Dementia

I.

INTRODUCTION
Dementia is defined as a decline in cognitive function that impairs the ability to perform
activities of daily living. Although impairment of any cognitive domain may be involved,
memory is the most common. The etiologies of dementia are diverse as discussed below;
while many patients will have progressive neurodegenerative disorders, some will suffer from
easily treatable causes that the clinician must recognize early in the course of the illness.
The term Mild Cognitive Impairment (MCI) is used when a patient has a measurable
cognitive deficit without impairment of activities of daily living. In some cases, MCI will
over time remain stable or even improve; however, many of these patients will progress to
dementia over subsequent years.
Elderly patients and their physicians often wonder if symptoms of cognitive decline represent
normal aging. A subtle slowing of processing or a decline in memory skills is common with
increasing age, but measurable cognitive deficits and impairment of activities of daily living
are not normal and should trigger further evaluation. Newer techniques discussed below have
helped our understanding of neurodegenerative processes and have led to the recognition that
some pathologies are present in the brain even decades before clinical symptoms begin. Many
patients with cognitive changes of "normal aging" may indeed be in the early stages of
neurodegeneration.

II. EPIDEMIOLOGY
The costs and consequences of dementia are staggering. Over 4 million Americans have
dementia with costs exceeding $5 billion per year to the health care system. Improvements in
prevention and treatment of vascular, infectious and neoplastic disorders have led to a
population with a longer life expectancy. Given that increasing age is the single biggest risk
factor for development of dementia, it is not surprising that the incidence of this disorder
continues to rise. Other risk factors for dementia include a family history of dementia
(although this is most significant in cases of early-onset disease); vascular risk factors such as
hypertension, smoking, diabetes and hypercholesterolemia; and the lack of social, mental and
physical activity.
III. PATHOPHYSIOLOGY
The neurodegenerative conditions that lead to dementia are all characterized by the
accumulation of abnormal proteins in neurons and/or supporting cells of the brain.
Accumulation leads to dysfunction of these cells and, in many cases, cell death. Each of the
neurodegenerative conditions has a characteristic protein or group of proteins that
accumulates and there is often a predilection for the process beginning in one specific area of
the brain. The initial clinical presentation of the disorder is dependent on the area of the brain
that is involved.
IV. CLINICAL PRESENTATIONS
The neurodegenerative disorders have relatively characteristic presentations. Patients and
their families typically report the slow progression of a cognitive deficit. A more rapid

presentation suggests a reversible etiology, delirium or specific causes of a rapidly

progressive dementia.
Alzheimer's disease (AD) is the most common neurodegenerative disorder in the elderly.
Some rare genetic mutations and the presence of the Apo 4 allele are additional risk factors.
-Amyloid neuritic plaques and tau-rich neurofibrillary tangles are the pathologic hallmarks
of the disorder. Since the pathology most commonly begins in the medial temporal lobes,
short-term memory impairment is a common first symptom. There is a deficit of
acetylcholine in the brain due to involvement of the nucleus basalis of Meynart.
Vascular dementia is the second most common etiology of dementia in many series, although
in some cases it can coexist with AD pathology, leading to a mixed picture. The classic
"Multi-Infarct Dementia," which features a step-wise decline in cognition corresponding to
repeated large cerebral infarctions, is less common. The more typical presentation is that of
progressive white matter disease (also known as small vessel ischemic disease, subcortical
leukoencephalopathy, or Binswanger's disease); the symptoms are that of a subcortical
dementia including slowness of processing and executive dysfunction.
Frontotemporal dementia (FTD) commonly begins in the 5th to 7th decade, at which time it
is nearly as common as AD. The pathology involves deposition of (usually) tau or TDP-43
protein and the clinical presentation follows from a temporal or frontal predilection. Memory
is often spared and deficits are in behavior (frontal) or language (temporal). Clinical forms of
FTD included behavioral-variant, semantic dementia, and progressive nonfluent aphasia.
Many patients are Incorrectly diagnosed as having a psychiatric illness.
Dementia with Lewy Bodies (DLB) is a common and underrecognized neurodegenerative
condition featuring parkinsonism and dementia with a fluctuating course and prominent
complex visual hallucinations. These patients are extremely sensitive to antipsychotic
medications, which should be avoided if possible, and are commonly mistakenly thought to
have delirium. The classic hallmark pathologically is the Lewy body, a cytoplasmic inclusion
in neurons made of -synuclein. These patients have a profound cholinergic deficit with
implications for treatment and prevention of episodic worsening.
A number of other neurodegnerative disorders associated with parkinsonism exist including
Parkinson's disease dementia (featuring dementia that occurs well after the motor symptoms
of Parkinson's disease begin), corticobasal degneration (presenting often with unilateral
rigidity, apraxia and dystonia), and progressive supranuclear palsy (in which early falls and
axial rigidity are accompanied by vertical eye movement abnormalities).
Prion disease deserves special mention given its tendency to present with a rapid course.
Prions are infectious proteins which occur sporadically (90%), genetically (10%) or via
transmission from infected neural tissue (very rare). The most common clinical disorder is
Creutzfeldt-Jakob disease (CJD) which features a rapidly progressive dementia with rigidity
and often startle myoclonus. EEG and MRI features assist with the clinical diagnosis.
Unfortunately, the disease is rapidly fatal without effective therapy.
V. DIAGNOSIS
The diagnosis of dementia is mainly a clinical exercise, focusing on the history. Since
patients have cognitive impairment, a collateral informant such as a family member is

essential in order to document cognitive changes and progression over time in various
domains (memory, executive, visuospatial, language, behavior and psychiatric). It is
important to screen for and treat depression when present as it can mimic the features of
dementia or contribute to its worsening. A careful neurologic examination looking for other
signs that provide clues to the etiology of dementia should follow. As part of the neurologic
examination, a careful cognitive evaluation should take place using simple bedside testing; in
some patients, formal neuropsychological batteries administered by a neuropsychologist will
be useful in more precisely defining cognitive involvement and for following the disorder's
progression over time.
All patients should undergo neuroimaging with MRI (preferred) or CT in order to exclude
mimics such as a tumor or subdural hematoma as well as to examine patterns of atrophy in
order to provide clues to the diagnosis.
The initial laboratory workup should focus on reversible etiologies including tests of thyroid
function and vitamin B12 levels. Other screening tests such as those for infections (e.g., HIV
and syphilis), renal failure and liver disease should be guided by the history and examination.
VI. TREATMENT
While some of the etiologies of dementia have specific treatments, general therapies that are
applicable to all forms of neurodegenerative disease are important to offer to patients.
Dementia patients should be screened for depression and, if present, mood disorders should
be treated with therapy or medications. Both physical exercise and cognitive exercise have
been shown to be effective; cognitive rehabilitation increasingly is leveraging computerbased and other technologies that allow patients to work at their own pace, in the comforts of
their home with added features so that progress can be tracked by the patient and their family.
A multidisciplinary team consisting of physicians, nurses, pharmacists, therapists and social
workers can be helpful in managing patients with dementia. Home safety should be assured,
often with an in-home evaluation by an occupational therapist. Identification of decisionmakers for both health care and finance when and if the patient becomes incapacitated should
be achieved early in the course of the disease.
End-of-life decision making including the possibility of nursing home placement and
insertion of a feeding tube (which has not been shown to be helpful in general in this
population) should ideally occur early in the disease when the patient can participate in these
future directives.
Specific treatments for Alzheimer's disease include administration of a cholinesterase
inhibitor (donepezil, rivastigmine, galantamine), which can lead to modest improvements or
stabilization of cognition. These medications are most effective in mild or moderate disease,
and have not been shown to change the rates of progression from MCI to dementia.
Memantine, a glutamate receptor antagonist, is usually added when progression occurs while
taking cholinesterase inhibitors, although data for the effectiveness of this agent is mixed. A
recent study suggested that vitamin E supplementation may be useful in the context of the
early stages of the disorder, but other studies have not shown this effect and the vitamin is not
effective in preventing dementia or in halting progression of MCI to dementia. Other drug
treatments, including herbal and over-the-counter medications, have not been shown to be
effective in AD.

Patients with vascular dementia likely benefit from cholinesterase inhibitors and should also
undergo modification and treatment of vascular risk factors, perhaps including antiplatelet
drug administration. Patients with Dementia with Lewy bodies particularly benefit from
cholinesterase inhibitors given their profound cholinergic deficit.
Perhaps the most difficult aspect of management of dementia patients occurs when behavioral
problems such as hallucinations and aggressive behavior occur, often in the later stages of the
disorder. These symptoms are a common source of stress for families and may lead to nursing
home placement. Unfortunately, cholinesterase inhibitors and antipsychotic medications have
each been shown to be relatively ineffective for this condition, and the latter is associated
with an increased risk of death in the elderly. Practically, low-doses of antipsychotics are
reserved only when the patient poses harm to themselves or others, keeping in mind a careful
risk/benefit ratio.
VII. FUTURE DIRECTIONS
Improved accuracy of diagnosis with radiologic, CSF and serum biomarkers will soon
hopefully be complemented by improved efficacy of treatment modalities. Increasingly, trials
of drugs include those focused on clearing or preventing build-up of the pathologic protein
specific to each neurodegenerative disorder; initiation of these therapies at an early
symptomatic stage or even a presymptomatic stage would seem to hold the most promise for
success.