
and improvement in memory.46 Further lowering lipid levels, modifying hor-
optimization of nutrient supplementa- mone levels, preconditioning, or in the
tion could make interventions more case of wine, antioxidant effects.52 The
effective, and future investigations into protective effect of different alcohol
changing dietary behaviors across the types is unclear, with some studies
life span, once confirmed, could have reporting benefits for all types and
significant public health impact. others for wine consumption only.51
Alcohol and Smoking SLEEP QUALITY

Both alcohol and smoking are impor- Sleep disturbances are common in
tant lifestyle risk factors that signifi- patients with dementia,53 and obser-
cantly affect dementia risk. Although vational studies indicate that sleep

Case 4-1
A 67-year-old woman presented with concerns about lowering her risk
of Alzheimer disease (AD). Her mother had been diagnosed with AD at
age 76 and recently died of AD-related complications at 88 years old.
The patient’s two siblings, aged 74 and 79, were both high-functioning
and had not reported any symptoms. Her aunts and uncle had never
been diagnosed with AD, and she had no other family history of
neurodegenerative disease. The patient reported that she had no cognitive
complaints or symptoms.
After neuropsychologic testing, she was diagnosed as being cognitively
normal. Her physical and neurologic examinations were also normal. She
was mildly obese with a body mass index (BMI) of 33.7 kg/m2. Four years
ago, she was diagnosed with hypertension and had been treated with a
low-dose beta-blocker since then; she did not take any other medications.
Her job as a lawyer was mostly sedentary, and she had little time for
physical activity. She was a former smoker and occasionally drank one to
two glasses of alcohol in social settings. Her partner had reported that the
patient’s snoring had worsened over the course of several years.
Comment. The patient may be at increased risk for AD because of her
family history in a first-degree relative; however, currently approved
treatment is not clinically indicated, as she has not reported any symptoms
and her neuropsychologic testing is normal. In this case, genetic testing
(if done at all) would primarily occur in a research setting and is unlikely to
be positive for autosomal dominant AD, considering the late age of the
mother’s disease onset and a less than 50% pattern of inheritance
among family members. She is encouraged to make an appointment for
additional evaluation if new symptoms emerge, and if possible, to bring an
informant in future visits to provide a collateral history.
The patient is counseled to adhere to her current treatment for
hypertension and encouraged to maintain her abstinence from smoking.
To decrease her cardiovascular and dementia risk, it is recommended that
she increase her weekly participation in moderate- to high-intensity
physical activity. Regular physical activity may also lower her BMI, which
would further reduce her risk profile. Increased social and cognitive
activities, such as volunteering, reading, or cognitive exercises, could also
be suggested. In addition, she could be referred to a sleep expert to test
her for sleep-disordered breathing and provide possible treatment options
if needed.
quality is related to cognitive function measures, which provides additional

in both early and late life. In children, support for this association in older
poor sleep quality is associated with adults; however, many prior investiga-
lower IQ and poor academic perfor- tions have only assessed cross-sectional
mance in school,54 and in older adults, associations, and the temporality of the
sleep disturbance and duration have relationship was uncertain. Recently, a
also been linked to poor cognitive prospective study of older adults found
outcomes.55 While most of these stud- that sleep-disordered breathing was
ies have assessed sleep quality with associated with an increased risk of
subjective questionnaires, a small dementia.56 Altered circadian rhythms,
number have used objective sleep including decreased amplitude and

KEY POINTS
h The evidence for sleep robustness as well as shifted time of sure a risk factor at one point in time
quality as a modifiable peak activity, have also been associated rather than assess the factor longitudi-
risk factor is preliminary, with an elevated risk of developing nally, but the effects can vary, and initial
but observational dementia.57 Because these findings are epidemiologic findings indicate that
studies support a recent, prevention trials have not yet there may be ‘‘critical windows’’ in the
possible role for begun; however, small trials of contin- life course during which a risk factor is
treatment of sleep uous positive airway pressure indicate particularly effective or detrimental.59
disturbances and that treatment of sleep-disordered In addition to lifelong evaluation of
sleep-disordered breathing may improve cognitive func- modifiable risk factors, studies have
breathing. tion in patients with dementia.58 yet to specify populations that would
h Epidemiologic studies most benefit from intervention. For
can provide critical CONCLUSION example, the possible modifying ef-
evidence to inform the Despite encouraging progress in iden- fects of genetic risk factors for non-
timing and duration of tifying nonpharmacologic risk factors, pharmacologic risk factors are still
nonpharmacologic
the translation of current observa- undefined.
interventions.
tional evidence to effective trials and These remaining questions not-
h Nonpharmacologic prevention has significant obstacles, withstanding, nonpharmacologic in-
interventions could play with many questions still unanswered. terventions have the potential for
a major role in reducing
These issues may be especially dif- significant public health impact. A
dementia prevalence,
ficult to resolve with randomized recent review of modifiable risk fac-
especially when their
effects are considered
controlled trials because they would tors for AD estimated that a 25% re-
collectively. require prolonged maintenance of an duction of cardiovascular risk factors
intervention study for large, diverse (diabetes, hypertension, and obesity)
cohorts. Early studies and trials indi- would decrease the number of AD
cate that nonpharmacologic interven- cases by 770,000 worldwide and
tions may face just as many challenges 233,000 in the United States, and a
as pharmacologic interventions, and 25% reduction of physical inactivity
because the NIH State of the Science behaviors would decrease the number
report concluded that the level of of cases by 1,000,000 worldwide and
evidence for nonpharmacologic inter- 232,000 in the United States. The
ventions is insufficient, the panel of study also provides support for tar-
experts also recommended more vigor- geting multiple modifiable factors to
ous standards for measures of exposure significantly reduce disease prevalence.
and cognitive outcomes, as well as the It was estimated that a 25% reduction of
continued utilization of long-term pop- a combination of seven modifiable risk
ulation-based studies.1 factors (ie, diabetes, hypertension, obe-
While most epidemiologic cohort sity, depression, physical inactivity,
studies have focused on mid- and late- smoking, and education/cognitive in-
life risk, and some studies have con- activity) would prevent up to 3 million
sidered early-life exposures, much less cases worldwide and 492,000 cases in
is known about the role of modifiable the United States.60
risk factors across the full life course. With the goal of targeting multiple
Because dementia has a prolonged modifiable pathways, a small number
prodromal phase, understanding ef- of randomized controlled trials have
fects across the life course can help started to test the efficacy of multi-
focus the timing and duration of pre- domain interventions. These include
vention targets. The evaluation of ex- the Finnish Geriatric Intervention Study
posures is complementary to this to Prevent Cognitive Impairment and
perspective. Many investigations mea- Disability (FINGER) with both physical

KEY POINT
and cognitive activity components, die- 8. Staessen JA, Thijs L, Richart T, et al. Placebo-
controlled trials of blood pressureYlowering h The latest
tary intervention, and vascular risk therapies for primary prevention of nonpharmacologic
factor management; and the Multi- dementia. Hypertension 2011;57(2):e6Ye7. randomized controlled
domain Alzheimer Preventive Trial 9. Systolic Blood Pressure Intervention Trial trials will test the
(MAPT), which will test omega-3 sup- (SPRINT). Clinicaltrials.gov. www.clinicaltrials. efficacy of targeting
plementation as well as a multidomain gov/ct2/show/NCT01206062. Updated multiple modifiable risk
December 6, 2010. Accessed November 1, 2012.
intervention with cognitive training, factors, and future
physical training, and nutritional educa- 10. Zeki Al Hazzouri A, Haan MN, Whitmer RA, interventions may
et al. Central obesity, leptin and cognitive incorporate both
tion.61 The Prevention of Dementia decline: the Sacramento Area Latino Study
by Intensive Vascular Care (PreDIVA) on Aging. Dement Geriatr Cogn Disord
pharmacologic and
2012;33(6):400Y409. nonpharmacologic
study will target multiple vascular risk
methods.
factors, including hypertension and 11. Anstey KJ, Cherbuin N, Budge M, Young J.
hyperlipidemia, through primary care Body mass index in midlife and late-life as a
risk factor for dementia: a meta-analysis of
management and counseling.62 In the prospective studies. Obes Rev 2011;12(5):
future, the most effective interventions e426Ye437.
may be those that are tailored for 12. Siervo M, Arnold R, Wells JCK, et al.
specific subpopulations and combine Intentional weight loss in overweight and
obese individuals and cognitive function: a
both pharmacologic and nonpharma-
systematic review and meta-analysis. Obes
cologic strategies. Rev 2011;12(11):968Y983.
13. Profenno LA, Porsteinsson AP, Faraone SV.
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Review Article
The Clinical Problem of

Dr Anna Burke, Banner
Alzheimer’s Institute 901 East
Willetta St, Phoenix, AZ 85006,
anna.burke@bannerhealth.com.
Dr Burke reports no disclosure.
Neuropsychiatric Signs
Dr Hall has served as an expert
witness for a legal case regarding
a resident care facility. Dr Tariot
and Symptoms in
has served as a consultant for
Abbott Laboratories; AC Immune;
Adamas Pharmaceuticals, Inc;
Allergan, Inc; AstraZeneca; Avanir
Dementia
Pharmaceuticals, Inc; Avid Anna Burke, MD; Geri Hall, PhD, ARNP, GCNS, FAAN;
Radiopharmaceuticals; Boehringer
Ingelheim; Bristol-Myers Squibb
Company; Eisai Co, Ltd; Elan
Corporation; Eli Lilly and Company;
Genentech, Inc; GlaxoSmithKline; ABSTRACT
MedAvante, Inc; Medivation, Inc;
Merck & Co, Inc; Novartis AG; Purpose of Review: This article reviews behavioral signs and symptoms of
Otsuka Pharmaceutical Co, Ltd; dementia that can lead to increased mortality, excessive cognitive and functional
Pfizer Inc; Sanofi-Aventis; Toyama
Pharmaceutical Association; and
disability, early institutionalization, and increased caregiver burnout.
Worldwide Clinical Trials, Inc. Recent Findings: Almost all patients with a dementia will develop significant
Dr Tariot holds stock options in behavioral disturbances at some point over the course of their illness. These
Adamas Pharmaceuticals, Inc,
recently forfeited options in
behavioral signs and symptoms rarely fit into usual diagnostic classifications or meet
MedAvante, Inc, and is a full criteria for a formal major psychiatric disorder.
contributor to a patent titled Summary: Treatment of behavioral signs and symptoms of dementia should in-
‘‘Biomarkers of Alzheimer’s
Disease.’’ Dr Tariot receives
clude both pharmacologic and nonpharmacologic interventions. There are currently
research support from Abbott no treatments for these disturbances approved by the US Food and Drug Ad-
Laboratories; Alzheimer’s ministration. Best judgment should be used in identifying dominant target symptoms
Association; Arizona Department
of Health Services, AstraZeneca;
and matching them to the most relevant drug class. Implementing nonpharmacologic
Avid Radiopharmaceuticals; interventions before the development of neuropsychiatric symptoms may prevent
Bristol-Myers Squibb triggers related to a progressively lowered stress threshold and therefore is key in the
Company; Elan Corporation; Eli Lilly
and Company; Genentech, Inc;
treatment of all patients with a dementia.
GlaxoSmithKline; Medivation, Inc;
Merck & Co, Inc; National Institute Continuum (Minneap Minn) 2013;19(2):382–396.
on Aging; National Institute of
Mental Health; Pfizer Inc; and
Toyama Pharmaceutical Association.
Unlabeled Use of INTRODUCTION TO THE CLINICAL or physical disruptiveness; resistance
Products/Investigational
Use Disclosure: PROBLEM OF NEUROPSYCHIATRIC to care; socially inappropriate behavior
Dr Burke discusses the unlabeled SIGNS AND SYMPTOMS IN 2. Depressive: sad affect, tearfulness,
use of atypical antipsychotics,
antidepressants, and anticonvulsants
DEMENTIA low mood, guilt, self-deprecatory
for the treatment of agitation in Almost all patients with dementia will or nihilistic ideation, suicidality,
dementia. Dr Hall reports no vegetative features, irritability; anxious
disclosure. Dr Tariot discusses the
develop significant behavioral problems
unlabeled use of cholinesterase at some point in the course of illness.1 features almost always co-occur
inhibitors and memantine for Signs and symptoms vary considerably 3. Apathetic: lack of initiative, interest,
people with dementia, as well as
the unlabeled use of antipsychotics, from one person to another, over time, or pleasure; limited affective response,
antidepressants, and anticonvulsants. and by type of dementia, and rarely fit psychomotor slowing
Information on drugs is provided
for general purposes only and into usual diagnostic classifications. It is 4. Psychotic: delusions, suspiciousness,
not relied on for prescribing. for this reason that we avoid using persecutory ideation, misidentification,
Before prescribing any of the drugs
discussed, the physician should typical diagnostic terminology and use misperception, hallucinations1
be knowledgeable about the full more descriptive terms instead. Most Symptom clusters and syndromes
prescribing information that can be
obtained from the manufacturers.
fall into four categories: can occur alone or in variable combina-
* 2013, American Academy 1. Agitated: verbal or physical aggression tions and often do not meet criteria for a
of Neurology. typical major psychiatric disorder. Left
toward self, others, or objects; verbal

KEY POINTS
untreated, neuropsychiatric signs and h Neuropsychiatric signs
TABLE 5-1 The Neuropsychiatric symptoms can lead to increased mortality,
Inventory as a and symptoms in
Checklist for early institutionalization, increased care- dementia are common,
Behavioral Issuesa giver burden, and excess cognitive and morbid, and distressing
functional disability, thereby becoming and occur in predictable
b Are the following features a major driver of increased cost of care.2 clusters.
present/absent? Unmitigated behavioral complica- h The Neuropsychiatric
Delusions tions pose a major clinical management Inventory trigger
Hallucinations challenge. The individual items from questions may be
Agitation/aggression the Neuropsychiatric Inventory (NPI) useful for detecting
Depression (Table 5-1) can be used as a yes/no and tracking
checklist to document behavioral issues neuropsychiatric
Anxiety
at baseline and in response to interven- signs and symptoms
Elation
tion.3 Caregivers will benefit from learn- in dementia.
Apathy
ing what behaviors to look for and how
Disinhibition
to label them, which will help them
Irritability
serve as the physician’s ‘‘eyes and ears’’
Aberrant motor behavior
during treatment. Research using the
Sleep disturbances NPI illustrates how frequent the indi-
Eating disturbances vidual behaviors are at a point in time
a
Data from Cummings JL, et al, Neurology.3 (Figure 5-1).4
www.neurology.org/content/44/12/2308.
abstract?sid=8e74243f-8085-4d9b-ae60-
9e63821c7fae. Agitation
Agitated behaviors are among the most
vexing aspects of dementia to evaluate,
manage, and treat. Clinicians should
FIGURE 5-1 Prevalence of neuropsychiatric symptoms in dementia using the neuropsychiatric

inventory.
4
Data from Lyketsos CG, et al, Am J Psychiatry. ajp.psychiatryonline.org/article.aspx?articleid=174106.

Neuropsychiatric Signs and Symptoms
KEY POINT
h Neuropsychiatric signs adhere to some basic principles, starting online resources such as Alzheimer
and symptoms in with educating the patient’s family Net and the Alzheimer’s Association.
dementia occur more about what behaviors can be expected Common precipitants of agitation and
readily as dementia and how things are likely to change over therapeutic opportunities are discussed
progresses because of time. Figure 5-25 shows that, as de- in the section on nonpharmacologic
progressively lowered mentia progresses, the patient’s abil- management.
stress threshold. ity to tolerate social or environmental New-onset agitation should be pre-
stressors will diminish. Families should sumed to be related to delirium until
anticipate this and manage accordingly; proven otherwise; in as many as 50% of
however, few receive education or train- cases, delirium proves to be the culprit.
ing on basic dementia management. Educating families to recognize the signs
Maybe ‘‘Dad used to be the life of the of a delirium and to immediately seek
party,’’ but now he gets upset if there medical treatment is essential. At the
are more than five people in the room same time that delirium is being ruled
or if the grandkids are running around. out, nonpharmacologic treatment ap-
Teaching the family or care partners to proaches should continue.
reduce these stressors will stave off a However, when nonpharmacologic
great deal of trouble. One or more edu- interventions are not enough or behav-
cational and support options should be iors result in safety issues, pharmacother-
offered, such as by providing basic in- apy may become necessary. The first-line
formation on dementia and behavioral choices of medication treatment, particu-
features; providing resources to help larly for Alzheimer-related dementia, are
with legal or financial information; the already approved agents for Alzheimer
addressing family conflict issues; and disease (AD), which are typically indicated
offering referral to support groups and anyway for treatment of the patient’s
FIGURE 5-2 Progressively lowered stress threshold in people with dementia. This figure
represents how the individual’s capacity to cope with stress and stimuli diminishes
over the course of dementing illness. Over time the capacity to cope decreases,
resulting in less calm baseline behavior and increased noncognitive behavioral symptoms (NCBS).
Anxiety and increased psychomotor agitation always precede the onset of NCBS. Steps can be
taken to intervene when anxiety occurs to thereby prevent NCBS. The x axis represents the timeline
for the disease trajectory. The dotted line represents how stress builds throughout any given day
to produce anxiety and NCBS. The y axis represents the degree of stress/stimulus the patient is able
to manage before developing NCBS.
5
Reprinted from Hall G, Buckwalter K. Arch Psychiatr Nurs. B 1987, with permission from Elsevier.

KEY POINTS
dementia. Data from trials suggest that there is a difference between regula- h A systematic approach
these agents may help relieve behav- tory and clinical considerations, and to help evaluate,
ioral symptoms.6,7 There is even a clinicians must use their best judg- manage, and treat
suggestion that early use may mitigate ment to decide what treatment a neuropsychiatric signs
emergence of behavioral symptoms. patient needs on a case-by-case basis. and symptoms in
Use of these agents in dementias not Table 5-3 offers some practical tips for dementia is helpful.
due to AD has not been studied ex- using psychotropics. h No medication for
tensively, but there is some evidence Antipsychotics. Antipsychotic agents treatment of
of benefit of cholinesterase inhibitors have been used and studied in patients neuropsychiatric signs
for dementia due to Lewy body dis- with a wide range of psychopathology. and symptoms in
ease and Parkinson disease.8,9 Consensus guidelines recommend them dementia is approved by
Currently, no psychotropic treat- as an appropriate choice for agitation the US Food and Drug
ments for agitation in dementia have associated with psychosis. There are two Administration,
been approved by the US Food and main classes of antipsychotics: conven- although this does not
preclude clinician
Drug Administration (FDA). Consensus tional antipsychotics and newer atypical
judgment regarding
guidelines have been set forth by the agents. For practical purposes, side
clinical necessity.
American Geriatrics Society and Ameri- effects typically guide selection of anti-
can Association for Geriatric Psychiatry psychotics in patients with dementia. h Cholinesterase inhibitors
and memantine are
in their 2004 statement suggesting use Prior reviews of the conventional
approved by the US Food
of target symptoms to guide selection of agents have concluded that the effects
and Drug Administration
drug class (Table 5-2).10 This article of these agents were consistent but for treatment of
more or less follows these guidelines, modest, and that no single agent was dementia due to
as shown in the algorithms: drug se- better than another.12 However, the use Alzheimer disease and may
lection is based on matching the dom- of conventional antipsychotics is lim- mitigate neuropsychiatric
inant target symptoms to the most ited by a side-effect profile that is un- signs and symptoms in
relevant drug class. For example, when acceptable for long-term use, including dementia.
verbal and physical agitation is present akathisia, tardive dyskinesia, parkinson- h There is no first-line
in a patient who is also irritable and ism, peripheral and central anticholin- recommendation for
negative, has become socially with- ergic effects, orthostatic hypotension, medications to treat
drawn, and appears dysphoric, a trial cardiac conduction abnormalities, seda- agitation without
of an antidepressant may be a reason- tion, and falls; in addition, there is psychosis.
able initial choice. Patients with aggres- evidence for increased mortality.2,12
sion and concurrent delusions or Older people treated with conventional
hallucinations will likely require initia- antipsychotics have a fivefold to sixfold
tion of an antipsychotic agent. A mood greater risk of tardive dyskinesia com-
stabilizer (eg, an anticonvulsant) is pared with younger populations.13 A
sometimes used in a patient displaying clinical issue that is of particular im-
agitation in the context of increased portance is dementia with co-occurring
motor activity, loud and rapid speech, extrapyramidal abnormalities such as
and affective lability, although evidence dementia with Lewy bodies, where oc-
from clinical trials for efficacy is incon- casional hypersensitivity to convention-
clusive at best. Although this general al agents is seen.14 In such cases,
approach to drug selection is reason- atypical antipsychotics have special util-
able, there is limited empirical support ity due to lesser blockade of the dopa-
for it thus far.2,11 Furthermore, the use mine type 2 receptor and reduced risk
of medications to treat any aspect of of extrapyramidal symptoms (EPS).
psychopathology in dementia is not In light of the considerable toxicity
recognized by the FDA and therefore of conventional agents, there was hope
is considered ‘‘off-label.’’ Nonetheless, that atypical antipsychotics would offer

KEY POINT
h Atypical antipsychotics TABLE 5-2 Modified Consensus Guidelines for Treatment of
may be first-line Psychiatric and Behavioral Symptoms in Alzheimer Diseasea
treatment for clinically
significant psychosis but b Use antidementia agents first for nonsevere symptoms
should be discontinued Cholinesterase inhibitors
if ineffective.
Memantine
Both cholinesterase inhibitors and memantine
b Atypical antipsychotics: first-line for psychosis with or without agitation
b No first-line recommendation for agitation without psychosis: consider
antipsychotic alone or with another agent, or another agent alone
Mood stabilizers
Serotonergic compounds
Trazodone: negative trials but positive clinical experience
Sertraline: anecdotes only
Citalopram: preliminary evidence for possible effect
Escitalopram: only by inference
a
Data from Alexopoulos GS, et al, J Clin Psychiatry.11 www.psychiatrist.com/pastppp/tocs.asp?toc=t65s02.
symptom relief in patients with demen- and atypical antipsychotics in people

tia while minimizing side effects seen with dementia: three comparing risper-
with older agents. However, meta- idone with haloperidol, and one study-
analyses show an overall treatment ef- ing quetiapine and haloperidol without
fect (ie, drug response minus placebo comparing them directly.2 Only one of
response) of about 18%, virtually identical these comparator trials found greater
to that seen with conventional agents.15 efficacy with the atypical than with the
There have been only four random- typical agent, while the others found
ized clinical trials investigating typical no significant difference. However, in
TABLE 5-3 Using Psychotropics in Dementia: What is the Clinician

to Do?
b Acknowledge that use of psychotropics is not approved by the US Food and Drug
Administration but this does not preclude use based on clinician judgment
b Document target signs and symptoms
b Try, and maintain, behavioral and environmental interventions
b Educate patients and their families and caregivers about the benefits, risks,
and goals of medication if it is needed
b Establish time frames in which to expect and evaluate effectiveness
b Assess (and document) treatment and adverse events frequently
b Use the lowest doses necessary for the shortest time period
b Stop if the treatment is ineffective
b Acknowledge that typical antipsychotics have considerable toxicity, but that
atypicals have considerable side effects as well
b Coordinate patient care with other health care professionals

all four studies, haloperidol was asso- zapine and aripiprazole. The increased
ciated with more EPS than the atypical risk for CVAEs was determined from
agent. Atypical antipsychotics were less research clinical trials and is based on
likely than typical antipsychotics (espe- unbiased estimates. It is important to
cially haloperidol) to cause or exac- note that subsequent studies, mainly
erbate EPS and tardive dyskinesia in involving large public databases, have
patients with dementia, but no other found similar or even higher death rates
advantages in terms of efficacy or safety among elders receiving conventional
have been demonstrated. Although this antipsychotics, which resulted in a
research indicates that atypical anti- second, broader ‘‘black box’’ warning
psychotics as a class are generally better for all antipsychotics in 2008.
tolerated than conventional antipsy- In 2004, the FDA issued a warning
chotics and at least as efficacious, they regarding all atypical antipsychotics,
are not without side effects. Differences indicating that in trials up to 3 months
in terms of efficacy, tolerability, and long the risk of death was about 1.6
side-effect profile exist within the class times greater with active treatment
of atypical antipsychotics that may be than with placebo (4.5% versus 2.6%,
useful in treatment selection. respectively)Vfindings supported by
Atypical antipsychotics have largely subsequent academic meta-analyses.2,15
replaced conventional agents in the A recent retrospective cohort study sug-
treatment of psychosis, aggression, and gested that there may be differences in
agitation in patients with dementia. mortality risks among individual anti-
However, these newer agents con- psychotic agents. While haloperidol use
tinue to have other acute and subacute was associated with the highest mor-
side effects in elderly patients (eg, tality rates, risperidone and olanzapine
sedation, postural hypotension, and also showed increased risk. The least
falls), especially at higher doses. As is likely to increase mortality was quetiapine.
true for younger people, antipsychotic- The mortality risk with haloperidol was
associated diabetes, obesity, and dys- highest in the first 30 days but de-
lipidemia are concerns despite the creased sharply thereafter. Among the
lack of large-scale studies addressing other agents, mortality risk differences
these issues in patients with dementia. were most significant in the first 120
In addition, EPS, cognitive impairment, days and declined in the subsequent
gait disturbance, and anticholinergic 60 days during follow-up. Although
effects have been reported in some these findings were limited to a single
instances.11 study, they indicate the necessity for
In 2003, the FDA issued a warning further investigation of specific mortal-
titled ‘‘Cerebrovascular Adverse Events, ity risk within this class of agents.
Including Stroke, in Elderly Patients with Anticonvulsants. One might con-
Dementia.’’2 It referred to cerebrovascular sider use of anticonvulsant medications
adverse events (CVAEs) (eg, stroke, first in patients with features of mania,
TIA), including fatalities, seen in trials perhaps as well as in those with prom-
of risperidone in elderly patients with inent impulsivity, lability, or episodic
dementia-related psychosis or agita- severe aggression. However, the best
tion; a significantly higher incidence of available evidence, coming from two
CVAEs was noted in patients treated carbamazepine and five valproate trials
with risperidone compared to those for agitation associated with dementia,
treated with placebo. Shortly thereafter, is conflicting and inconclusive.16 At
a similar warning was applied to olan- present the data do not support their

widespread use, although they appear Agents for Alzheimer dementia.

to be beneficial in some patients.16 It is There is mounting evidence that cho-
likely because of anecdotal experience linesterase inhibitors can have positive
more than trial data that some consen- behavioral effects in terms of either re-
sus statements suggest a possible role duction of symptoms or delayed emer-
as a second- or third-line treatment for gence of symptoms. A meta-analysis of
agitation and aggressive behaviors in the behavioral effects of cholinesterase
selected patients with dementia. The inhibitors indicated overall benefit,6
authors are not aware of any controlled which was supported by results from a
studies of the newer anticonvulsants, trial of donepezil in mild-moderate AD
including lamotrigine, gabapentin, and that showed improvement in global
topiramate, although a few case reports neuropsychiatric symptoms during open-
and case series suggest benefit with label treatment for 3 months, followed
gabapentin.17 by symptomatic worsening in patients
Based in part on putative neuro- treated with placebo during the subse-
protective effects of valproate discerned quent randomized discontinuation
in animal studies, the Alzheimer’s Dis- phase of the trial.23 However, donepezil
ease Cooperative Study (ADCS) con- proved ineffective for treatment of se-
ducted a 2-year, placebo-controlled trial vere agitation.24 Similarly, at least one
of low doses (about 10 mg/kg/d) of dival- trial7 and a pooled analysis of three
proex sodium in over 300 people with placebo-controlled trials’ treatment with
AD not yet complicated by agitation or memantine in patients with moderate-
psychosis.18 The primary outcome was severe AD showed overall benefit in
survival until incident agitation or psycho- terms of either symptom reduction or
sis; key secondary measures addressed delayed emergence of symptoms,25
measures of cognitive, functional, and while a study in patients with severe
global progression of dementia. There agitation did not show benefit.26 Finally,
was no benefit of active treatment for a recent study of cessation of long-term
any of the clinical outcomes, and sig- treatment of donepezil in patients with
nificant brain volume loss was noted in moderate to severe dementia showed
the treated group. behavioral benefit in those who were
Antidepressants. Patients with agi- newly treated with memantine.27 Since
tation accompanied by evidence of de- these agents are indicated anyway in
pressive features may benefit from AD dementia, and the evidence for be-
initiation of an antidepressant; agita- havioral benefit is encouraging, our al-
tion without depressive features may gorithm reflects our view that they
potentially respond as well.2,17 Most of should be used as the first line of defense
the studies reporting favorable effects for drug treatment of behavioral features.
were small or uncontrolled; the largest
failed to show clear-cut benefit,19Y22 with Depression
further results pending from unpublished The diagnosis of depression, or at least
citalopram research (clinicaltrials.gov/ the recognition of clinically significant
ct2/show/NCT00898807). These agents depressive features, in dementia can
have a good tolerability profile, which be difficult. Diagnosis is frequently
is a main driver of their use: gastroin- made based on caregiver observations,
testinal distress, loss of appetite and since patients with dementia may not
weight, sedation, insomnia, sexual dys- be able to describe their feelings or
function, and occasional paradoxical give an accurate history of their mood.
agitation are the main side effects. In general, elders may not meet full

criteria for a major depressive disorder ning, and goal-setting), and emotions
since they often tend to present with (eg, decreased emotional responsive-
more somatic complaints. Many symp- ness to both positive and negative
toms of depression, such as insomnia, events, flat affect). There is insufficient
fatigue, and difficulty with concentra- research to dictate best practice regard-
tion, may be attributed by clinicians ing drug use. Anecdotal evidence in-
solely to comorbid medical conditions dicates possible benefit in some cases
and dementia. with use of cholinesterase inhibitors,
Treatment of depressive symptoms dopaminergic antidepressants (eg, sertra-
in dementia should include a thorough line, bupropion), stimulants (eg, methyl-
evaluation of potential environmental phenidate, dextroamphetamine), and
and psychosocial triggers, which can dopamine agonists.
exacerbate the condition. Surprisingly,
the evidence from clinical trials of anti- PRINCIPLES OF
depressants comes from generally small NONPHARMACOLOGIC
studies, showing only weak support for INTERVENTIONS
their widespread use.28 Anecdotal expe- The Role and Limitations of
rience and guidelines typically support Nonpharmacologic Interventions
use for clinically significant depressive Families are the primary source of care
features. If pharmacotherapy is war- for people with dementia.29 Over a
ranted, selective serotonin reuptake in- period of about 10 years, caring for a
hibitors are recommended as first-line person with dementia includes meeting
therapy because of their relatively be- instrumental needs such as managing
nign side-effect profile. Monoamine finances, procuring food, maintaining
oxidase inhibitors and tricyclic antide- the household, planning activities,
pressants should be avoided because of maintaining safety, providing for basic
their adverse effects on cognition and needs, and personal care. Because of
greater potential for other serious ad- increasing susceptibility to environmen-
verse effects. tal stimuli, neuropsychiatric signs and
symptoms increase in frequency, sever-
Apathy ity, and presentation with disease pro-
Depressive features should be distin- gression. These behaviors result in poor
guished from apathy, which is a disorder outcomes for patients and their families
of motivation characterized by reduced and providers, including caregiver bur-
goal-directed activity in domains of den, institutionalization, and increased
behavior, cognition, and emotion. Apa- use of psychotropic medications.30Y32
thy is a frequent symptom of many Neuropsychiatric signs and symptoms
neuropsychiatric conditions. Unlike apa- are primary barriers to providing care;
thy, depression involves considerable caregiver response to them is the most
emotional distress, frequently character- common reason for residential place-
ized by tearfulness, sadness, anxiety, ment.33 Therefore, residential facilities
agitation, sleep and appetite distur- (nursing homes and assisted living fa-
bances, feelings of worthlessness and cilities) are likely to have residents with
hopelessness, and recurrent thoughts of more challenging neuropsychiatric signs
death. Clinical features of apathy gener- and symptoms. While medications are
ally present through behaviors (eg, lack often prescribed for management of neu-
of effort, productivity, structure, and ropsychiatric signs and symptoms, po-
initiative), cognitions (eg, diminished tentially serious complications mandate
interest, curiosity, concern, insight, plan- minimizing the use of medications in

Case 5-1
A 76-year-old man presented with a 5-year history of progressive memory and functional loss. He lived
at home with his wife and needed supervision or direction with basic activities of daily living. He
refused to bathe, shave, clean his teeth, and change into clean clothes more than once a week; he also
refused all assistance and became physically aggressive with his wife when she tried to help him.
The patient spent his days watching legal dramas and soap operas and believed that the characters
he saw on television lived next door and were committing crimes. He routinely saw imagined silent
children in the house.
He usually became agitated starting at 4:00 PM, insisting that the house was not his and refusing his
wife’s explanations that it was their home. The patient did not nap during the day and went to bed
at about 7:00 PM. He generally woke around 2:00 AM, believed it was morning, and tried to go to work.
The patient’s wife was exhausted and, despite her stated goal of keeping the patient at home, was
considering residential placement, where she feared the patient would be overmedicated (leading
to sedation, falls, and immobility).
Comment. The patient was assessed by an interdisciplinary care team, which found that he was
experiencing several behavioral triggers, identification of which led to mitigation strategies:
1. FatigueVIt was recommended that the patient receive a rest period of 30 minutes after his morning
activities of daily living, and a 90-minute nap in his recliner after lunch. After his afternoon nap,
the patient’s wife has him help her sort family pictures. All activities are kept to 90 minutes or less.
These interventions stopped the patient’s 4:00 PM confusion and, with the addition of ice cream
at 8:30 PM, keep him awake until 9:30 PM. He now sleeps until 7:30 AM.
2. Loss of meaningful activitiesVThe patient was enrolled in an adult day program for 3 days each
week. Initially, he thought he was a volunteer helping the older people, but within 2 weeks settled
in and looked forward to attending in order to ‘‘spend time with the guys.’’ The patient now
eagerly accepts help with bathing, since he understands that it is a requirement in order to attend
the day program, and his wife is considering increasing his participation to 5 days each week. He
has also been given some modified chores he can do with his wife, such as sweeping the patio. He
reports that he enjoys helping her.
3. Misleading stimuliVThe patient was developing illusions, also called pseudohallucinations, from his
exposure to television dramas. He no longer watches television except for occasional sports in
the evening. His illusions of people in the house have disappeared, as have his worries about the
criminal activity next door.
4. Communication issuesVThe patient’s wife was trained in nonconfrontational communication
techniques and now manages by agreeing with him, correcting him only when safety is an issue.
Although relearning how to respond has been difficult for her, she acknowledges that it is
successful, and is no longer considering residential placement for the patient.
While many single interventions have been studied, there are limits on study methods. Few have
evidence from randomized controlled trials; however, there are a growing number of caregiver
training programs that are theory-based and provide a comprehensive 24/7 view of the person with
dementia and the needs of his or her caregivers. When these programs are used consistently,
neuropsychiatric signs and symptoms decline significantly.
favor of nonpharmacologic measures One problem for providers is that

whenever possible. Thus, nonpharma- although there is a vast array of such
cologic measures are the primary in- interventions, relatively few are based
terventions to use in preventing or on randomized controlled trials (RCTs).
relieving neuropsychiatric signs and Most studies were relatively brief and
symptoms (Case 5-1). involved small convenience samples.34

As a result, evidence for guiding best is to meet patient needs and minimize
practice is viewed as inferior to that neuropsychiatric signs and symptoms
available for medications, which have by creating a supportive environment
undergone RCTs.35,36 Another problem and through modified communica-
is that many RCTs were conducted in tion. Caregiver counseling programs
nursing homes and may not generalize result in statistically significant de-
to home environments. clines in patients’ psychosis and de-
Further, interventions such as bright lusions. 42,43 These findings were
light therapy, music, aromatherapy, use significant among groups of white,
of pets and animal-like robots in lieu of Latino, and African American fami-
pets, and multisensory environments lies.31,44 A secondary goal of these
are helpful at a ‘‘micro’’ level, meaning programs is to reduce caregiver bur-
they are not part of an overarching 24- den, hopefully permitting the patient
hour program.35 Few studies of indi- to stay at home longer.
vidual interventions have theoretical For purposes of brevity and provider
underpinnings that point to broader usefulness, this discussion will focus
or prescribed use, which leaves care- on one evidence-based theoretical
givers uncertain regarding when to use model, the Progressively Lowered Stress
the intervention and for what duration. Threshold.5,41,45 The model hypothe-
Moreover, few individual interventions sizes that the majority of neuropsychi-
have been studied in the context of atric signs and symptoms are responses
relieving or preventing neuropsychiat- to stress resulting from the interaction
ric signs and symptoms.36 of neurodegenerative changes with the
Comprehensive evidence-based
environment. With dementia, the pa-
programs. There are comprehensive
tient’s capacity for dealing with stress
evidence-based caregiver training pro-
diminishes over time as the disease
grams available nationwide. Evidence-
progresses, and stress responses occur
based caregiver training programs have
with increasing frequency. The stress
been evaluated for efficacy and are
leads to anxiety and, if unrelieved,
cataloged by the Rosalyn Carter Insti-
neuropsychiatric signs and symptoms.
tute for Caregiving for consumer use,
Figure 5-2 demonstrates this concept.5
for community program development,
and to provide frameworks for future The model identifies six triggers that
research. These programs range from increase stress leading to neuropsychi-
several hours of caregiver training to 6 atric signs and symptoms. Caregivers
months with an average of 8 to 9 weeks learn that by avoiding or minimizing
(www.rosalynncarter.org/caregiver_ these triggers, they can both prevent
intervention_database/).37 The data- and relieve neuropsychiatric signs and
base provides information on how to symptoms:
access authors or investigators for infor- 1. Fatigue
mation and materials for implementation. 2. Change of routine, environment, or
The comprehensive programs focus caregiver
primarily on caregiver education about 3. Excessive demand to achieve activ-
the disease process, caregiver behavior, ity beyond limitations
environmental modification, commu- 4. Excessive or misleading stimulus
nication skills, and suggestions for 5. Perception of losses resulting in
meeting patient needs in order to min- depression or anger (at loss of
imize neuropsychiatric signs and symp- cherished activities or at inadequate
toms.38Y41 The focus of these programs activities)

TABLE 5-4 Triggers for Behavioral Symptoms
Trigger/Stressor Concern Intervention/Strategies

Fatigue Patients fatigue easily with Rest periods 2 to 3 times per day
concentration on daily activities.
If the patient is up at night or retiring
early, increase daytime rest
Change in routine, Change forces the person to think Consistent patterns during daily routines
environment, or about the sequence of an activity. If
Minimize or carefully plan environmental
caregiver an activity requires thought, it will be
changes such as travel, holiday
much more difficult for the patient
decorations, and guests in the home
to accomplish, resulting in frustration
and stress.
Inappropriate stimulus Overwhelming stimuli: people with Limit group sizes
levels: overwhelming or dementia often get confused in
Be aware of excessive noise
misleading stimuli uncomfortable, crowded, or loud
settings; the patient may act out with Avoid misleading, upsetting stimuli in
angry outbursts or rude statements. later disease, including graphic television
shows or movies
Misleading stimuli: people with
dementia may be confused by television, Respect the patient’s wishes to leave a
mirrors, and pictures and believe the stimulating setting such as a party or
people they see in these stimuli are real restaurant
and/or in their home.
Excessive demand Changes in planning abilities and Let the patient determine what he or
executive function result in increased she can achieve
difficulty performing activities
Do not ask the patient to ‘‘try harder’’
requiring conscious thought. This is
often precipitated by caregiver Minimize correcting and testing the
demand or family conflict. patient
Perception of losses Patients with insight often experience Discuss illness with the patient and
depression. Patients who lose cherished encourage expressions of grief
activities or possessions such as driving
Encourage participation in daily
or guns will also grieve the loss.
activities that include socialization and
intellectual stimulation
Delirium Anything that causes physical changes, Exercise
such as infection, pain, medication
Adequate fluid intake
reactions, and acute conditions, will
produce acute confusion syndrome, Immunizations
also known as delirium.
Adequate rest
6. Physical changes causing delirium, ric signs and symptoms including falls,
such as acute illness, pain, medica- pacing and fidgeting, refusing care, late
tion reactions, or infections day confusion, wandering, aggression,
Table 5-4 demonstrates interven- and psychosis.5,41,45 The model outlines
tions used to prevent triggers for excess the basic knowledge caregivers need to
disability in the categories identified provide for planning days throughout
above. When used by family or profes- the illness.
sional caregivers, this approach results One key to minimizing the triggers
in significant declines in neuropsychiat- for stress is to understand the symptoms

KEY POINT
of dementia that complicate the presen- communication techniques.46 Demen- h Predictable triggers for
tation of memory loss. Providers must tia produces progressive losses in lan- neuropsychiatric signs
understand that the following symptoms guage function, rendering the patient and symptoms in
are critically important to the patient’s more vulnerable to nonverbal commu- dementia can be
sense of well-being in their environ- nications such as gestures, facial ex- identified.
ment: altered visual perception, includ- pression, body language, and vocal
ing loss of depth perception, and altered tone. Caregivers using less than optimal
ability to perceive moving objects; di- communication styles, including ‘‘elder-
minished sense of time; inability to plan, speak,’’ a pejorative, childlike ap-
initiate, and carry through to a goal proach, will elicit more neuropsychiat-
(activities that require thought); in- ric signs and symptoms.46 Escape/
creased self-absorption; progressively avoidance approaches such as ignoring
lowered insight; and gradual diminish- the patient also increase neuropsychi-
ment of endurance. atric signs and symptoms, especially
agitation and aggression.46,47 Evidence-
Activities based training programs are available
People who remain active and engaged nationally to help caregivers develop
in pleasurable activities tend to be func- techniques to avoid confrontation.
tional longer, have less depression, and The most widely recognized pro-
manifest fewer problems with neuropsy- grams to enhance caregiver communi-
chiatric signs and symptoms. Activities cations are the Resources for Enhancing
are thought to be the most important Alzheimer’s Caregiver Health (REACH)
aspect of care for patients with dementia. programs. Developed to assist caregivers
A variety of activities is important; how- with modifying their own behavior and
ever, they must be modified and indi- responses to their patients’ neu-
vidualized continuously as the disease ropsychiatric signs and symptoms, the
progresses.35 This may include varied REACH programs have been developed
and, at times, mildly challenging activi- and tested in many sites with group edu-
ties. In moderate dementia, each activity cation and telephone-based educational
should not exceed 90 minutes. programs.31,48 REACH interventions in-
Activities that are enjoyable, safe, and clude provision of information, didactic
hold the patient’s attention should be instruction, role-playing exercises, problem-
encouraged. Many books are available solving strategies, skills training, stress
for caregivers on how to plan activities management, and telephone support
for people with dementia. It is impor- groups. These programs were devel-
tant for caregivers and the patient’s oped using twelve 90-minute sessions
family members to understand that the over 6 months, in addition to resource
time the patient is able to spend en- notebooks with educational materials
gaged in activities will be shorter as the and telephones linked to a computer-
disease progresses because of fatigue integrated system. Interventions were
and diminished attention span. Occupa- developed based on findings that active
tional therapists, recreational therapists, techniques are more effective at improv-
and adult day programs can be sources ing outcomes than passive techniques.
of help in modifying or finding new
activities.39,40 Bathing
Caregivers often encounter issues when
Communication attempting to bathe patients with AD.
Many neuropsychiatric signs and symp- Many patients with AD may refuse to
toms are correlated with problematic bathe or say they have already bathed

KEY POINT
h Refer to basic precepts TABLE 5-5 Principles of Care for People With Dementia
for care of people with
dementia. b Something can be done at all stages of illness
b The specific dementia diagnosis matters
b Excess disability is often multifactoral, meaning caused by multiple triggers
b Residual strengths matter
b Presume that the patient has feelings and needs
b Approach the patient and family as a unit
b Treat the patient and family with respect and compassion
b Ensure safety, dignity, and comfort
b Enhanced quality of life is always the goal
when they have not, which can be ciation for Geriatric Psychiatry, or the
frustrating, especially if the person de- American Psychiatric Association.10,11
velops body odor. Many older adults are Best judgment should be used in iden-
modest about disrobing; those with AD tifying dominant target symptoms and
may also become afraid of bathwater or matching them to the most relevant
the shower or feel overwhelmed by the drug class. Practice models need to
complexity of the task. A new evidence- evolve to allow the time and expertise
based practice guideline has been issued to offer the best behavioral ap-
outlining effective bathing practices, in- proaches. Treating AD dementia be-
cluding towel baths.49 It is available from fore behavioral features are evident
www.nursing.uiowa.edu/sites/default/ may be the best treatment for behav-
files/documents/hartford/EBP_Catalog ioral symptoms in the long run, and
2012.pdf. agents now in development will hope-
fully prove to alter the course of the
CONCLUSION illness. In the meantime, the guiding
Behavioral disturbances are common, principles depicted in Table 5-5 are
morbid, and distressing for patients recommended; there is always some-
with dementia and their caregivers. thing that can be done to help,
There are no FDA-approved psychotro- regardless of the problem or stage of
pic treatments for these disturbances. illness. Giving this message to patients
Nonpharmacologic management can and families is by itself therapeutic.
often be effective; however, when this
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Review Article
The Diagnostic
Dr Douglas Galasko,
Department of Neurosciences,
UC San Diego, 9500 Gilman
Evaluation of a Patient Drive 0948, La Jolla, CA 92093

Dr Galasko serves as a
With Dementia consultant for Elan Corporation

and serves on the data and
safety monitoring boards of
Elan Corporation and Janssen
Douglas Galasko, MBBCh Pharmaceuticals, Inc.
Dr Galasko serves as an
editor-in-chief of Alzheimer’s
Research and Therapy.
ABSTRACT
Unlabeled Use of
Purpose of Review: This review outlines a practical approach to the history, mental Products/Investigational
state, neurologic examination, and laboratory tests in the diagnosis of dementia. Use Disclosure:
Dr Galasko reports no
Recent Findings: Proposed new diagnostic criteria for Alzheimer disease recognize disclosure.
that nonamnestic presentations with symptoms that predominantly affect language, * 2013, American Academy
visuospatial abilities, or executive function may occur, particularly with onset before the of Neurology.
age of 65. New criteria assign greater likelihood to diagnosis if progressive cognitive
decline is documented through serial assessment, or if biomarkers are supportive. In
patients aged 80 or older, more than one cause of dementia is often present, for
example, Alzheimer disease plus vascular dementia. Clinical diagnostic criteria for non-
Alzheimer dementias are evolving, particularly in areas such as frontotemporal
dementia. Imaging and CSF biomarkers have been proposed in recent diagnostic
criteria for Alzheimer disease. Although biomarkers can provide a higher level of
certainty that Alzheimer pathology may or may not be present, biomarkers for non-
Alzheimer dementias are lacking.
Summary: The availability of biomarkers does not replace or diminish the need for a
thorough clinical evaluation. A structured clinical approach helps to define the diag-
nosis and collects information essential for establishing a comprehensive care plan for
patients with dementia and their families.
INTRODUCTION the diagnosis of Alzheimer disease (AD)

Dementia is defined as an acquired have improved the clinical description
decline of cognitive abilities sufficient of variants such as progressive aphasia
to result in social or occupational im- or posterior cortical atrophy, and al-
pairment. The usual presentation is the though they indicate that biomarkers
gradual onset and progressive loss of may improve diagnostic accuracy, they
memory and other cognitive abilities also emphasize the importance of the
occurring in elderly people; the preva- clinical evaluation.1
lence rises from about 1% to 2% at age The key goals of a clinical evaluation
65 to 10% to 15% at age 80, and may be are to establish whether dementia is
as high as 40% by age 90. When present; to characterize the impaired
someone younger develops significant areas of cognition, the severity of im-
cognitive decline or behavioral changes, pairment, and functional consequences;
the diagnosis of dementia may often be and to determine the likely etiology.
delayed because of a lower index of However, it is worth framing the evalu-
suspicion or a less typical clinical pre- ation more broadly. With the serious
sentation. Recently revised criteria for implications of dementia for the patient

Diagnostic Evaluation
KEY POINT
h It is useful to determine and family, the evaluation must collect shallow content of their speech. Pa-
the patient’s degree of enough information to allow the clini- tients will often steer conversation
insight into problems, cian to discuss the diagnosis and its toward experiences that they are able
because this will immediate and long-term implications, to recall in detail. On the other hand,
influence his or her and formulate a comprehensive overall when patients provide a rich and de-
acceptance of elements care plan. tailed account of their memory lapses,
of a care plan. The evaluation of dementia is best this usually indicates their awareness
staged over two clinic visits. The first of age-associated cognitive changes or
visit should allow enough time to obtain may raise the possibility of anxiety or
a detailed history and examination, depression. The key to obtaining an
interview family members (often sepa- accurate history is to interview a knowl-
rately from the patient), and order edgeable informant. This is often best
diagnostic tests. The second visit usu- done when the patient is not present in
ally consists of a conference with the order to avoid arguments or distress
patient and family members, for which when the caregiver describes problems.
the goals are to present and discuss the A separate interview with one or more
diagnosis and etiologic factors; review family members may be particularly
medical treatment options; develop a important when the patient is referred
plan for overall management, including against his or her will or is resistant to
issues such as driving, financial matters, the evaluation. Some patients may be
medications, and legal issues (eg, dura- sensitive to or alarmed by the use of the
ble power of attorney for health care); words ‘‘Alzheimer disease,’’ and dis-
exchange information about social and cussing the problem as ‘‘memory loss’’
community resources; and, when rele- or in other general terms (eg, ‘‘This is
vant, discuss research options. Some a checkup of how well you’re doing’’)
clinicians who perform detailed cogni- can smooth over the initial clinical
tive or neuropsychological assessments encounter.
themselves may divide the evaluation It is helpful to characterize the nature
into three visits. of the onset and the early symptoms in
detail. AD and other neurodegenerative
THE HISTORY causes of dementia are characterized by
Initiating the Visit a gradual onset of cognitive decline,
Many patients with dementia lack in- whereas in vascular dementia the onset
sight into their deficits and tend to deny may be more abrupt. The course of AD
the existence of a problem. Patients is also gradual and relatively slow,
with AD will often make excuses for measured over years. In early or mild
their memory problems, for example, stages, patients may have occasional
saying they do not do particular ac- lapses, but over time these become
tivities anymore or do not remember more frequent in AD and other neuro-
things because ‘‘that isn’t important.’’ It degenerative causes of dementia. Vas-
is useful to determine the patient’s cular dementia may show a stepwise
degree of insight into problems, be- decline; a history of stroke or strokelike
cause this will influence his or her ac- episodes increases the confidence of
ceptance of elements of a care plan. this diagnosis but is not essential. Some
Early in the course of AD, patients may events may accelerate the symptoms of
have striking preservation of social and dementiaVfor example, patients with
interpersonal skills, and a superficial AD may decline after undergoing major
conversation may show no obvious surgical procedures or become deliri-
signs of impairment other than the ous after a medical illness such as

KEY POINT
pneumonia. This should not be taken as ficulty with multitasking, or susceptibil- h Symptoms that point
evidence of cerebrovascular pathology. ity to interference. Careful questioning to a major memory
Rapid cognitive decline with a subacute can reveal that the patient is able to problem include asking
course over weeks or months raises a complete a complex task, given enough questions repeatedly;
different set of diagnostic concerns. time and the absence of distraction. forgetting details
This may not be the case for someone of conversations,
Characterizing Cognition with early dementia. appointments, and
The informant interview should charac- Symptoms of other areas of cognitive plans; not paying bills
terize the patient’s cognition, behavior, decline are shown in Table 6-1. Lan- on time; and not
and function to develop a detailed guage problems may include difficulty recalling the details of TV
shows or movies. These
clinical picture and to help in diagnosis with names of people or objects,
types of problems need
and staging. Although the cognitive shorter sentences, circumlocution (ie,
to be distinguished from
history will generally focus on memory empty speech when describing things complaints that are
skills, some patients may present with or answering a question), paraphasic usually blamed on
other areas of impairment, such as errors, or mispronunciation of words. memory but reflect
language, executive function (ie, judg- Speech problems such as dysarthria age-associated cognitive
ment, planning, and reasoning) or may be associated with decreased or changes.
visuospatial abilities. Patients with slower language output. Patients with
frontotemporal dementia (FTD) typi- executive problems may have difficulty
cally have striking changes in behavior initiating activities, making plans, per-
or personality, with relatively preserved forming complicated tasks at work or
memory and visuospatial abilities. Since in hobbies, or following multistep pro-
history taking should be detailed and cesses such as using a cell phone,
may involve interviewing the informant computer, or remote control. Ques-
separately from the patient, it may be tioning about executive abilities there-
helpful to have the informant complete fore often overlaps with functional
a questionnaire or a series of rating abilities. Patients with visuospatial prob-
scales about these symptoms while the lems may report unusual symptoms
patient is undergoing the examination. such as difficulty using their hands for
Symptoms that point to a major fine coordinated activities (eg, typing
memory problem include asking ques- on a keyboard, using a screwdriver, or
tions repeatedly; forgetting details of knitting) or misjudging where objects
conversations, appointments, and are in space. They may have vague
plans; not paying bills on time; and not difficulty in reading or distinguishing
recalling the details of TV shows or objects or people’s faces, and often re-
movies. These types of problems need ceive an ophthalmologic evaluation
to be distinguished from complaints before the problem is attributed to
that are usually blamed on memory the brain rather than the eyes.
but reflect age-associated cognitive
changes. In particular, difficulty finding History of Functional Ability
words or recalling people’s names is An assessment of functional abilities is
related to problems with retrieval rather best obtained from a knowledgeable
than memory and is a hallmark of aging. informant. For clinical assessment, it is
It is often accompanied by the ‘‘tip of helpful to divide activities of daily living
the tongue’’ phenomenon, in which (ADL) into two categories. Basic ADL
the word or name comes back some include activities that are essential to
time later. Two other cognitive changes self-maintenance: grooming, bathing,
associated with aging are slowing of dressing, eating, and continence. In
cognitive processing and increased dif- most patients with AD, independence

TABLE 6-1 Clinical Presentations of Alzheimer Disease and Other Degenerative Dementias
Clinical Presentations Symptoms Clinical Findings MRI/Imaging Findings

Typical amnestic Forgets conversations, Impaired learning and Atrophy, especially in
Alzheimer disease (AD) appointments, and plans memory the hippocampus and
temporal lobe, and
Normal neurologic
ventricular enlargement
examination
Posterior cortical Difficulty recognizing faces or Simultagnosia, Balint Occipital lobe atrophy
atrophy objects, locating or manipulating syndrome
objects that are in view,
Difficulty reading or
reading, and judging distances
drawing intersecting or
visually complex figures
AD with Difficulty with Impaired single-word Left posterior perisylvian
aphasiaVlogopenic word-finding and retrieval in spontaneous or parietal atrophy, or
pauses during speech speech hypometabolism
Impaired repetition of
phrases or longer sentences
Lewy body dementia Variable alertness and Cognitive impairment, Less atrophy than in AD
attention often with relative
Occipital hypometabolism
sparing of memory
Visual hallucinations on fluorodeoxyglucose
Impaired visuospatial tests (FDG) positron emission
REM sleep behavior disorder
tomography (PET)
Parkinsonism
Behavioral-variant Disinhibition: change in Executive impairment, Frontal or anterior
frontotemporal personal decorum, inappropriate relatively preserved memory, temporal lobe atrophy
dementia interpersonal behavior, and and visuospatial skills (CT or MRI) or
rash/impulsive behavior hypometabolism
Normal neurologic
(FDG PET)
Apathy or inertia examination; some
Loss of empathy patients may have ALS
or mild parkinsonism
Repetitive, ritualistic behavior
Hyperorality and diet changes
Primary progressive Difficulty thinking of words Impaired confrontation Anterior temporal

aphasiaVsemantic (eg, names of objects) naming lobe atrophy or
variant hypometabolism on
Fluent language output Impaired single-word
FDG PET
comprehension
Loss of object knowledge
Surface dyslexia (misreading
of irregularly pronounced
words)
Primary progressive Slow, halting speech Agrammatism Left posterior
aphasiaVnonfluent frontoinsular atrophy
Halting speech, sometimes
or hypometabolism
speech sound distortions
or errors
Spared word
knowledge/comprehension
Continued on next page

TABLE 6-1 Continued
Clinical Presentations Symptoms Clinical Findings MRI/Imaging Findings

Corticobasal syndrome Variable: eg, difficulty with Rigidity, apraxia, cortical Asymmetrical cortical
movement, clumsiness, stiffness sensory loss, alien limb, atrophy, often parietal
of affected limb; visual or limb dystonia, reflex focal
language symptoms myoclonusVoften starts
in one limb
Progressive supranuclear Slow speech, dysarthria, Impaired eye movements, Atrophy of midbrain,
palsy and dysphagia especially vertical gaze ‘‘hummingbird sign’’
Slow gait, falls Postural instability
Apathy Akinesia, rigidity,
retrocollis
Slowed cognition,
dysexecutive syndrome
in basic ADL is preserved until late in Vehicles performing a driving evalua- KEY POINT
the course; early problems with basic tion through a written or observed h The clinician should
ADL may be due to physical problems driving test. Handling medications ac- always inquire about
activities that could pose
such as a gait disorder or urological curately, managing small sums of mon-
significant safety risks in
problem. Identifying impairments in ey, balancing a checkbook or credit
the setting of dementia.
more complex tasks, referred to as card statement, paying bills, and com-
instrumental activities of daily living pleting income tax returns are other
(IADL), is a critical part of the history. examples of IADL that could pose
Structured questionnaires such as the substantial risks.
AD8 (which combines cognition and Other IADL matters worth probing
function)2 or functional activities ques- include trouble using gadgets such as
tionnaire3 can be useful tools. Alterna- a remote control, cell phone, or com-
tively, tailoring functional inquiries to puter; difficulty with pastimes or
the patient’s activities and lifestyle can hobbies, particularly when they are
also provide useful information. The cognitively complex; and declining abil-
clinician should always inquire about ities to prepare food or perform house-
activities that could pose significant hold maintenance activities. Patients
safety risks in the setting of dementia; with dementia may have problems
for example, even though the potential remembering appointments and plans
loss of driving privileges is a highly even when they use a calendar, diary, or
sensitive issue, the clinician must ask electronic device as a reminder. When
whether the patient has had problems there are changes in functional abilities,
such as getting lost while driving, a physical health factor (eg, severe ar-
having accidents (even minor ones), thritis, impaired mobility, or poor vision
or being unable to locate the car in a or hearing) may need to be taken into
large parking lot. The clinician must be account.
aware of local legal reporting require-
ments for dementiaVin many states, a Assessing Changes in Behavior
report does not automatically lead to a Behavioral symptoms are common
suspension of driving privileges but in patients with dementia, may pro-
may result in the Department of Motor vide diagnostic clues, and should be

KEY POINT
h Behavioral symptoms considered when formulating a treat- Social history should focus on marital
are common in patients ment plan. Patients with behavioral- status, the existence of a social support
with dementia, may variant frontotemporal dementia network of family and friends, and ex-
provide diagnostic clues, (bvFTD) characteristically have early posure to alcohol and drugs. Physical
and should be considered symptoms reflecting a deterioration of activity, including walking or other
when formulating a personality, social conduct, and inter- forms of exercise, should be document-
treatment plan. personal relations; loss of interest; ed. Medical history should highlight risk
withdrawal; and difficulty with plan- factors that could contribute to demen-
ning.4 Although apathy, inertia, and tia. Vascular risk factors such as heart
poor planning may also occur in AD, disease, diabetes, hypertension, tran-
the manifestation of these distinctive sient ischemic attack, and stroke should
symptoms of social and personality be recorded in detail. Traumatic brain
changes in a patient with preserved injury, particularly with loss of con-
memory abilities points to bvFTD. sciousness, and coexisting neurologic
Symptoms such as depression, delu- problems such as seizures, Parkinson
sions, and hallucinations (particularly disease, multiple sclerosis, or other
visual) can provide clues to specific disorders that could affect cognition
types of dementia. In addition, these should be noted. Problems with vision
behavioral changes are often distressing and hearing can contribute, and a his-
to family members and make care more tory of major psychiatric disorders may
difficult. Although the treatment of be relevant.
behavioral problems can be challeng- Medications may also be relevant to
ing, it is important to inquire about and the assessment and management of de-
treat them whenever possible. mentia. Drugs with strong anticholiner-
Changes in sleep are important be- gic actions6 or sedating side effects can
havioral symptoms that also provide play a role in worsening cognitive
clues to specific types of dementia. For impairment, although it is unusual for
example, REM sleep behavior disorder them to be the sole cause. If cardio-
occurs in Parkinson disease and Lewy vascular risk factors are present, the
body dementia and can be assessed by adequacy of their medical treatment
asking whether patients appear to act should be assessed.
out their dreams during sleep.5 Insom- Hints of a family history of dementia
nia or sleep apnea may affect memory should be systematically reviewed. It is
consolidation and daytime cognitive often helpful to record a detailed pedi-
abilities. Excessive daytime sleepiness gree, particularly for patients with cog-
usually occurs in moderate to severe nitive or behavioral symptoms before
dementia, although it can be a prom- the age of 65. The family history should
inent and early feature of Lewy body inquire broadly about different symp-
dementia. toms or phenotypes among relatives;
for example, some inherited disorders
Points to Emphasize in the Rest may produce a picture of progressive
of the History dementia in one relative and ALS or a
Other components of the medical his- combination of cognitive and motor
tory color the background of evolving dysfunction in another.
cognitive problems. A patient’s hand-
edness and educational and work his- THE NEUROCOGNITIVE (OR
tory are relevant to the interpretation of MENTAL STATE) EXAMINATION
cognitive testing and may influence the The neurocognitive examination is of
health literacy of the patient and family. prime importance in the diagnosis of

KEY POINT
dementia. During a clinical office visit, sessment Resources, Inc, which holds a h The goals of cognitive
cognitive testing needs to strike a bal- publishing copyright to the MMSE. testing are to document
ance between comprehensiveness and There may also be problems in applying performance of memory
practicality. The goals are to document the MMSE to criteria for the diagnosis and other key cognitive
performance of memory and other key of AD or other forms of dementia. domains, to define
cognitive domains, to define areas of Although a cutoff score of 24 or below areas of strength and
strength and weakness that may support may support the diagnosis, it is difficult weakness that may
a diagnosis, and to help stage the se- to use the MMSE to formally document support a diagnosis, and
verity of dementia. There are two main impairment of memory and an addi- to help stage the
approaches: overall cognitive tests and tional area of cognition. Recall of three severity of dementia.
detailed batteries that cover specific words is an insensitive and inaccurate
cognitive domains. test of memory, although combining it
with orientation may improve the as-
Overall Cognitive Tests sessment. Moreover, language is super-
Overall cognitive tests provide a brief, ficially assessed, and visuospatial abilities
structured approach and are widely and executive function are minimally, if
used for screening in general neurolog- at all, assessed by the MMSE.
ic and medical practices.7 The Mini- Slightly longer overall tests such as
Mental State Examination (MMSE) is the Montreal Cognitive Assessment
one of the best known of these tests. It (MoCA) (www.mocatest.org)8 and the
probes memory (through the task of Saint Louis University Mental Status
learning and recalling three words), (SLUMS) examination9 offer greater
orientation (predominantly through a sensitivity than the MMSE, as well as
memory test), working memory the ability to sample cognitive domains
(through the task of serial 7 subtrac- more widely. The MoCA and SLUMS
tion or spelling world backward), lan- examination both take about 7 to 10
guage (through tasks of naming, minutes to administer and yield scores
repetition, reading, writing, and follow- that range from 0 to 30. The MoCA is
ing a three-step command), and visuo- available in three alternative versions in
spatial abilities (through the task of English, and translations of the original
copying interlocking pentagons). Ad- version are available in many languages.
vantages of the MMSE are its ease of Diagnostic cutoffs for AD and for mild
use, familiarity to physicians and fami- cognitive impairment have been sug-
lies of patients with AD, and moderate gested based on several studies. The
sensitivity for the diagnosis of demen- MoCA screens attention and compo-
tia. It is also helpful in staging and nents of executive function and probes
tracking progression over time. How- language and memory in more detail
ever, there are many problems with than the MMSE. However, one needs
the MMSE, including insensitivity for to be cautious about using a cutoff
mild dementia, test-retest variability of score as a diagnostic test. The five-item
a patient’s scores, and a lack of readily word list on the MoCA is a more
available translations and alternative difficult learning and recall task than
versions (some patients rehearse the the three-word test on the MMSE. The
date and words typically used to test MoCA uses only two encoding trials
recall in the MMSE while en route to (compared to formal psychometric
the clinic). In addition, the MMSE is not word list tasks, which typically use four
available for use free of charge; a fee of to five trials of longer word lists), and
$1.20 for each administration is sup- some subjects with no dementia may
posed to be paid to Psychology As- show a falsely positive apparent memory

deficit if they do not attend adequately to confirm impairment in suspected

to the learning trials. Repetition of domains. If uncertainty remains, formal
complex sentences on the MoCA can neuropsychological testing will provide
be nonspecifically affected by problems a clearer picture of cognitive strengths
such as decreased hearing. The MoCA and weaknesses.
adjusts for people with fewer than 12
years of formal education by rec- Evaluating Cognitive Domains
ommending adding one point to the Some dementia specialists with appro-
total score, but cutoffs and test perfor- priate expertise may perform and bill
mance among less well-educated infor detailed cognitive evaluations. Al-
dividuals have not been widely studied. though many formal psychometric tests
A test like the MoCA can form the with norms for age and education are
foundation of a detailed cognitive eval- available,10 it is often beyond the re-
uation in clinic (Case 6-1). Besides sources or time availability of a general
considering the total score for the neurologist to perform such testing.
MoCA, the domains that are affected Computerized batteries have been
should be examined. Additional cogni- used in research settings, but few
tive testing may be carried out to help have been validated in clinical practice.
Case 6-1
A 77-year-old retired college professor was brought to the clinic by his
wife. He denied any problems, although she stated that he sometimes
asked questions repeatedly, forgot details of conversation, had trouble
remembering computer passwords, and struggled to recall details or the
plots of novels. He could write emails and letters, drive, and manage a
credit card without difficulty. His wife thought that he sometimes forgot
to take his medications. His problems had been present for about
12 months. Medical history was notable for hypertension and increased
cholesterol; family history was negative for cognitive or neurologic
problems. Medications included antihypertensives, a statin, and aspirin. He
sometimes slept poorly, and his general health was notable for slowing
of gait. He showed less interest in attending social functions but did not
have symptoms of depression. A primary care physician noted that he
scored 29/30 on the Mini-Mental State Examination.
On mental state examination, he scored 26/30 on the Montreal
Cognitive Assessment, losing three points for recall and one for executive
function. Results of the remainder of the neurologic examination and of
laboratory blood tests were normal. Brain MRI showed cortical atrophy
consistent with age and a few hyperintensities in the periventricular white
matter. Neuropsychological testing revealed impairment of learning and
memory on both a list-learning test and a task of copying and recalling a
complex figure. He had impairment on category fluency, the Trail-Making
Test Part B, and the Stroop Color-Word Association Test. The diagnosis
of Alzheimer disease was made and discussed in detail with the patient
and his family at a follow-up visit.
Comment. This case illustrates the importance of detailed history taking
from a knowledgeable informant, the exclusion of other contributory factors
in the evaluation, the insensitivity of screening cognitive tests in patients
with high levels of education, and the value of neuropsychological testing.

KEY POINT
Suggestions for testing a variety of narratives are read to the patient, who h The term ‘‘memory
cognitive domains in a clinical setting is asked to repeat as many details as impairment’’ is often
are outlined below. An important con- possible and then to recall as much of used loosely in relation
sideration in interpreting tests is that the story as possible after a delay. The to Alzheimer disease.
relatively few of them probe a single logical memory test (part of the The major feature of
cognitive domain exclusively. For ex- Wechsler Adult Intelligence Scale) in- memory impairment in
ample, drawing a clock and setting the volves recall of two stories, each of Alzheimer disease is
time depends on judgment and plan- which consists of 25 embedded factoids. episodic memory, which
ning (executive function) as well as Nonverbal memory and learning can be depends on the
visuospatial abilities. Patients with im- tested through copying a complex draw- structural integrity of
the hippocampus and
pairment in a key domain such as ing (eg, the Rey-Osterreith figure) and
allows us to encode and
language may show impairment across drawing it after a delay. Without re-
remember where or
tests with verbal instructions and re- course to the time or structured testing when something
sponses, and patients with markedly environment needed for these proce- happened.
impaired attention may show difficulty dures, testing memory and learning can
with learning and memory due to be difficult for a clinician. Some sugges-
failure to encode material. tions for additional office-based tests of
The term ‘‘memory impairment’’ is memory include having the patient learn
often used loosely in relation to AD. and recall a five-item name and address,
The major feature of memory impair- asking the patient to describe what she
ment in AD is episodic memory, which or he ate for each meal the day before,
depends on the structural integrity of and asking about an outing or event the
the hippocampus and allows us to patient attended in the past month or
encode and remember where or when two, if there is an informant who can
something happened. Semantic mem- verify the details. Asking the patient to
ory (the knowledge of what objects, describe details of major recent news
words, or ideas are) may be impaired events can also be informative, provided
later in the course of AD and is a de- that they have heard about these events
fining feature of a form of progressive (eg, through reading a newspaper or
aphasia called semantic dementia. Pro- watching TV); recent bad-weather
cedural memory (the memory of skilled events, earthquakes, accidents, sports
or sequential motor tasks) is preserved events, or news involving celebrities or
in AD. Among the most widely used politicians are examples.
tests of memory is list-learning, in which Attention includes the important ca-
10 to 16 words are read to the patient, pacity of working memory: the ability to
who is asked to repeat as many as he or maintain a short piece of information,
she can remember. A series of trials is such as a telephone number, in memory
given and an index of immediate recall storage for a short interval. It is impor-
or learning across these trials is calcu- tant to test in its own right, early in a
lated. After a typically 15-minute or cognitive examination, because inability
longer delay filled with distractor tests, to attend can markedly affect other
the patient is asked to recall as many of cognitive domains. Digit span is a typical
the words as possible. Impaired recall, approach. Most people can remember at
in particular rapid forgetting (defined as least six digits forward and four back-
recalling less than 50% of the words that ward (the MoCA is more lenient, using
were learned), is suggestive of a major four digits forward and three backward).
memory disorder such as AD. Another Language testing begins by listening
psychometric approach to memory to the patient’s spontaneous output.
testing is story recall, in which brief Naming objects or their parts, including

KEY POINT
h Focal findings consistent some lower-frequency words, can be a fields, examining eye movements, as-
with stroke, or a gait good screen for anomia, a common sessing praxis, or looking for signs of
disorder not explained finding in many types of aphasia. Asking motor neuron disease when evaluating
by other factors, may the patient to repeat or read consonant a patient who does not have a typical
support a cerebrovascular sounds (eg, P-T-K) and single words of AD presentation.
contribution to dementia. increasing length can screen for dysar- In a patient with AD, normal neuro-
thria. Fluency tests, such as naming as logic examination results are expected.
many words as possible in 1 minute During the neurologic examination of
belonging to a specific category or with an elderly patient, the examiner will
a specific first letter, probe language as often identify findings associated with
well as executive function. Assessment normal aging, such as decreased large-
procedures and criteria for diagnosing fiber sensation in the toes, decreased or
subtypes of primary progressive aphasia absent ankle reflexes, a mildly stooped
were recently proposed.11 posture, and marked difficulty with
There are many aspects of executive tandem gait. Frontal release signs or
function, and testing for it often places primitive reflexes (such as the glabellar
demands on other cognitive abilities as tap, snout, suck, palmar-mental reflex,
well. Clock drawing, for example, de- and grasp reflex) are of dubious diag-
pends on judgment, planning, and nostic value because they occur in many
visuospatial abilities. Explaining similar- normal elderly people as well as in
ities between word pairs is a better test patients with AD or frontotemporal
of reasoning than explaining proverbs, dementia. Procedures to elicit them
because the meanings of proverbs are (eg, the number of glabellar taps that
typically learned at school rather than continue to produce a blink beyond
solved on the spot. Attention tasks such what is thought of as normal) are not
as reciting the months backward (or, agreed upon, and many specialists in
more difficult, letters of the alphabet neurodegenerative or cognitive disor-
backward) also depend on executive ders do not assign any special signifi-
function. Calculation tasks, such as se- cance to these signs.
rial 7 subtraction or making change, The neurologic examination is some-
depend on attention, right parietal times revealing. Focal findings consis-
abilities, and frontal lobe function. tent with stroke, or a gait disorder
As visuospatial tests, clock drawing not explained by other factors, may
and copying complex intersecting fig- support a cerebrovascular contribution
ures can extend a screening examina- to dementia. The gait in vascular de-
tion. If the examiner suspects posterior mentia due to multiple lacunes is often
cortical atrophy, then asking the patient described as marche à petits pas, re-
to describe a visually rich and complex ferring to a slow gait with short steps
drawing or photograph can help to and an upright posture. Normal pres-
screen for simultagnosia. sure hydrocephalus classically results in
a magnetic gait, in which the patient’s
THE REMAINDER OF THE feet appear stuck to the ground; how-
NEUROLOGIC EXAMINATION ever, nonspecific gait slowing with poor
Beyond mental status testing, the re- balance may be a more common pic-
mainder of the neurologic examination ture. Signs of parkinsonism may point
can yield important clues about etiol- to Lewy body dementia. These can be
ogy, particularly for less common disor- subtle; a common pattern is slowing of
ders. The clinician should be prepared movement, slightly increased tone, par-
to apply extra diligence in testing visual kinsonian gait and postural instability

(demonstrated on a backward pull), Progressive supranuclear palsy may
and the absence of rest tremor. Par- have several clinical variants.13 It is
kinsonian findings are less specific easiest to diagnose when the charac-
in patients with moderate to severe teristic eye-movement abnormalities
dementia. appear, including slow saccades and
In posterior cortical atrophy, ele- impaired vertical then horizontal gaze,
ments of Balint syndrome may be which are correctable with the doll’s
present, namely difficulty perceiving head maneuver. In some patients,
the entire visual field, fixating the eyes, these findings may appear late. Other
and moving a hand to a precise location features are dysarthria, increased tone
or specific object by using vision.12 (especially axial rigidity), and slowing
These features can be identified by of gait with retropulsion. Corticobasal
careful testing of visual fields, having syndrome may be difficult to diag-
the patient reach into space to a de- nose, especially early in the course.14
fined location and move his or her The typical motor features such as
eyes to selected areas of gaze. Asking akinesia, rigidity, dystonia, focal myoc-
the patient to describe a photograph lonus, ideomotor apraxia, and alien-
or painting of a complex scene and limb phenomenon, affecting one limb
looking for elements of Gerstmann or one side of the body predominant-
syndrome or apraxia can help with ly, are not always present. Presenta-
the clinical characterization (Case 6-2). tions with dysarthria, aphasia (usually
Case 6-2
A 61-year-old journalist had difficulty typing on a keyboard and trouble
reading for 18 months. He had a car accident 6 months ago in which he
had difficulty judging how close a traffic barrier was when he changed
lanes. He saw an ophthalmologist and received new glasses, but problems
persisted. He reduced his workload and stopped driving on freeways
because of his symptoms. There were no visual hallucinations. He had no
significant medical history.
On the Montreal Cognitive Assessment he lost two points for recall, one
for copying a cube, and one for poor layout of numbers on a clock, with a
final score of 26/30. Visual fields were grossly intact. He had difficulty
describing details of a painting, with some slowing and a need to direct
his gaze carefully. When reading, he sometimes omitted words at the
ends of lines. The remainder of his neurologic examination was otherwise
unremarkable. Neuropsychological testing revealed impairment on
visuospatial tasks, borderline performance on recall of a word list, and
slowing on the Trail-Making Test Part B.
A brain MRI showed slight atrophy of the left parieto-occipital area.
CSF biomarkers showed a decreased level of amyloid-"42, increased total
tau, and borderline phosphorylated tau. An amyloid imaging positron
emission tomography (PET) scan was positive, with widespread binding of
tracer throughout the brain. A diagnosis of posterior cortical atrophy
due to Alzheimer disease was made; the patient was started on a
cholinesterase inhibitor and reported mild improvement of reading ability.
Comment. This patient has typical symptoms and findings of posterior
cortical atrophy. Biomarkers enable the underlying diagnosis of Alzheimer
disease to be made with greater confidence.

KEY POINT
h In cases in which a nonfluent), or executive dysfunction plasma reagin, HIV testing, or workup
decision about dementia may make the specific diagnosis diffi- for unusual CNS inflammatory disorders
could substantially alter cult. Underlying pathology is variable, are not part of a standard evaluation but
the patient’s life (eg, a with corticobasal degeneration and should be used when clinical suspicion
patient who is still AD the most common. arises. Lumbar puncture is not recom-
working) or in which Suspicion for prion disorders should mended as a routine test but may be
there are legal questions arise when patients have subacute or helpful to rule out meningitis or enceph-
(eg, competency to rapidly progressing dementia.15 Confu- alitis, confirm suggested neurosyphilis,
manage assets), detailed sion or a deliriumlike picture may dom- or measure CSF pressure in suspected
neuropsychological inate, or focal cognitive deficits may be normal-pressure hydrocephalus. An EEG
evaluation can strengthen
present. Myoclonus, while often pres- does not have a place in the routine
the clinical diagnosis and
ent, tends to occur later in the course. evaluation of dementia.
provide sensitive indices of
the degree of
Other presentations include ataxia and A structural brain imaging studyV
impairment. extrapyramidal signs. either MRI or head CTVis rec-
ommended in the AAN guidelines for
NEUROPSYCHOLOGICAL TESTING AD. MRI has higher resolution and is
Although not mandatory to diagnose strongly preferred. In addition to atro-
dementia, neuropsychological testing phy, stroke (including lacunes), and
is valuable in a number of situations. white matter changes, MRI can also
When dealing with an unusual presen- detect microhemorrhages, which may
tation of dementia, a comprehensive indicate amyloid angiopathy, and prob-
neuropsychological evaluation can de- lems such as subdural hematoma. The
fine areas of impairment and preserved ability to obtain volumetric readout on
abilities. In cases in which a decision MRI is not widely available.
about dementia could substantially alter It is extremely helpful to review neu-
the patient’s life (eg, a patient who is roimaging tests and not merely to read
still working) or in which there are legal a report. Findings such as hippocampal
questions (eg, competency to manage atrophy, focal atrophy affecting the
assets), detailed neuropsychological cortex, and an appreciation of the ext-
evaluation can strengthen the clinical ent and location of subcortical white
diagnosis and provide sensitive indices matter changes are three areas where
of the degree of impairment relative to careful examination of the images can
normal performance. For details of clarify the diagnosis.
neuropsychological testing and inter-
pretation in dementia, see reference 10 The Workup for Rapidly
in the list below. Progressive Dementia
Brain imaging and CSF evaluation should
LABORATORY WORKUP be obtained in patients with rapidly
AND IMAGING progressive dementia. MRI may show
The American Academy of Neurology evidence of unusual problems such as
(AAN) guidelines for laboratory eval- encephalitis, vasculitis, carcinomatous
uation in suspected AD recommend meningitis, primary or metastatic brain
routinely measuring B12 and thyroid- cancer, or other brain mass lesions.
stimulating hormone levels.16 Other Diffusion-weighted MRI is the most
tests that provide information about sensitive way to detect findings consis-
factors that contribute to or worsen tent with prion disease.17 Findings such
cognitive function include complete as a cortical ribbon appearance or al-
blood count (anemia) and creatinine tered appearance of basal ganglia struc-
(renal failure). Tests such as rapid tures should be carefully examined.

The CSF biomarkers of tau, P-tau, and readout or a definite positive or nega-
14-3-3 protein are often increased in tive interpretation regarding suspected
prion disorders, but they have sub- AD. Insurance coverage for biomarker
stantially lower sensitivity than abnor- tests is under negotiation. One of the
malities on diffusion-weighted MRI. few currently approved procedures,
Autoantibodies against a variety of namely fluorodeoxyglucose PET brain
brain proteins have been reported in scan to distinguish between AD and
patients with rapidly progressive or frontotemporal dementia, may need to
unusual dementia syndromes. These be reappraised once amyloid PET im-
were reviewed comprehensively in aging, which may address this question
2010;16:31Y56. with greater accuracy,18 is available.
As mentioned above, a brain imaging
BIOMARKERS test, typically MRI, is recommended as
Biomarkers for AD are beginning to part of the dementia workup to rule out
transition from research to practice, a structural (surgical) cause of dementia
and the evidence for their use is cov- and estimate the extent of vascular
ered by Drs Sperling and Johnson changes. Volumetric measurements of
( , this issue). New re- the whole brain, hippocampus, and
search criteria for AD proposed by the ventricles can help support the diagno-
National Institute on Aging and sis of AD. At present these are available
Alzheimer’s Association workgroup1 primarily through research, although
and similar efforts by an international computerized (automated) volumetric
working group have divided biomarkers programs have been developed. Care-
into categories according to the type of ful examination of a brain MRI can
brain processes they measure. For reveal whether there is focal atrophy
example, MRI volumetric analysis or affecting brain areas implicated in spe-
fluorodeoxyglucose positron emission cific diagnoses.
tomography (PET) scans can measure
regional atrophy or hypometabolism, REFERENCES
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et al. The diagnosis of dementia due to
generative changes in AD. Finding an Alzheimer’s Disease: recommendations from
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proteins provides an index of neuro- Association workgroups on diagnostic
guidelines for Alzheimer’s disease.
degeneration. Amyloid imaging using Alzheimers Dement 2011;7(3):263Y269.
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2. Galvin JE, Roe CM, Xiong C, Morris JC.
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Drug Administration approved the li- interview in dementia. Neurology 2006;
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yloid deposition in the brain. Functional impairment in elderly patients
with mild cognitive impairment and mild
Guidelines for the clinical use of Alzheimer disease. Arch Gen Psychiatry
biomarkers in the diagnosis of dementia 2011;68(6):617Y626.
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search criteria proposed for AD1 pro- Sensitivity of revised diagnostic criteria for
vide some suggestions and caveats. In the behavioural variant of frontotemporal
dementia. Brain 2011;134(pt 9):2456Y2477.
particular, efforts to standardize bio-
5. Ferman TJ, Boeve BF, Smith GE, et al.
marker measurement and interpreta-
Inclusion of RBD improves the diagnostic
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do not always provide a quantitative Neurology 2011;77(9):875Y882.

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13. Schofield EC, Hodges JR, Macdonald V, et al.
7. Appels BA, Scherder E. The diagnostic Cortical atrophy differentiates Richardson’s
accuracy of dementia-screening instruments syndrome from the parkinsonian form of
with an administration time of 10 to 45 progressive supranuclear palsy. Mov Disord
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Clinicopathological correlations in
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Profiles of cognitive subtest impairment on 2011;70(2):327Y340.
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16. Knopman DS, DeKosky ST, Cummings JL,
9. Tariq SH, Tumosa N, Chibnall JT, et al.
et al. Practice parameter: diagnosis of
Comparison of the Saint Louis University
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mini-mental state examination for detecting
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Review Article
Mild Cognitive
Dr Oscar L. Lopez, 3501
Forbes Ave, Suite 830, Oxford
Building, Pittsburgh, PA
Impairment 15213, lopezol@upmc.edu.

Dr Lopez serves as a
Oscar L. Lopez, MD consultant for Lundbeck,
Mertz, Lilly, and Baxter.
Unlabeled Use of
ABSTRACT Use Disclosure:
Dr Lopez reports no
Purpose of Review: The term mild cognitive impairment (MCI) is used to describe disclosure.
older subjects with demonstrable cognitive impairment who have not crossed the * 2013, American Academy
threshold for dementia. Because patients with MCI have an increased risk of of Neurology.
developing dementia, especially Alzheimer disease (AD), there is significant interest
in the clinical characterization of these subjects and in understanding the
pathophysiology of the transition from MCI to AD.
Recent Findings: The MCI syndrome, as an expression of an incipient disorder that
may lead to dementia, is extremely heterogeneous and may coexist with systemic,
neurologic, or psychiatric disorders that can cause cognitive deficits. Recent clinical
criteria were designed to take into account the different forms of clinical presentation
of the syndrome, and introduced the possible contribution of biomarkers to the clinical
diagnosis. Bedside diagnosis of MCI can be difficult, since patients who report having
cognitive problems may have normal scores in global cognitive scales or in brief neu-
ropsychological instruments.
Summary: This article presents the evolution of the clinical concept of MCI, the
operationalization of its current definitions, the development of biomarkers that can
help to identify an underlying neurodegenerative process as the etiology of the
syndrome, and its proposed treatments.
INTRODUCTION heterogeneous and may coexist with

Aging is associated with cognitive de- systemic, neurologic, or psychiatric dis-
cline,1,2 and older subjects can have orders that can cause cognitive deficits.
demonstrable cognitive impairment In addition, data from community-based
without crossing the threshold for de- studies have shown a greater variability
mentia. This condition has been termed in the clinical course of the syndromes
‘‘mild cognitive impairment’’ (MCI), and than that observed in referral clinics:
these patients have an increased risk of some patients with MCI progress to
developing dementia, especially Alzhei- dementia, some remain stable, some
mer disease (AD).3Y6 Studies conducted improve over time,8,9 and some who
in referral clinics have shown that pa- return to normal can go back to MCI
tients with MCI progress to AD at a rate and eventually develop dementia.10
of 10% to 15% per year,5,7 and 80% of This article discusses the evolution of
these patients have converted to AD af- the clinical concept of MCI, the
ter approximately 6 years of follow-up.5 operationalization of the current defini-
The identification and classification tion of MCI, the development of bio-
of MCI can be a major challenge. The markers that can help to identify an
MCI syndrome, as an expression of an underlying neurodegenerative process
incipient neurodegenerative disorder as the etiology of the syndrome, and its
that may lead to dementia, is extremely treatment.

Mild Cognitive Impairment
KEY POINTS
h Patients with mild MILD COGNITIVE IMPAIRMENT deficits.16 In addition, longitudinal stud-
cognitive impairment CRITERIA ies showed that patients with MCI with
are at risk of developing Initially, the criteria for MCI followed two or without memory deficits can prog-
dementia, especially conceptual models: one associated only ress to AD,18 and epidemiologic studies
Alzheimer disease. with memory deficits, and the other with showed that the prevalence of the MCI
h The mild cognitive a broader range of deficits (memory and syndrome with isolated memory deficits
impairment syndrome is other areas of cognition). Because mem- was lower than that observed in subjects
not restricted to memory ory deficits are the clinical hallmark of who presented with a wider range of
deficits, and these AD, most of the criteria developed to cognitive problems.10 Table 7-111Y17,19Y22
patients can present characterize MCI required the presence shows the different diagnostic criteria
with a much broader of memory deficits in isolation.11Y15 used to identify subjects with MCI.
cognitive syndrome, However, other clinicians felt that the The most recent criteria for MCI en-
which may not include memory-centered definition of MCI was compassed all possible cognitive mani-
memory impairments. too restrictive because it did not cap- festations of the syndrome and four
ture other cognitive problems that often subgroups have been proposed: deficits
occur in the elderly.16,17 For example, only in memory functions; memory
the International Psychogeriatric Associ- deficits plus deficits in another cognitive
ation and the World Health Organiza- domain; deficits in a single nonmemory
tion proposed the term ‘‘age-associated domain; and deficits in more than one
cognitive decline’’ (AACD) to describe nonmemory domain.21,22 This has ex-
subjects with a wider range of cognitive panded the knowledge of the MCI
TABLE 7-1 Criteria Developed to Characterize Cognitive

Impairments in Nondemented Elderly Subjects
Criteria Year
Benign senescent forgetfulness14 1962
12
Age-associated memory impairment 1986
11
Late-life forgetfulness 1989
19
Mild cognitive impairment 1991
Mild cognitive declinea20 1993
16
Age-associated cognitive decline 1994
17
Age-related cognitive decline 1994
a17
Mild neurocognitive decline 1994
Cognitive impairment no dementia13,26 1995
15
Mild cognitive impairment 1996
b 21
Modified mild cognitive impairment (four subtypes ) 2004
Modified mild cognitive impairment (three subtypesc)22 2004
Diagnostic guidelines for mild cognitive impairment due to Alzheimer 2011
disease from the National Institute on Aging and Alzheimer’s Associationd24
a
Criteria developed to identify mild cognitive deficits in subjects with neurologic or medical disorders.
b
(1) Deficits in memory functions, (2) deficits in memory functions plus another cognitive domain,
(3) deficits in a single nonmemory domain, and (4) deficits in more than one nonmemory domain.
c
(1) MCI amnestic, (2) MCI multiple domain, and (3) MCI single nonmemory domain.
d
Evidence of lower performance in one or more cognitive domains (ie, memory, executive
functions, language, visuospatial functions) for the patient’s age and education level.

syndrome and allowed examination of deficits (or awareness of cognitive prob-
the relationship between MCI syn- lems); (2) deficits in memory or other
dromes and other dementias that do cognitive domain function demonstra-
not have memory deficits. For example, ble by testing; and (3) intact activities of
the MCI with isolated executive deficits daily living (ADLs), although mild prob-
has been reported to be associated with lems in instrumental activities of daily
cerebrovascular disease and a predictor living (IADLs) could be present. The
of vascular dementia.23 majority of the published criteria ex-
The National Institute on Aging and clude cases with other medical condi-
Alzheimer’s Association (NIA-AA) tions that may cause cognitive deficits.26
criteria for MCI were created to charac- Complaints of memory deficits. A
terize a syndrome that is most likely certain level of concern about their
associated with AD pathology.24 The cognitive problems should be present
purpose of these criteria was to identify in these patients, which in turn moti-
subjects in the pre-AD state, and they vates the visit to a memory clinic.
require that patients with MCI must Indeed, all of the criteria for MCI require
have impairments in one or more cog- that the patient report having cognitive
nitive domains. Although the criteria problems, and studies conducted with
emphasized the presence of memory subjects who have no dementia have
deficits as the central characteristic of shown that complaints of cognitive
the syndrome that can progress to AD, problems were predictors of incident
they recognized that there are forms of dementia.7,27 However, there are stud-
AD (eg, visual or language variants) that ies that have not identified complaints
do not have memory deficits in their of cognitive problems as risk factors for
early stages. In addition, the syndrome dementia,28 and mood-related com-
should not be present in the context of plaints were found to be better pre-
vascular, traumatic, or other causes of dictors of cognitive decline.29 A study
mild CNS dysfunction. However, while conducted in a German population
these criteria maximized the likelihood found that subjects who reported
that subjects with MCI who participate memory problems and were worried
in prevention trials for AD or other about these problems had an increased
research studies will have an underlying risk of progressing to dementia com-
AD pathology, the use of the criteria in pared to those who did not report or
clinical practice is difficult. MCI subjects worry about memory problems.30
with multiple disease processes that can Examination of the types of subjects
affect cognition can progress to AD,18 enrolled in MCI studies is critical to
and not all AD patients have memory understand the validity of complaints of
loss at initial presentation;25 usually, mild memory problems as a predictor of
nonmemory function deficits are difficult dementia and as a component of the
to detect with brief cognitive evaluations syndrome. The fact that subjects request
(Case 7-1). evaluations through specialized clinics is
an indication that they or their families
Operationalization of Mild or physicians have noticed cognitive
Cognitive Impairment Criteria problems. By contrast, population-based
The MCI syndrome is centered on the studies identify a more heterogenous
presence of an abnormal neuropsy- group, including those whose symp-
chological performance associated with toms are minimal; those who think that
other signs and symptoms26 (Table 7-2), their cognitive problems are not rele-
specifically: (1) complaints of cognitive vant, in spite of the presence of a more

Case 7-1
A 65-year-old man with 16 years of education presented with a 2-year history
of progressive memory problems that affected his job performance. His
colleagues had not noticed these problems, nor had his wife reported him
having any cognitive problems at home. He had recently been diagnosed
with hypertension, but his vital signs were normal. He denied any symptoms
of major depression. The results of his neurologic examination were normal,
and his Mini-Mental State Examination (MMSE) score was 29/30 (he forgot
the floor on which the doctor’s office was located in the orientation subtest).
His clock-drawing test results were normal, and his verbal fluency for animals
was 11. Laboratory tests and brain MRI showed no abnormalities. Because
of the patient’s concerns about his progressive memory problems, he was
referred for a comprehensive neuropsychological assessment. The test
showed that his memory functions were 1.5 standard deviations (SD) below
the mean adjusted for people of his age and education level, and his
executive functions were between 1.0 and 1.5 SD below the mean. He had
normal language, visuospatial, and visuoconstructional functions.
Two years later, the patient retired from his job due to the worsening in
his cognition, and his wife noticed problems in his instrumental activities of
daily living (eg, the patient forgot to pay bills and got lost while driving).
His MMSE score dropped to 25/30, and his comprehensive cognitive
evaluation showed deficits in memory, language, and executive functions,
consistent with a dementia syndrome, most likely Alzheimer disease.
Comment. This is a highly educated man who noticed that his cognitive
functions were severe enough to interfere with his occupational affairs.
Initially, his wife and colleagues did not detect these problems, and the brief
neuropsychological evaluation conducted at the neurologist’s office was
within normal limits. However, detailed cognitive assessment by a
neuropsychologist revealed the presence of memory and executive function
deficits. This patient presented with the memory plus other cognitive domain
subtype of mild cognitive impairment (MCI), which later progressed to
dementia. This case illustrates two important aspects of the clinical diagnosis
of MCI: (1) it is difficult to detect the syndrome with bedside cognitive
instruments, especially in highly educated people; and (2) additional
cognitive evaluations are an important tool to detect not only impaired
cognitive domains during the MCI stage, but also during the early stages of
Alzheimer disease.
advanced syndrome; those with a more this issue and stated that the subjective
advanced syndrome who do report cognitive complaints or reports of cog-
cognitive problems (similar to those nitive change can come from the pa-
seen in referral clinics); and those with tient, an informant, or the physician
multiple comorbidities that explain observing the patient.
the presence of cognitive problems. Neuropsychological assessment.
Therefore, the subjects seen in referral Detailed cognitive assessments are the
clinics are likely to have a more ad- most important tool in the diagnosis of
vanced disease (possibly related to MCI and its subgroups, since these
neurodegeneration) than those identi- patients tend to perform normally in
fied in population-based studies. The global cognitive measures such as the
NIA-AA MCI guidelines have addressed Mini-Mental State Examination.31 The

TABLE 7-2 Components of the Mild Cognitive Impairment Syndrome
Associated With Alzheimer Disease Required by the
Majority of the Criteria
Signs and Symptoms Comments

Complaints of cognitive deficits Some patients with early mild cognitive
impairment do not report cognitive
deficits
Global measures of cognition could For example, the Mini-Mental State
be within normal limits Examination
Cognitive deficits identified by Deficits in memory and nonmemory tests
neuropsychological testing
Evidence of progression in cognitive
testing supports the diagnosis
Preservation of activities of daily Some instrumental activities of daily
living living could be impaired
Absence of neurologic, psychiatric, Patients with mild cognitive impairment
or systemic disorders that may cause with comorbid conditions (for example,
cognitive deficits metabolic disorders, depression) can also
progress to Alzheimer disease. Similarly,
Alzheimer disease pathology can coexist
with other neurologic disorders
(eg, Parkinson disease and strokes).
Dementia has been excluded For example, impairments in at least two
cognitive domains are severe enough to
interfere with the patient’s instrumental
activities of daily living or activities of
daily living. Clinical judgement is
recommended in borderline cases.
neuropsychological battery should patients should be referred for neuro-

cover a range of areas of cognition and psychological evaluation.
must be sensitive enough to detect MCI Memory loss predicts progression to
subgroups as well as the possible AD in the amnestic form of MCI.3,7,15,32,33
contributions of other disease pro- However, there have been studies dem-
cesses (eg, cerebrovascular disease) to onstrating that verbal fluency, atten-
the manifestation of the syndrome. tional, and executive function deficits
Although no consensus has been are also predictors of dementia,8,34 and
reached about the components of the others found the severity of deficits in
neuropsychological battery to identify memory and verbal fluency8 or executive
MCI, the battery should include tests function35 in MCI to be the best pre-
that can clearly identify performance in dictors of incident AD. In addition,
at least four cognitive domains: mem- patients with MCI who presented with
ory, language, attention/executive, and a demonstrable progression of their
visuoperceptual/visuoconstructional deficits were shown to be more likely
functions. This represents a limitation to develop dementia than those whose
to the bedside diagnosis of the syn- deficits remained stable.19 Indeed, the
drome, since extensive cognitive evalu- NIA-AA guidelines stated that support for
ations are difficult to perform in a busy the diagnosis of MCI could be provided
clinical practice. Consequently, these by evidence of a decline on serial testing.

KEY POINTS
h The prevalence of mild The overall prevalence of MCI in the Comorbid conditions. There are
cognitive impairment in general elderly population ranges from several neurologic, systemic, and psychi-
the general elderly 2% to 20%,6,9 and the neuropsycholog- atric syndromes that can cause cognitive
population ranges from ical definition of MCI has been instru- impairment (eg, depression, vascular
2% to more than 20%. mental in the determination of the disease).37,38 The distinction of MCI
h The mild cognitive prevalence of the syndrome in epide- groups based on the possible etiology
impairment syndrome miologic studies. The MCI memory-only of the cognitive deficits is essential to
with memory-only subtype has a lower prevalence (eg, 2% identify a syndrome that has increased
deficits is less prevalent to 4%)9 compared to the much broader likelihood of progression to AD. How-
than mild cognitive MCI definition that includes all subtypes ever, the reality is that patients with
impairment with a (eg, 18% to 21%).6 The prevalence of MCI with multiple comorbidities are
much broader cognitive the MCI syndrome is very dynamic, and the most common in clinical practice
syndrome in the it has been reported that up to 30% to and progress to AD at the same rate as
general population. 55% of the cases can return to normal those without comorbidities.18 Conse-
h The mild cognitive during follow-up,9 although 19% to 20% quently, even in the presence of a dis-
impairment syndrome, is a more conservative estimate.10 The ease process that could explain the MCI
as an expression of MCI memory-only subtype is more fre- syndrome, it could be an underlying
an incipient quent in specialized referral clinics and neurodegenerative process that will
neurodegenerative
consequently has been the most exten- eventually lead to the dementia symp-
disorder that may lead to
sively examined MCI syndrome in neu- toms. In this case, the biomarkers have a
dementia, is extremely
heterogeneous and may
roimaging and biomarker studies. critical role in identifying AD pathology
coexist with systemic, Activities of daily living. Patients in patients with MCI with comorbid
neurologic, or psychiatric with MCI should have normal ADLs (eg, conditions. Figure 7-1 shows that the
disorders that can cause getting dressed or controlling sphinc- majority of the MCI cases detected in
cognitive deficits. ters), although they can have mild def- the general population had medical
h Approximately 20% of icits in IADLs (eg, problems in job processes that can explain the presence
patients with diagnosis performance, forgetting to pay a bill). of cognitive deficits.6 In addition, other
of mild cognitive However, the determination of abnor- neurodegenerative disorders that cause
impairment return to mal IADLs can be difficult in an older dementia either in isolation or in com-
normal cognition on population. For example, subjects who bination with AD pathology can develop
follow-up examination. remain active in their careers (eg, physi- an MCI syndrome before progressing to
h Patients with mild cians) may report mild changes affecting dementia (eg, Parkinson disease).
cognitive impairment their professional activities. By contrast,
can present with mild subjects with sedentary lifestyles after BIOMARKERS
deficits in instrumental retirement (or with lower-skill jobs that The use of CSF and neuroimaging bio-
activities of daily living. they have practiced throughout their markers can improve the identification
h Increased CSF lives), who perform activities that do of AD pathology in patients with MCI
phosphorylated tau and not require significant intellectual chal- and predict the likelihood of progression
decreased A$-42 lenge, may not report IADL problems to dementia, especially within a relatively
protein levels increase (Case 7-2). These examples represent short period.39Y42 The altered pattern of
the short-term risk of the two extremes generally encountered CSF protein levels usually seen in pa-
conversion to Alzheimer in clinical practice: high-functioning patients with AD can also be seen in those
disease in mild cognitive
tients may be overly sensitive in reporting with MCI (especially in those who will
impairment patients.
IADL deficits, whereas less challenged convert to AD): high levels of tau or
subjects may be unaware of changes. Fi- phosphorylated tau (P-tau) with de-
nally, it has been shown that the neuro- creased amyloid-$42 (A$42) protein
psychological characteristics of the MCI levels.41 However, because there is a
syndrome can be present in subjects great variability in the tau and A$42
who do not report memory deficits.36 levels in patients with AD,43 negative

Case 7-2
A 78-year-old woman with 12 years of education presented for evaluation
with a 3-year history of cognitive decline associated with symptoms of
major depression. According to her family, she had depression associated
with cognitive problems, which had worsened over the past 6 months.
She had depressed mood, apathy, anxiety, crying spells, suicidal ideation,
insomnia, and lack of appetite; she had lost 15 pounds in 1 year. She also
had short-term memory problems and difficulty managing her finances
and using the pillbox for her daily medication. However, the effects of her
cognitive problems on her activities of daily living were difficult to
determine, since she did not do much at home because of her depressed
mood and lack of motivation. She had a history of breast cancer (treated
with mastectomy), coronary artery disease, glaucoma, and arthritis, but
no history of depression or other psychiatric illness. The patient was
medicated with sertraline 25 mg/d for her symptoms of depression 3
months ago. Her laboratory test results were normal and MRI of her brain
showed mild atrophy. No infarcts or white matter lesions were noted.
On examination, the patient looked tearful and had minimal
bradykinesia. Her Mini-Mental State Examination (MMSE) score was 24 (1/3
recall and 1/5 in attention subtests). Her clock-drawing test results were
normal, and verbal fluency for animals was 7. Her Hamilton Depression
Rating Scale score was 20; she met criteria for major depression.
Because of the severity of the patient’s depression, sertraline was
gradually increased to 150 mg/d. She was re-examined 6 months after
her initial examination, after she had remained stable on sertraline 150 mg/d
for a month. Her MMSE score was 30, her clock-drawing test results were
normal, and her verbal fluency for animals was 14. Her Hamilton Depression
Rating Scale score was 5; she met criteria for major depression in full
remission.
Comment. This patient developed late-life major depression that was
severe enough to affect her cognition and instrumental activities of daily
living. She initially presented with the memory plus other cognitive
domain subtype of mild cognitive impairment (MCI). After treatment with
antidepressant medication, her cognition and depression improved, and
she returned to normal. This case illustrates that late-life mood disorders
can cause an MCI syndrome, and with proper treatment these patients can
return to normal. However, close follow-up of the symptoms of depression
and its treatment is recommended, since they may return; repeat cognitive
evaluations on an annual basis are also recommended, since depressed
mood has been identified as a risk factor for incident Alzheimer disease.
CSF studies may not completely ex- to AD. However, the authors cautioned
clude the presence of AD pathology in against the use of biomarkers as pre-
patients with MCI. In addition, CSF dictors of incident dementia until more
studies are an important tool to exclude experience is gained, and recommended
other disease processes that can cause their use only for research purposes or in
cognitive problems (eg, infections). special clinical cases. A recent report
Table 7-3 shows the proposed found that single-marker models were
NIA-AA biomarker criteria to grade the as effective as multiple-marker models,
certainty that the MCI syndrome is due and their accuracy was only 64%.44 It is

difficult because brain structure can

vary greatly in elderly subjects. 45
Quantitative analyses have shown that
hippocampal and other brain regions
are different in patients with MCI than
in people who are cognitively normal.46
Patients with AD can be differentiated
from normal subjects based on the
volume of medial temporal lobe struc-
tures,47,48 although it is more difficult
to differentiate MCI from normal aging.
A study of hippocampal volumes con-
FIGURE 7-1 Prevalence of mild cognitive impairment ducted in 166 subjects (55 with AD, 43
(MCI) in the Pittsburgh Cardiovascular Health with MCI, and 62 controls) found that
Study according to the presence of comorbid
conditions. Probable MCI is indicated when the etiology of hippocampal volumes could differenti-
the MCI syndrome was most likely associated with a ate AD from controls in 92% of the
neurodegenerative process. Possible MCI is indicated when
the etiology of the MCI syndrome could be secondary to cases, but there were no differences
medical (eg, cancer), psychiatric (eg, depression), or neurologic between controls and MCI.47 By con-
(eg, stroke) processes.
trast, other studies have shown that
Reprinted with permission from Lopez OL, et al, Arch Neurol.6 B 2003, patients with MCI can have smaller
American Medical Association. All rights reserved. archneur.jamanetwork.
com/article.aspx?articleid=784823. hippocampal volumes compared to
controls.49 While the amnestic type
also critical to understand that the had a greater volume loss in the
presence of the APOE*E4 allele is not hippocampus and amygdala compared
diagnostic but should be considered a to normal subjects, the MCI type
risk factor for AD. with impairments in multiple cognitive
domains had a greater volume loss in
Structural MRI the parietal, superior temporal, and
The visual determination of regional frontal regions, with less involvement
or global atrophy in MCI cases is of the hippocampus.50
TABLE 7-3 The National Institute on Aging and Alzheimer’s

Association Criteria for Biomarker Certainty That the
Mild Cognitive Impairment Syndrome is Caused by
Alzheimer Disease
b High Likelihood
The core clinical symptoms and both amyloid-$a and neuronal damageb
biomarkers are present
b Intermediate Likelihood
The core clinical symptoms and a single positive biomarker (either amyloida
deposition or neuronal damageb) are present
b Unlikely to Be Due to Alzheimer Disease
The core clinical symptoms are present and neither types of biomarkers are positive
a
Amyloid markers identified by CSF or amyloid ligand scans.
b
Neuronal damage identified by CSF, MRI, or fluorodeoxyglucose positron emission tomography
(PET) scans.
Data from Alberts MS, et al, Alzheimers Dement.24 www.alzheimersanddementia.com/article/
S1552-5260(11)00104-X/fulltext.

KEY POINTS
Hippocampal51,52 and other cere- Amyloid Ligands
h Decreased metabolism
bral structure53Y57 volumes can predict The approval by the US Food and Drug in temporal-parietal
the development of AD in subjects Administration (FDA) of florbetapir in regions, including the
with MCI, and those who progressed 2012 has brought to the market an precuneus (detected with
to AD had smaller entorhinal, superior important tool for the diagnosis of AD, fluorodeoxyglucose-PET),
temporal, and occipitotemporal corti- although it was recommended only for and increased amyloid
ces and anterior cingulate gyrus vol- the differential diagnosis of AD.68 The deposition (detected with
umes compared to those who did not use of clinical amyloid ligands in normal amyloid ligands) increase
progress.53,54 Changes over time in subjects or those with MCI should be the risk of conversion to
hippocampal and entorhinal cortex Alzheimer disease.
avoided, since there is a dearth of
volumes have been reported in sub- longitudinal information that would h Biomarker studies
jects with MCI who progressed to allow prediction of incident dementia should be interpreted
dementia compared to those who in amyloid-positive subjects or of with caution. Although
did not,58Y60 as well as an accelerated they indicate that
whether amyloid-negative subjects can
Alzheimer disease
expansion of the lateral ventricles.61 progress to AD syndromes.
pathology is present,
The combination of multiple neu- they do not provide
Functional Imaging roimaging techniques has permitted information about when
Clinical fluorodeoxyglucose positron improved examination of the patho- the patient will progress
emission tomography (FDG-PET) and physiology of the transition from MCI to an Alzheimer disease
single-photon emission computed to- to dementia. The finding that amyloid clinical dementia.
mography (SPECT) studies show the deposition detected with carbon-11
‘‘classic’’ AD pattern in subjects with Pittsburgh Compound B (PiB) precedes
MCI whose cognitive symptoms are structural changes in subjects with MCI
thought to be related to an incipient suggests that the amyloid deposition
AD-related dementia.39 The FDG-PET occurs first, which is followed by neuro-
scan has shown a good correlation with nal loss.69 In addition, there is a positive
cognitive measures in patients with correlation between PiB deposition and
MCI,62 with a sensitivity of 92% and a brain metabolism, as measured with
specificity of 89% to predict conversion FDG-PET, suggesting the presence of
to AD.63 Although the SPECT scan can a compensatory process in the MCI
be a useful tool to identify regions of state.70 A recent study in cognitively
hypoperfusion in MCI cases, it has normal subjects showed that PiB depo-
shown little predictive value.64 Func- sition was associated with increased
tional MRI studies are usually conducted PET metabolism, gray matter volume
in research settings and have found that loss, and visual memory measures.71
subjects with MCI have a greater activa- These studies indicated the presence
tion of the hippocampus compared to of concomitant pathologic and (com-
normal controls and subjects with AD in pensatory) physiologic mechanisms in
memory tasks.65 Studies that used exec- subjects destined to develop AD, and
utive tasks found increased activation in that amyloid deposition has already
the parietal lobes, with decreased acti- started to exert its effect on brain
vation in the prefrontal cortex and function before subjects reach the MCI
anterior cingulate gyrus.66 Perfusion state (Case 7-3).
MRI studies have shown that subjects
with MCI have increased cerebral blood TREATMENT
flow in anterior cingulate, basal ganglia, There is no consensus about the
and hippocampal regions and decreased pharmacologic and nonpharmacologic
cerebral blood flow in the precuneus treatment of MCI. Because the MCI
and temporal-parietal regions.67 syndrome is considered the earliest

Case 7-3
An 80-year-old man with 12 years of education presented with a 3-year
history of progressive memory problems, which started approximately 1 year
after he had a stroke. His wife had also noticed mild problems with his
instrumental activities of daily living (eg, the patient forgot to pay bills and
had difficulty with hobbies). He had a history of hypertension and coronary
artery disease, but his vital signs were normal. He denied any symptom of
major depression. The neurologic examination showed mild weakness in his
left arm, sequelae of the stroke. His Mini-Mental State Examination (MMSE)
score was 27/30 (2/5 in attention subtests). The results of his clock-drawing
test were borderline, and his verbal fluency for animals was 12. Laboratory
test results were normal. MRI of his brain showed mild atrophy and a 3- to
4-mm infarct in the right caudate nucleus. A comprehensive neuropsychological
assessment showed that his executive functions were 1.5 standard deviations
(SD) below the mean adjusted for people of his age and education level,
and his memory function was between 1.0 and 1.5 SD below the mean. The
patient had read about the use of biomarkers in the clinical diagnosis of
dementia and expressed concerns about the possible neurodegenerative
etiology of his problems. Therefore, his neurologist requested a
fluorodeoxyglucose positron emission tomography (FDG-PET) scan, which
showed decreased metabolism in the right basal ganglia and in the
temporoparietal cortex, including the posterior cingulate gyrus, bilaterally.
One year later, the patient’s wife noted progression of his difficulties in
instrumental activities of daily living (eg, getting lost while driving).
However, the results of his MMSE and other tests performed at the office
remained unchanged. The neuropsychological examination showed that
his executive function deficits remained stable, but there was progression
in his memory deficits, although they remained 1.0 and 1.5 SD below the
mean. The neurologist prescribed a cholinesterase inhibitor.
Comment. This is a patient with a history of cerebrovascular disease who
presented with a memory plus other domain subtype of mild cognitive
impairment (MCI). Because of the presence of an abnormal FDG-PET that
showed an Alzheimer disease pattern, and the reported worsening of his
instrumental activities of daily living, he was initiated on dementia
medication. This case illustrates the complexity of the clinical aspects of the
MCI diagnosis and management: (1) the bedside examination showed that
this patient had the nonmemory single-domain MCI subtype, while the
more extensive cognitive assessment showed a memory plus other domain
subtype, which suggests that the sensitivity of the cognitive battery defined
the MCI type; (2) although the patient’s family perceived a worsening of his
performance on instrumental activities of daily living, the cognitive testing
was not indicative of dementia, but it led the treating neurologist to initiate
dementia treatment; (3) the presence of an abnormal biomarker (FDG-PET)
was not associated with imminent conversion to dementia, although it
supported the decision to initiate treatment.
manifestation of AD (in those patients ined whether ChEIs can improve cogni-
with underlying AD pathology as the tion in patients with MCI and prevent
cause of their MCI), and cholinesterase the conversion from MCI to AD. The
inhibitors (ChEIs) are used to treat use of donepezil in subjects with MCI
patients with AD, several studies exam- during a 48-week period showed modest

KEY POINT
improvements,72,73 and three large- modest symptomatic response. It is im- h There are no therapies
scale studies showed that ChEIs failed portant to point out that all of the that can prevent the
to prevent conversion from MCI to prevention trials using ChEIs were con- conversion from mild
AD.74Y76 A 3-year double-blind study ducted in subjects with amnestic MCI, cognitive impairment to
that examined the effects of 2000 IU of and there are no studies on the other Alzheimer disease.
vitamin E daily or 10 mg of donepezil clinical forms of MCI. However, studies
daily on conversion from MCI to AD conducted with
found that vitamin E had no benefit in ACKNOWLEDGMENTS cholinesterase inhibitors
patients with MCI. Although donepezil have shown a modest
This article was supported, in part, by
was associated with a lower rate of cognitive improvement
grants AG01533 and AG20098 from
in subjects with mild
progression to AD during the first year the National Institute on Aging. cognitive impairment
of treatment, the rate of progression to
treated with these
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Review Article
Understanding and
Dr Philip B. Gorelick, Saint
Mary’s Health Care, 220
Cherry Street SE, H3037,
Treating Vascular Grand Rapids, MI 49503,

pgorelic@trinity-health.org.
Cognitive Impairment Dr Gorelick has received

personal compensation for
activities with AstraZeneca/
Quinteles; BrainsGate;
Philip B. Gorelick, MD, MPH, FAAN; David Nyenhuis, PhD, ABPP Dendreon Corporation;
Daiichi Sanko Co., Ltd;
F. Hoffmann-La Roche
Ltd./PAREXEL International
ABSTRACT Corporation; Forest
Purpose of Review: It is estimated that one in three people will experience a stroke, Laboratories, Inc./Watermark
dementia, or both during their lifetime. The goal of this article is to assist clinicians in Medical; Takeda
the identification and treatment of patients with vascular cognitive impairment (VCI). Limited. Dr Gorelick’s
To that end, we will discuss the scope and definition of VCI; how this definition employer receives
can be applied in clinical practice; VCI epidemiology and pathogenesis, its clinical compensation for
Dr Gorelick’s research work
features, and assessment; and prevention and treatment of this disorder. from Lundbeck and for
Recent Findings: During the past decade, we have gained a more complete Dr Gorelick’s service on the
understanding of clinical manifestations of VCI (eg, the importance of executive speakers’ bureau of
Boehringer Ingelheim.
function and memory), what it looks like pathologically (eg, the role of cerebral Dr Nyenhuis reports no
amyloid angiopathy, microinfarcts, and ‘‘silent’’ strokes), and how VCI relates to disclosure.
other disease processes (eg, co-occurrence with Alzheimer disease). A recent Unlabeled Use of
American Heart Association and American Stroke Association guidance statement Use Disclosure:
clarified the construct of VCI, including the severity of cognitive and behavioral Dr Gorelick discusses the
dysfunction contained under the definition of VCI and the presence of both ‘‘pure’’ unlabeled use of treatment of
cardiovascular risk factors in
and ‘‘mixed’’ VCI forms. VCI treatments approved by the US Food and Drug the prevention of cognitive
Administration are still lacking, and challenges remain regarding how to convert impairment and the unlabeled
promising observational study findings that link stroke and coronary heart disease use of cholinesterase
inhibitors for the treatment of
risk factors to cognitive impairment and dementia into evidence-based preventive vascular cognitive
methods. impairment. Dr Nyenhuis
Summary: VCI is a common contributor to cognitive impairment in later life. reports no disclosure.
Because the risk of Alzheimer disease may be heightened by the same risk factors * 2013, American Academy
of Neurology.
that make us susceptible to stroke and coronary heart disease, these borderlands
merit careful consideration as we strive to preserve cognitive function throughout
the aging process.
DEFINITION AND SCOPE OF ciation (AHA-ASA), VCI is defined as ‘‘a

VASCULAR COGNITIVE syndrome with evidence of clinical
IMPAIRMENT stroke or subclinical vascular brain injury
The construct of cognitive impairment and cognitive impairment affecting at
and dementia associated with cerebro- least one cognitive domain.’’1 VCI there-
vascular disease and stroke has gone fore encompasses all of the potential
through many permutations, from multi- levels of cognitive severity, from its
infarct dementia to vascular dementia mildest form detectable by neuropsy-
(VaD) to the presently used term, vas- chological assessment to full-blown VaD.
cular cognitive impairment (VCI).1 In a VCI also includes both ‘‘pure’’ (cerebro-
recent statement of the American Heart vascular disease alone) and ‘‘mixed’’
Association and American Stroke Asso- (cerebrovascular disease with other

Vascular Cognitive Impairment
KEY POINTS
h Vascular cognitive pathology, such as that of Alzheimer outnumber clinically manifest ones by
impairment is defined as disease [AD]) pathologic conditions. a factor greater than 11 to 1 and are not
‘‘a syndrome with The National Institute of Neurological so silent, as they are harbingers of
evidence of clinical Disorders and Stroke and Association future stroke and cognitive impair-
stroke or subclinical Internationale pour la Recherché et ment. In addition, about one in 10
vascular brain injury and l’Enseignement en Neurosciences adults in the community harbor a silent
cognitive impairment (NINDS-AIREN) criteria2 are currently stroke by an average age of approxi-
affecting at least one most widely used in VaD clinical trials. mately 63 years.4
cognitive domain.’’ These criteria require neuroimaging Traditionally, after AD, VaD has been
Vascular cognitive evidence of focal brain damage, focal considered the second leading cause of
impairment therefore
clinical signs, and cognitive deficits in at progressive and irreversible dementia;
encompasses all of the
least three cognitive domains, one of however, currently Lewy body dementia
potential levels of
cognitive severity, from
which must be memory. The cognitive is considered the second leading cause
its mildest form deficits must be linked to functional by some experts. Epidemiologic studies
detectable by impairment. The strength of association suggest that the incidence of dementia
neuropsychological between cerebrovascular disease and in Europe is highest for AD (60% to 70%
assessment to full-blown cognitive impairment is the primary of all cases), with VaD accounting for
vascular dementia. determinant of probable versus possible about 15% to 20% of cases.5 In addition,
h Strokes and Alzheimer VaD diagnoses. In clinicopathologic incidence rates of these disorders in-
disease often occur study, the NINDS-AIREN criteria have crease with age but show geographical
concomitantly and pose shown high specificity but low sensitiv- variation, such as being higher in
risks for one another. ity, meaning that many true cases of northwestern than southern European
h Vascular dementia has VaD were not detected by the criteria. countries,5 and there may not be gen-
been considered the The recent AHA-ASA VCI statement der differences in the rates of risk for
second leading cause of includes updated diagnostic criteria for VaD as once thought.6 Furthermore,
progressive and VCI. The guidelines include both VaD considerable evidence indicates that
irreversible dementia and vascular mild cognitive impairment stroke increases the risk of dementia,7
after Alzheimer disease. (VaMCI) criteria, require fewer impaired and in some studies dementia after
cognitive domains than NINDS-AIREN stroke has been reported in almost
criteria, and do not require memory one-third of post-stroke patients within
impairment. They also introduce the 3 months’ time. The results of some
term unstable VaMCI for use in patients epidemiologic studies in Asian coun-
who shift from an impaired to an tries suggest that, because of high
unimpaired cognitive stateVfor exam- stroke rates in the region, VCI may be
ple, if the patient demonstrates cogni- more common there than AD.8,9 The
tive recovery from a vascular event. The discordancy in rates among epidemio-
AHA-ASA criteria have not yet been the logic studies may in part reflect differ-
subject of clinicopathologic study, so ences in classification systems used for
their sensitivity and specificity are not dementia or cognitive impairment, other
yet known. issues of disparate study methodologies,
and the influence of improved stroke-
EPIDEMIOLOGY prevention efforts.
Incidence, Prevalence, Other groups that have been shown
and Mortality to be at risk for VCI include African
It is estimated that one in three people Americans, patients with AD who have
will experience a stroke, dementia, or strokes, and the very elderly (who are
both. Strokes and AD often occur con- also at risk of AD).10 Neuropathologic
comitantly and pose risks for one an- studies show an additive influence or
other.3 Interestingly, ‘‘silent’’ strokes correlation between AD pathology and

KEY POINTS
cerebral infarction in the manifestation vanced age, lower educational attain- h Neuropathologic studies
of cognitive impairment.11 Furthermore, ment, history of myocardial infarction, show an additive
mixed neuropathology (ie, AD plus VCI and recent cigarette smoking, whereas influence or correlation
changes) is common in people with higher systolic blood pressure was between Alzheimer
dementia or AD.12 associated with not having dementia.16 disease pathology and
Cognitive impairment is associated The findings were among the earliest cerebral infarction in the
with decreased survival. People with ad- to suggest that risk factors for stroke manifestation of
vanced dementia are subject to medical and coronary heart disease (CHD) were cognitive impairment.
complications such as pneumonia, fe- risks for VCI as well. The relationship h Traditionally, survival in
brile episodes, and eating problems between blood pressure and risk of Alzheimer disease is
associated with eventual death when cognitive impairment is a complex one, longer than in vascular
there is cognitively impairing disease.13 discussed in greater detail in the section dementia or mixed
Older people who survive severe sep- below on prevention and treatment of dementia, but survival
sis are at risk of substantial and per- VCI. Conventional knowledge suggests varies according to the
patient’s age, race or
sistent new cognitive impairment and that lowering blood pressure in patients
ethnic group, and
functional disability that may decrease who do not have cognitive impairment
severity of cognitive
their ability to live independently.14 can reduce the risk of subsequent cog- impairment.
Traditionally, survival in AD is longer nitive impairment, whereas lowering
than in VaD or mixed dementia, but blood pressure to preserve cognition h Lowering blood pressure
in patients who do not
survival varies according to the patient’s among patients who already have cog-
have cognitive
age, race or ethnic group, and severity nitive impairment remains unproven impairment can reduce
of cognitive impairment. In a hospital- as a successful strategy. the risk of subsequent
based study of African Americans with In a subsequent companion study in cognitive impairment,
AD, VaD, or stroke without dementia which an AD comparison group was whereas lowering blood
who were followed for up to 7 years, included, it was found that African pressure to preserve
there were no substantial differences in Americans with a clinical diagnosis of cognition among
survival between any of the diagnostic AD frequently had risks for stroke (eg, patients who already have
groups after adjusting for age.15 50% had hypertension, 15% CHD, and cognitive impairment
13% diabetes mellitus).17 When brain remains unproven as a
Risk Markers and Factors necropsy was performed in a subgroup successful strategy.
In the context of this review, risk of these patients who had a clinical h Risks for stroke, such
marker refers to an exposure that in- diagnosis of AD and stroke or cardio- as hypertension,
creases the risk of a disease state or vascular risk factors, there was good hypercholesterolemia,
disorder, and risk factor refers to an agreement between the neuropatho- hyperhomocysteinemia,
elevated body mass
exposure that not only increases the logic diagnosis and the clinical diag-
index and fat intake,
risk of the disease state or disorder but nosis of AD.18 The findings provided
atrial fibrillation,
also has such a direct impact that the some of the early evidence to suggest diabetes mellitus,
target disease or disorder is reduced that modifiable cardiovascular risks cigarette smoking, and
when this factor is treated or modified. tend to be present in people with AD metabolic syndrome,
In some examples, the term ‘‘risk fac- (Case 8-1). are now considered
tor’’ is used interchangeably with ‘‘risk Indeed, strokes and AD often occur risks not only for
marker’’ for sake of simplicity and concomitantly and pose risks for one vascular cognitive
consistency in the literature. It has long another.3 Risks for stroke, such as impairment but also
been held that risks for stroke are also hypertension, hypercholesterolemia, hy- for Alzheimer disease.
risks for VCI.16 In a case-control study perhomocysteinemia, elevated body
among 61 patients with multi-infarct mass index and fat intake, atrial fibril-
dementia and 86 patients with stroke lation, diabetes mellitus, cigarette smok-
without cognitive impairment, stroke ing, and metabolic syndrome, are now
with dementia was predicted by ad- considered risks not only for VCI but

Case 8-1
A 79-year-old man presented with slight anomia, difficulty with recall at 5 minutes, and slightly
unsteady gait. He scored 25/30 on the Mini-Mental State Examination. Instrumental and routine
activities of daily living were not impaired. His medications included ramipril for high blood pressure
and pioglitazone for diabetes (glycosylated hemoglobin was 7.0%). Blood pressure was 163/93 mm
Hg. Other results of his general physical examination were unremarkable. MRI brain study (Figure 8-1)
showed cerebral microbleeds on gradient-echo sequences, periventricular white matter disease
predominantly in the subfrontal regions, and several scattered basal ganglia small vessel infarcts
(not pictured).
Comment. The
subfrontal white
matter disease
and cerebral
microbleeds are
manifestations
of cerebral small
vessel disease
(cerebral amyloid
angiopathy
underlying the
cerebral
microbleeds, and
deep penetrating
vessel occlusive
cerebral vascular
disease underlying
the lacunar infarcts FIGURE 8-1 Cerebral microbleeds. Gradient-echo MRI brain study showing multiple cortical
cerebral microbleeds (small, dark, circular areas in both hemispheres) (A) with
and periventricular remnant of macrobleed in frontal area (larger, frontal, dark, circular area) (B).
subfrontal white
Figure courtesy of Chelsea Kidwell, MD, Georgetown University, Washington, DC.
matter disease).
Given the presence
of cerebrovascular disease, mild cognitive deficits, and intact activities of daily living, the diagnosis
was classified as vascular mild cognitive impairment. Formal neuropsychological testing supported the
diagnosis with predominant executive dysfunction. The presence of cerebral microbleeds, however,
raised concern about underlying Alzheimer disease and, therefore, a mixed vascular cognitive
impairment and Alzheimer disease mechanistic process.19
The addition of a diuretic gently lowered the patient’s blood pressure to reach a systolic blood
pressure of approximately 150 mm Hg, with no immediate complications.
While lowering blood pressure is not a well-established strategy for prevention of cognitive
impairment or its progression, it does reduce stroke risk. The presence of silent strokes on brain MRI is
a risk for clinically manifest stroke and cognitive impairment. The administration of antiplatelet therapy
in the presence of cerebral microbleeds is controversial.19 Cerebral microbleeds can be harbingers of
cerebral macrobleeds, and some studies have suggested that when cerebral microbleeds are abundant,
antithrombotic therapy elevates the risk of macrohemorrhage of the brain (this has not been
definitively proven but remains a potential concern). After a patient-focused discussion, it was decided
not to administer antiplatelet therapy. A glycosylated hemoglobin target of approximately 7.0% is
reasonable, according to stroke prevention guidelines.
also for AD.20 Cardiovascular factors rosis. The recently published AHA-ASA
have now been linked to AD as well as guidance statement includes a list of
to cardiovascular disease and atheroscle- key risk markers that may be linked to

KEY POINTS
VCI (Table 8-1).1 Most of these factors addition to clinically manifest strokes, h In addition to clinically
are typical or usual cardiovascular risks or VCI may have an underpinning of manifest strokes,
concomitant disorders or diseases. Fac- subclinical cerebrovascular brain injury vascular cognitive
tors labeled as uncertain in Table 8-1 (CVBI). As a person ages, common vas- impairment may have
have relatively less epidemiologic sup- cular brain pathologies include white an underpinning
porting evidence of association with VCI. matter degeneration, primary vessel of subclinical
All of the factors (including those labeled disease such as arteriolosclerosis and cerebrovascular brain
as uncertain with respect to VCI), how- lipohyalinosis, atherosclerosis, cerebral injury.
ever, are associated with reduction of amyloid angiopathy (CAA), and cerebral h At the microscopic
stroke or major CHD outcomes.1 The microbleeds.1 Cerebral microbleeds at level of the brain, the
AHA-ASA guidance statement serves as a the surface of the brain are thought to neurovascular unit is a
resource of key contributions of many be caused by CAA and have been conduit for neurovascular
research groups to the field of VCI. associated with macrohemorrhage of dysfunction.
the brain and cognitive impairment.21
PATHOGENESIS At the microscopic level of the brain,
VCI can be caused by clinically manifest the neurovascular unit is a conduit for
strokes that may be large or small and of neurovascular dysfunction. The neuro-
ischemic or hemorrhagic origin.1 In vascular unit is made up of neurons,
TABLE 8-1 Key Risk Markers ThataMay Be Linked to Vascular

Cognitive Impairment
b Demographic Factors
Advancing age
b Lifestyle Factors
Low education
Diet (antioxidants, fish oil, vitamin D, B-complex vitamins, Mediterranean
diet, and moderate alcohol consumption of uncertain protective influence)
Lack of physical activity or exercise
Obesity
Smoking habit
Lack of social support/networks
b Depression (Uncertain)
b Physiologic Factors
Hypertension
Hyperglycemia, insulin resistance, metabolic syndrome, and diabetes mellitus
Hyperlipidemia (uncertain)
b Concomitant Clinical Vascular Disease
Coronary artery disease
Stroke
Chronic kidney disease
Atrial fibrillation
Peripheral arterial disease
Low cardiac output
a
Data from Gorelick PB et al, Stroke.1 stroke.ahajournals.org/content/42/9/2672.long.

KEY POINTS
h The most common form glia, and perivascular and vascular cells, linating disorder of the cerebral white
of vascular cognitive and maintains structural and functional matter referred to as leukoaraiosis (liter-
impairment is the homeostasis of the cerebral micro- ally, rarefaction or thinning of the white
subcortical type. environment.1 Vascular oxidative stress matter). Leukoaraiosis may manifest
h Regional white matter and inflammation are believed to be neuroradiologically on brain CT or MRI
integrity (whether on mediators of neurovascular dysfunc- as slight, moderate, or severe intensity.
the side of a recent tion induced by traditional vascular risk White matter changes and lacunar in-
acute cerebrovascular factors and amyloid-". A complex inter- farcts are correlated and have been
brain injury or not) and action ensues between oxidative stress- associated with cognitive impairment.22
thalamic density have mediated vascular leakage, protein Stroke-related factors that can be
been suggested as extravasation, and cytokine production; identified on brain imaging or at brain
possible pathogenetic and inflammation that upregulates ex- necropsyVsuch as volume of cerebral
links for risk of vascular pression of reactive oxygen speciesY tissue loss, infarct location (eg, strategi-
cognitive impairment producing enzymes and downregulates cally located brain infarction in the
based on diffusion
antioxidant defenses.1 As a result, with thalamus, angular gyrus, or subfrontal
tensor imaging and
neurovascular dysfunction, the brain’s pathways), infarct number, presence of
voxel-based morphometry
study, respectively.
susceptibility to injury increases with cerebral atrophy, presence of white mat-
altered regulation of cerebral blood ter lesions or volume of these lesions,
h The clinical picture of supply, disruption of blood-brain bar- and silent cerebral infarctsVare com-
patients with vascular
rier function, and potential for reduced monly believed to indicate risk for VCI.1
cognitive impairment
may be linked with the
trophic support and repair of CVBI. It With sophisticated neuroimaging tools
volume and location of is hypothesized, therefore, that control such as diffusion tensor imaging,
the underlying of vascular risk factors, reactive oxygen tractography, functional MRI and voxel-
pathology. species, and inflammation could lead based morphometry, researchers are
to preventive or treatment strategies discovering new structural and function-
in VCI.1 al alterations that can occur in the brains
The most common form of VCI is of people with stroke and cognitive
the subcortical type.22 Cerebral arterial impairment. Regional white matter in-
small vessels arise superficially from the tegrity (whether on the side of a recent
subarachnoid circulation as termina- acute CVBI or not) and thalamic density
tions of medium-sized arteries and have been suggested as possible patho-
deeply as arterial perforators from larger genetic links for risk of VCI based on
vessels at the base of the brain. These diffusion tensor imaging and voxel-based
vessels supply deep white matter struc- morphometry study, respectively.23,24
tures, for example, but are not visible by Furthermore, imaging studies are clarify-
standard neuroimaging. Therefore, their ing the possible roles of the blood
clinical disease signature is white matter glucose level and infarcts of the hippo-
disease, lacunar infarcts, and cerebral campus as causal pathways whereby
microbleeds detectable on MRI of the memory decline may occur in the
brain.22 Whereas small cerebral arteries dentate gyrus subregion, based on blood
may have pathologic changes such as glucose level, whereas the CA1 subre-
arteriolosclerosis and CAA, the deep gion has been linked to infarction
cerebral veins tend to be affected by a associated with hypoperfusion and cog-
process called venous collagenosis, nitive impairment.25 Finally, micro-
which can also play a role in the path- infarcts of the brain diagnosed at
ogenesis of cognitive impairment. necropsy have been shown to be asso-
Occlusive disease of deep, small ciated with brain atrophy and cognitive
arterial vessels of the brain is believed impairment even before dementia man-
to lead to lacunar infarcts and a demye- ifests clinically.26

KEY POINTS
CLINICAL FEATURES ment is common in patients with VCI.27 h Individual patients may
The clinical picture of patients with VCI The pattern of memory impairment in show both focal
may be linked with the volume and VCI can be qualitatively different from neurocognitive deficits
location of the underlying pathology. If that of AD in that a rapid forgetting of associated with the
there is clinical stroke, the location, newly learned information may not be location of their stroke
number, and volume of the stroke(s) seen. Instead, patients with cerebrovas- lesions and a more
determine the pattern and extent of cular disease are often inefficient in diffuse pattern,
cognitive impairment and behavior their encoding of the new information, depending on the
change. Juxtaposed with the focal fea- resulting in less information acquired. presence and extent of
tures of specific stroke-related lesions is Depression is the most common subcortical cerebrovascular
brain injury.
the more diffuse pattern of cognitive post-stroke psychiatric disturbance, with
impairment associated with subcortical approximately one-third of patients h Given the lack of clarity
CVBI. This pattern is marked by slowed experiencing depression in the months from research studies
mentation (bradyphrenia), executive following their stroke.30 Also, there may and the fact that many
elderly patients with
dysfunction, memory deficits marked be important vascular contributions to
dementia and cognitive
by inconsistent acquisition rather than late-life depression or so-called vascular
impairment have
rapid forgetting, and mood distur- depression.31 For these reasons, it is multiple sources of
bance.27 Individual patients may show important to screen for depressive symp- brain pathology,
both focal neurocognitive deficits as- toms in patients with suspected CVBI. clinicians should be
sociated with the location of their Commonly used screening tests in pa- cautious about basing
stroke lesions and a more diffuse pat- tients with suspected VCI include the their clinical diagnosis
tern, depending on the presence and geriatric depression scale, the Beck De- solely on the pattern of
extent of subcortical CVBI. pression Inventory, and the Center for cognitive deficits.
Two specific cognitive domains de- Epidemiologic Studies Depression h The pattern of memory
serve special mention: executive func- Scale. Other neurobehavioral disorders impairment in vascular
tion (which refers to higher cognitive associated with stroke and cerebrovas- cognitive impairment
skills such as planning, organizing, and cular disease include dysexecutive be- can be qualitatively
synthesizing) and memory. Although havior and apathy or abulia. different from that of
many clinicians consider deficits in exec- Consultation with psychiatry or another Alzheimer disease.
utive function to be a hallmark of VCI, health care provider with expertise in h It is important to screen
such deficits are not specific to ce- neurobehavioral disorders may assist in for depressive symptoms
rebrovascular disease.28 Given the lack treatment of patients with post-stroke in patients with suspected
of clarity of this research, and the fact behavior disturbance. cerebrovascular brain
that many elderly patients with demen- A review of the pivotal clinical trials in injury.
tia and cognitive impairment have mul- VaD reveals inconsistent demonstrations h Reliably differentiating
tiple sources of brain pathology,12 of global functional improvement in functional disability due to
clinicians should be cautious about relation to assessment of functional be- physical (eg, hemiparesis)
basing their clinical diagnosis solely on havior in VCI.32,33 Reliably differentiating versus cognitive and
behavioral impairment is a
the pattern of cognitive deficits. Memory functional disability due to physical (eg,
specific difficulty in
is a second important cognitive domain. hemiparesis) versus cognitive and be-
examining for impaired
The NINDS-AIREN criteria for VaD havioral impairment is a specific diffi- activities of daily living
require memory impairment.2 However, culty in examining for impaired activities after stroke.
perhaps in fear of the ‘‘Alzheimerization’’ of daily living after stroke. The Barthel
of all dementia, subsequent groups of Index is one of the most popular func-
VCI investigators have argued that tional outcome measures used with
memory impairment should not be stroke patients but can be unreliable in
required,29 and the AHA-ASA criteria older patients, especially those with
do not require it for the diagnosis of cognitive impairment. By contrast, the
VaD or VaMCI.1 Still, memory impair- Disability Assessment for Dementia

scale, with its separate scores for initia- Table 8-2, one should keep in mind
tion, planning, and performance of ac- that a relatively limited number of
tivities, is better equipped to distinguish highest-evidence studies are available,
between physical and cognitive disability and the studies are graded based on the
in VCI. Finally, several studies have level of evidence (ie, estimate of cer-
shown that executive function tests best tainty [precision] of the treatment
predict decline in instrumental activities strategy’s effect) and class of evidence
in daily living in both AD and VaD.34 (ie, size of the treatment strategy’s ef-
fect) according to an AHA-ASA grading
PREVENTION AND scheme (see reference 1). Terms such
TREATMENT OF VCI as recommended, reasonable, may be
Prevention reasonable, and not recommended are
As previously mentioned, prospects used to guide the clinician based on
for prevention of VCI by risk factor level and class of evidence, with rec-
modification have been summarized in ommended being the highest level of
a recently published AHA-ASA guidance recommendation for a treatment strate-
statement.1 Key recommendations from gy in this grading scheme.
this work are summarized in Table 8-2.1 In this review, treatment of hyperten-
In interpreting the information in sion received the highest evidence-based
TABLE 8-2 Key Recommendations for Prevention of Vascular Cognitive Impairment in People
at Riska
Class and Level

Factors of Evidence Prevention Designations
Lifestyle factors
Smoking cessation Class IIa, level of Reasonable strategy
evidence (LOE) A
Moderation of alcohol intake Class IIb, LOE B May be a reasonable strategy
Weight control Class IIb, LOE B May be a reasonable strategy
Physical activity Class IIb, LOE B May be a reasonable strategy
Use of antioxidants and B vitamins Class III, LOE A Not beneficial
Physiologic factors
Treatment of hypertension Class I, LOE A Recommended strategy
b
Treatment of hyperglycemia Class IIb, LOE C May be a reasonable strategy
Treatment of hypercholesterolemiab Class IIb, LOE B May be a reasonable strategy
Treatment of inflammation Class IIb, LOE C Uncertain strategy
Other interventions in relation to cognitive decline or impairment
Mediterranean diet Class IIb, LOE B Recommended strategy
Vitamin supplementation Class IIb, LOE B Not proven, even if homocysteine levels have been
positively modified, or of uncertain usefulness
Physical activity Class IIb, LOE B May be considered
Antiaggregant therapy Class IIb, LOE B Not well established
a
Data from Gorelick PB et al, Stroke.1 stroke.ahajournals.org/content/42/9/2672.long.
b
The effectiveness of treatment of diabetes or hyperglycemia for the prevention of dementia has not been well established (Class IIb,
LOE C), and the treatment of hyperlipidemia for the prevention of dementia remains uncertain (Class IIb, LOE C).

KEY POINTS
grade for the prevention of VCI: treating More recently, attention has turned h There is reasonable
hypertension was recommended for to cholinesterase inhibitors according to evidence to suggest
people at risk of VCI (Class I, Level of the rationale that cholinergic pathways blood pressureYlowering
Evidence [LOE] A recommendation), from the nucleus basalis of Meynert may therapy as a useful
and in people with a history of stroke, be disrupted by subcortical cerebrovas- intervention for people
lowering blood pressure was deemed cular disease and there may be mixed who are middle-aged and
to be an effective means to reduce the AD and VCI.38 In large VCI clinical trials younger elderly (Class IIa,
risk of post-stroke dementia (Class I, of the cholinesterase class of drugs, the Level of Evidence B);
LOE B).1 There was reasonable evidence key findings show inconsistent benefits however, the usefulness
to suggest blood pressureYlowering ther- of lowering blood
across primary or other key end points,
pressure for those over
apy as a useful intervention for people or an effect that may be primarily lim-
80 years of age for the
who were middle-aged and younger ited to those with mixed AD plus prevention of dementia is
elderly (Class IIa, LOE B); however, the VCI.32,40Y42 A similar result was noted not well established
usefulness of lowering blood pressure with the administration of donepezil (Class IIb, Level of
for those over 80 years of age for the in cerebral autosomal dominant arterio- Evidence B).
prevention of dementia was not well pathy with subcortical infarcts and h Further robust and
established (Class IIb, LOE B).1 See leukoencephalopathy (CADASIL), a ge- consistent studies are
Table 8-2 for management recommen- netic model of subcortical VCI, as the necessary to provide
dations of other risk markers or factors. primary end point of the trial was not clear, concise answers
A recently published NIH Consensus realized; however, measures of executive to important research
Panel work on reducing risk of AD or function were improved (Case 8-2).44 questions regarding the
cognitive decline in older people con- The failure of the cholinesterase inhibitors role of vascular risks for
cluded that the quality of evidence was to successfully treat patients with VaD cognitive impairment
generally low and inadequate to deter- and dementia.
on an across-the-board cognitive and
mine that therapeutic interventions functional basis has raised questions h Currently no drugs that
would be able to delay the onset of AD regarding whether there is an absence have gained wide
or reduce cognitive decline.35 Further of cholinergic deficits in pure VaD.45 acceptance for use in
robust and consistent studies are nec- practice have been
Memantine, an uncompetitive N-
essary to provide clear, concise answers approved by the US Food
methyl-D-aspartate (NMDA) receptor and Drug Administration
to important research questions regard- antagonist, has statistically significantly for the treatment of
ing the role of vascular risks for cog- improved cognitive outcome in some vascular cognitive
nitive impairment and dementia.36 key cognitive study end points in large impairment.
trials.33 Nimodipine showed similar re- h The failure of the
Treatment
sults for influencing cognitive function.46 cholinesterase inhibitors
Many treatments have been tried for VCI, Overall, the various treatment mo- to successfully treat
but none have proven unequivocally to dalities reviewed above do not provide patients with vascular
be efficacious and safe.37,38 At one time, consistent cognitive and functional ben- dementia on an
it was thought that control of blood across-the-board
efit. Keeping this feature in mind, the
pressure in the range of 135 to 150 mm cognitive and functional
following are recommendations for
Hg might be useful to maintain cogni- basis has raised questions
drug treatments of VCI in an evidence-
tive function in people with hyperten- regarding whether there
based guidance statement in collabora-
sion and VCI, and that aspirin therapy is an absence of
tion with the AHA-ASA:1
might be useful to improve cerebral per- cholinergic deficits in
fusion, cognitive performance, quality of 1. Donepezil may be useful for pure vascular dementia.
life, and independence. Currently, how- improving cognition in patients with
ever, no drugs that have gained wide VaD (Class IIa, LOE A).
acceptance for use in practice have been 2. Galantamine may be useful for
approved by the US Food and Drug Ad- patients with mixed AD/VaD
ministration for the treatment of VCI. (Class IIa, LOE A).

Case 8-2
A 67-year-old woman was transferred to the inpatient stroke unit with a diagnosis of possible
vasculitis. She had a medical history of hypertension and unexplained left-side weakness and slight
gait difficulty at age 38, from which she had recovered almost completely. Her daughter described the
patient’s cognition as ‘‘not quite normal’’ from that time onward and said that it had worsened
slightly over time with periods of confusion, which the family blamed on her frequent headaches.
Several days before her transfer to the stroke unit, the patient developed slurred speech and
weakness of the right face, arm, and leg. She was treated at the referral hospital with IV steroids, as
she had waxing and waning mental status in addition to the right-side weakness. Physical
examination in the stroke unit showed slight left arm and leg weakness and rather profound right
face, arm, and leg weakness with dysarthria. The brain MRI (Figure 8-2 and Figure 8-3) performed at
the referral hospital showed prominent white matter disease with involvement of the external
capsule and possible early involvement of the temporal lobe tips. In addition, diffusion-weighted
image showed a left periventricular signal consistent with a small, deep acute infarction.
Results of a lumbar puncture performed at the stroke unit
upon her arrival showed a slight elevation in the protein
content, but all other
parameters were
unremarkable,
including a 14-3-3
protein study. Blood
study results for
prothrombotic states
were unremarkable,
as were sedimentation
rate, a high-sensitivity
C-reactive protein test,
and a panel for
collagen-vascular
abnormalities.
Conventional cerebral
angiography showed FIGURE 8-3 Brain MRI. Note extensive
white matter disease
several areas of FIGURE 8-2 Diffusion-weighted brain with involvement of
MRI. Note increased signal external capsule. Other MRI sequences
possible vasculitic intensity of periventricular showed slight involvement of the
changes, but the area on the left side. temporal tips bilaterally.
neuroradiologist was
not fully convinced of
the findings. After the conventional cerebral angiography study, and at the urging of the family
members, the patient had a leptomeningeal-brain biopsy, which did not show evidence of a
vasculitic process.
Comment. The brain MRI findings are consistent with cerebral autosomal dominant arteriopathy
with subcortical infarcts and leukoencephalopathy (CADASIL), a monogenetic disorder mapped to
chromosome 19q12.43 CADASIL typically begins in early adulthood; symptoms comprise migraine with
aura, mood disturbance, recurrent strokes, cognitive impairment, and extensive white matter disease.
Most cases have a missense mutation of the Notch 3 gene and ultrastructural changes in skin and
muscle vessels including granular osmophilic material in the arteriolar media. Because CADASIL is an
autosomal dominant disorder, it is important to discuss screening other members of a patient’s
immediate family. There is no definitive prevention or treatment, and many cases go on to develop
significant cognitive impairment.
Notch 3 gene mutation study was obtained on the serum of this patient and was consistent with a
diagnosis of CADASIL, as was the brain biopsy electron microscopy study.

3. The benefits of rivastigmine and strokes, big trouble’’. Stroke 2008;39(9):
2407Y2408.
memantine are not well established.
5. Fratiglioni L, Launer LJ, Andersen K, et al.
Cholinesterase inhibitors have been Incidence of dementia and major subtypes
shown to benefit cognition and may also in Europe: a collaborative study of
improve behavior and ability to perform population-based cohorts. Neurologic
Diseases in the Elderly Research Group.
activities of daily living more than place- Neurology 2000;54(11 suppl 5):S10YS15.
bo therapy in some forms of dementia
6. Andersen K, Launer LJ, Dewey ME, et al.
such as AD or VCI.39 However, a sys- Gender differences in the incidence of AD
tematic review of pharmacologic treat- and vascular dementia: The EURODEM
ment of neuropsychiatric symptoms Studies. EURODEM Incidence Research
Group. Neurology 1999;53(9):1992Y1997.
associated with dementia suggests that
7. Ivan CS, Seshardri S, Beiser A, et al.
such therapies are not particularly ef-
Dementia after stroke: the Framingham
fective and can be complicated by Study. Stroke 2004;35(6):1264Y1269.
increased risk of some types of cardio- 8. Zhang Z-X, Zahner GEP, Roman GC, et al.
vascular disease, such as stroke.47 A Dementia subtypes in China: prevalence in
review of the management of noncog- Beijing, Xian, Shanghai, and Chengdu.
nitive symptoms in dementia by Drs Arch Neurol 2005;62(3):447Y453.
Burke, Hall, and Tariot can be found in 9. Yamada M, Mimori Y, Kasagi F, et al.
Incidence of dementia, Alzheimer disease,
this issue. and vascular dementia in a Japanese
Finally, although aspirin has not been population: Radiation Effects Research
conclusively shown to benefit cognitive Foundation adult health study.
function in people at risk,48 there is an Neuroepidemiology 2008;30(3):152Y160.
ongoing, large-scale trial (Aspirin for 10. Honig LS, Tang M-X, Albert S, et al. Stroke
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Reducing Events in the Elderly) for the Neurol 2003;60(12):1707Y1712.
primary prevention of major adverse
11. Bennett DA, Schneider JA, Bienias JL, et al.
cardiovascular events and VaD,49 and Mild cognitive impairment is related
an ongoing systolic blood pressureY to Alzheimer disease pathology and
control study (the Systolic Blood Pres- cerebral infarctions. Neurology 2005;64(5):
834Y841.
sure Intervention TrialVMemory and
Cognition in Decreased Hypertension, 12. Schneider JA, Arvanitakis Z, Bang W,
Bennett DA. Mixed brain pathologies
commonly referred to as SPRINT-MIND) account for most dementia cases in
to discern the influence of blood pres- community-dwelling older persons.
sure control on cognitive function).50 Neurology 2007;69(24):2107Y2204.
13. Mitchell SL, Teno JM, Keily DK, et al. The
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Review Article
Incorporating New
Dr Tiffany W. Chow, Baycrest
Rotman Research Institute,
3560 Bathurst Street, 8th Floor
Brain Health Complex,
Toronto, ON M6A 2E1, Canada,
tchow@research.baycrest.org.
Diagnostic Schemas,
Dr Chow has served as an
independent medical examiner
Genetics, and
and medicolegal consultant to
Lesser & Associates.
Dr Alobaidy reports no
disclosure.
Proteinopathy into
Unlabeled Use of
Use Disclosure:
the Evaluation of
Drs Chow and Alobaidy
discuss the use of medications
for the treatment of behavioral
Frontotemporal
and psychiatric symptoms of
dementia, none of which carry
indications from the US Food
and Drug Administration. The
Degeneration
text cites reviews of clinical Tiffany W. Chow, MD; Ammar A. Alobaidy, MD
trials in frontotemporal
degeneration as applicable,
as well as case reports, but
clinicians are urged to ABSTRACT
specify that any such use of Purpose of Review: Within the continuously growing body of knowledge in the
medications should be openly
discussed with patients and
field of dementia, frontotemporal degeneration stands out in importance as the
substitute decision makers as second most common cause of early-onset dementia after Alzheimer disease. Neu-
off-label prescriptions. rologists, neuropsychologists, and speech pathologists are particularly involved in
* 2013, American Academy the diagnosis and recognition of etiologies for patients with deficits in frontal lobe
of Neurology.
function and language.
Recent Findings: The recent discovery of a novel mutant gene (C9ORF72) and the
new nomenclature adopted for subclassification have significantly promoted our
understanding of this disorder.
Summary: This article relates the most recent consensus criteria for diagnosis of the
two forms of frontotemporal degeneration (ie, behavioral and primary progressive
aphasia variants) to basic neurologic principles and remind clinicians of the neuro-
psychiatric and neuroradiologic components that clarify frontotemporal degenera-
tion diagnoses and guide management.
FRONTOTEMPORAL (bvFTD) and primary progressive apha-

DEGENERATION FACTS sia (PPA) subtypes.1,2 The bvFTD sub-
AND FIGURES type can carry the simpler acronym
While the term ‘‘frontotemporal demen- FTD, while each of the PPAs is referred
tia’’ has been used to refer to the overall to more specifically as a nonfluent/
syndrome of neurodegenerative disor- agrammatic, semantic, or logopenic var-
ders involving mainly the frontal and iant of PPA. Although it is tempting to
temporal lobes, more recent diagnostic continue to refer to all of the disorders
criteria have promoted a separation of as FTD since many overlapping symp-
the behavioral and language forms of toms occur over the span of bvFTD and
the overall syndrome into the behavioral PPA courses of illness, this article will
variant frontotemporal degeneration state ‘‘frontotemporal degeneration’’

without use of an acronym when refer- throughs in dementia was the discovery
ring to both bvFTD and PPA. Some that 80% to 95% of the patients with
writers use frontotemporal lobar degen- FTLD who were tau-negative harbored
eration (FTLD) to refer to the overall TDP-43 inclusions instead. Especially in-
syndrome, but others, including the au- teresting is the preponderance of TDP-43
thors of this article, prefer to save the inclusions in the von Economo neurons
FTLD designation as a neuropathologic concentrated in the anterior insula.7
diagnosis.3 Clinicians should be aware
that patients and their family advocates Syndromic Symptomatology
shun the term ‘‘dementia’’ and have ex- Behavioral variant frontotemporal
pressed their preference for FTD to degeneration. Neurologists are trained
stand for frontotemporal degeneration to recognize patients with frontal lobe
(www.theaftd.org). dysfunction in the contexts of traumatic
brain injury, stroke, or multiple sclero-
Epidemiology sis. The relationship in time to a head
Frontotemporal degeneration is the injury, sudden onset, or episodic charac-
second most common form of early- ter of frontal lobe dysfunction distin-
onset dementia after Alzheimer disease guishes these etiologies from the gradual
(AD), with prevalence between 2.7 and onset and progression of a neurodegen-
15.1 per 100,000 in adults younger than erative dementia. When loss of sustained
65 years.4 The bvFTD subtype accounts attention, self-monitoring, appropriate
for more than 50% of patients with task-shifting, abstract thinking, and judg-
frontotemporal degeneration and typi- ment appear in the context of dementia
cally presents before the age of 65 to a degree that surpasses memory loss
years, with an average onset age of 58 or visuospatial impairment, the diagnos-
years. The nonfluent/agrammatic vari- tician brings bvFTD to the top of the
ant of PPA is the second most prevalent differential diagnosis.
subtype of frontotemporal degenera- In a patient younger than 65 years at
tion, accounting for 25% of cases, but onset of marked behavioral changes or
semantic PPA runs a close third, with aphasia symptoms and gradual progres-
only a slightly smaller percentage (20% sion over time, a history from an infor-
to 25%).5,6 mant is key to ascertaining a diagnosis of
bvFTD. Because of the loss of insight
Etiologies According to and other behavioral and psychiatric
Proteinopathy symptoms of dementia (BPSD), it may
Autopsies confirming FTLD can report be impossible to finalize a diagnosis of
several types of proteinopathy evi- bvFTD without history from an infor-
denced by the presence of abnormal, mant who has known the patient well
ubiquitinated protein inclusions in cyto- premorbidly.
plasm or nuclei of neuronal and glial The 1998 Neary criteria for clinical
cells.3 The majority of reports from neu- diagnosis of frontotemporal degenera-
ropathology will conclude one of the tion provided an important launchpad
following, in order of prevalence: (1) for researchers to produce convergent
transactive response (TAR) DNA bind- studies on the neuroimaging of these
ing protein 43 (TDP-43), (2) hyper- dementias and to conduct multicenter
phosphorylated tau protein (not the trials.8 The criteria did not allow flexi-
same as in Alzheimer tangles), or (3) bility to include patients who might be
fused in sarcoma (FUS) protein. In the in an early stage of illness, and to ad-
last decade, one of the biggest break- dress these difficulties in behavioral

Frontotemporal Degeneration
KEY POINT
h Diagnostic criteria now neurology clinics, the International Be- events or stable conditions such as
allow for a subclass of havioral Variant FTD Criteria Consor- long-standing psychiatric disease (see
possible behavioral tium recently developed new consensus Case 9-1). For these diagnostic criteria,
variant frontotemporal criteria for bvFTD, based on multicenter ‘‘early’’ refers to symptom presentation
degeneration, which autopsy-confirmed case histories.1 As within the first 3 years.
represents earlier stages shown in Figure 9-1, these criteria now For these criteria, a history of apathy
of illness in which allow for a subclass of possible bvFTD, may be elicited by asking about a
neuropsychological which represents earlier stages of ill- marked change in the patient’s level
testing in high-functioning ness in which neuropsychological test- of motivation, a new passivity, or a lack
patients may not reveal ing in high-functioning patients may of spontaneity in the patient’s ac-
executive deficits or in tions or conversation (see Case 9-2).
not reveal executive deficits or in which
which neuroimaging does
neuroimaging does not yet support Patients with early loss of sympathy
not yet support regional
regional atrophy or regional dysfunc- or empathy have shown poor or ab-
atrophy or regional
dysfunction. tion. In light of this decade’s discover- sent responsiveness to family mem-
ies about the pathogenic mutations and bers’ needs and feelings, or they no
proteinopathies implicated in the ma- longer relate well to others emotion-
jority of cases of FTLD, a definite ally. The stereotypies and compulsive/
bvFTD diagnosis no longer relies solely ritualistic behaviors reported in bvFTD
upon brain biopsy or autopsy. range from simple movements (such
The core symptoms were specified to as clapping) to more complex actions
distinguish bvFTD from acute medical (such as cleaning rituals and hoarding).
FIGURE 9-1 The diagnostic process for behavioral variant frontotemporal dementia (bvFTD)
according to Rascovsky and colleagues.1 Note the change from the 1998 Neary and
colleagues8 criteria away from the use of supportive criteria for the equivalent of
probable cases in order to diagnose early-stage possible bvFTD and the dropping of blood pressure
lability and early incontinence from the list of features. As in accompanying text, clinicians can also
consider the bvFTD diagnosis in patients who have onset after age 65, but are encouraged to keep
Alzheimer disease high on the differential.

Case 9-1
A 77-year-old, right-handed woman with 13 years of education was referred for possible behavioral
variant frontotemporal degeneration (bvFTD). Her husband warned the clinic that she had insisted on
completing the history form herself and that he would not challenge her during the appointment.
After the appointment, he hid in the basement of their home to submit a history by telephone.
She had a baseline personality of being ‘‘the life of the party’’ and sometimes telling inappropriate
jokes to her grandchildren. Diagnoses of depression and anxiety lifted after treatment with
citalopram 5 years ago. Since then, memory loss and further behavioral changes had been in place
for 3 years. The patient’s husband was most concerned about physically violent behavior related to
feelings of frustration: she sometimes slammed fragile items onto the kitchen counter, breaking them
and injuring herself. She also sang continuously. She had lost her way in familiar places at times,
but her husband felt that she was safe driving a car. She denied requiring assistance with activities
of daily living, but her husband had to prompt her to dress appropriately and brush her teeth.
The only family history of neuropsychiatric illness was of paranoid delusions in her eldest sister
during adolescence.
The patient’s husband had been quite isolated in caregiving and felt unable to share his concerns
about her symptoms or his anxiety, exhaustion, and frustration with family or friends.
On mental status examination, the patient was awake, alert, attentive, articulate, pleasant, and
efficient to test. She was even euphoric at times. She scored 28/30 on the Mini-Mental State
Examination, missing one verbal recall item and not following all three commands. She scored only
70/114 on the short form of the behavioral neurology assessment (well into the dementia range
of scores), which reflected mild difficulty with sustained attention, problems with memory and
confrontation naming, and greatly reduced verbal fluency for both F words and animals. She did well
on mathematical word problems.
Elemental neurologic examination showed no parkinsonism, a postural tremor in the right more
than left hand, and no primitive reflexes. The patient’s gait had a normal base and arm swing;
her tandem gait was normal despite her age and history of daily alcohol use until 2 years ago.
MRI of the patient’s brain (Figure 9-2) showed severe atrophy of the temporal lobes only.
Single-photon emission computed tomographic (SPECT) scan of the brain reported right greater than
FIGURE 9-2 Brain MRI for Case 9-1. A, Midsagittal T1-weighted view shows no widening of the sulcus above the anterior
cingulate (arrows), but B, more lateral sagittal view shows definite anterior temporal lobe atrophy. C, The
right temporal horn is more enlarged than the left, and hippocampal atrophy is also more apparent on
that side. The degree of atrophy may have made it difficult for nuclear medicine to distinguish mesial from lateral
hypoperfusion signal in this patient.
Continued on page 442

Continued from page 441

left hypoperfusion of the temporal lobes but lacked specificity regarding whether the deficit was
located more mesially (supportive of Alzheimer disease [AD]) or laterally.
Comment. This patient does not meet clinical criteria for bvFTD, although her behavior has been
alarming and she has some selective frontal lobe impairment clinically. Her history of having a
colorful, outspoken personality makes the current symptoms less of a change in personality than is
typically seen in bvFTD. Although the patient appears younger than her stated age, she did have
onset after age 65, and at this age, along with memory loss and anomia, the most likely dementia
etiology is AD, regardless of the details of the clinical history. However, a significant number of
late-onset, autopsy-confirmed frontotemporal degeneration cases have been reported.9,10 Vascular
dementia is also a possibility, given the patient’s advanced age, but she has been quite healthy and
has no other stroke risk factors, and no mention of cerebrovascular disease was made on imaging
reports. In this case, neuroimaging did not help make the diagnostic decision.
Management for this patient, even if she were to remain defiant to a diagnosis of dementia,
includes addressing some important ‘‘collateral damage’’ issues, including the inappropriateness of
her driving given both the severity of her dementia and her aggressive behavior, which could lead to
disaster if it were to manifest while she were operating a vehicle. The other important issue in
this case is caregiver support; the husband’s approach to the patient’s care is a serious concern. He
refused to allow the clinician to call a family meeting to get his children involved, and he chose a
very nonconfrontational approach (ie, ‘‘Don’t tell her she has dementia’’), which has contributed to
his isolation and exhaustion. He was advised to take advantage of resources such as outreach
programs from the Alzheimer’s Association. The clinician anticipated that medication management
would be difficult if the patient’s husband could not be contacted for progress reports by telephone.
In addition, because of her physically violent behaviors, quetiapine is recommended; however,
given the black box warnings for atypical antipsychotics,11 careful explanation of the rationale
behind using quetiapine for this patient’s specific symptoms should be specified, and informed
consent to use this medication despite the potential risk of early mortality, stroke, or myocardial
infarction should be obtained from the husband and documented.
Case 9-2
A 58-year-old, right-handed man with 17 years of education was referred for assessment of functional
decline with marked progressive apathy. He had been seeing a psychiatrist since a major depressive
episode at age 45. At that time, he was able to continue work as an engineer and his household
instrumental activities of daily living (eg, home repairs) in his usual fastidious manner, but by
age 55 he began to show declining activity levels. By the time of this referral, he had withdrawn
from almost all of his former activities other than watching basketball on television. His current
symptoms included marked apathy and hypersomnolence (he slept 9 hours each night plus daytime
naps for a total of 15 hours a day), but he did not report feelings of sadness, worthlessness, or
hopelessness. Prior treatment with selective serotonin reuptake inhibitors had no effect. He had
become much more passive than his original personality.
He had not been irritable and showed no signs of social disinhibition; he acted appropriately around
other people except for excusing himself from social interactions. He had a new preference for sweets.
The patient stated that he felt flat and did not know what to do with himself. Family history was
significant for depression in the patient’s father and older sister (responsive to electroconvulsive therapy).
Neither parent was known to have had dementia despite surviving into old age.

On mental status examination, the patient was awake, alert, attentive, and pleasant. He was
passive during his family’s reporting of his history, neither disagreeing with them nor minimizing the
reported symptoms; he admitted freely that he did not care. He was flat in bearing and speech, but
his speech was otherwise fluent, with no paraphasic errors and intact prosody.
The patient performed relatively well on bedside testing with a score of 14/18 on the Frontal
Assessment Battery,12 but he had poor lexical (also known as phonemic or letter) fluency. Formal
neuropsychological testing revealed inconsistent comprehension of instructions and poor sustained
effort on tasks when he did comprehend. The patient scored within the low average range on
intellectual function and verbal and perceptual abilities, which was inconsistent with his level of
career achievement. He was also in the low average range on naming to confrontation and on block
construction. He was impaired on the Trail Making Test Part B and semantic fluency.
Figure 9-3 shows this patient’s atrophy in the right anterior cingulate13 and atrophy in the right
greater than left frontal lobes. Baseline 18F-fluorodeoxyglucose positron emission tomography (PET)
imaging showed reduced metabolism bilaterally in the patient’s frontal and temporal lobes and insulae.
FIGURE 9-3 Brain MRI of a 58-year-old man with apathetic behavioral variant frontotemporal dementia. A, Coronal
T1-weighted view shows widening of right-more-than-left perisylvian fissure and asymmetric frontal
atrophy. B, Asymmetry may be better appreciated on transaxial view. C, Midsagittal view indicates more
frontal than posterior atrophic changes; it is more difficult to locate the anterior cingulate gyrus on this slice than on the
midsagittal slice in Figure 9-2 from another patient.
Comment. This patient is not recognizable to the casual observer as ‘‘demented.’’ However, he is no
longer independent in his basic activities of daily living, and his neuropsychological test results were
consistent with a diagnosis of dementia. Because of his apathy, new preference for sweets, partial
insight (ie, he understands that he has changed but not that he has an illness or that it is significantly
affecting his loved ones), positive neuropsychological testing, and positive neuroimaging, he meets
criteria for probable bvFTD, even though he does not demonstrate the socially inappropriate,
outlandish behavior commonly associated with bvFTD. Depression was considered, but he did not
report the sadness and feelings of guilt or worthlessness that would help to make that diagnosis.
Repetitive trips to the bathroom with- stance abuse), and oral exploration of
out need can be especially disruptive nonfood objects.
to the household. Hyperorality and A patient meeting only criteria for
dietary changes include altered craving possible bvFTD may still be functioning
for sweets, binge eating, increased con- with independence in the community,
sumption of alcohol or cigarettes (which although once bvFTD is suspected as a
may at first be perceived as new sub- diagnosis, implications of this progressive

dementia should be discussed with the decreased verbal fluency.17 The preva-
patient with regard to driving privileges, lence of PSP was reported as 1.00 to
liabilities at work, and long-term care 1.39 per 100,000 of the general popu-
planning. Patients with probable bvFTD lation in the United Kingdom and
exhibit significant functional decline, as United States.18
described by their caregivers during Corticobasal syndrome may also pres-
the history; alternatively, the Clinical ent with bvFTD symptoms, and patients
Dementia Rating Scale Modified for develop limb apraxia shortly thereafter.19
FTD14 or a functional questionnaire15 The ‘‘textbook’’ case of CBS presents
can be used to document or track loss as a focal cortical deficit (eg, aphasia,
of instrumental and basic activities of frontal lobe syndrome, or cortical sen-
daily living. sory loss) accompanying a progressive
In order to meet criteria for definite asymmetrical movement disorder (eg,
bvFTD, a patient must first meet the limb apraxia, alien-limb phenomenon,
criteria of either possible or probable bradykinesia, myoclonus, dystonia, or
bvFTD and have either (1) histopatho- tremor). Cognitive dysfunction even-
logic evidence of FTLD on biopsy or at tually reflects frontal20 and parietal
postmortem or (2) presence of a known lobe involvement, consistent with neu-
pathogenic mutation, such as progranulin roimaging findings of frontoparietal
or tau (see Genetic Testing, below). and ipsilateral subcortical abnormali-
Progressive supranuclear palsy (PSP) ties that are contralateral to the asym-
and corticobasal syndrome (CBS) are metrically affected limb(s). The onset
two additional tauopathies that can age can range from the early twenties
cause clinical symptoms of bvFTD. to the late eighties, with an average age
Some patients may be referred with of 50 years. There is little or no evidence
personality change (eg, apathy and dis- to support use of levodopa therapy in
inhibition) and other features of bvFTD CBS, despite parkinsonism.21 Cortico-
as the chief complaint but will show basal syndrome can alternatively cause
signs of PSP on neuropsychiatric evalu- nonfluent/agrammatic PPA.
ation. The presentation may resemble Another rare tauopathy is argyrophilic
bvFTD in early onset age (sixth decade). grain disease (AGD), which accounts for
Otherwise-unexplained falls are the approximately 5% of neurodegenerative
most common symptom of PSP and are dementia cases, with an increasing prev-
required for the clinical diagnosis. In alence in the elderly age group. Al-
earlier stages, the differentiation be- though the majority of patients with
tween PSP and CBS may be difficult for AGD will present with a clinical picture
clinicians, but the onset of falls earlyVas resembling mild cognitive impairment
opposed to in advanced illnessVcan for many years, a small number of
help to accurately indicate PSP over patients present with prominent abnor-
CBS.16 The other main feature is vertical mal behavior that may bring bvFTD to
gaze abnormality (ie, increased latency, mind. If present, the aphasia resembles
decreased range of motion, or de- that seen in AD, transcortical sensory
creased saccadic speed). In the early aphasia, as opposed to the three PPA
stages of PSP, blink rate usually be- variants described herein. AGD is not yet
comes profoundly sparse. Dysarthria, fully understood, and the diagnosis is
dysphagia, and parkinsonism unre- usually made through biopsy or autopsy,
sponsive to levodopa therapy are other as opposed to clinically.22
motor features. Cognitive disturbances Primary progressive aphasia sub-
include impaired abstract thought and types. Figure 9-4 shows how a neurologist

KEY POINTS
h Consultation with
speech and language
pathologists (especially
in mildly affected cases)
is invaluable, as some of
the features of the
primary progressive
aphasias are difficult to
identify without
subspecialty training.
h Unlike probable
behavioral variant
frontotemporal
degeneration, activities
of daily living are
maintained well into
illness, except those
related to language (eg,
using the telephone).
h The description of
The diagnostic process for three variants of primary progressive aphasia as written logopenic progressive
FIGURE 9-4
by Gorno-Tempini and colleagues,2 based upon characteristics of fluency, aphasia is new to the
comprehension, and repetition. Alzheimer disease remains high on the differential consideration of
for semantic dementia and logopenic progressive aphasia.
frontotemporal
degeneration syndromes,
and its inclusion remains
can use fluency, comprehension, and ual progression of a mostly isolated somewhat controversial
repetition to navigate the diagnostic language deficit. Language must be because of the Alzheimer
criteria recently devised by Gorno- impaired in production, object naming, disease pathology found
Tempini and colleagues.2 There are (1) syntax, or word comprehension. Unlike in a fair number of
nonfluent/agrammatic, (2) semantic, probable bvFTD, activities of daily living logopenic variant cases.
and (3) logopenic variants. An over- are maintained well into illness, except
simplified rule of thumb is that the those related to language (eg, using the
nonfluent/agrammatic variant is the telephone).
least fluent of the three; the semantic Unlike the possible, probable, and
variant has the worst comprehension definite subclassifications of the bvFTD
deficit early in the illness; and repetition diagnostic criteria, the latest criteria for
is a particular impairment for patients PPA variants specify (1) clinical, (2)
with logopenic variant PPA. However, imaging-supported, or (3) definite path-
patients frequently manifest signs that ologic diagnosis (Table 9-1).2 The de-
meet a few criteria for each of the var- scription of the third variant, logopenic
iants but more criteria for one variant progressive aphasia, is new to the
than the other two. Consultation with consideration of frontotemporal degen-
speech and language pathologists (es- eration syndromes, and its inclusion re-
pecially in mildly affected cases) is mains somewhat controversial because
invaluable, as some of the features of of the AD pathology found in a fair
the PPAs are difficult to identify without number of logopenic variant cases.3,23
subspecialty training. The clinical diag- Nonfluent/agrammatic variant PPA is
nosis of any of the three variants of PPA distinct from the other two variants in
first requires insidious onset and grad- apraxia of speech, which refers to an

TABLE 9-1 Clinical, Imaging-Supported, and Definite Diagnoses of the Variants of Primary
Progressive Aphasia
Nonfluent/
Agrammatic
Signs Variant Semantic Variant Logopenic Variant
Agrammatism (
Apraxia of speech Slow rate of speech
with pauses
Impaired comprehension of ( ( +/j
syntactically complex sentences
Impaired single-word (
comprehension
Impaired object knowledge (
Impaired confrontation naming ( +/j
Surface dyslexia or dysgraphia (
Impaired repetition:
Single words ( +/j
Phrases/sentences ( (
Impaired prosody (
Paraphasia:
Semantic ( +/j +/j
Phonemic ( +/j (
Regional imaging abnormality Predominant left Left anterior temporal Predominant left
to support diagnosis posterior lobe worse than right posterior perisylvian
fronto-insular or parietal
Type of inclusions seen on Tau more common TDP-43 Amyloid plaques and
neuropathology than TDP-43 neurofibrillary tangles
(most common)
KEY POINT articulation planning deficit that can bvFTD features, it has been shown as
h Semantic variant primary sound like stuttering or word pronun- the underlying cause of nonfluent/
progressive aphasia ciation distortions.2 The apraxia of agrammatic variant PPA19 often enough
(formerly known as
speech may be difficult for neurologists to drive the impression that this variant
semantic dementia) may be
to distinguish from the hypokinetic of PPA will usually show tauopathy at
most easily distinguished
by the loss of single-word
dysarthria due to Parkinson disease or autopsy (Case 9-3).
meaning. PSP. The hypokinetic dysarthria of Semantic variant PPA (formerly
Parkinson disease has a hoarseness known as semantic dementia) may be
and hypophonia; in PSP, there is a most easily distinguished by the loss of
nasal, rushed, and slurred aspect to single-word meaning. Patients will ask
speech production. Consultation from the examiner to define commonly used
a speech and language pathologist is nouns that are part of the neurologic
very helpful, unless the patient has examinationVfor example, ‘‘What is a
progressed so far into PPA as to be chair?’’ after the invitation, ‘‘Be seated
nearly mute and has lost comprehen- in that chair.’’ This aphasia can greatly
sion. While CBS can present with limit the neuropsychiatric evaluation.

Case 9-3
A 50-year-old, right-handed woman with 16 years of education was referred for possible primary
progressive aphasia. She reported an approximately 18-month history of slowly progressive difficulties
in expressing herself, which were insidious in onset.
She initially could not express herself in long, complex sentences, then with shorter sentences, and now
she even struggled with large words. Fatigue exacerbated her difficulties. She had reduced her
spontaneous speech, mostly out of embarrassment. She stuttered frequently. Although she had some
difficulty articulating, her speech made sense and was understood by other people. Furthermore, she had
no difficulty understanding what others were saying to her and specifically had not lost word meaning.
She reported no major changes to her personality. She showed excellent insight into her condition
and exercised good judgment; she expressed feeling sad and depressed when thinking about her
current difficulties, but this was not a constant mood, and there was no anhedonia. She also reported
approximately 1 year of mild weakness and lack of coordination in her left hand.
On examination, the patient was awake, alert, cooperative, and anxious. Overall, her cognitive
testing revealed some difficulties with attention and calculation, mild executive dysfunction, and
prominent difficulties with expressed language. Despite that, she scored 30/30 on the Mini-Mental
State Examination and 24/30 on the Montreal Cognitive Assessment (MoCA), losing one point for
calling a camel a ‘‘giraffe,’’ two points for repetition, one point for verbal fluency, one point for
abstraction, and one point for delayed verbal recall. On the short form of the behavioral neurology
assessment, she scored 87/114, above the cut-point for dementia.
Reduction of phrase length and simplification of grammar were evident in the patient’s spontaneous
speech and description of the ‘‘cookie theft’’ picture. She showed surface dyslexia with difficulty in
pronouncing orthographically irregular words as tested by the North American Reading Test (eg, simile,
lingerie). Her isolated buccal (‘‘ma ma’’), lingual (‘‘la la’’), and palatal (‘‘koo koo’’) sounds were normal,
but there was an apraxia of her speech when pronouncing whole words, especially with multiple
complex syllables (eg, artillery). Her comprehension was intact at the phrase-length level, but she had
mild difficulty with comprehending complex syntactical relationships, especially with multiple
prepositional phrases (eg, ‘‘This is the book given to the boy by the fireman from the same hometown
as the boy’s father’’). Her verbal fluency was decreased, particularly for F-word generation (nine
words in 1 minute) as opposed to animal-name generation (16 in 1 minute), and her sentence repetition
was markedly impaired, although single-word repetition was intact.
The patient performed below expectations for her educational level on tests of abstraction
(eg, ‘‘How are a man and a tree alike?’’) and proverb interpretations. She had difficulty with
visuoconstruction and placing the hands in the correct position on a clock.
On the remainder of the neurologic examination, she had very mild bilateral rigidity, slightly
elevated in the left arm more than the right, which was elicited with augmentation. Fine finger
movements and other rapid alternating movements were reduced in amplitude and precision in the
left hand and foot.
Assessments by a speech and language pathologist confirmed deficits in fluency and judgment of
semantic associations for abstract words and concepts, phonemic and mixed-phonemic/semantic
paraphasias, dyslexia, agrammatic speech output, and speech apraxia with lack of coordination of
alternating lip movements. A subsequent formal neuropsychological assessment revealed impairments
in verbal fluency, auditory working memory, and left finger-tap, with only selective executive
dysfunction and mild impulsivity in responses.
MRI of the patient’s brain showed a stable, small, linear hyperintensity in the posterior limb of the right
internal capsule; mild, generalized atrophy; and no diffusion weighting or susceptibility-weighted
imaging abnormalities (Figure 9-5). Single-photon emission computed tomographic (SPECT) scan of her
brain showed hypoperfusion in the right (but not left) frontal lobe.


Comment. The
most likely diagnosis is
a neurodegenerative
disease, and the
patient’s aphasia
resembles a
nonfluent/agrammatic
progressive variant.
However, her rigidity
in the left upper
extremity and loss of
left-hand agility
raise suspicion for
corticobasal
syndrome as the
underlying cause of
the aphasia, or (less
likely) an incipient
motor neuron
disease.
The finding
of right frontal
hypoperfusion may
indicate that she is
right-hemisphere
dominant for
language, and it
may indicate the FIGURE 9-5 Brain MRI slices from nonfluent/agrammatic aphasia due to corticobasal syndrome
were chosen for easier comparison to the other cases. A, Coronal section through
asymmetry of brain the anterior commissure shows right-greater-than-left mild frontal atrophy that
involvement seen radiologists reported as mild, general atrophy. Note absence of hippocampal atrophy. B, Slice to
right of midsagittal plane shows no anterior cingulate atrophy and impression of anterior more so
in corticobasal than posterior cortical atrophy. Arrows indicate anterior cingulate gyrus. C, Transaxial section
syndrome (CBS), shows subtle asymmetric atrophy of basal ganglia, and the right perisylvian fissure is enlarged.
which would explain D, More posterior coronal view, behind the hippocampus, indicates right high parietal atrophy.
her left-sided
motoric difficulties. Other patients have had right limb apraxia to go with nonfluent/agrammatic
progressive aphasia caused by CBS.
Patients with speech changes due to Parkinson disease may report lack of fluency, but Parkinson-related
speech changes (eg, hypokinetic dysarthria and hypophonia) leave grammar intact. Patients with
speech changes due to progressive supranuclear palsy (PSP) also experience hypokinetic dysarthria instead
of speech apraxia. Patients with CBS and PSP can both manifest vertical gaze palsy, but those with CBS
tend not to have the falls that are required for the diagnosis of PSP.16
The patient responded to active speech and language pathology intervention, as well as 100 mg
amantadine twice daily for approximately 1 year; she reported that the amantadine helped with
her subjective sense of fluency.24 There was no objective gain observable with this medication, however.
She transitioned into use of a communication device on her tablet computer to help communicate,
but as her CBS symptoms became more severe, she lost the ability to tap accurately on the screen.
Two years after diagnosis, the patient developed a decreased left arm swing. Dysphagia progressed
slowly, requiring jejunal tube placement 3 years after receiving the diagnosis of CBS.

KEY POINTS
TESTS described in the new clinical diagnostic h Given the early age
Neuroimaging criteria, may precede noticeable atrophy of onset of patients
Given the early age of onset of patients on structural imaging.25,30,31 Left pos- with frontotemporal
with frontotemporal degeneration, it is terior frontoinsular or left posterior degeneration, it is
important to rule out neoplasm or other perisylvian or parietal regions may be important to rule out
mass lesion. Brain MRI is preferred to CT abnormal in patients with a PPA neoplasm or other
in demonstrating the disproportionate syndrome.30 mass lesion.
frontal, insular, or anterior temporal lobe Another type of functional imaging h When structural imaging
atrophy in bvFTD, although structural that is becoming available to clinicians is inconclusive or the
changes are not necessarily present in is amyloid imaging. Imaging of typical patient is still within the
all cases or at very early stages of the early-onset cases with frontotemporal first few years of symptom
disease.1,13,25 In the advanced case of degeneration has not revealed any onset, functional
frontotemporal degeneration, neuroim- significant amyloid burden,32 leading neuroimaging may help
aging might show a preponderance of some neurologists to foresee a role for rule in the diagnosis (but
cannot rule it out).
atrophy in frontal and temporal lobes, Pittsburgh Compound B PET or
but more often patients show the same florbetapir PET in differentiating be- h Any unexpected or
severe global atrophy as seen in ad- tween AD and frontotemporal degener- abrupt changes in
vanced cases of the other neurodegen- ation. Comorbidity with amyloid plaques symptomatology, new
seizure onset, losses of
erative dementias. If moderate to (due to aging or to coincident AD) has
consciousness, or falls
severe white matter hyperintensities not yet been ruled out in late-onset
with head trauma could
are found on MRI, clinicians may con- cases of frontotemporal degeneration, warrant reimaging.
sider adult leukoencephalopathy with and this consideration may restrict clin-
axonal spheroids as a diagnosis.26 icians’ decisions to expose patients to
With advances in neuroimaging tech- the radiation involved in PET imaging
niques, several tools have emerged that unless the results can be illuminating.
are fairly effective at sorting the patterns Patients’ family members may ask
of atrophy among different subtypes about repeat imaging. As with other de-
from each other and from other dis- cisions regarding resource utilization, it
orders.27 However, semiautomated may be most appropriate to discuss with
volumetrics are not available through the family whether the results of a re-
routine clinical MRI facilities, nor are peat scan would change the patient’s
cortical thickness measurements.28 At- management. Certainly any unexpected
tempts to identify the same patterns or abrupt changes in symptomatology,
identified through these methods by new seizure onset, losses of conscious-
visual inspection have failed to show ness, or falls with head trauma could
either diagnostic accuracy or inter-rater warrant reimaging, but in those cases
reliability.29 acute neurologic care principles super-
When structural imaging is incon- sede the history of the frontotemporal
clusive or the patient is still within degeneration.
the first few years of symptom onset,
functional neuroimaging may help Formal Neuropsychological
rule in the diagnosis (but cannot rule Testing
it out). Predominant frontal or fronto- Depending on the educational level of
temporal hypometabolism on 18F- the patient or on the stage of illness, it
fluorodeoxyglucose positron emission may be difficult to elicit the neuropsy-
tomography (PET) or hypoperfusion on chological profile of bvFTD or the PPAs
99mTc-hexamethylpropyleneamine ox- with standard bedside testing. Additions
ime (HMPAO) single-photon emission to the bedside mental status test that may
computed tomography (SPECT), as help in evaluation of a frontotemporal

KEY POINTS
h It may be more helpful for degeneration should assess frontal toms. In one cohort of 40 patients with
the examiner to monitor lobe function. It may be more helpful frontotemporal degeneration, five pa-
the quality of performance for the examiner to monitor the quality tients (12.5%) had EMG results con-
for sustained attention; of performance for sustained attention; firming MND but not necessarily ALS.
response variability, set response variability, set shifting, and Of the five, three had bvFTD and two
shifting, and mental mental flexibility; monitoring and utili- had nonfluent progressive aphasia by
flexibility; monitoring and zation of feedback; and sequencing33 1998 Neary criteria.36 Conversely, when
utilization of feedback; than to concentrate on total scores for neuropsychological disturbances were
and sequencing than to the instruments administered. Clini- evaluated in patients diagnosed pri-
concentrate on total cians may wish to administer the Fron- marily with sporadic ALS, 5% met
scores for the instruments
tal Assessment Battery12 along with criteria for bvFTD and 9% met criteria
administered. Clinicians
the Mini-Mental State Examination34 for a primary progressive aphasia by the
may wish to administer
the Frontal Assessment
(MMSE) or the MoCA35 as a fairly time- 1998 Neary criteria.37 Patients meeting
Battery along with the efficient way to glimpse the frontal lobe criteria for both frontotemporal degen-
Mini-Mental State functions listed above. eration and ALS have the shortest
Examination or the Early in the illness, the patient may survival of all frontotemporal degener-
Montreal Cognitive be able to respond well enough to score ation subtypes, with a mean survival of
Assessment as a fairly within normal limits on tests such as the 2 to 3 years from the onset of first
time-efficient way to MMSE or the MoCA, but the quality of symptoms.6
glimpse the frontal lobe performance may betray the neuropsy-
functions listed above. chological profile sought for the diag- Speech and Language Pathology
h Symptoms of behavioral nosis of frontotemporal degeneration, Given the specifics of the new diagnostic
variant frontotemporal especially in the case of bvFTD. criteria for PPA, speech and language
degeneration may When bedside evaluation fails to pathology (SLP) consultation can assist
precede, follow, or coincide shed light on the diagnosis, consultation greatly in the differentiation among var-
with the onset of motor with a neuropsychologist can be helpful. iants of PPA; this evaluation can also help
neuron symptoms.
There are limitations to valid formal distinguish the aphasia seen in fronto-
h A referral to a genetics neuropsychological testing, however. temporal degeneration from the anomia
counselor should They include a need for a modicum of and semantic deficits seen in AD.
precede any collection of cooperation from the patient and clear
samples for genetic Genetic Testing
communication between the examiner
testing, unless the testing
and the patient. The patient’s behav- Families who are alerted to the possi-
is done for research
purposes and the results
ioral disturbances cannot keep him or bility of frontotemporal degeneration
will not be disclosed to her from participating; language must developing in future generations fre-
participants. be intact to at least show validity of the quently ask the neurologist to order
MMSE score; and a professional trans- genetic testing. A referral to a genetics
lator, not family member, may need to counselor should precede any collec-
be arranged for the testing to be valid. tion of samples for genetic testing,
unless the testing is done for research
EMG purposes and the results will not be
EMG is not routinely requested in an disclosed to participants. The impact of
evaluation for frontotemporal degener- genetic results (even if negative) is
ation unless there is suspicion of motor different for each member of the family,
neuron disease (MND) from a com- and the genetic counselor will explain
bination of upper and lower motor the importance of identifying who
neuron features on the elemental neu- should be privy to the results and edu-
rologic examination. Symptoms of cate the patient about how a negative
bvFTD may precede, follow, or coincide result relates to the diagnosis. A negative
with the onset of motor neuron symp- result will not rule out frontotemporal

KEY POINTS
degeneration; it may instead indicate ing diagnoses such as PPA and CBS. h Not all patients with
that the patient carries an as-yet- A major recent discovery identified family histories of similar
unidentified mutation that has caused C9ORF72,41,42 which appears to be the symptoms, Parkinson
his or her illness.38,39 Not all patients most common genetic abnormality disease, ALS, or primary
with family histories of similar symp- both in familial bvFTD (11.7% of cases) psychiatric disorder have
toms, Parkinson disease, ALS, or pri- and ALS (23.5%). This new mutation is an positive genetic testing.
mary psychiatric disorder have positive expansion of a noncoding GGGGCC h Positive family histories
genetic testing. Up to 40% of patients hexanucleotide repeat located in chro- are most commonly
with autopsy-confirmed FTLD have a mosome 9p.41,42 Whereas mutations elicited from patients
history that is suggestive of familial in MAPT are associated with deposi- with behavioral variant
transmission,40 with roughly 10% of tion of the hyperphosphorylated pro- frontotemporal
patients showing an autosomal domi- tein tau, both the GRN and C9ORF72 degeneration and
nant inheritance pattern.4 Positive fam- gene mutations are associated with de- frontotemporal
ily histories are most commonly elicited position of TDP-43.43 degeneration with ALS
and infrequently
from patients with bvFTD and fronto- Other rare mutations explain less
from patients with
temporal degeneration with ALS and than 1% of familial FTLD. Mutations in
semantic dementia.
infrequently from patients with seman- the gene encoding valosin-containing
tic dementia.4 protein on chromosome 9p13 can cause h The most common
clinical phenotype
Because it is rare for a patient with a syndrome associated with Paget dis-
associated with both
frontotemporal degeneration to have ease and inclusion body myositis. Muta-
MAPT and GRN mutations
any of the known mutations without a tions in the charged multivesicular body is behavioral variant
positive family history, genetics clinics protein 2B (CHMP2B) on chromosome frontotemporal
will generally consider the patient eligi- 3p11 are linked, like GRN and C9ORF72, degeneration, although
ble for testing only if he or she had an to MND and ALS.4 a more varied clinical
early age of onset and at least one af- spectrum has been
fected first-degree relative. Genetic test- CSF biomarkers associated with GRN
ing should not be considered a tool for There is no CSF biomarker specific mutations, including
differentiating between frontotemporal for the diagnosis of frontotemporal diagnoses such as primary
degeneration and AD, since so many degeneration. progressive aphasia and
cases may carry either type of pro- corticobasal syndrome.
teinopathy (eg, TDP-43 versus amyloid TREATMENT h A major recent discovery
plaques and neurofibrillary tangles) There is no cure or disease-modifying identified C9ORF72,
without also carrying one of the few therapy approved specifically for fronto- which appears to be the
known mutations for these dementias. temporal degeneration. Current man- most common genetic
abnormality both in
A significantly greater proportion of agement strategies rely on symptomatic
familial behavioral variant
frontotemporal degeneration cases than pharmacologic treatment and non-
frontotemporal
AD cases have known genetic muta- pharmacologic approaches to improve degeneration (11.7% of
tions. The three genes that may be quality of life for patients with fronto- cases) and ALS (23.5%).
sequenced at the lab for frontotempo- temporal degeneration and to mitigate
h There is no CSF biomarker
ral degeneration are the microtubule- the stress burden perceived by their
specific for the diagnosis
associated protein tau (MAPT), progranulin caregivers. of frontotemporal
(GRN), and C9ORF72. The first two genes degeneration.
account for 10% to 20% of familial cases Pharmacologic
and are both located on chromosome Readers are referred to the 2010 review
17q21. The most common clinical phe- by Kaye and colleagues44 for rationales
notype associated with both MAPT and behind drug categories used for symp-
GRN mutations is bvFTD, although a toms of frontotemporal degeneration
more varied clinical spectrum has been and a summary of the levels of evi-
associated with GRN mutations, includ- dence to support those prescriptions.

KEY POINTS
h The clinical trial yielding Clinical trials have been mainly negative, The numbers needed to harm may be
the highest level of and the few positive results are high- useful in obtaining informed consent
evidence (through a lighted below. A more general review from lay substitute decision-makers to
randomized, double-blind, about neuroprotective agents has been use these medications (as in Case 9-2).
placebo-controlled written by Lauterbach and Mendez.45 Acetylcholinesterase inhibitors de-
crossover trial) in Selective serotonin reuptake inhibi- veloped to improve symptoms of AD
frontotemporal tors (SSRIs) have shown some success do not seem to be effective in managing
degeneration used in treating compulsions and carbohy- symptoms of frontotemporal degener-
trazodone at a dose of drate cravings in patients with fronto- ation, perhaps because the cholinergic
100 mg orally three times temporal degeneration, although many neurons in the nucleus basalis of
a day.
of these studies were open-labeled and Meynert are relatively spared in fronto-
h One challenge for the not controlled trials. The clinical trial temporal degeneration. Furthermore,
clinician is to determine yielding the highest level of evidence acetylcholinesterase inhibitors may
whether the behavioral (through a randomized, double-blind, cause agitation in patients with fronto-
and psychiatric
placebo-controlled crossover trial) in temporal degeneration and are particu-
symptoms of dementia
frontotemporal degeneration used traz- larly dangerous for patients with
are a manifestation
along the anxiety
odone at a dose of 100 mg orally three frontotemporal degeneration with
spectrum (including times a day for a mixed group of BPSD.46 MND, since these medications may
obsessive-compulsive Because obsessive-compulsive behav- cause increased production of oral
features) or represent iors can be among the top challenges secretions.44
agitation. for caregivers, it is worth noting a re- Regardless of the medication pre-
h Acetylcholinesterase cent case series of clomipramine re- scribed, it behooves the clinician to
inhibitors developed to sponders.47 One challenge for the make sure that the caregiver under-
improve symptoms of clinician is to determine whether the stands the symptoms targeted by the
Alzheimer disease do BPSD are a manifestation along the an- medication so that there can be an on-
not seem to be effective xiety spectrum (including obsessive- going dialogue about whether the med-
in managing symptoms compulsive features) or represent ication is working or is still indicated.
of frontotemporal agitation. Medication recommenda- BPSD shift over the course of illness in
degeneration, perhaps tions for either of these can differ all dementias,48 and a medication that
because the cholinergic (anxiolytics versus sedatives), but empir- was once necessary likely needs to be
neurons in the nucleus
ic treatment recommendations for them tapered off as the brain regions corre-
basalis of Meynert are
can cut across dementia etiologies. lated to the BPSD lose connectivity and
relatively spared in
frontotemporal
Patients who do not respond to SSRIs function. Once the patient loses moti-
degeneration. and who show aggressive or delusional vation to communicate and ambulate,
behaviors may benefit from low doses the prescriber should review whether
h Regardless of the
of atypical antipsychotic drugs such as any remaining psychotropics are still
medication prescribed,
it behooves the clinician
olanzapine, quetiapine, or risperidone. warranted.
to make sure that the Typical and atypical antipsychotic drugs
caregiver understands known to result in extrapyramidal side Nonpharmacologic
the symptoms targeted effects should be avoided, since those While a patient’s sexual disinhibition
by the medication so with advanced frontotemporal degener- and hyperorality generally result in care-
that there can be an ation are likely to show parkinsonism. givers making changes to the environ-
ongoing dialogue about Maher and colleagues recently reported ment to remove stimuli and avoid the
whether the medication the numbers needed to harm for atyp- associated behaviors, repetitive and pur-
is working or is still ical antipsychotics frequently used in poseless behaviors such as pacing and
indicated. patients with dementia, as a follow-up to bruxism can be more challenging to
the US Food and Drug Administration relieve. One of the most influential
black box warnings about increased changes in behavioral management has
mortality due to cardiovascular events.48 been the shift away from medical

KEY POINTS
models of treatment for BPSD toward degeneration at the authors’ institution h One of the most
the reconceptualization of BPSD as was created through the hire of more influential changes in
responsive behaviors. Gentle, persua- recreational therapy staff, as opposed to behavioral management
sive approaches are being taught to more nursing.51 has been the shift away
long-term care facility staff, companions, from medical models of
and family members to address these Supporting Family and treatment for behavioral
behaviors without using chemical or Caregivers and psychiatric
physical restraints.49 When caregivers In the absence of a cure and the symptoms of dementia
begin with the assumption that an un- presence of a dementing illness that toward the
usual or dysfunctional behavior is the can go on for more than a decade, pro- reconceptualization
of behavioral and
patient’s way of signaling an unmet viding support to family members and
psychiatric symptoms of
need, they can open the door to cre- caregivers is a crucial part of the ongoing
dementia as responsive
ative thinking about how to address care in frontotemporal degeneration. behaviors.
those behaviors (for an example of an The equivalent of the Alzheimer’s Asso-
online resource for caregivers, see http:// ciation for these families is the Associa- h Because patients with
early-onset dementia
www.marep.uwaterloo.ca/products/ tion for Frontotemporal Degeneration
may have children with
managing.html). (www.theaftd.org). This organization a wide range of ages
provides education and support to care- who are active informal
CONSULTATIONS FOR givers, caregiver support group leaders, caregivers, there is a
MANAGEMENT and health care professionals seeking need for groups that
Speech and Language Pathology more information about frontotemporal support children and
SLP interventions for patients with PPA degeneration. emphasize balance
are often appreciated by the patient and Because patients with early-onset de- between growing up
family, even if the temporary gains it mentia may have children with a wide and caregiving.
offers are eventually overwhelmed by range of ages who are active informal
the illness. Swallow evaluations con- caregivers, there is a need for groups that
ducted by an SLP specialist later in support children and emphasize balance
the illness can help safeguard quality between growing up and caregiving.52
of life regarding nutrition, prevention Online resources for children and their
of infectious disease, and end-of-life well parents are available through
planning. www.theaftd.org, www.lifeandminds.
ca/whendementiaisinthehouse, and
Occupational, Physical, and http://research.baycrest.org/chow-lab.
Recreational Therapies Behavioral changes figure promi-
Clinicians naturally perceive a role for nently in the disease, so the safety of
occupational therapy in the context of the patient and those with whom he or
limb apraxia in CBS and PSP, but tips on she interacts must be a primary concern.
feasible activities to offset BPSD may also Having a social worker familiar with the
be gleaned from the experience.50 In in-home, financial, and long-term plan-
addition to occupational therapy, phys- ning needs of these families is a valuable
ical therapists may be important allies resource for clinics managing these
for maintaining safe ambulation and patients. As with all types of dementia,
mobility as a frontotemporal degenera- removing dangerous items from the
tion proceeds. Recreational therapists home (eg, firearms), deactivating driv-
are helpful in community, day program, ing privileges, and limiting access to
and hospital settings to identify some bank accounts must be facilitated by the
degree of meaningful activity that can health care team. Staff at caregiver
help distract the patient from BPSD. support agencies often do not have the
The day program for frontotemporal authority to write letters to officials or

bank managers to explain the illness and One strategy for future therapeutic
the family’s special needs. The social modalities would target protein-
worker or case manager can also pre- opathies. Thus far, clinical trials for
pare families for end-of-life decisions or tauopathy related to frontotemporal
organize family meetings to bring the degeneration have focused on PSP,
clinician, a nurse, and important decision- because it is a quicker model of demen-
makers for the patient together. It may tia due to tauopathy. Results of these
be useful to hold such family meetings clinical trials should be available within
shortly after the diagnosis has been the next few years. It is hoped anti-
made, and again as the cadence of ill- TDP-43 interventions will also become
ness is shifting more clearly toward end- available. Patients interested in trial
of-life decision-making.48 At the cur- enrollment can be referred to www.
rent level of knowledge, it is difficult to clinicaltrials.gov for IRB-approved clini-
anticipate with accuracy any patient’s cal trial details that are searchable by
survival at the outset of frontotemporal diagnosis and geographic location.
degeneration, but reviewing where the The authors also anticipate more
patient is relative to landmarks of be- evidence to support or refute the role
havioral disturbance, loss of motivation of prions in the spread of neurodegen-
and communication, and withdrawal erative disorders, including fronto-
from his or her former sphere of ac- temporal degeneration. Wong and
tivities and interests can help families colleagues are hopeful that prions can
understand where they are in the be counteracted with antibody ther-
course of illness and what the next 2 apy,56 and this could be an exciting
years may bring. Caregivers for all new modality of intervention for all
dementias are able to cope with their types of dementia.
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Review Article
Dementia in the
Dr Maria M. Corrada, University
of California, Irvine, 1513
Hewitt Hall, Irvine, CA 92697,
Oldest Old mcorrada@uci.edu.

Dr Bullain has received a
Szófia S. Bullain, MD; Marı́a M. Corrada, ScM, ScD travel scholarship from the
Orange County Chapter of the
Alzheimer’s Association to
attend an international
ABSTRACT conference and receives grant
support and other salary
Purpose of Review: This article discusses some of the unique features of dementia support from the National
in the oldest old, including some of the most common diagnostic challenges, and Institute on Aging. Dr Corrada
potential strategies to overcome them. receives research support from
the Alzheimer’s Association
Recent Findings: Advances include new insight into the role of common risk factors and the National Institute on
and the effects of multiple underlying neuropathologic features for dementia in the Aging.
oldest old. In addition, this article contains the latest age-specific normative data for Unlabeled Use of
commonly used neuropsychological tests for the oldest old. Use Disclosure:
Summary: The oldest oldVpeople aged 90 years and olderVare the fastest-growing Drs Bullain and Corrada
segment of society and have the highest rates of dementia in the population. The risk report no disclosure.
factors, diagnostic challenges, and underlying neuropathologic features of dementia * 2013, American Academy
of Neurology.
are strikingly different in the 90-years-and-older population compared to younger
elderly. Special consideration of these unique features of dementia is necessary when
evaluating oldest-old subjects with cognitive impairment.
THE OLDEST OLD years and older. In 2010, the oldest old
In this article, the oldest old refers to represented 4.7% of the elderly popu-
people who are 90 years old or older. A lation, and that number is expected to
report from the US Census Bureau pub- increase to 9.9% by 2050.1 Thus, the
lished in 2011 concluded that the com- oldest-old cohort is increasing not only
monly used definition of ‘‘oldest old’’ as in number but also in its proportion
those 85 and older was no longer within the population as a whole and
appropriate and argued for a new within the elderly population. The pro-
definition: those 90 and older.1 The jected expansion of this group is largely
90-and-older age group represents the due to the continued increase in hu-
fastest-growing segment of the US pop- man life expectancy,7 declining birth
ulation2 and is growing at a faster rate rate, and the aging of the populous
than the 85- to 89-year-old cohort. In ‘‘baby boom’’ generation.
2010, the oldest old accounted for ap- According to the US Census Bureau
proximately 1.9 million people in the report, the current oldest-old popula-
United States (0.6% of the US population is surprisingly homogenous across
tion). According to population projec- the United States.1 Most of the old-
tions by the US Census Bureau, this est old in the United States are well
number is estimated to more than quad- educated (over 60% have at least a
ruple to over 8.7 million by 2050 (2% of high school education), white (88%),
the total US population) (Figure 10-1).2Y6 and female (women outnumber men
The oldest-old population is also grow- 3 to 1 at this age). Nonetheless, the
ing as a proportion of the US elderly median annual personal income for the
population, defined as people aged 65 oldest old was only $14,760 from 2006

Dementia in the Oldest Old
slightly higher educational attainment

and socioeconomic status in the latter.
EPIDEMIOLOGY
The incidence of dementia, or the
frequency with which new cases devel-
op, doubles every 5 years after the
age of 65.13 Although previous studies
suggested that the incidence may pla-
teau in nonagenarians, this does not
appear to be the case. Based on find-
ings from the 90+ Study, the incidence
of dementia from all causes continues
to increase exponentially and is very
Projected growth of the 90+ population from similar in both men and women, even
FIGURE 10-1
1980 to 2050. in those of very advanced age: from
Data from US Census Bureau.2Y6 13% per year in the 90 to 94 age group,
to 21% per year in the 95 to 99
age group, to 41% per year in cente-
KEY POINTS to 2008, and 14.5% of them lived in narians; a doubling every 5.5 years
h The oldest oldVpeople poverty.1 (Figure 10-2).9 The overall incidence
aged 90 years and The rapid growth of the oldest-old rate of dementia in the study was
olderVare the
population will bring unprecedented around 18% per year. Other studies
fastest-growing
challenges for clinicians and public report a wide range of dementia inci-
segment of the society.
By 2050, the oldest old
health officials. With the oldest-old co- dence rates for the oldest old (from 6%
will account for 2% hort maintaining the population’s to 21% per year)14,15 most likely due to
of the US population. highest rates of disability1,8 and demen- differences in methodologies as well as
tia,9 the social and financial challenges in characteristics and number of sub-
h The oldest old have the
highest incidence and
of caring for the very elderly in the jects studied.
prevalence rates of coming decades will be enormous.10 Although incidence rates of dementia
dementia in the The 90+ Study, created to address in the oldest old are similar between
population. Women important questions about this under- men and women, a significant sex
have a higher prevalence studied age group, is a population-based difference exists in prevalence, or the
of dementia than men. study of dementia and aging in people proportion of men versus women with
The incidence of aged 90 years and older,11 with a subset dementia. In the 90+ Study, the disor-
dementia is similar in of participants who agree to eventual der is more common in women (45%)
men and women and postmortem examination. The study than in men (28%),16 similar to other
doubles approximately was established in 2003 and comprises studies.17 Moreover, after age 90, the
every 5 years after the
the survivors of the Leisure World Co- doubling of prevalence was observed
age of 90.
hort Study, an epidemiologic investi- in women but not in men. The sex dif-
gation of a retirement community in ference in dementia prevalence in the
Orange County, California, established 90+ Study may be explained by longer
in the early 1980s.12 Participants of survival of women after a diagnosis of de-
the 90+ Study are mostly white, well mentia compared to men; just as women
educated, and female; thus, representa- in general live longer than men, women
tive of the overall oldest-old population with dementia may live longer than men
in the United States.1 The main differ- with dementia. Longer survival in youn-
ences between the oldest old in general ger elderly women with dementia has
and participants of the 90+ Study are the been reported by other studies.18,19

KEY POINT
h Risk factors for cognitive
decline and dementia
appear to change with
age. In the oldest old,
some risk factors are no
longer relevant (eg, the
apolipoprotein E (4
allele) and some may
have a protective effect
(eg, hypertension).
FIGURE 10-2 Age-specific and sex-specific incidence rates

and 95% confidence intervals of all-cause
dementia in the 90+ Study. Note that rates
are plotted at the average age for each
category.
Data from Corrada MM et al, Ann Neurol.9 onlinelibrary.wiley.com/doi/
10.1002/ana.21915/abstract.
Age remains the most important risk mentia at ages over 85 years.27,28 Thus,
factor for dementia even in the oldest at older ages the highest risk of de-
old. However, the effect of common mentia and cognitive impairment ap-
risk factors for all causes of dementia pears to be in people with normal or
appears to change in late life, with some low blood pressure.27Y29 Possible mech-
risk factors losing their effects or having anisms for this effect have been pro-
opposite effects on the risk of dementia posed. In late life, vessel stiffness due to
in the oldest old. atherosclerosis, loss of elasticity, and
The APOE*E4 allele has been shown other age-related processes can lead to
to represent genetic susceptibility for changes in blood vessels, resulting in
Alzheimer disease (AD)20 and other cerebral hypoperfusion.30 Moreover,
types of dementia in younger elderly21; factors such as aggressive treatment with
however, its effect appears to diminish antihypertensive medications and age-
with age.22 As shown in several studies, associated autonomic dysfunction can
including the 90+ Study,23 APOE*E4 is lead to hypotension and subsequent
no longer a risk factor for dementia or hypoperfusion. Sustained hypoper-
AD in people who survive to very old fusion can result in hypoxic and ische-
age without dementia. mic injuries, such as microinfarcts,31
Midlife hypertension is a known risk which can directly result in dementia
factor for the development of dementia or affect its clinical expression. Main-
and AD later in life,24Y26 but evidence taining a certain level of blood pressure
indicates that hypertension is no longer may theoretically be necessary to sustain
a risk factor when present at very adequate blood perfusion and main-
advanced ages. In several studies, in- tain cognitive health in the oldest old.
creased blood pressure was associated Further research is needed to deter-
with risk of dementia at ages under 74 mine the exact role of blood pressure
years but was protective against de- levels and dementia in the oldest old.

KEY POINT
DIAGNOSIS OF DEMENTIA to his or her previous performance. In
h Cognitive performance
declines with age even Several diagnostic criteria are used in clinical practice, longitudinal data are
in subjects who are research and clinical settings to diag- generally not available, and performance
cognitively intact. Using nose dementia. One of the most widely is instead compared to standardized age-
age-specific normative used criteria is from the Diagnostic specific norms. In most investigations,
data is crucial to avoid and Statistical Manual of Mental the cognitive performance of oldest-old
overestimation of Disorders, Fourth Edition.32 According participants continues to decline with
cognitive impairment to these criteria, the diagnosis of age even in the absence of dementia.33
in oldest-old subjects. dementia (regardless of etiology) re- The availability of normative data for
quires the presence of several condi- the oldest old is therefore imperative
tions: (1) impairment in memory and because using normative data from
one additional cognitive domain, (2) younger populations could lead to over-
decline from a previous level of func- estimating the degree of cognitive im-
tioning due to cognitive impairment, pairment in the oldest old.
and (3) presence of cognitive deficits Table 10-1 shows normative data for
not only during delirium. several commonly used neuropsycho-
In an ideal setting, to determine logical tests to aid in the evaluation of
whether a person has cognitive impair- oldest-old patients with cognitive diffi-
ment, the subject’s cognition is compared culties. The norms derived from 655
a,b
TABLE 10-1 Age-Specific Norms for 10 Common Neuropsychological Tests: The 90+ Study
Number of
Test Age Participants Mean SD 5% 10% 25% Median 75% 90% 95%
Mini-Mental Status 90Y91 225 26.9 2.6 22 24 26 27 29 30 30
Examination 92Y94 229 26.5 2.5 21 23 25 27 28 29 30
95+ 132 25.4 2.8 20 22 24 26 27 28 29
Overall 586 26.4 2.7 21 23 25 27 28 29 30
Modified Mini-Mental 90Y91 224 90.8 7.5 77 83 87 92 96 98 99
Status Examination 92Y94 228 89.8 7.2 77 79 87 91 95.5 97 99
95+ 131 85.3 9.3 68 74 81 87 92 96 96
Overall 583 89.2 8.1 74 79 85 91 95 98 99
Boston Naming Test 90Y91 181 12.7 2.3 8 10 12 13 14 15 15
92Y94 177 12.0 2.4 8 9 11 12 14 15 15
95+ 81 11.2 2.4 8 8 9 11 13 14 15
Overall 439 12.1 2.4 8 9 11 13 14 15 15
Animal fluency 90Y91 241 13.4 4.5 7 8 10 13 16 20 21
92Y94 248 13.2 3.8 7 8 10 13 16 19 20
95+ 160 11.4 3.8 6 7 9 11 13.5 16 18
Overall 649 12.8 4.2 6 8 10 12 15 18 20
Letter F fluency 90Y91 191 12.1 4.2 5 7 9 12 15 18 20
92Y94 176 11.7 4.1 5 6 8.5 12 15 17 18
95+ 108 10.7 3.8 5 6 8 10 13 16 18
Overall 475 11.6 4.1 5 7 9 11 14 17 19

TABLE 10-1 Continued
Number of
Test Age Participants Mean SD 5% 10% 25% Median 75% 90% 95%
California Verbal 90Y91 201 4.6 1.7 2 2 4 5 6 7 7
Learning Test trial 1 92Y94 212 4.3 1.6 2 2 3 4 5 6 7
95+ 106 3.8 1.6 1 2 3 4 5 6 6
Overall 519 4.3 1.6 2 2 3 4 5 6 7
Learning Test 92Y94 209 4.9 2.7 0 1 3 5 7 8 9
long delay 95+ 105 4.1 2.5 0 0 2 4 6 7 8
Overall 515 5.0 2.7 0 1 3 5 7 8 9
Learning Test 92Y94 209 5.4 2.4 1 2 4 6 7 8 9
cued delay 95+ 105 4.9 2.2 0 2 3 5 6 8 8
Overall 514 5.6 2.4 1 2 4 6 8 8 9
Trails A 90Y91 188 60.2 27.4 32 36 42 51 71 97 110
92Y94 175 65.1 28.8 30 35 48 59 78 90 129
95+ 85 91.0 45.1 41 44 53 81 117 176 180
Overall 448 68.0 33.9 32 37 45 58 81 114 150
Trails B 90Y91 186 183.6 80.1 72 89 112 166 273 300 300
92Y94 167 197.8 84.4 80 91 123 185 300 300 300
95+ 76 249.0 72.8 99 127 186 300 300 300 300
Overall 429 200.7 83.7 80 92 127 188 300 300 300
Trails C 90Y91 179 26.7 14.6 13 14 18 23 32 42 50
92Y94 163 29.2 17.7 14 15 20 25 34 47 55
95+ 65 32.7 16.0 14 16 21 29 40 50 65
Overall 407 28.7 16.2 13 15 19 24 34 46 55
Clock drawing 90Y91 205 5.7 1.8 3 3 4 6 7 8 8
92Y94 201 5.4 1.9 2 3 4 6 7 8 8
95+ 114 5.0 2.0 2 2 4 5 6 8 8
Overall 520 5.4 1.9 2 3 4 6 7 8 8
SD = standard deviation.
a
Update to Whittle C, et al, J Clin Exp Neuropsychol.34
b
The Mini-Mental Status Examination and the Modified Mini-Mental Status Examination are tests of global cognition. The Boston
Naming Test is a 15-item test of confrontational naming. Animal fluency and letter F fluency tests are administered for 60 seconds. The
California Verbal Learning Test is a 9-word list to assess short-term memory with a 10-minute delay immediately followed by a cued
recall. Trails A and B are tests of executive function. In Trails A, participants connect dots in numerical order (1-2-3, etc). In Trails B,
participants connect dots by shifting sets 1-A-2-B-3-C etc. Trails C tests psychomotor speed by asking participants to trace a dotted line
connecting 25 circles. The clock drawing test asks participants to place numbers and hands at ‘‘ten after eleven’’ on a predrawn circle and
tests visuospatial abilities.
nondemented individuals from the tions (SDs), and percentiles for three age
90+ Study are an update to previously categories. Impairment is often defined as
published norms34 and include almost performance below the 10th percentile
twice as many subjects. Age-specific norms or performance 1.5 SDs below the mean
are presented as means, standard devia- of people in the same age category.

KEY POINT
h Vision and hearing Assessing the contribution of cogni- pacity. Functional disability due to
impairment, frailty, and tive impairment due to loss of func- physical impairment, cognitive impair-
fatigue are common in tional abilities in the oldest old can be ment, or both is very common in the
oldest-old patients and challenging. The prevalence of sensory oldest old.35 Because the diagnosis of
can easily affect loss, medical comorbidities, disability, dementia requires functional loss spe-
cognitive performance. and frailty are extremely high in the 90- cifically due to cognitive impairment, it
Modifications to years-and-older population. These con- is essential to accurately determine the
neuropsychological ditions can all contribute to loss of causes of the disability. To determine
testing to accommodate abilities in activities of daily living such more accurately the reasons for the
these limitations are as eating, bathing, and dressing, and in functional disability, information about
important to avoid
instrumental activities of daily living, function must be obtained from a va-
misdiagnosis of dementia
such as shopping for food, cooking, riety of sources, including the patient
in oldest-old subjects.
and managing medications. and his or her family, friends, and care
In the 90+ Study, over 70% of the providers.
participants have experienced some de- When gathering information from
gree of visual loss, hearing loss, or collateral sources, it is vital to factor in
both.33 To overcome these challenges, cultural and environmental expecta-
modifications were implemented in the tions. Social, occupational, and func-
design of the neuropsychological test- tional expectations of individuals over
ing forms and their administration to 90 years old are traditionally modest at
participants aged 90 years and older. best and often further attenuated by
Visual stimuli are presented in a large physical limitations, medical illness, or
font to all subjects to maximize visibil- sensory losses. The contribution of
ity, and sound amplifiers are given to memory impairment to functional loss
participants with hearing difficulties. In may also be minimized because of the
addition, the administration of several presence of preserved long-term mem-
common neuropsychological tests was ory. Although collateral information is
modified. For example, for the Mini- crucial for the diagnosis, the validity of
Mental State Examination (MMSE) and such information is sometimes question-
the short form of the California Verbal able because of reduced expectations
Learning Test-II, the words for recall are toward oldest-old subjects. Therefore, to
spoken in a loud, clear voice and simul- determine the contribution of cognitive
taneously shown to the participants on loss to functional disability, clinical judg-
a card with a large typeface. This type of ment is essential to evaluate and synthe-
multimodal presentation promotes the size the gathered information, especially
participant’s ability to register the appro- in light of the limited cultural and envi-
priate word despite sensory limitations. ronmental expectations.36 Case 10-1 illus-
Frailty and fatigue are also common trates the typical diagnostic challenges
in the oldest old and can have a det- clinicians face when evaluating oldest-
rimental effect on the subjects’ cognitive old patients for cognitive impairment.
performance and functional abilities. To
accommodate these limitations, exam- NEUROPATHOLOGY
iners shorten the standard evaluations, AD remains the most common underly-
provide frequent breaks, and divide the ing pathology of dementia in the oldest
evaluations into multiple visits as nec- old. In a recent clinicopathologic study,
essary to reduce the burden of pro- as many as 61% of participants met
longed testing. criteria for AD defined as intermediate
Another common diagnostic chal- or high likelihood according to National
lenge is the evaluation of functional ca- Institute on Aging and Reagan Institute

KEY POINT
Case 10-1 h Alzheimer disease

remains the most
A 94-year-old, right-handed woman with a medical history of severe
common pathology
osteoarthritis, macular degeneration, and paroxysmal atrial fibrillation
underlying dementia.
was referred for a neurologic evaluation by her primary care physician of
However, the relationship
more than 15 years. The primary care physician was concerned that the
between Alzheimer
patient’s forgetfulness was beyond age-related changes and requested
disease pathology and
further evaluation and possible treatment for dementia.
cognitive impairment
The patient was a widowed homemaker who had lived in an assisted
weakens in the oldest old.
living facility since the death of her husband 20 years ago. At the time of
Alzheimer disease
the first visit, the patient was accompanied by her son, who lived nearby.
pathology is also
As part of the initial evaluation, the patient underwent a comprehensive common in nondemented
neuropsychological evaluation and neurologic examination. Results of oldest old; about half of
the general and neurologic examinations were unremarkable, but the nondemented subjects
neuropsychological evaluation revealed impairment in global cognition have high levels of
(in the Mini-Mental State Examination and the Modified Mini-Mental State Alzheimer disease
Examination,37 memory (in the California Verbal Learning Test short, pathology at death.
long, and cued long delays), and visuospatial abilities (in a clock-drawing
exercise). The patient scored below the 10th percentile on these tests
compared to age-adjusted norms. When the patient was asked about her
functional abilities, she denied any impairment or decline in her functional
capacity. She stated that, although all of her instrumental activities of
daily living are done for her, she could do them on her own if she wanted.
When the patient’s son was asked confidentially about his mother’s
functional abilities, he denied any functional limitation due to cognitive
impairment. He stated that his mother had never handled the finances, so
it was natural for him to take over after his father’s death; he added
that she had a history of osteoarthritis and macular degeneration, and
these physical impairments were the sole reason she required help with
shopping, cooking, dressing, and bathing. He stated that the patient was
‘‘sharp as a tack’’ and remembered every detail of his childhood. However,
he admitted that she had a hard time remembering the grandchildren’s
names, ‘‘only because those names are too modern for her.’’
Comment. This patient had significant cognitive impairment in two
domains. She was likely in the early stages of dementia; however, the
diagnosis was difficult to establish because of insufficient evidence of
functional loss due to decline in cognition. At this early stage of dementia,
initiation of pharmacotherapy should be considered. This case illustrates
some of the typical diagnostic difficulties in the oldest old. Physical
limitations, such as visual loss or decreased mobility, often conceal the
degree of functional loss due to cognitive impairment. In addition,
although gathering reliable collateral information is crucial, diminished
cultural and environmental expectations may limit the validity of collateral
information in certain cases. The use of clinical judgment is critical.
criteria.38 Similarly, in the 90+ Study, exists between these two groups. The
54% of autopsied participants had in- high prevalence of AD pathology found
termediate or high likelihood of AD in nondemented participants in the
pathology.39 Although the proportion 90+ Study suggests that the clinical ex-
of AD pathology is higher in demented pression of the neuropathologic fea-
(57%) versus nondemented (49%) par- tures of AD changes in the oldest old. A
ticipants, great overlap in AD pathology population-based study by the Medical

Research Council Cognitive Function versus 1.42), hippocampal neurofibril-

and Ageing Study40 showed that the lary tangles (OR 8.61 versus 2.11),
association between AD pathology and neocortical neuritic plaques (OR 8.63
dementia diminished significantly with versus 2.48), and neocortical neurofi-
age. The prevalence of moderate or brillary tangles (OR 35.2 versus 7.0).
severe AD neuropathology increased Vascular pathology (which includes
with age in nondemented subjects, lacunar infarcts, large vessel infarcts, and
whereas it remained stable or decreased microinfarcts) is the second most com-
slightly with age in subjects with demon pathologic feature found in the
mentia (Figure 10-3). These changes oldest old (Figure 10-4). As described
resulted in weaker associations between in a recent review, between 75% and
AD pathology and dementia with ad- 90% of autopsied participants aged 90
vancing age. When comparing the odds years and older have some vascular
ratio (OR) for dementia between peo- pathology.41 Similarly, in the National
ple who died at age 75 and those who Alzheimer’s Coordinating Center neuro-
died at age 95, the OR declined for hip- pathologic dataset, which combines data
pocampal neuritic plaques (OR 10.19 from 25 Alzheimer Disease Research
FIGURE 10-3 Modeled and observed prevalence of moderate or severe pathologic lesions
according to age. Solid lines (people without dementia) and dotted lines
(people with dementia) represent the modeled prevalence of moderate to
severe pathologic lesions, whereas solid symbols represent the observed prevalence with 95%
confidence intervals depicted by the I bars.
40
Modified and reprinted from Savva GM, et al, N Engl J Med. B 2009, with permission from Massachusetts Medical
Society. www.nejm.org/doi/full/10.1056/NEJMoa0806142.

KEY POINT
h Vascular pathology is
the second most
common pathologic
feature in the oldest old.
Although the number of
large-vessel infarcts
decreases in the
90-years-and-older
population, the prevalence
of microinfarcts increases
significantly in the
oldest old.
FIGURE 10-4 Frequency of neuropathologies in demented and nondemented participants

from the 90+ Study.
NFT = neurofibrillary tangles; NP = neuritic plaques; CAA = cerebral amyloid
angiopathy; HS = hippocampal sclerosis; LBD = Lewy body disease.
Center sites in the United States, contribution to cognitive impairment is

cerebrovascular pathology was found often underestimated.
in more than 70% of autopsied partic- Similar to vascular pathology, the
ipants over the age of 90 years.42 frequency of hippocampal sclerosis in-
Interestingly, there is a notable shift creases with age. In the 90+ Study, hip-
in the frequency of the morphologic pocampal sclerosis was found in over
subtypes of vascular lesions in the oldest one-quarter of participants with demen-
old. At extreme ages, the frequency of tia but was rarely present in non-
large-vessel infarcts decreases, while demented subjects (Figure 10-4).47 In
smaller lacunar and microinfarcts be- other cohorts, the frequency of hippo-
come more common.43 Microinfarcts campal sclerosis increases noticeably
were found in 64% of autopsy partici- after age 95 to about one-fifth of all
pants in the Honolulu-Asia Aging Study, autopsies.42
an epidemiologic study of Japanese Other neuropathologies, such as de-
American men,44 with a mean age at mentia with Lewy bodies (DLB) and
death of 85.5 years, and in 48% of frontotemporal dementia and related
autopsied participants in a community disorders, are relatively rare in the
sample in the United Kingdom with a oldest old. The 90+ Study estimates
mean age at death of 90.7 years.45 the prevalence of DLB as less than 10%
Microinfarcts are increasingly being (Figure 10-4). Neuropathologic fea-
investigated as an important cerebro- tures of frontotemporal dementia and
vascular pathology in relation to cogni- related disorders, including corticobasal
tion and may be as strong a predictor degeneration and other Parkinson-plus
for dementia as AD.46 Because these syndromes, are rarely encountered in
lesions cannot be detected through subjects aged 90 or older, with an es-
conventional imaging procedures, their timated prevalence of each below 1%.42

KEY POINTS
h Accumulation of The accumulation of multiple pa- by almost threefold (OR of 2.8, 95% CI
multiple neuropathologic thologies is more common in the oldest of 1.2 to 6.7).48 In a report from two
features is common in the old than in the younger elderly. Where- community-based samples, mixed pa-
oldest old. The odds of as the association between dementia thologies were more common than
dementia increase with and AD neuropathology weakens from single pathologies in the oldest old.
increasing number of age 75 to age 95,40 the presence of Furthermore, the presence of multiple
pathologies. multiple neuropathologic features in- pathologies was more strongly related
h Approximately a quarter creases the odds of dementia signifi- to dementia than when AD was the only
of oldest-old people cantly in the oldest old. A community- neuropathology present.38
develop dementia based clinicopathologic cohort study of In spite of the multiple pathologies
without obvious older persons (mean age at death 87.9 T present in many participants aged 90 or
underlying pathology. 5.6) concludes that having one versus older, a relatively high percentage of
more than one underlying neuropathol- participants with dementia (22%) still
ogy (AD, vascular dementia, or DLB) have no obvious significant underlying
increases the odds of having dementia pathology to explain their cognitive
Case 10-2
A woman was 99 years old at the time of her death in a nursing home
after a 15-year history of slowly progressive cognitive decline. She was
a retired veterinarian and had been widowed at the age of 75. Her
symptoms were first noticed in her eighties, when she began getting lost
while driving; her license was revoked after she caused an accident by
driving against traffic on a one-way street. The visuospatial impairment
was soon followed by mild memory impairment and executive dysfunction.
The patient was no longer able to take care of her finances and required
help to remember her appointments. These changes prompted her
daughter to move in with her and seek formal neurologic evaluation when
the patient was 91 years old. At the time of the first evaluation, the
patient displayed significant impairment in memory (on the California
Verbal Learning Test), executive function (on the Trail-Making Test Parts A
and B), and praxis (performing learned skilled movements), scoring below the
10th percentile of her age-specific norms. Her score on the Mini-Mental State
Examination (MMSE) was 22; results of the neurologic examination were
otherwise normal. Noncontrast CT of the head revealed moderate diffuse
central and cortical atrophy and moderate periventricular white matter
disease. No additional acute or chronic intracranial pathologies were
identified. The diagnosis of probable Alzheimer disease was made, and
donepezil was initiated. The patient continued to decline gradually. Over
3 years her MMSE score dropped to 11, and she became dependent in all
activities of daily living and instrumental activities of daily living. Memantine
was added to her medications. A year later, her MMSE score was 10; she
started wandering and required constant supervision. The patient was moved
to a nursing home at the age of 96 when her daughter could no longer care
for her even with additional help. By age 98 she was completely bedbound,
incontinent, and mute. She died of aspiration pneumonia at the age of 99.
Despite the typical clinical course for Alzheimer disease, the autopsy
revealed minimal pathologic changes in the brain. Although the brain was
severely atrophic (brain weight 940 g), neurofibrillary degeneration was

KEY POINT
Continued from page 466 h The oldest old are
particularly susceptible
Braak and Braak stage III, and only sparse neuritic plaques were found to the unwanted
(Consortium to Establish a Registry for Alzheimer’s Disease plaque side effects of
score A). Neuropathologic evaluation also revealed mild atherosclerosis pharmacotherapy;
and two microinfarcts. No Lewy bodies, Pick bodies, or achromatic neurons therefore, the ‘‘start
were noted. In addition, the examination failed to reveal any signs of large low, go slow’’ approach
vessel or lacunar infarction, microhemorrhages, or hippocampal sclerosis. and nonpharmacologic
Comment. This case, in which individual pathologies are insufficient to alternatives are
explain the patient’s clinical presentation, occurs frequently in the oldest-old important in the
population. In the 90+ Study, 22% of participants with dementia did not treatment of dementia.
have sufficient pathology to account for their cognitive loss. The association
between common pathologic lesions and dementia in the oldest old is
poor, but growing evidence suggests that low levels of multiple pathologies
may be additive and may include some pathologies yet to be identified.
symptoms.39 Case 10-2 demonstrates a mentia, whereas others might be erro-

common scenario in which an oldest- neously diagnosed with dementia due
old patient with dementia presents to frailty, sensory losses, or comorbidi-
with a typical clinical manifestation ties that impair cognitive performance
and course of Alzheimer disease but is on neuropsychological testing. A mis-
found to have insufficient pathology on diagnosis of dementia may decrease
autopsy to explain cognitive deficits. the strength of association between the
The high prevalence of these discor- clinical diagnosis and the neuropatho-
dant cases (ie, cognitive impairment logic features of AD.
without significant underlying path-
ology) suggests that certain underlying TREATMENT
pathomechanisms of dementia in the Although the treatment strategies are
oldest old need better quantification or virtually the same for oldest-old subjects
are yet to be identified. as they are for the younger elderly, the
As discussed in the sections above, ‘‘start low, go slow’’ approach is particu-
several factors may be contributing to larly important in this patient population.
the weakened association between the Pharmacokinetics and pharmacodynam-
neuropathologic features of AD and ics change with aging. These age-related
dementia. First, the higher prevalence changes are particularly noticeable in
of coexisting non-AD pathologies may the oldest old and associated with a
weaken the association between the higher incidence of adverse events.49
clinical and neuropathologic features. Therefore, consideration of therapeutic
Second, the neuropathologic features alternatives (ie, nonpharmacologic in-
of AD may develop at a slower rate in terventions) should always be the first
people who survive beyond age 90, step. When pharmacologic manage-
allowing for compensatory mechanisms ment is initiated, close monitoring,
to take place.40 Finally, because of the careful evaluation of the duration of
diagnostic challenges discussed earlier, the therapy, and frequent reassessment
the diagnosis of AD might be less of indications for discontinuation of
accurate in the 90-years-and-older pop- medications are crucial in the medical
ulation. Some oldest-old subjects might management of dementia in oldest-old
be classified as nondemented when patients. In the current issue of
they are in the preclinical stages of de- , Dr Lon Schneider and

Dr Kristine Yaffe provide expert re- 11. Kawas CH. The oldest old and the 90+ Study.
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LIFELONG LEARNING IN NEUROLOGY ® \
Biomarkers of Alzheimer Disease:

Current and Future Applications to
Diagnostic Criteria
Sperling, Reisa MD; Johnson, Keith MD. CONTINUUM: Lifelong Learning in Neurology.
Volume 19(2) Dementia. April 2013: p 325Y338.
Abstract
ABSTRACT:
Purpose of Review:
This article reviews recent advances in imaging and fluid biomarkers for Alzheimer disease (AD)
and their application to newly proposed diagnostic criteria across the continuum of AD.
Recent Findings:
There have been remarkable developments in neuroimaging markers for AD over the past decade,
most notably the advent of positron emission tomography (PET) amyloid imaging using
radiotracers that label fibrillar forms of amyloid-A (AA). Similarly, new research in CSF markers
suggests CSF levels of AA1Y42 and phosphorylated tau may be useful in the early diagnosis of AD
and prediction of cognitive decline. The National Institute on Aging and the Alzheimer’s
Association recently convened three workgroups to develop joint recommendations for new
diagnostic guidelines across the spectrum of AD. These recommendations incorporate
biomarkers and propose updated criteria for the previously recognized stage of AD dementia, the
evolving definition of mild cognitive impairment, and a newly proposed concept of stages of
preclinical AD.
Summary:
Recent advances in AD biomarkers have increased the ability to detect evidence of early AD
pathology in vivo. These biomarkers have been incorporated into new diagnostic
recommendations, but a number of challenges remain for the biomarkers to become widely
applied in clinical practice.
Copyright * 2013, American Academy of Neurology. All rights reserved.

Key Points
& Biomarkers are conceptualized into two broad categories: (1) markers of amyloid-A
accumulation and (2) markers of neuronal injury or neurodegeneration.
& Paradoxically, Alzheimer disease is associated with a decrease in CSF amyloid-A1Y42 that
is generally thought to represent evidence that amyloid-A is polymerizing and depositing
as fibrillar plaques. PET imaging of amyloid-A utilizes derivatives of histopathologic
stains, such as thioflavins, that bind to fibrillar forms of amyloid-A.
& Recent studies suggest that amyloid PET is likely equivalent to demonstration of amyloid
plaque pathology at autopsy.
& A negative amyloid PET study signifies few or no amyloid deposits and indicates that the
likelihood of cognitive impairment due to Alzheimer disease is low.
& The most important concept to recognize in considering the high image-to-pathology
correlation is that amyloid positivity does not reliably distinguish clinical diagnoses.
& Increased levels of CSF tau and phosphorylated tau have also been demonstrated to
predict progression to dementia in subjects with mild cognitive impairment and are
already elevated in clinically normal mutation carriers in autosomal dominant familial
Alzheimer disease.
& The characteristic pattern of fluorodeoxyglucose abnormalities associated with
Alzheimer disease is bilateral temporoparietal hypometabolism.
& Convergent studies suggest that atrophy begins years before the diagnosis of dementia.
& Atrophy is not specific to Alzheimer disease.
& Amyloid might be necessary but not sufficient to result in Alzheimer disease dementia.
& The most common presentation of Alzheimer disease dementia is the amnestic form,
which involves impairment in episodic memory (ie, the ability to learn and retain new
information). However, some patients have initial involvement of other cognitive
domains, such as language or visuospatial or executive functioning.
& Alzheimer disease is increasingly recognized as a continuum.
Alzheimer Disease Pharmacologic

Treatment and Treatment Research
Schneider, Lon S. MD, MS. CONTINUUM: Lifelong Learning in Neurology. Volume 19(2)
Dementia. April 2013: p 339Y357.
Abstract
ABSTRACT:
Purpose of Review:
This article reviews marketed pharmacologic treatments for Alzheimer disease as well as their
efficacy, effectiveness, adverse effects, and issues involved in their use, including duration of
treatment, adverse events, and controversies. Current experimental drug development, including
challenges to developing successful drugs for Alzheimer disease, are also reviewed and assessed.

Recent Findings:
Cholinesterase inhibitors and memantine are the available pharmacologic treatment options.
They show limited clinical effects over the shorter term for some patients, mild to moderate
cholinergic adverse effects in a minority of patients, and potentially underappreciated toxicity
over the longer term. No subsequent experimental drug in development has been successful thus
far; there has not been a new drug marketed for Alzheimer disease since 2003.
Summary:
Cholinesterase inhibitors and memantine are marketed for the treatment of Alzheimer disease.
Drug development programs aimed at new targets, including the amyloid-A cascade, have been
unsuccessful thus far despite their designs to detect very small or minimal clinical effects from the
experimental drugs. Marked advances in preclinical science nevertheless support a basis for
considerable optimism that effective interventions will be found soon.
Key Points
& The cholinergic hypothesis of memory impairment implies that cholinergic deficits are
responsible for cognitive and behavioral changes in patients with dementia and
age-related memory impairment, and that augmentation of central cholinergic function
will improve cognitive function.
& Historically, the targeted cholinergic treatment approaches have included using (1)
acetylcholine precursors; (2) direct cholinergic agonists; and (3) cholinesterase inhibitors.
& The most common adverse events due to cholinesterase inhibitors include nausea,
diarrhea, vomiting, anorexia, and weight loss. Muscle cramps are common with
donepezil.
& Early cholinergic effects are frequently related to the initial dosing and titration of the
medications.
& Anorexia varies in incidence from 8% to 25% at higher doses of cholinesterase inhibitors
compared with 3% to 10% in patients on placebo and may be dose related. The proportion
of patients with weight loss in clinical trials ranges from 10% to 24% in patients taking
higher doses compared to 2% to 10% of placebo-treated patients.
& An analysis of Canadian medical and prescription records showed that patients on
cholinesterase inhibitors were hospitalized for syncope nearly twice as often as people
with dementia who did not receive these drugs.
& Despite differences in mechanism of action and dosing levels, no evidence exists for
efficacy differences between the three cholinesterase inhibitors. In a Cochrane review, the
drugs are associated with an overall mean 2.4 points effect over placebo on the Alzheimer
Disease Assessment ScaleVCognitive Subscale.
& A 23-mg extended release formulation of donepezil is intended to be used after a patient
has been treated with 10 mg/d for at least 3 months and when the clinician is uncertain
whether the patient is benefiting from the 10-mg dose.
& Cholinesterase inhibitors are not indicated for mild cognitive impairment, yet their use
may be common practice. Clinical trials of cholinesterase inhibitors in MCI were not
positive on their primary outcomes and showed an excess in adverse events.
& Memantine was approved by the US Food and Drug Administration in late 2003 for
moderate to severe Alzheimer disease. The basis for approval was positive outcomes on
two 6-month-long placebo-controlled clinical trials. In one trial cholinesterase inhibitors

were not allowed, and in another, patients had been taking donepezil for at least 6 months
(over 2 years on average). A third trial did not show significant effects.
& Only one of three trials of memantine in mild to moderate Alzheimer disease showed
significant improvement on the Alzheimer Disease Assessment ScaleVCognitive
Subscale and global assessment. Memantine has not been approved by the US Food and
Drug Administration for patients with mild Alzheimer disease.
& A Cochrane review concluded that memantine had a small beneficial effect in moderate to
severe Alzheimer disease and was well tolerated.
& Adverse events with memantine are infrequent but can include headache, dizziness,
confusion, somnolence, and infrequent hallucinations. In clinical trials, the frequency of
gastrointestinal symptoms is less than placebo; diarrhea occurred half as often.
& Extracts from leaves of the Ginkgo biloba, or maidenhair, tree are widely sold in the
United States as food supplements for which health claims are not permitted. A specific
standardized extract, EGb 761, is approved by the formularies of Germany and France.
& G biloba extract is also used as a memory enhancer in people without Alzheimer disease;
however, clinical trials in older and younger adults who do not have cognitive impairment
show mixed results at best.
& A Cochrane review that included 35 clinical trials reported inconsistent evidence that
G biloba had clinically significant benefits for dementia or cognitive impairment.
& A medical food is a food formulated for the dietary management of an illness that has
distinctive nutritional requirements, and is intended to be used under medical supervision.
& A formulation of medium-chain triglycerides is marketed as a medical food for Alzheimer
disease in the United States. Another medical food, marketed in late 2012 in Europe and
Brazil, is a combination of compounds including uridine, choline, omega-3 fatty acids,
phospholipids, B vitamins, and antioxidants, intended to enhance synaptic function and
neurotransmitters, presumably improving cognitive function. Controlled trials of these
two medical foods have not been positive.
& It is difficult to identify the individual patient who benefits from cholinesterase inhibitors
or memantine because the outcome measures and mean changes on scale scores do not
identify responders.
& Discontinuation of cholinesterase inhibitors has been associated with worsening of
cognition and confusion in some patients in trials. Yet worsening of behavior and
confusion do not appear common when the drugs are stopped in clinical practice. In
clinical practice, 19% to 23% of patients continued to take donepezil or rivastigmine for
more than 1 year, and about one-third discontinued the drugs within 2 months.
& In a withdrawal trial after maintenance treatment with donepezil for 2 to 3 years in
severely impaired patients with Alzheimer disease, continuing donepezil was associated
with better cognitive scores and activities of daily living. Many patients discontinued
donepezil without difficulty, and only half of the patients assigned to continue donepezil
actually continued treatment beyond the 1-year follow-up. Thus, the outcomes support
decisions either to continue medication or to taper and discontinue it when physicians are
uncertain of continuing benefit.
& Only three of 14 trials showed significant effects for cholinesterase inhibitors improving
behavior; none of these effects was large. Trivial effects were reported in the more mildly
cognitively impaired patients, but no effect was reported in the more severely impaired.
& Regulatory criteria for marketing symptomatic and disease-modifying therapies require
demonstrating improvements in cognition and activities of daily living, overall
improvements compared to placebo, and adequate safety.
& The gist of the amyloid cascade hypothesis is that amyloid-A deposition drives tau
phosphorylation, tangle formation, and neuron death.

& There are several amyloid-AYtargeted experimental approaches, including modulation of
amyloid-A production, inhibition of amyloid-A aggregation, enhancement of amyloid-A
degradation, and use of passive and active immunization to raise antibodies that target and
remove amyloid-A.
& The range of anti-tau therapeutic approaches under development include inhibiting
tau kinases; enhancing phosphatase activity in an effort to enhance microtubule stability;
blocking or inhibiting tau hyperphosphorylation, tau aggregates, and filament formation;
and enhancing clearance of aggregates with drugs or antibodies.
& Challenges to developing effective treatments for Alzheimer disease include the
uncertainty and lack of validated drug and molecular targets and the ability to conduct
efficient clinical development programs. Establishing validated drug targets requires
greater understanding of the pathogenic processes leading to illness.
New Genes and New Insights from Old

Genes: Update on Alzheimer Disease
Ringman, John M. MD, MS; Coppola, Giovanni MD. CONTINUUM: Lifelong Learning in
Neurology. Volume 19(2) Dementia. April 2013: p 358Y371.
Abstract
ABSTRACT:
Purpose of Review:
This article discusses the current status of knowledge regarding the genetic basis of Alzheimer
disease (AD) with a focus on clinically relevant aspects.
Recent Findings:
The genetic architecture of AD is complex, as it includes multiple susceptibility genes and likely
nongenetic factors. Rare but highly penetrant autosomal dominant mutations explain a small
minority of the cases but have allowed tremendous advances in understanding disease
pathogenesis. The identification of a strong genetic risk factor, APOE, reshaped the field and
introduced the notion of genetic risk for AD. More recently, large-scale genome-wide association
studies are adding to the picture a number of common variants with very small effect sizes.
Large-scale resequencing studies are expected to identify additional risk factors, including rare
susceptibility variants and structural variation.
Summary:
Genetic assessment is currently of limited utility in clinical practice because of the low frequency
(Mendelian mutations) or small effect size (common risk factors) of the currently known
susceptibility genes. However, genetic studies are identifying with confidence a number of novel
risk genes, and this will further our understanding of disease biology and possibly the
identification of therapeutic targets.

Key Points
& Although cases of Alzheimer disease inherited in a Mendelian fashion are rare
(accounting for approximately 1% of cases), genetic factors are likely to play an important
role in all forms of the disease.
& Studying large populations with sensitive techniques has allowed the identification of
several new genes consistently associated with Alzheimer disease risk. However, the
overall magnitude of the risk conferred by each of these is small, and therefore the clinical
relevance of these findings is as yet undefined. Nonetheless, study of the pathways
through which these genes contribute to Alzheimer disease pathology is an avenue toward
the identification of potential therapeutic targets.
& Although substantive disease-modifying interventions do not yet exist, these
advances have enabled definitive diagnosis of familial Alzheimer disease and
therefore can have significant effects on patients and their families in terms of
understanding the illness, its inheritance, and its prognosis. Furthermore, this progress
allows for the possibility of presymptomatic testing in unaffected at-risk subjects.
Therefore, clinicians should have a thorough understanding of the phenotypes and of
testing that is available.
& The existence of these groups of familialYAlzheimer disease families of specific ethnic
and geographic origins indicates that inquiring about patients’ ancestral origins can be
informative.
& In a retrospective chart review comparing clinical features between 32 patients
with familial Alzheimer disease due to PSEN1 mutations and 81 patients with
nonfamilial early-onset Alzheimer disease, those with PSEN1 mutations tended to be
younger (42 versus 56 years of age at onset), more likely to have memory complaints
as the presenting feature (84% versus 58%, with nonfamilial cases frequently
presenting with visuospatial and language deficits) and more likely to experience
significant headaches, myoclonus, gait abnormalities, and pseudobulbar affect.
The presence of such features in a young-onset case of Alzheimer disease when
the family history is unavailable should prompt the clinician to consider
genetic testing.
& Because the pathogenicity of identified variants in PSEN2 (and other familial Alzheimer
disease genes) is not always clear, caution needs to be exercised when interpreting results
of genetic testing with patients and their families.
& Trials to prevent familial Alzheimer disease by administering experimental
medications to asymptomatic mutation carriers are in development and should
commence in 2013.
& In humans, APOE is highly polymorphic; the APOE*E3 allele is the most common,
followed by the *E4 allele, which is in turn more common than the *E2 allele. The *E3,
*E4, and *E2 alleles, which differ in only one or two amino acids, have been reproducibly
shown to have differential effects on risk of late-onset Alzheimer disease, with *E4
conferring a greater risk than *E3, which in turn confers a higher risk than the *E2 allele,
with odds ratios between approximately 4 for heterozygous and approximately 15 for
homozygous carriers of the *E4 allele.
& There is ample convergent evidence for ApoE as a potential therapeutic target for
disease-modifying interventions in Alzheimer disease.
& The prevalence of the *E4 allele in the population varies depending on ethnicity but is
typically in the range of 15% to 20%. Among people with Alzheimer disease, the
prevalence is around 50%, again depending on the specific population being studied. The
increased risk conferred by the *E4 allele is generally thought to be a three- to fourfold

increase, and the lifetime risk of developing Alzheimer disease in someone with this
polymorphism is 50% among those who live to be 80 years of age.
& Although hundreds of genes have been implicated or studied at some point over the past
20 years in relationship with Alzheimer disease, only recent, large-scale studies and
rigorous statistical analyses (including correction for population stratification) have
allowed the identification of robust and replicable genetic risk factors for Alzheimer
disease.
& Ten Alzheimer diseaseYassociated variants explain approximately 20% of the total
variation of risk and approximately 33% of the risk attributable to genetic effects.
& Because of the small effect size (for common variants) and low frequency (for rare
variants), the advances in genetics still have very limited clinical utility.
Nonpharmacologic Treatment and

Prevention Strategies for Dementia
Yaffe, Kristine MD; Hoang, Tina MSPH. CONTINUUM: Lifelong Learning in Neurology.
Volume 19(2) Dementia. April 2013: p 372Y381.
Abstract
ABSTRACT:
Purpose of Review:
Epidemiologic studies can provide critical evidence to inform the timing and duration of
nonpharmacologic interventions. Although more studies are needed to further determine
long-term efficacy, the evidence supporting modifiable risk factors for prevention is compelling,
and prevention strategies that incorporate multidomain nonpharmacologic factors may have the
most impact.
Recent Findings:
Epidemiologic studies have identified a number of promising nonpharmacologic factors that have
the potential to lower the risk of developing dementia.
Summary:
Potential modifiable strategies for dementia prevention include cardiovascular risk factors;
lifestyle risk factors such as physical, cognitive, and social activity as well as nutrition, smoking,
and alcohol use; and sleep quality. Results of randomized controlled trials for the treatment of
cardiovascular risk factors have not been consistent, while interventions that increase physical,
cognitive, and social activity have demonstrated protective effects for dementia risk. Trials of
single-nutrient dietary supplementation have also been conflicting, but focus on multinutrient
supplementation shows promise. Observational data also indicate that sleep quality may be a
modifiable risk factor for dementia prevention.

Key Points
& Cardiovascular risk factors (including hyperlipidemia, hypertension, obesity, and
diabetes) are associated with increased risk of dementia.
& Results of previous treatment trials for hyperlipidemia and hypertension have been
mixed, but additional randomized controlled trials are needed to understand the potential
impact for dementia prevention.
& Epidemiologic studies indicate that physical activity may delay cognitive decline, and
evidence from early randomized controlled trials supports these findings.
& Interventions that increase a patient’s cognitive and social activity may have
the potential to serve as a buffer against the neuropathologic damage associated
with dementia.
& Nutrient deficits have been associated with increased risk of dementia. Single-nutrient
supplementation trials have not consistently demonstrated benefits, but results from
multinutrient trials are promising.
& Smoking is associated with increased risk of dementia, whereas moderate alcohol use
may have a protective effect.
& The evidence for sleep quality as a modifiable risk factor is preliminary, but observational
studies support a possible role for treatment of sleep disturbances and sleep-disordered
breathing.
& Epidemiologic studies can provide critical evidence to inform the timing and duration of
nonpharmacologic interventions.
& Nonpharmacologic interventions could play a major role in reducing dementia
prevalence, especially when their effects are considered collectively.
& The latest nonpharmacologic randomized controlled trials will test the efficacy of
targeting multiple modifiable risk factors, and future interventions may incorporate both
pharmacologic and nonpharmacologic methods.
The Clinical Problem of

in Dementia
Burke, Anna MD; Hall, Geri PhD, ARNP, GCNS, FAAN; Tariot, Pierre N. MD.
CONTINUUM: Lifelong Learning in Neurology. Volume 19(2) Dementia. April 2013:
p 382Y396.
Abstract
ABSTRACT:
Purpose of Review:
This article reviews behavioral signs and symptoms of dementia that can lead to increased
mortality, excessive cognitive and functional disability, early institutionalization, and increased
caregiver burnout.

Recent Findings:
Almost all patients with a dementia will develop significant behavioral disturbances at some point
over the course of their illness. These behavioral signs and symptoms rarely fit into usual
diagnostic classifications or meet full criteria for a formal major psychiatric disorder.
Summary:
Treatment of behavioral signs and symptoms of dementia should include both pharmacologic and
nonpharmacologic interventions. There are currently no treatments for these disturbances
approved by the US Food and Drug Administration. Best judgment should be used in identifying
dominant target symptoms and matching them to the most relevant drug class. Implementing
nonpharmacologic interventions before the development of neuropsychiatric symptoms may
prevent triggers related to a progressively lowered stress threshold and therefore is key in the
treatment of all patients with a dementia.
Key Points
& Neuropsychiatric signs and symptoms in dementia are common, morbid, and distressing
and occur in predictable clusters.
& The Neuropsychiatric Inventory trigger questions may be useful for detecting and
tracking neuropsychiatric signs and symptoms in dementia.
& Neuropsychiatric signs and symptoms in dementia occur more readily as dementia
progresses because of progressively lowered stress threshold.
& A systematic approach to help evaluate, manage, and treat neuropsychiatric signs and
symptoms in dementia is helpful.
& No medication for treatment of neuropsychiatric signs and symptoms in dementia is
approved by the US Food and Drug Administration, although this does not preclude
clinician judgment regarding clinical necessity.
& Cholinesterase inhibitors and memantine are approved by the US Food and Drug
Administration for treatment of dementia due to Alzheimer disease and may mitigate
neuropsychiatric signs and symptoms in dementia.
& There is no first-line recommendation for medications to treat agitation without
psychosis.
& Atypical antipsychotics may be first-line treatment for clinically significant psychosis but
should be discontinued if ineffective.
& Predictable triggers for neuropsychiatric signs and symptoms in dementia can be identified.
& Refer to basic precepts for care of people with dementia.
The Diagnostic Evaluation of a Patient

With Dementia
Galasko, Douglas MBBCh. CONTINUUM: Lifelong Learning in Neurology. Volume 19(2)
Dementia. April 2013: p 397Y410.

Abstract
ABSTRACT:
Purpose of Review:
This review outlines a practical approach to the history, mental state, neurologic examination, and
laboratory tests in the diagnosis of dementia.
Recent Findings:
Proposed new diagnostic criteria for Alzheimer disease recognize that nonamnestic presentations
with symptoms that predominantly affect language, visuospatial abilities, or executive function
may occur, particularly with onset before the age of 65. New criteria assign greater likelihood to
diagnosis if progressive cognitive decline is documented through serial assessment, or if
biomarkers are supportive. In patients aged 80 or older, more than one cause of dementia is often
present, for example, Alzheimer disease plus vascular dementia. Clinical diagnostic criteria for
non-Alzheimer dementias are evolving, particularly in areas such as frontotemporal dementia.
Imaging and CSF biomarkers have been proposed in recent diagnostic criteria for Alzheimer
disease. Although biomarkers can provide a higher level of certainty that Alzheimer pathology
may or may not be present, biomarkers for non-Alzheimer dementias are lacking.
Summary:
The availability of biomarkers does not replace or diminish the need for a thorough clinical
evaluation. A structured clinical approach helps to define the diagnosis and collects information
essential for establishing a comprehensive care plan for patients with dementia and their families.
Key Points
& It is useful to determine the patient’s degree of insight into problems, because this will
influence his or her acceptance of elements of a care plan.
& Symptoms that point to a major memory problem include asking questions repeatedly;
forgetting details of conversations, appointments, and plans; not paying bills on time; and
not recalling the details of TV shows or movies. These types of problems need to be
distinguished from complaints that are usually blamed on memory but reflect
age-associated cognitive changes.
& The clinician should always inquire about activities that could pose significant safety risks
in the setting of dementia.
& Behavioral symptoms are common in patients with dementia, may provide diagnostic
clues, and should be considered when formulating a treatment plan.
& The goals of cognitive testing are to document performance of memory and other key
cognitive domains, to define areas of strength and weakness that may support a diagnosis,
and to help stage the severity of dementia.
& The term ‘‘memory impairment’’ is often used loosely in relation to Alzheimer disease.
The major feature of memory impairment in Alzheimer disease is episodic memory,
which depends on the structural integrity of the hippocampus and allows us to encode and
remember where or when something happened.
& Focal findings consistent with stroke, or a gait disorder not explained by other factors,
may support a cerebrovascular contribution to dementia.

& In cases in which a decision about dementia could substantially alter the patient’s life
(eg, a patient who is still working) or in which there are legal questions (eg, competency to
manage assets), detailed neuropsychological evaluation can strengthen the clinical
diagnosis and provide sensitive indices of the degree of impairment.

Lopez, Oscar L. MD. CONTINUUM: Lifelong Learning in Neurology. Volume 19(2) Dementia.
April 2013: p 411Y424.
Abstract
ABSTRACT:
Purpose of Review:
The term mild cognitive impairment (MCI) is used to describe older subjects with demonstrable
cognitive impairment who have not crossed the threshold for dementia. Because patients with
MCI have an increased risk of developing dementia, especially Alzheimer disease (AD), there is
significant interest in the clinical characterization of these subjects and in understanding the
pathophysiology of the transition from MCI to AD.
Recent Findings:
The MCI syndrome, as an expression of an incipient disorder that may lead to dementia, is
extremely heterogeneous and may coexist with systemic, neurologic, or psychiatric disorders that
can cause cognitive deficits. Recent clinical criteria were designed to take into account the
different forms of clinical presentation of the syndrome, and introduced the possible contribution
of biomarkers to the clinical diagnosis. Bedside diagnosis of MCI can be difficult, since patients
who report having cognitive problems may have normal scores in global cognitive scales or in
brief neuropsychological instruments.
Summary:
This article presents the evolution of the clinical concept of MCI, the operationalization of its
current definitions, the development of biomarkers that can help to identify an underlying
neurodegenerative process as the etiology of the syndrome, and its proposed treatments.
Key Points
& Patients with mild cognitive impairment are at risk of developing dementia, especially
Alzheimer disease.
& The mild cognitive impairment syndrome is not restricted to memory deficits, and these
patients can present with a much broader cognitive syndrome, which may not include
memory impairments.
& The prevalence of mild cognitive impairment in the general elderly population ranges
from 2% to more than 20%.

& The mild cognitive impairment syndrome with memory-only deficits is less prevalent
than mild cognitive impairment with a much broader cognitive syndrome in the
general population.
& The mild cognitive impairment syndrome, as an expression of an incipient
neurodegenerative disorder that may lead to dementia, is extremely heterogeneous
and may coexist with systemic, neurologic, or psychiatric disorders that can cause
cognitive deficits.
& Approximately 20% of patients with diagnosis of mild cognitive impairment return to
normal cognition on follow-up examination.
& Patients with mild cognitive impairment can present with mild deficits in instrumental
activities of daily living.
& Increased CSF phosphorylated tau and decreased AA-42 protein levels increase the
short-term risk of conversion to Alzheimer disease in mild cognitive impairment patients.
& Decreased metabolism in temporal-parietal regions, including the precuneus (detected
with fluorodeoxyglucose-PET), and increased amyloid deposition (detected with amyloid
ligands) increase the risk of conversion to Alzheimer disease.
& Biomarker studies should be interpreted with caution. Although they indicate that
Alzheimer disease pathology is present, they do not provide information about when the
patient will progress to an Alzheimer disease clinical dementia.
& There are no therapies that can prevent the conversion from mild cognitive impairment to
Alzheimer disease. However, studies conducted with cholinesterase inhibitors have
shown a modest cognitive improvement in subjects with mild cognitive impairment
treated with these medications compared to placebo.
Understanding and Treating Vascular

Cognitive Impairment
Gorelick, Philip B. MD, MPH, FAAN; Nyenhuis, David PhD, ABPP. CONTINUUM: Lifelong
Learning in Neurology. Volume 19(2) Dementia. April 2013: p 425Y437.
Abstract
ABSTRACT:
Purpose of Review:
It is estimated that one in three people will experience a stroke, dementia, or both during their
lifetime. The goal of this article is to assist clinicians in the identification and treatment of patients
with vascular cognitive impairment (VCI). To that end, we will discuss the scope and definition of
VCI; how this definition can be applied in clinical practice; VCI epidemiology and pathogenesis,
its clinical features, and assessment; and prevention and treatment of this disorder.
Recent Findings:
During the past decade, we have gained a more complete understanding of clinical manifestations
of VCI (eg, the importance of executive function and memory), what it looks like pathologically
(eg, the role of cerebral amyloid angiopathy, microinfarcts, and ‘‘silent’’ strokes), and how VCI

relates to other disease processes (eg, co-occurrence with Alzheimer disease). A recent American
Heart Association and American Stroke Association guidance statement clarified the construct of
VCI, including the severity of cognitive and behavioral dysfunction contained under the
definition of VCI and the presence of both ‘‘pure’’ and ‘‘mixed’’ VCI forms. VCI treatments
approved by the US Food and Drug Administration are still lacking, and challenges remain
regarding how to convert promising observational study findings that link stroke and coronary
heart disease risk factors to cognitive impairment and dementia into evidence-based
preventive methods.
Summary:
VCI is a common contributor to cognitive impairment in later life. Because the risk of Alzheimer
disease may be heightened by the same risk factors that make us susceptible to stroke and
coronary heart disease, these borderlands merit careful consideration as we strive to preserve
cognitive function throughout the aging process.
Key Points
& Vascular cognitive impairment is defined as ‘‘a syndrome with evidence of clinical stroke
or subclinical vascular brain injury and cognitive impairment affecting at least one
cognitive domain.’’ Vascular cognitive impairment therefore encompasses all of the
potential levels of cognitive severity, from its mildest form detectable by
neuropsychological assessment to full-blown vascular dementia.
& Strokes and Alzheimer disease often occur concomitantly and pose risks for one another.
& Vascular dementia has been considered the second leading cause of progressive and
irreversible dementia after Alzheimer disease.
& Neuropathologic studies show an additive influence or correlation between Alzheimer
disease pathology and cerebral infarction in the manifestation of cognitive impairment.
& Traditionally, survival in Alzheimer disease is longer than in vascular dementia or mixed
dementia, but survival varies according to the patient’s age, race or ethnic group, and
severity of cognitive impairment.
& Lowering blood pressure in patients who do not have cognitive impairment can reduce the
risk of subsequent cognitive impairment, whereas lowering blood pressure to preserve
cognition among patients who already have cognitive impairment remains unproven as a
successful strategy.
& Risks for stroke, such as hypertension, hypercholesterolemia, hyperhomocysteinemia,
elevated body mass index and fat intake, atrial fibrillation, diabetes mellitus, cigarette
smoking, and metabolic syndrome, are now considered risks not only for vascular
cognitive impairment but also for Alzheimer disease.
& In addition to clinically manifest strokes, vascular cognitive impairment may have an
underpinning of subclinical cerebrovascular brain injury.
& At the microscopic level of the brain, the neurovascular unit is a conduit for
neurovascular dysfunction.
& The most common form of vascular cognitive impairment is the subcortical type.
& Regional white matter integrity (whether on the side of a recent acute cerebrovascular
brain injury or not) and thalamic density have been suggested as possible pathogenetic
links for risk of vascular cognitive impairment based on diffusion tensor imaging and
voxel-based morphometry study, respectively.
& The clinical picture of patients with vascular cognitive impairment may be linked with the
volume and location of the underlying pathology.

& Individual patients may show both focal neurocognitive deficits associated with the
location of their stroke lesions and a more diffuse pattern, depending on the presence and
extent of subcortical cerebrovascular brain injury.
& Given the lack of clarity from research studies and the fact that many elderly patients with
dementia and cognitive impairment have multiple sources of brain pathology, clinicians
should be cautious about basing their clinical diagnosis solely on the pattern of
cognitive deficits.
& The pattern of memory impairment in vascular cognitive impairment can be qualitatively
different from that of Alzheimer disease.
& It is important to screen for depressive symptoms in patients with suspected
cerebrovascular brain injury.
& Reliably differentiating functional disability due to physical (eg, hemiparesis) versus
cognitive and behavioral impairment is a specific difficulty in examining for impaired
activities of daily living after stroke.
& There is reasonable evidence to suggest blood pressureYlowering therapy as a useful
intervention for people who are middle-aged and younger elderly (Class IIa, Level of
Evidence B); however, the usefulness of lowering blood pressure for those over
80 years of age for the prevention of dementia is not well established (Class IIb, Level of
Evidence B).
& Further robust and consistent studies are necessary to provide clear, concise answers
to important research questions regarding the role of vascular risks for cognitive
impairment and dementia.
& Currently no drugs that have gained wide acceptance for use in practice have been
approved by the US Food and Drug Administration for the treatment of vascular
cognitive impairment.
& The failure of the cholinesterase inhibitors to successfully treat patients with vascular
dementia on an across-the-board cognitive and functional basis has raised questions
regarding whether there is an absence of cholinergic deficits in pure vascular dementia.
Incorporating New Diagnostic

Schemas, Genetics, and Proteinopathy
into the Evaluation of
Chow, Tiffany W. MD; Alobaidy, Ammar A. MD. CONTINUUM: Lifelong Learning in
Abstract
ABSTRACT:
Purpose of Review:
Within the continuously growing body of knowledge in the field of dementia, frontotemporal
degeneration stands out in importance as the second most common cause of early-onset dementia

after Alzheimer disease. Neurologists, neuropsychologists, and speech pathologists are
particularly involved in the diagnosis and recognition of etiologies for patients with deficits in
frontal lobe function and language.
Recent Findings:
The recent discovery of a novel mutant gene (C9ORF72) and the new nomenclature adopted for
subclassification have significantly promoted our understanding of this disorder.
Summary:
This article relates the most recent consensus criteria for diagnosis of the two forms of
frontotemporal degeneration (ie, behavioral and primary progressive aphasia variants) to basic
neurologic principles and remind clinicians of the neuropsychiatric and neuroradiologic
components that clarify frontotemporal degeneration diagnoses and guide management.
Key Points
& Diagnostic criteria now allow for a subclass of possible behavioral variant frontotemporal
degeneration, which represents earlier stages of illness in which neuropsychological testing
in high-functioning patients may not reveal executive deficits or in which neuroimaging
does not yet support regional atrophy or regional dysfunction.
& Consultation with speech and language pathologists (especially in mildly affected cases)
is invaluable, as some of the features of the primary progressive aphasias are difficult to
identify without subspecialty training.
& Unlike probable behavioral variant frontotemporal degeneration, activities of daily living
are maintained well into illness, except those related to language (eg, using the telephone).
& The description of logopenic progressive aphasia is new to the consideration of
frontotemporal degeneration syndromes, and its inclusion remains somewhat
controversial because of the Alzheimer disease pathology found in a fair number of
logopenic variant cases.
& Semantic variant primary progressive aphasia (formerly known as semantic dementia)
may be most easily distinguished by the loss of single-word meaning.
& Given the early age of onset of patients with frontotemporal degeneration, it is important
to rule out neoplasm or other mass lesion.
& When structural imaging is inconclusive or the patient is still within the first few years
of symptom onset, functional neuroimaging may help rule in the diagnosis (but cannot
rule it out).
& Any unexpected or abrupt changes in symptomatology, new seizure onset, losses of
consciousness, or falls with head trauma could warrant reimaging.
& It may be more helpful for the examiner to monitor the quality of performance for sustained
attention; response variability, set shifting, and mental flexibility; monitoring and utilization
of feedback; and sequencing than to concentrate on total scores for the instruments
administered. Clinicians may wish to administer the Frontal Assessment Battery along with
the Mini-Mental State Examination or the Montreal Cognitive Assessment as a fairly
time-efficient way to glimpse the frontal lobe functions listed above.
& Symptoms of behavioral variant frontotemporal degeneration may precede, follow, or
coincide with the onset of motor neuron symptoms.
& A referral to a genetics counselor should precede any collection of samples for genetic
testing, unless the testing is done for research purposes and the results will not be
disclosed to participants.

& Not all patients with family histories of similar symptoms, Parkinson disease, ALS, or
primary psychiatric disorder have positive genetic testing.
& Positive family histories are most commonly elicited from patients with behavioral
variant frontotemporal degeneration and frontotemporal degeneration with ALS and
infrequently from patients with semantic dementia.
& The most common clinical phenotype associated with both MAPT and GRN mutations is
behavioral variant frontotemporal degeneration, although a more varied clinical spectrum
has been associated with GRN mutations, including diagnoses such as primary
progressive aphasia and corticobasal syndrome.
& A major recent discovery identified C9ORF72, which appears to be the most common
genetic abnormality both in familial behavioral variant frontotemporal degeneration
(11.7% of cases) and ALS (23.5%).
& There is no CSF biomarker specific for the diagnosis of frontotemporal degeneration.
& The clinical trial yielding the highest level of evidence (through a randomized,
double-blind, placebo-controlled crossover trial) in frontotemporal degeneration used
trazodone at a dose of 100mg orally three times a day.
& One challenge for the clinician is to determine whether the behavioral and psychiatric
symptoms of dementia are a manifestation along the anxiety spectrum (including
obsessive-compulsive features) or represent agitation.
& Acetylcholinesterase inhibitors developed to improve symptoms of Alzheimer disease
do not seem to be effective in managing symptoms of frontotemporal degeneration,
perhaps because the cholinergic neurons in the nucleus basalis of Meynert are relatively
spared in frontotemporal degeneration.
& Regardless of the medication prescribed, it behooves the clinician to make sure that the
caregiver understands the symptoms targeted by the medication so that there can be an
ongoing dialogue about whether the medication is working or is still indicated.
& One of the most influential changes in behavioral management has been the shift away
from medical models of treatment for behavioral and psychiatric symptoms of dementia
toward the reconceptualization of behavioral and psychiatric symptoms of dementia as
responsive behaviors.
& Because patients with early-onset dementia may have children with a wide range of ages
who are active informal caregivers, there is a need for groups that support children and
emphasize balance between growing up and caregiving.

Bullain, Szófia S. MD; Corrada, Marı́a M. ScM, ScD. CONTINUUM: Lifelong Learning in
Abstract
ABSTRACT:
Purpose of Review:
This article discusses some of the unique features of dementia in the oldest old, including some of
the most common diagnostic challenges, and potential strategies to overcome them.

Recent Findings:
Advances include new insight into the role of common risk factors and the effects of multiple
underlying neuropathologic features for dementia in the oldest old. In addition, this article
contains the latest age-specific normative data for commonly used neuropsychological tests for
the oldest old.
Summary:
The oldest oldVpeople aged 90 years and olderVare the fastest-growing segment of society and
have the highest rates of dementia in the population. The risk factors, diagnostic challenges, and
underlying neuropathologic features of dementia are strikingly different in the 90-years-and-older
population compared to younger elderly. Special consideration of these unique features of
dementia is necessary when evaluating oldest-old subjects with cognitive impairment.
Key Points
& The oldest oldVpeople aged 90 years and olderVare the fastest-growing segment of the
society. By 2050, the oldest old will account for 2% of the US population.
& The oldest old have the highest incidence and prevalence rates of dementia in the
population. Women have a higher prevalence of dementia than men. The incidence of
dementia is similar in men and women and doubles approximately every 5 years after the
age of 90.
& Risk factors for cognitive decline and dementia appear to change with age. In the oldest
old, some risk factors are no longer relevant (eg, the apolipoprotein E D4 allele) and some
may have a protective effect (eg, hypertension).
& Cognitive performance declines with age even in subjects who are cognitively intact.
Using age-specific normative data is crucial to avoid overestimation of cognitive
impairment in oldest-old subjects.
& Vision and hearing impairment, frailty, and fatigue are common in oldest-old patients and
can easily affect cognitive performance. Modifications to neuropsychological testing to
accommodate these limitations are important to avoid misdiagnosis of dementia in
oldest-old subjects.
& Alzheimer disease remains the most common pathology underlying dementia. However,
the relationship between Alzheimer disease pathology and cognitive impairment weakens
in the oldest old. Alzheimer disease pathology is also common in nondemented oldest
old; about half of nondemented subjects have high levels of Alzheimer disease pathology
at death.
& Vascular pathology is the second most common pathologic feature in the oldest old.
Although the number of large-vessel infarcts decreases in the 90-years-and-older
population, the prevalence of microinfarcts increases significantly in the oldest old.
& Accumulation of multiple neuropathologic features is common in the oldest old. The odds
of dementia increase with increasing number of pathologies.
& Approximately a quarter of oldest-old people develop dementia without obvious
underlying pathology.
& The oldest old are particularly susceptible to the unwanted side effects of
pharmacotherapy; therefore, the ‘‘start low, go slow’’ approach and nonpharmacologic
alternatives are important in the treatment of dementia.

Ethical Perspectives
‘‘Will I Get Alzheimer

Dr B. Joy Snider, Washington
University, Campus Box 8111
(BT 229), 660 S Euclid Ave,
St Louis, MO 63110,
sniderj@neuro.wustl.edu.
Disease?’’ When
Dr Snider receives research
support from Eli Lilly and
Company for a clinical drug
Cognitively Normal
trial and anticipates serving as
a site principal investigator
and coinvestigator on such
trials in the future. Dr Buckles
Patients Ask to be Tested
reports no disclosure.
Unlabeled Use of
for Alzheimer Disease
Use Disclosure: B. Joy Snider, MD, PhD; Virginia D. Buckles, PhD
Drs Snider and Buckles report
no disclosures.
of Neurology. ABSTRACT
This article presents the case of a cognitively normal patient who is requesting a
procedure (amyloid imaging) recently approved for the diagnosis of Alzheimer
disease (AD) in patients with cognitive impairment. The predictive value of this test
in unaffected people is not clearly established. Knowing the results of the test will
have no effect on therapeutic options, although the patient may make lifestyle
decisions based on the results. There is potential risk to the patient in terms of
insurability, employability, and psychological consequences. Physicians will face this
situation with increasing frequency as the AD biomarker field progresses.
Case
Note: This is a hypothetical case.
A 62-year-old insurance agent presents with the complaint that her
memory is ‘‘terrible.’’ She reports that she can no longer recall the names
of her clients, which has led to embarrassing situations on a couple of
occasions. The patient’s husband accompanies her to the clinic and reports
that she has an excellent memory for recent events and remains very
active: she runs a successful business, volunteers at the local library, serves
on several committees at their church, manages the household finances,
planned a recent family vacation, and is an excellent cook. She scores 30/30
on the Mini-Mental State Examination (MMSE), and the results of her
neurologic examination are normal. She is able to provide a thorough
medical history. After being reassured that her cognition is normal, the
patient reports that her mother developed dementia at age 70. She read
online about spinal fluid and imaging tests that can detect Alzheimer disease
(AD) before symptoms appear and she would like to be tested so she and her
husband can plan their retirement.

DISCUSSION
Alzheimer disease (AD) is the most common cause of dementia in older adults;
as the population ages, the number of patients who are concerned about AD
will increase. The diagnosis of dementia and the determination of whether AD
is the likely etiology of dementia is typically based on a careful history to assess
intra-individual change in cognition and functional performance, neurologic
examination, and if needed, cognitive or neuropsychological testing. More
specific diagnostic testing, such as analysis of CSF or positron emission tomog-
raphy (PET) imaging using amyloid imaging agents, has not been widely used
in clinical practice. Online and print media coverage has increased public
awareness of this testing,1 particularly since May 2012, when the US Food and
Drug Administration approved florbetapir, an 18F-labeled PET imaging agent
that detects amyloid deposition in the brain. Patients and their families will
likely request this testing even in cases like this one, in which the patient
appears not to have any cognitive impairment.2
What is the physician’s responsibility in this setting? What ethical issues are
raised by this patient’s request?
1. Does the principle of autonomy mean that the physician is obligated to
order amyloid imaging (florbetapir PET scan) or AD-specific CSF studies
because the patient requests them, or can the physician decide whether to
order these tests?
2. Given the uncertainty around test interpretation in cognitively normal
patients, how do the principles of informed consent apply in counseling the
patient about the risks, benefits, and interpretation of this testing?
3. Imaging with florbetapir is indicated for the evaluation of patients with
cognitive impairment. How does the physician weigh potential risks versus
benefits and apply the principles of beneficence and nonmaleficence for a
patient who has no evidence of cognitive impairment?
Clinicians should first determine whether patients have had a decline in
cognitive function. In this case, self-reported concerns are limited to mild word-
finding difficulty. The patient’s husband confirms that her thinking remains
good compared to her baseline, and her performance on recall of personal
autobiographical events, a sensitive indicator of cognitive change,3 is excellent.
The results of her MMSE, although not a sensitive indicator of cognitive change,
are reassuringly normal as well. If further testing were needed, other tests of
memory, language, and executive function could be performed in the office or
by a neuropsychologist. Repeat testing in 6 to 12 months might also be helpful
to document whether the patient’s cognitive function is stable or declining.
Supporting Patient Autonomy and Providing Information Needed

for the Patient to Participate in Decision Making
It is important to understand why patients have concerns about their memory.
In this case, the patient is nearing the age when her mother developed
dementia, and she may have symptoms of anxiety or depression that merit
further investigation or treatment. She requests information about her future
risk of developing dementia in order to guide decisions regarding retirement
and long-term care. She may simply want more certainty about the future and
better insight about when she might experience cognitive decline. To address

Biomarker Testing in Normal Patients
these issues, the physician should determine whether the testing offers
prognostic value for a patient with no apparent cognitive impairment. In
patients with cognitive changes, even those with mild cognitive impairment,
CSF biomarkers and PET amyloid imaging ligands may play a role in differential
diagnosis.4Y6 In cognitively normal participants, however, the diagnostic and
prognostic value of these tests are not established. Patients with biomarker
evidence and possibly pathologic changes of AD are more likely to have brain
atrophy and lower cognitive test scores and are at higher risk of developing
cognitive changes in the future.7Y10 The only study to date looking at the
predictive value of positive florbetapir imaging included 10 cognitively normal
participants with a florbetapir scan interpreted as positive for amyloid de-
position. This group had slightly more decline than those with a negative scan
on two out of seven cognitive tests over an 18-month period.11
Clearly, the presence of brain amyloid is not benign, but there has not been
sufficient longitudinal research to know whether it predicts risk of disease or
time to disease onset. The few longitudinal studies published find that the risk
of developing cognitive changes in the near future (1.5 to 4.0 years) is around
fivefold greater when CSF or amyloid imaging biomarkers (eg, Pittsburgh
Compound B or florbetapir) are positive.7,11 Perhaps more importantly to the
patient in this case, many to most participants (one-third to two-thirds) with
positive biomarkers remained cognitively normal throughout the follow-up period.
The lifetime risk for developing AD in a 65-year-old woman is about 20%12; what, if
any, additional prognostic information a positive CSF or amyloid imaging bio-
marker study provides in an asymptomatic person remains unknown. The
physician could address the patient’s concerns by recommending repeat cog-
nitive testing in 3 to 6 months or formal neuropsychological testing to monitor
for mild cognitive changes.
The process of informed consent presumes that information is shared in
such a way that the patient can understand it to make an informed decision.
However, relative risk and statistical significance are concepts that may not
easily be understood by patients. For example, 64% of participants who were
counseled about the risk of developing AD associated with their APOE status
could correctly (ie, with a 5% margin of error) recall their risk 6 weeks later, but
almost half of these participants perceived their personal risk for AD as different
from the accurately recalled risk.13 Despite such challenges, physicians must
make the best effort possible to explain the implications of the test results and
what they might mean for the individual patient.
Balancing Benefit and Harm

Results of florbetapir testing in a cognitively normal patient could have both
beneficial and harmful effects, so the principles of beneficence and non-
maleficence apply. Although a negative test might be reassuring, it does not
preclude development of AD in the future. Furthermore, because no medications
have been shown to prevent the onset of AD, a positive test would not change
treatment. Arguably, a patient with a positive test could be more strongly
encouraged to undertake measures such as prevention or control of cerebrovas-
cular risk factors (eg, blood pressure and lipid control) and to make other
potentially beneficial changes in lifestyle (eg, diet, exercise, intellectual and social
engagement) that are thought to play a significant role in the development of

dementia, but these risk-reduction strategies are appropriate for all patients. Even
in people with cognitive impairment, from mild impairment to frank dementia, test
results often do not change treatment, although they do provide more diagnostic
certainty (eg, AD dementia versus a frontotemporal dementia) and can offer
prognostic information.
Physicians are obligated to minimize harm, which includes anticipating and
mitigating the potential for negative psychological effects of learning that one is
more likely to develop a progressive and potentially fatal disease. Dementia
diagnosis disclosure has not received significant research attention, but in a
controlled study, Carpenter and colleagues14 found little evidence of cata-
strophic reaction even in patients with mild dementia, and some evidence of
relief that an explanation for symptoms was provided. However, the situation in
this case study may be more similar to disclosure of susceptibility or deterministic
genetic test results in asymptomatic patients. When paired with genetic coun-
seling, two studies found no negative psychological reactions after deterministic
disclosure15 and no difference in test-specific distress between patients receiving
susceptibility (APOE*E4-positive) versus deterministic (PSEN1) results.16 Studies
in people tested for dominantly inherited forms of dementia including AD and
Huntington disease suggest that, with appropriate screening and counseling,
disclosure of test results may produce anxiety and depression in some par-
ticipants, but these reactions are not severe.17Y19 Health care reform in the
United States regarding ‘‘preexisting conditions’’ may negate the threat a positive
test might hold toward future insurability for long-term care and health insurance.
Ramifications for employability could be moot if retirement is imminent. Were
the patient to receive results positive for brain amyloid, the physician could
consider referring the patient for subsequent counseling and follow-up.
CONCLUSION
While the patient might argue that results of this testing could provide
information useful in making decisions about her future, the principle of
autonomy does not give the patient the right to demand a test, particularly one
that is not approved for that indication (predicting risk of dementia in cognitively
normal patients) and has no known diagnostic or prognostic value given the
patient’s current condition. However, the physician does have an obligation to
address the patient’s concerns and can do so by offering appropriate evaluation
and follow-up (ie, repeat cognitive testing and neuropsychological evaluation)
and reassuring her that the observed changes are not suggestive of the
beginnings of a dementia. Some patients may not be reassured and may con-
tinue to request testing; the physician must then weigh the potential benefit of
testing (eg, relief or reduced anxiety if the result is negative; planning for long-
term care, estate planning, or other lifestyle changes if the result is positive)
versus potential harms of a positive test (eg, emotional harm of patients
concluding they will certainly develop AD). If a physician decided to agree with
testing in this setting, counseling before and after testing (similar to that done for
patients with genetic forms of dementia) should be strongly considered.
NOTE
New guidelines by the Amyloid Imaging Taskforce of the Alzheimer’s
Association and the Society of Nuclear Medicine and Molecular Imaging have

Biomarker Testing in Normal Patients
recently been published recommending that amyloid imaging is inappropriate

in asymptomatic individuals (www.alz.org/research/downloads/appropriate_
use_criteria_for_amyloid_pet_alz_and_dem_january_2013.pdf ).
REFERENCES
1. Doraiswamy PM. Answers about Alzheimer’s, part 1. The New York Times. November 12, 2012.
www.nytimes.com/2012/11/14/booming/answers-about-alzheimers-part-1.html?pagewanted=
all&_r=0. Accessed January 2, 2013.
2. Hauser SL, Josephson SA, Johnston SC. Florbetapir: knowing one’s future. Ann Neurol 2012;
71(6):A6.
3. Dreyfus DM, Roe CM, Morris JC. Autobiographical memory task in assessing dementia. Arch
Neurol 2010;67(7):862Y866.
4. Clark CM, Schneider JA, Bedell BJ, et al. Use of florbetapir-PET for imaging beta-amyloid
pathology. JAMA 2011;305(3):275Y283.
5. Holtzman DM. CSF biomarkers for Alzheimer’s disease: current utility and potential future use.
Neurobiol Aging 2011;32(suppl 1):S4YS9.
6. Matsuda H, Imabayashi E. Molecular neuroimaging in Alzheimer’s disease. Neuroimaging
Clin N Am 2012;22(1):57Y65, viii.
7. Fagan AM, Roe CM, Xiong C, et al. Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction
of cognitive decline in nondemented older adults. Arch Neurol 2007;64(3):343Y349.
8. Stomrud E, Hansson O, Blennow K, et al. Cerebrospinal fluid biomarkers predict decline in
subjective cognitive function over 3 years in healthy elderly. Dement Geriatr Cogn Disord 2007;
24:118Y124.
9. Fagan AM, Head D, Shah AR, et al. Decreased cerebrospinal fluid Abeta(42) correlates with brain
atrophy in cognitively normal elderly. Ann Neurol 2009;65(2):176Y183.
10. Fagan AM, Mintun MA, Shah AR, et al. Cerebrospinal fluid tau and ptau(181) increase with
cortical amyloid deposition in cognitively normal individuals: implications for future clinical trials
of Alzheimer’s disease. EMBO Mol Med 2009;1(8Y9):371Y380.
11. Doraiswamy PM, Sperling RA, Coleman RE, et al. Amyloid-$ assessed by florbetapir F 18 PET and
18-month cognitive decline: a multicenter study. Neurology 2012;79(16):1636Y1644.
12. Weinstein G, Wolf PA, Beiser AS, et al. Risk estimations, risk factors, and genetic variants
associated with Alzheimer’s disease in selected publications from the Framingham Heart Study.
J Alzheimers Dis 2012;Epub ahead of print.
13. Linnenbringer E, Roberts JS, Hiraki S, et al. ‘‘I know what you told me, but this is what I
think:’’ perceived risk of Alzheimer disease among individuals who accurately recall their
genetics-based risk estimate. Genet Med 2010;12(4):219Y227.
14. Carpenter BD, Xiong C, Porensky EK, et al. Reaction to a dementia diagnosis in individuals with
Alzheimer’s disease and mild cognitive impairment. J Am Geriatr Soc 2008;56(3):405Y412.
15. Molinuevo JL, Pintor L, Peri JM, et al. Emotional reactions to predictive testing in Alzheimer’s
disease and other inherited dementias. Am J Alzheimers Dis Other Demen 2005;20(4):233Y238.
16. Cassidy MR, Roberts JS, Bird TD, et al. Comparing test-specific distress of susceptibility versus
deterministic genetic testing for Alzheimer’s disease. Alzheimers Dement 2008;4(6):406Y413.
17. Meiser B, Dunn S. Psychological impact of genetic testing for Huntington’s disease: an update of
the literature. J Neurol Neurosurg Psychiatry 2000;69(5):574Y578.
18. Steinbart EJ, Smith CO, Poorkaj P, Bird TD. Impact of DNA testing for early-onset familial
Alzheimer disease and frontotemporal dementia. Arch Neurol 2001;58(11):1828Y1831.
19. Dufrasne S, Roy M, Galvez M, Rosenblatt DS. Experience over fifteen years with a protocol for
predictive testing for Huntington disease. Mol Genet Metab 2011;102(4):494Y504.

Practice
Genetic Testing for

Dr Jack W. Tsao, Department
of Neurology, Uniformed
Services University of the
Early-Onset Alzheimer Health Sciences, 4301 Jones

Bridge Rd, Room A1036,
Bethesda, MD 20814,
Disease jack.tsao@usuhs.edu.
Dr Tsao holds stock in
Illumina and Biogen.
Jack W. Tsao, MD, DPhil, FAAN Unlabeled Use of
Use Disclosure:
Dr Tsao describes preliminary
ABSTRACT findings with genetic testing.
The availability of testing for identified risk genes for Alzheimer disease (AD) in Disclaimer:
The opinions or assertions
patients with clinically probable AD or their at-risk family members raises important contained herein are the
questions for the neurologist. Because the potential benefits and risks of testing private views of the author
vary for each patient, physicians need to evaluate whether it is appropriate on a and are not to be construed as
official or as reflecting the
case-by-case basis. This article outlines the testing decision process and serves as a views of the Department of
guide to assist clinicians with associated counseling and result disclosure. Because the Navy or the Department
genetic testing is relatively new and preventive and therapeutic options for AD of Defense.
remain limited, it is important to remain sensitive to and understand the specific * 2013, American Academy
of Neurology.
challenges associated with obtaining these tests in the routine clinical setting.
Case
NOTE: This is a hypothetical case.
A 60-year-old man is brought by his family for evaluation of several
years of progressive memory loss and apathy. He recently became unable
to balance his checkbook and has had several episodes of being unable to
remember where he parked his car. His family history is notable for a
paternal cousin and a maternal aunt who, by report, were also diagnosed
with dementia (unknown ages). The patient and his family would like to
clarify the diagnosis but are concerned because they have read about
early-onset Alzheimer disease and its genetic linkages, and they are unsure
whether genetic testing should be performed. Upon examination, the
patient’s speech is slow but fluent with some secondary naming errors
(ie, referring to more specific parts of objectsVthe patient properly
identified the wrist band of a watch but was unable to name the buckle of
a belt) and normal repetition. His performance on the Trail-Making Test
Part B is slow but accurate. The patient is unable to perform the serial 7’s
or serial 3’s tasks and scores below normal when asked to name words
beginning with the letters F, A, and S. He is able to follow two-step but
not three-step commands. His abilities in both figure copying and clock
drawing are inaccurate. The results of his routine dementia laboratory
studies are normal, and the neurologist confirms that the presentation
is most consistent with Alzheimer disease (AD). Should genetic testing
be pursued?

Genetic Testing for Alzheimer Disease
DISCUSSION
Genetic Risk Factors
Several genetic risk factors for AD have been identified. The major susceptibility
genes for early-onset AD (less than 65 years of age) are PSEN1, PSEN2, and APP.
Mutations in each gene alter APP metabolism, resulting in increased production
of a toxic form of the amyloid-" peptide.1 The major susceptibility gene for late-
onset AD (aged over 65 years) is the APOE gene, particularly the *E4 allele,
although recently TREM2 has been identified as another susceptibility gene. The
presence of this allele is associated with increases in the risk of disease as well
as a lower age of onset. Homozygous *E4 carriers have a greater risk and an
earlier age of onset than heterozygous carriers.2 Additionally, several common
genes are linked to the development of AD, but individually hold less predictive
value.3 For people who live a normal lifespan, PSEN1 or APP mutations are
associated with complete penetrance, and PSEN2 mutation is associated with
95% penetrance.4,5
Genetic Testing
Because AD treatment is currently focused on managing clinical symptoms rather
than on affecting a cure, the issue of genetic testing is controversial. Physicians
must evaluate the risk-to-benefit ratio of genotyping for patients and their
families on a case-by-case basis. In the case example, it would first be important
to obtain a detailed, three-generational family history to help determine whether
a familial inheritance pattern exists. Generally, testing is conducted when there is
evidence of autosomal dominant inheritance, as mutations are otherwise unlikely
to be easily detected. Testing is preferred for symptomatic patients, such as the
patient described in the case, rather than for those who are asymptomatic or only
mildly symptomatic. Similarly, predictive testing is somewhat uncommon. Ge-
netic tests are rarely used diagnostically because a positive autosomal dominant
test can only confirm diagnosis in an affected patient. A negative test does not
necessarily exclude disease, as tests can produce false negatives and positive
biomarkers are not a prerequisite for AD diagnosis.
Because both known and presumed unknown mutations associated with AD
exist, a negative test does not rule out genetic components to the dementia. A
typical genetic test examines the three known autosomal dominant AD genes:
PSEN1, PSEN2, and APP. APOE gene testing is generally not performed, as a
mutation in this gene is neither necessary nor sufficient to cause AD, the testing
has low sensitivity and specificity, and the role of APOE*E4 has not been fully
elucidated and is not subject to mitigation strategies.6Y9 However, the public
seems to have an interest in this type of genotypingV15% of primary care
physicians receive APOE genotyping requests from their patients with AD.10,11
Pediatric and prenatal testing is not recommended because of the great
variability in symptomology and age of onset.8
Nonetheless, genetic testing does hold the potential to help inform families of
a possible cause of disease, to offer an explanation for the symptoms observed in
the affected individual, and to give family members an answer regarding whether
they might be affected in a similar manner, which allows for earlier life-planning
decisions. People who test positive for various genetic mutations may become

eligible for therapeutic research studies, thereby allowing them the opportunity
to contribute to general AD research.
A plethora of additional concerns need to be considered when advising on
whether a patient should undergo testing. Results are not straightforward, as
multiple genes are known to be associated with AD. The presence or absence of
a mutation cannot serve to singularly confirm or exclude a disease diagnosis.
Variability regarding phenotypic changes, age of onset, and disease course cannot
be definitively explained or predicted by genetic testing. Further, the expense of
testing, compounded with a general lack of insurance coverage for the tests,
creates financial barriers to genotyping. Although the 2008 Genetic Information
Nondiscriminatory Act (GINA) offers protection against genetic discrimination in
relation to employment and health insurance, clinical testing is still relatively new,
and problems with application of the law continue to exist.
Genetic Counseling
Physicians should always pair testing with genetic counseling. Sometimes,
patients and their families may benefit from receiving such counseling even
before the tests are performed. This facilitates a thorough discussion of all the
risks and benefits and clarifies that there are currently no established methods
for preventing the onset or halting the progression of AD. Clinicians are en-
couraged to serve as a source of information regarding progress with AD re-
search and established and experimental treatments. It is beneficial to have at
least one family member present for the patient’s counseling, as informed
consent for testing is required and decisions are likely to be especially difficult
for patients with dementia.12 Furthermore, positive test results may implicate
family members as being at risk, and this impact should be discussed.
Patients should be advised to consider their course of action for each po-
tential outcome, including how they will communicate the results to their family
members. Physicians are advised to keep in mind that results cannot be re-
scinded and to thoroughly assess the psychosocial impact of testing. Testing
positive for a genetic mutation may be especially overwhelming for patients or
family members not experiencing disease symptoms. A follow-up appointment
should be scheduled before initiating testing so that the patients will be assured
that they have the opportunity to discuss next steps.
Disclosure of Results
Clinicians face social and ethical challenges when disclosing test results to
patients. People who learn that they are genetically predisposed to developing
AD may become anxious or depressed. They may undertake risky lifestyle
changes, such as pursuing unsupported prevention or treatment efforts. Also,
patients who test positive for APOE mutations have been recognized as being
nearly 6 times more likely to alter their long-term care insurance than those
who remain unaware of genotyping results.13 Because there is a lack of con-
clusive evidence supporting the value of risk assessment and early intervention,
any lifestyle change made by a patient is a cause for concern.
Physicians should be aware that their patients are likely to fear AD. A survey-
based study conducted by the MetLife Foundation found that Americans fear
AD more than heart disease, diabetes, and stroke.14 For Americans of at least 55
years of age, AD is the most feared disease.14

Genetic Testing for Alzheimer Disease
The results can be beneficial when disclosure is handled properly; some

studies indicate a lack of emotional distress in subjects who learn of their
results. For example, in one study, PSEN1, PSEN2, and TAU genes were analyzed
in 22 subjects at risk for AD or frontotemporal dementia.15 All participants
received genetic counseling and disclosure. One year after disclosure, par-
ticipants who received negative results reported a level of testing-specific
distress similar to those who received positive results. Consistent with these
findings, the Risk Evaluation and Education for Alzheimer’s Disease (REVEAL)
project conducted APOE genotyping in 162 asymptomatic adults who had a
parent with AD and who were randomized to a disclosure or nondisclosure
group.16 The two groups did not differ on measures of anxiety, depression, or
test-related distress after up to 1 year; however, participants in the disclosure
group who received positive APOE results were more distressed than those who
received negative results.15,16 In addition, high levels of emotional distress be-
fore testing were correlated with emotional difficulties after disclosure, sug-
gesting the value of psychological screening.16
The REVEAL methodology is a model for the AD community concerning the
disclosure of results. It successfully demonstrates that separating education
about the risks and benefits of disclosure from the actual disclosure, monitoring
mood and anxiety after disclosure, requiring an emergency contact, and refer-
ring participants to mental health professionals when appropriate are all critical
factors.16,17 Although REVEAL is an excellent starting point, larger controlled
studies examining possible disclosure methods may help further inform testing
and disclosure.
CONCLUSIONS
Given the current general lack of therapeutic benefit from genetic testing, and
the uncertain implications of results for patients and their families, the decision
of whether to conduct testing for a patient who is clinically probable for AD
remains uncertain. In the case example, depending on the perceptions of the
patient and his family, a decision to either proceed or defer testing might be
reasonable. The decision to proceed should be coupled with appropriate gen-
etic counseling. The potential for future improvements in test sensitivity, spec-
ificity, and clinical utility holds promise for an increased understanding of AD
mechanisms and application of genotyping efforts.
ACKNOWLEDGMENT
The author wishes to thank Briana Perry, BA for substantial contributions to this
article.
REFERENCES
1. Hardy J. Amyloid, the presenilins and Alzheimer’s disease. Trends Neurosci 1997;20(4):154Y159.
2. Prasad KN, Cole WC, Prasad KC. Risk factors for Alzheimer’s disease: role of multiple
antioxidants, non-steroidal anti-inflammatory and cholinergic agents alone or in combination
in prevention and treatment. J Am Coll Nutr 2002;21(6):506Y522.
3. Alonso Vilatela ME, López López M, Yescas Gómez P. Genetics of Alzheimer’s disease. Arch Med
Res 2012; PII:S0188-4409(12)00299-8.
4. Sherrington R, Froelich S, Sorbi S, et al. Alzheimer’s disease associated with mutations in
presenilin 2 is rare and variably penetrant. Hum Mol Genet 1996;5(7):985Y988.

5. Tanzi RE, Vaula G, Romano DM, et al. Assessment of amyloid beta-protein precursor gene
mutations in a large set of familial and sporadic Alzheimer disease cases. Am J Hum Genet
1992;51(2):273Y282.
6. Cohn-Hooke PE, Elting MW, Pijnenburg YAL, Swieten JCV. Genetics of dementia: update and
guidelines for the clinician. Am J Med Genet B Neuropsychiatr Genet 2012;159B(6):638Y643.
7. Burgunder JM, Finsterer J, Szolnoki Z, et al. EFNS guidelines on the molecular diagnosis of
channelopathies,epilepsies, migraine, stroke, and dementias. Eur J Neurol 2010;17(5):641Y648.
8. Goldman JS, Hahn SE, Catania JW, et al. Genetic counseling and testing for Alzheimer disease:
joint practice guidelines of the American College of Medical Genetics and the National Society of
Genetic Counselors. Genet Med 2011;13(6):597Y605.
9. Mayeux R, Saunders AM, Shea S, et al. Utility of the apolipoprotein E genotype in the diagnosis
of Alzheimer’s disease. Alzheimer’s Disease Centers Consortium on Apolipoprotein E and
Alzheimer’s Disease. N Engl J Med 1998;338(8):506Y511.
10. Roberts JS, LaRusse SA, Katzen H, et al. Reasons for seeking genetic susceptibility testing among
first-degree relatives for people with Alzheimer disease. Alzheimer Dis Assoc Disord 2003;
17(2):86Y93.
11. Neumann PJ, Hammitt JK, Mueller C, et al. Public attitudes about genetic testing for Alzheimer’s
disease. Health Aff (Millwood) 2001;20(5):252Y264.
12. Goldman JS. New approaches to genetic counseling and testing for Alzheimer’s disease and
frontotemporal degeneration. Curr Neurol Neurosci Rep 2012;12(5):502Y510.
13. Zick CD, Mathews CJ, Roberts S, et al. Genetic testing for Alzheimer’s disease and its impact on
insurance purchasing behavior. Health Aff (Millwood) 2005;24(2):483Y490.
14. MetLife Foundation. MetLife Foundation Alzheimer’s survey: what America thinks. New York,
NY: MetLife Foundation, 2006.
15. Cassidy MR, Roberts JS, Bird TD, et al. Comparing test-specific distress of susceptibility versus
deterministic genetic testing for Alzheimer’s disease. Alzheimers Dement 2008;4(6):406Y413.
16. Green RC, Roberts JS, Cupples LA, et al. Disclosure of APOE genotype for risk of Alzheimer’s
disease. N Engl J Med 2009;361(3):245Y254.
17. Karlawish J. Addressing the ethical, policy, and social challenges of preclinical Alzheimer disease.
Neurology 2011;77(15):1487Y1493.

Practice
Coding for Behavioral

John Hart Jr., MD, Center for
BrainHealth, 2200
W. Mockingbird Ln. Dallas,
TX 75235
Dr Hart has served on the
Neurology
speakers bureau for Forest John Hart Jr, MD; Kyle B. Womack, MD; Laura B. Powers, MD, FAAN;
Laboratories, Inc, and as a
medicolegal consultant. Marc R. Nuwer, MD, PhD, FAAN
Dr Womack has received
research support from Allon
Therapeutics, Inc, and Bayer
AG. Dr Powers serves as
ICD-9-CM Advisor for the
Coding Subcommittee of the
AAN Medical Economics and
Management Committee and
Accurate coding is an important function of neurologic practice. This contribution
serves in an editorial capacity to is part of an ongoing series that presents helpful coding
for Neurology: Clinical information along with examples related to the issue topic. Tips for diagnosis
Practice. Dr Nuwer serves
as a medical reviewer
coding, evaluation and management coding, procedure coding, or a combination
for SleepMed. are presented, depending on which is most useful for the subject area of the issue.
Unlabeled Use of
Use Disclosure:
Drs Hart, Womack, Powers,
and Nuwer report EVALUATION AND MANAGEMENT
no disclosures. Evaluation and Management (E/M) coding in behavioral neurology is complicated
of Neurology.
by the length of time required to perform both a standard neurologic evaluation
and the additional and more extensive neurobehavioral examination. The Mini-
Mental State Examination does not fulfill the requirements for the neu-
robehavioral status examination, which must include ‘‘clinical assessment of
thinking, reasoning, and judgment, eg, acquired knowledge, attention, language,
memory, planning and problem solving, and visual spatial abilities.’’1 These two
components have distinct and somewhat independent coding implications. The
optimal way to document the neurobehavioral examination is with a separate
report that includes the tests administered, results, interpretation of the results,
as well as time spent. There are two choices for billing:
1. Current Procedural Terminology (CPT) E/M code plus CPT code 96116 for
neurobehavioral status examination (the most conventional choice)
2. Coding by time alone with E/M code plus prolonged service codes, and
bundling both services into one
The following is a case example of a plausible behavioral neurology
consultation.
Case
A 68-year-old patient who was new to the clinic presented with her spouse
with the chief complaint of slowly progressive memory problems that had
been occurring over the past 2 years. This problem had not gotten her
fired from her job, but she found she needed to double-check everything
she did and think much harder than before to complete tasks. She
was fatigued in the evenings and said that it took ‘‘12 hours of mental
energy to do what was previously an 8-hour job.’’ At home, she found
keeping up with receipts and checks more difficult than in the past. She

was unaware of any other neurologic deficits, although her husband had
noted an occasional tremor of her hands for the past 6 months. She still
played bridge with friends monthly but had some problems remembering
what cards had been played. She had never become lost while driving.
She felt no depression, although she admitted feeling anxious, especially
about losing her job. Current medications were hydrochlorothiazide and
atorvastatin. She had a history of treated and controlled hypertension
and high cholesterol and a family history significant for a mother with
autopsy-confirmed Alzheimer disease. She drank two to three drinks each
night after work but less on the weekend. Review of 14 systems was
documented in her chart. Notable positives included anxiety, negative
ruminations, lack of energy, and sleep disruption.
On examination the patient appeared healthy. Her blood pressure was
130/72 mm Hg, her pulse was 70/min, and her weight was 68 kg (150 lb).
There were no carotid bruits, or cardiac murmurs, and peripheral pulses
were normal. She was alert and oriented to time, date, and place. She
could name 3/3 common objects and recall 2/3 objects after 5 minutes; her
fluency was 10 words that begin with the letter F in 1 minute. Fund of
knowledge was good, and she attended well. Optic fundoscopy was
normal. Visual fields were full to confrontation, and she had full
extraocular movements. Facial sensation was normal. Her face was
symmetric and moved normally. Hearing was intact to whisper. Palate
moved symmetrically. Sternocleidomastoid muscles were normal in
strength. Her tongue protruded in the midline and moved normally.
Sensation was normal to touch, pinprick, vibration, and joint position
sense. Muscle tone and strength were normal in four extremities. A
mild resting tremor of the hands was present. Reflexes were normal
and symmetric, and toes were downgoing with plantar stimulation.
Finger-to-nose and heel-to-knee-to-shin coordination were normal, and
there was no Romberg sign. Gait was normal.
The patient was administered the following neurobehavioral tests:
attention (digit span), verbal fluency (Controlled Oral Word Association
Test), naming (15-item version of the Boston Naming Test), verbal episodic
memory (Hopkins Verbal Learning Test), visuoconstructional skills (the
copy condition of the Rey-Osterreith Complex Figure test), and executive
and cognitive control functions (Trail-Making Test Parts A and B). The
patient scored approximately 1.75 standard deviations (SD) below the
mean on verbal episodic memory but otherwise performed around the
mean on the other tests.
The impression was that the patient had amnestic mild cognitive
impairment. Further evaluation included ordering a brain MRI, laboratory
studies, and referral for evaluation for possible anxiety disorder. Counseling
surrounding her diagnosis, alcohol use, anxiety level, and employment
status concerns was given.
Total time spent face to face was 1 hour and 40 minutes. Thirty-five
minutes were spent with the neurobehavioral examination. Of the
remaining 65 minutes, 40 minutes were spent in counseling and
coordination of care.

Coding for Behavioral Neurology
Discussion
Using the conventional reporting method, the E/M code for the new patient
visit, level 4 (99204), is billed with a code for the separately reported neuro-
behavioral status examination (96116). Also note that a five-bullet mental status
examination must be reported separately from the neurobehavioral status
examination to qualify for using 99204 and 99205. The total visit time for the
E/M code is 65 minutes and for the neurobehavioral examination, 35 minutes.
The ‘‘typical’’ time for code 99204 is 45 minutes; therefore, code 99205 may be
used instead of 99204 based on time (typical 60 minutes for 99205), with the
documentation that more than 50% of that time was spent on counseling
and coordination of care. Code 96116 is billed ‘‘per hour’’ of face-to-face time.
An hour is 31 to 90 minutes in the CPT world, so 96116 may be used here.
Had the time been shorter, the examination must be bundled into the E/M
code.
A second method of coding would not require a separate report (although
the neurobehavioral status examination information should be included in
the chart). Prolonged service codes 99354 (first hour 30 to 74 minutes) and
99355 (each additional time up to 30 minutes) are used for face-to-face time
spent beyond the typical time for an E/M service. For this visit of 140 minutes,
99204 would be reported with 99354 and 99355. The counseling and co-
ordination of care coding method would not increase the level of the E/M code
because the counseling time is less than 50% of the total time spent. In both
cases, the specific documentation of time is paramount! Reimbursement rates
change yearly and vary by region, so absolute numbers are not given here.
For 2013, billing 99204 with 99354 and 99355 has a higher reimbursement
than billing 99205 with 96116, but the face-to-face encounter must total more
than 134 minutes to use the first set of codes. The caveat to bundling the two
individual examinations is that payers might eventually insist that the
neurobehavioral status examination is a part of the E/M service and not billable
separately.
Regardless of coding prolonged services time or the neurobehavioral ex-
amination, the E/M level of complexity or decision making for this neurologic
consultation should take into account that both interpretation of the results of
neurobehavioral testing in conjunction with the history and the neurologic
examination are used in the diagnostic formulation.
ICD-10-CM CODING
International Classification of Diseases, Ninth Revision, Clinical Modification
(ICD-9-CM)2 codes will be replaced on October 1, 2014, with International
Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM)
codes.3 Only billing claims using the new codes will be accepted as of that date.
ICD-10-CM codes are up to seven characters long and alphanumeric. The first
character is the letter corresponding to the chapter (body system). A partial
overview of relevant new behavioral neurology codes follows (note that, for
space reasons, codes for dementia associated with behavioral disturbance have
been omitted).

ICD-9-CM Code ICD-10-CM Code
290.0 Senile dementia, uncomplicated F03.90 Unspecified dementia without behavioral disturbance
Includes: presenile dementia not otherwise specified (NOS),
presenile psychosis NOS, primary degenerative dementia NOS,
senile dementia NOS, senile dementia depressed or paranoid
type, senile psychosis NOS
Excludes1: senility NOS (R41.81)

Excludes2: mild memory disturbance due to known
physiologic condition
senile dementia with delirium, or
acute confusional state (F05)
290.10 Presenile dementia, uncomplicated F03.90 Unspecified dementia without behavioral disturbance
Includes: presenile dementia NOS, presenile psychosis NOS,
primary degenerative dementia NOS, senile dementia NOS,
senile dementia depressed or paranoid type, senile psychosis
NOS

290.13 Presenile dementia with depressive F03.90 Unspecified dementia without behavioral disturbance
features
senile dementia depressed or paranoid type, senile psychosis
NOS
290.20 Senile dementia with delusional or F03.90 Unspecified dementia without behavioral disturbance
depressive features
senile dementia depressed or paranoid type, senile psychosis NOS

Continued
F05 Delirium due to known physiologic condition
Acute or subacute brain syndrome
Acute or subacute confusional state (nonalcoholic)
Acute or subacute infective psychosis
Acute or subacute psycho-organic syndrome
Delirium of mixed etiology
Delirium superimposed on dementia
Sundowning
Code first the underlying physiologic condition.

Excludes1: delirium NOS
Excludes2: delirium tremens alcohol-induced or unspecified
(F10.231, F10.921)
290.40 Vascular dementia, uncomplicated F01.50 Vascular dementia without behavioral disturbance
Use additional code to identify cerebral Includes: arteriosclerotic dementia

atherosclerosis (437.0) or other condition
resulting in this diagnosis. Code first the underlying physiologic condition or sequelae
of cerebrovascular disease.
291.1 Alcohol-induced persisting amnestic F10.96 Alcohol use, unspecified, with alcohol persistent
disorder memory disorder
291.2 Alcohol-induced persisting dementia F10.27 Alcohol dependence with alcohol-induced persisting dementia
293.0 Delirium due to conditions classified F05 Delirium due to known physiologic condition
elsewhere
Includes: acute or subacute brain syndrome, acute or subacute
Code first the associated physical or confusional state (nonalcoholic), acute or subacute infective
neurologic condition. psychosis, acute or subacute organic reaction, acute or subacute
psycho-organic syndrome, delirium of mixed etiology, delirium
superimposed on dementia, sundowning

Excludes1: delirium NOS (R41.0)
Excludes2: delirium tremens alcohol-induced
294.0 Amnestic disorder in conditions classified F04 Amnestic disorder due to known physiologic condition
elsewhere
Includes: Korsakov’sa psychosis or syndrome, nonalcoholic
Korsakoff’sa psychosis or syndrome
(non-alcoholic) Code first the underlying physiologic condition.
Code first underlying condition. Excludes1: amnesia NOS (R41.3), anterograde amnesia (R41.1),
dissociative amnesia (F44.0), retrograde amnesia (R41.2)
(This is also the default code for posttraumatic
amnesia.) Excludes2: alcohol-induced or unspecified Korsakov’s syndrome
(F10.26, F10.96), Korsakov’s syndrome induced by other
psychoactive substances (F13.26, F13.96, F19.16, F19.26, F19.96)

Continued
294.10 Dementia in conditions classified F02.80 Dementia in other diseases classified elsewhere,
elsewhere without behavioral disturbance without behavioral disturbance
Code first the underlying condition. Dementia in other diseases classified elsewhere not otherwise
specified
294.8 Other persistent mental disorders due F06.8 Other specified mental disorders due to known
to conditions classified elsewhere physiologic condition
Code first the underlying condition. Code first the underlying physiologic condition.
294.9 Unspecified persistent mental disorders F06.8 Other specified mental disorders due to known
due to conditions classified elsewhere physiologic condition
Code first the underlying condition. Code first the underlying physiologic condition.
310.2 Post-concussion syndrome F07.81 Postconcussional syndrome

Postcontusional syndrome (encephalopathy)
Post-traumatic brain syndrome, nonpsychotic
Use additional code to identify associated post-traumatic
headache (G44.3-)
Excludes1: current concussion (brain) (S06.0-), postencephalitic
syndrome (F07.89)
310.8 Other specified non-psychotic mental F07.89 Other personality and behavioral disorders due to
disorders following organic brain damage. known physiologic condition
(This is the ‘‘default’’ code for mild memory Postencephalitic syndrome

disturbance after brain damage.) Right hemispheric organic affective disorder
331.0 Alzheimer’s disease G30.0 Alzheimer’s disease with early onset

Use additional code, where applicable, to identify G30.1 Alzheimer’s disease with late onset
dementia: with behavioral disturbance (294.11),
without behavioral disturbance (294.10) G30.8 Other Alzheimer’s disease
G30.9 Alzheimer’s disease, unspecified
Use additional code to identify: delirium, if applicable (F05);
dementia with behavioral disturbance (F02.81); dementia
without behavioral disturbance (F02.80)
331.11 Pick’s disease G31.01 Pick’s disease
Circumscribed brain atrophy
Progressive isolated aphasia
Use additional code to identify: delirium, if applicable (F05);
dementia with behavioral disturbance (F02.81); dementia
without behavioral disturbance (F02.80)
331.19 Other frontotemporal dementia G31.09 Other frontotemporal dementia
331.6 Corticobasal degeneration G31.85 Corticobasal degeneration

Continued
331.7 Cerebral degeneration in diseases G94 Other disorders of brain in diseases classified elsewhere
classified elsewhere.
Code first the underlying disease.
Code first the underlying disease.
331.82 Dementia with Lewy bodies G31.83 Dementia with Lewy bodies
Dementia with Parkinsonism
Lewy body dementia
Lewy body disease
331.83 Mild cognitive impairment, so stated G31.84 Mild cognitive impairment, so stated
Excludes: altered mental status (780.97), cerebral Excludes1:age related cognitive decline (R41.81), altered
degeneration (331.0-331.9), change in mental mental status (R41.82), cerebral degeneration (G31.9), change
status (780.97), cognitive deficits following (late in mental status (R41.82), cognitive deficits following
effects of) cerebral hemorrhage or infarction (sequelae of) cerebral hemorrhage or infarction (I69.01,I69.11,
(438.0), cognitive impairment due to intracranial I69.21, I69.31, I69.81, I69.91), cognitive impairment due to
or head injury (850-854, 959.01), cognitive intracranial or head injury (S06.-), dementia (F01.-, F02.-, F03),
impairment due to late effect of intracranial injury mild memory disturbance (F06.8), neurologic neglect
(907.0), cognitive impairment due to skull fracture syndrome (R41.4), personality change, nonpsychotic (F68.8)
(800-801, 803-804), dementia (290.0-290.43, 294.8),
mild memory disturbance (310.8), neurologic
neglect syndrome (781.8), personality change,
nonpsychotic (310.1)
331.89 Other cerebral degeneration, Other G31.89 Other specified degenerative diseases of nervous system
(Corticobasal degeneration)
(Dementia in) G20 Parkinson’s disease
332.0 Parkinson’s disease F02 Dementia in other diseases classified elsewhere
Use additional code to identify dementia,
if present, from 294.10 to 294.11.
332.2 Senile degeneration of brain G31.1 Senile degeneration of brain, NEC
333.0 Other degenerative diseases of the G23.1 Progressive supranuclear ophthalmoplegia
basal ganglia [Steele-Richardson-Olszewski]
Progressive supranuclear palsy (PSP)
G23.2 Striatonigral degeneration
(Multiple system atrophy [MSA])
G23.8 Other specified degenerative disease of the basal ganglia
Includes: progressive supranuclear palsy
348.31 Metabolic encephalopathy G93.41 Metabolic encephalopathy

348.39 Other encephalopathy G93.49 Other encephalopathy
(Paraneoplastic encephalopathy)
(Other non-neoplastic limbic encephalopathy)
349.82 Toxic encephalopathy G92 Toxic encephalopathy
Toxic encephalitis
Toxic metabolic encephalopathy
Code first (T51-T65) to identify toxic agent.

Continued
780.09 Alteration of consciousness, other R40.0 Somnolence
Drowsiness Drowsiness
Semicoma R40.1 Stupor
Somnolence Catatonic stupor
Stupor Semicoma
Unconsciousness
(This is the default code for delirium when

no associated cause is known.)
780.93 Memory loss R41.1 anterograde amnesia
R41.2 Retrograde amnesia
R41.3 Other amnesia
780.93 Memory loss R41.2 Retrograde amnesia

Amnesia (retrograde) R41.3 Other amnesia
Memory loss NOS Amnesia NOS
Excludes memory loss due to: Memory loss NOS
Intracranial injuries(850.0-854.19) Excludes: amnestic disorder due to known physiologic
Skull fractures (800.00-801.99, 803.00-804.99) condition (F04), amnestic syndrome due to psychoactive
Mild memory disturbance due to organic substance use (F10-F19 with fifth character .6), transient
brain damage (310.8) global amnesia (G45.4)
Transient global amnesia (437.7)
781.8 Neurologic neglect syndrome R41.4 Neurologic neglect syndrome
Asomatognosia Asomatognosia
Hemi-akinesia Hemi-akinesia
Hemi-inattention Hemi-inattention
Hemispatial neglect Hemispatial neglect
Left-sided neglect Left-sided neglect
Sensory extinction Sensory extinction
Visuospatial neglect Visuospatial neglect
784.3 Aphasia R47.01 Aphasia
Excludes aphasia due to late effects of Excludes1: aphasia following cerebrovascular disease (I69. with
cerebrovascular disease (438.11) final characters -20), progressive isolated aphasia (G31.01)
784.60 Symbolic dysfunction, unspecified R48.9 Unspecified symbolic disturbance
Excludes developmental disorders
784.61 Alexia and dyslexia R48.0 Dyslexia and alexia

Alexia (with agraphia) Excludes developmental disorders
(If congenital, use 315.01)

Continued
784.69 Other symbolic dysfunction, other R48.1 Agnosia
Acalculia Astereognosia (astereognosis)
Agnosia Autotopagnosia
Agraphia (absolute) Excludes1: visual object agnosia (R48.3)
Apraxia R48.2 Apraxia
Anomia Excludes1: Apraxia following cerebrovascular disease
(I69.with final characters -90)
R48.8 Other symbolic dysfunctions
Acalculia
Agraphia
All the above exclude developmental disorders.
799.51 Attention or concentration deficit R41.840 Attention and concentration deficit

Excludes1: attention-deficit hyperactivity disorders (F90.-)
799.52 Cognitive communication deficit R41.841 Cognitive communication deficit
799.53 Visuospatial deficit R41.842 Visuospatial deficit
799.54 Psychomotor deficit R41.843 Psychomotor deficit
799.55 Frontal lobe and executive function deficit R41.844 Frontal lobe and executive function deficit
799.59 Other signs and symptoms involving R41.849 Other signs and symptoms involving cognitive
cognition functions and awareness
a
ICD-9-CM uses the spelling ‘‘Korsakoff,’’ whereas ICD-10-CM uses ‘‘Korsakov.’’
REFERENCES
1. American Medical Association. Current Procedural Technology (CPT) 2012. Chicago, IL: American
Medical Association Press, 2012.
2. Centers for Medicare & Medicaid Services, National Center for Health Statistics. ICD-9-CM official
guidelines for coding and reporting. www.cdc.gov/nchs/data/icd9/icdguide10.pdf. Accessed
October 18, 2012.
3. Centers for Medicare & Medicaid Services, National Center for Health Statistics. ICD-10-CM official
guidelines for coding and reporting 2012. www.cdc.gov/nchs/data/icd10/10cmguidelines2012.pdf.
Updated October 1, 2011. Accessed December 27, 2012.

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Continuum: Lifelong Learning in Neurology—Dementia, Volume 19, Issue 2, April 2013

Dementia, April 2013;19(2)

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