A

 self-­‐portrait  of  dementia

William  Utermohlen’s paintings  as  his  Alzheimer  symptoms  progress

http://www.williamutermohlen.org/images/stories/Press/Ottawa-­‐Citizen-­‐Alzheimers-­‐Part-­‐6.pdf
Neurodegeneration – the dementias

Karen Cullen
Anatomy and Histology
COMMONWEALTH OF AUSTRALIA

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2019
 Neurodegeneration
Objectives

• Recap  the  fundamental  memory-­‐related  pathways  and  auxiliary  

structures  
– Hippocampus  and  entorhinal cortex  
– Modality-­‐specialised cortical  areas

• To  introduce  two  major  forms  of  dementia*:  Alzheimer’s  disease  (AD)  

and  frontotemporal  dementia  (FTD)  
– from  a  functional  neuroanatomical/histopathologic point-­‐of-­‐view
You  should  be  able  to
Identify  the  key  regions  involved  in  declarative  memory  formation  and  retrieval
Describe  the  major  features  of  Alzheimer’s  disease
1. Symptoms,  clinical  progression,  age  structure
2. Gross  brain  regions  affected
3. Histopathology  
4. Components  of  lesions
Describe  the  major  features  of  frontotemporal dementia
1. Symptoms,  clinical  progression  and  age  structure
2. Gross  brain  regions  affected
3. Histopathology    (uhm,  well,  some  of  the  known  lesions  anyway  as  there  are  
gaps  in  knowledge)
4. Subtypes  of  FTD  based  on  clinical  symptoms,  location  of    cortical  gross  
atrophy,  histopathology  and  some  genetics
 Summary  of    
Memory  Pathways
• Hippocampus  &  entorhinal  cortex  required  for  reinforcement  (consolidation)  
of  declarative  memory

• Strengthened  connections  between  cortical  areas  is  the  basis  of  declarative  
memory

• Activation  of  strengthened  networks  is  the  basis  of  recall

• Areas  such  as  the  DLPF  cortex  important  in  network  activation  (recall)  and  
storage  

DLPF    dorsolateral  prefrontal  cortex

 Current  paradigm  for  memory  encoding
Declarative  memory  is  both  localised &  distributed

Memory  stored  across  modality-­‐specific  

areas  (e.g.  visual,  auditory,  verbal)  and  
association  areas  – distributed  networks

Particular  brain  regions  direct  storage  -­‐

localised

Medial  temporal  lobe  structures  (hippocampus,  entorhinal cortex)  direct  

memory  consolidation
 uncus
parahippocampal  gyrus
rhinal  sulcus

Duvernoy  HM,  Cattin  F  (2005)  The  human  hippocampus:  functional  

anatomy,  vascularization,  and  serial  sections  with  MRI:  Springer.
 L.ventricle (inf horn)
hippocampus
dentate

subiculum

occipitotemporal Lateral  ventricle  (inferior    horn)

(fusiform)  gyrus
Entorhinal cortex  
(within  the  parahippocampal gyrus) choroid  plexus
CA2 CA3 alveolus

Hilus dentate  gyrus fimbria

fornix  (not  shown)

subiculum
CA1

parahippocampal
gyrus

occipitotemporal
(fusiform)  gyrus
rhinal  
sulcus
 The  nature  of  hippocampal  circuits:  reverberating,  amplifying

Unimodal  and  polymodal areas,  especially  prefrontal  and  cingulate  areas

Parahippocampal  and  perirhinal  cortex

key  circuitry  in  
major input  to  hippocampus Entorhinal  cortex major output  from  hippocampus declarative  memory  
PF
MF SC
Dentate   CA3 CA1 subiculum

Lateral  ventricle  (inf  horn) fimbria/fornix  to  mammillary  body

choroid  plexus
CA2 CA3 alveolus

dentate  gyrus

interoceptive &  emotional  

fimbria/fornix

subiculum
Anterior  n.  thalamus
CA1
memory  and  motivation?
part  of  Papez circle
parahippocampal  gyrus Cingulate  cortex

occipitotemporal  (fusiform)  gyrus…

rhinal  sulcus

Fibre pathways
PF perforant pathway
SC Schaffer collaterals
MF Mossy fibres
 Network  activation  during  
consolidation  and  recall

Hypothesis  for  memory  networks

1.  Hippocampal  activity  (via  entorhinal  cortex)  maintains  activity  in  
relevant  network  of  distributed  brain  areas
2.Efficiency  of  network  enhanced
3.  ‘Recall’  reactivates  enhanced  network
 Non-­‐pathological  brain  ageing
What  happens  to  the  brain  with  age?
Data  from  large  population,  longitudinal  studies  emerging
The  Nun  study,  the  Baltimore  Project,  the  Sydney  Older  Persons  study    and  many  more...

Minimal  brain  changes:

There  may  be  minor  loss  of  neurons  
Mild  cortical  atrophy   TIME magazine
May 14, 2001
Mainly  white  matter  shrinkage  
Minor  grey  matter  atrophy
Increased  peroxidised lipids  – lipofuscin    (benign)  – fluoresces!
Most  people  will  have  some  AD-­‐type  pathology  but  not  sufficient  to  affect  function

lipofuscin  inside  neurons

 Most  changes  that  do  occur  with  age  in  the  brain  – permanent  or  temporary    -­‐ relate  to  the  
cerebrovasculature
Stroke  is  the  most  common  neurological  disorder  (and  a  major  cause  of  death)  
More  subtle  vascular  changes  also  occur  – mild  ischaemia,  especially  with  atherosclerosis

Corrosion  cast  of  human  cerebral  vessels

From:  Strategies  to  Circumvent  Vascular  Barriers  of  the  Central  Nervous  System  Neurosurgery.  1998;43(4):877-­‐878.  doi:10.1097/00006123-­‐199810000-­‐00089
 Myths
Ageing  involves  inexorable  cognitive  decline  
and  brain  degeneration
Brain  weight  at  different  ages  
single  time  point  data
Severe  cognitive  problems  do  not  occur  for  most  people

Mild  cognitive  decline  is  common  in  late  age

‘Late  age’  refers  to  more  advanced  years.  

With  increased  population  health,  what  is  old  in  2018?

Caution  :  consider  cross-­sectional  vs

longitudinal  design  of  population  ageing  studies

Purves et  al  (eds)  (2008)  Neuroscience.  Sinauer &  Assoc,  Sunderland  CT.
1901 1993

2049
2017

http://www.abc.net.au/news/specials/census-­‐2011/
Dementia  prevalence estimates  Australia
~1/3  of  
people  
50
aged    80-­‐90  
years
45
males females
40
%  of  the  population

35

30
>1700  new  cases  every  week
25

20

15

10

5
-­‐
<60 60-­‐64            65-­‐69          70-­‐74          75-­‐79        80-­‐84        85-­‐89          90-­‐94          95+
age  (years)

Estimated  ~  1,000,000  cases  in  Australia  in  next  30-­35  years.

From  Access  Economics  2009,  Alzheimers Australia
 The  Dementias
Definition  
A  significant  decline  in  at  least  2  areas  of  higher  cognition  such  as  memory,  language,  
planning,  judgment,  abstraction,  calculation,  personality.    

2013:    DSMV* abandoned  the  term  ‘dementia’  in  lieu  of:

Mild  cognitive  impairment  MCI  

Some  cases  of  MCI  may  be  prodromal  dementia  that  is,  person  will  go  on  to  develop  dementia  
Major  area  of  research  clinically  – which  MCIs  will  progress?

Severe  cognitive  impairment  (dementia)

*American  Psychiatric  Association.  (2013).  Diagnostic  and  statistical  manual  of  mental  
disorders (5th  ed.).  Arlington,  VA:  American  Psychiatric  Publishing.
 The  Dementias
Dementia  – major  cognitive  disorder  – is  a  ‘category’,  an  umbrella  term,  not  a  disease,  not  a  cause

Specific  types of  dementia  include  

Alzheimer’s  disease*,  vascular  dementia,  
frontotemporal dementias*,  Lewy body  disease,  
HIV/AIDS-­‐related  dementia,  Korsakoff’s dementia. Alzheimer  
Vascular

Dementia
Some  dementias  may  be  treatable:  intracranial  
masses,  encephalitis,  meningitis,  vitamin  deficiency,  
Lewy  body
depression-­‐related  dementia.
Frontotemporal
Alzheimer’s  disease*  accounts  for  50-­‐70%  of  all  
dementia  cases other

*Focus  of  today’s  lecture:    Alzheimer’s  disease,  frontotemporal dementias

 Clinicopathological correlations

Dementia  is  a  collection  of  clinical  

symptoms  not  a  disease
modality  specific  
areas
Higher  
A  constellation  of  symptoms  define  the   language  areas association  areas  
e.g.  parietal  
syndrome  
Behaviour:      
memory  areas  in   amygdala  
Working  out  the  underlying  basis  of  the   MTL hypothalamus  
symptoms  and  relating  these  to  brain   prefrontal  areas

changes  and  cellular  mechanisms  (the  

disease)  is  the  aim  of  ongoing  research.  
prefrontal  areas  
affect  judgment  
specific  
impulsivity,  
emotional  
dementia   striatum  :    habits,  
personality
expression
symptoms
 Alzheimer’s  disease    -­‐ the  basics
‘Probable’  diagnosis  during  life  based  on  cognitive  features  and  progression  
Definitive  diagnosis  is  post  mortem,  however  the  clinical  assessment  is  now  highly  accurate

Insidious  onset  
Slow  (rather  than  abrupt  or  stepwise)  progression Early  on,  daily  activities  of  living  are  
intact  but  may  need  instruction,  
Duration  ~5-­‐12  years  ,  but  likely  long  prodromal  period breaking  down  tasks.
Memory  signs  appear  early:  
repetition,  getting  lost,  inability  to  do  calculations  and  follow  conversations,  
trouble  orienting  to  space  and  time,  losing  things,  hiding  things
Other  cognitive  signs  appear  later:
behavioural changes  (e.g.  agitation,  paranoia),  aphasias,  apraxias,  activities  of  
daily  living  (dressing,  eating,  bathing),  agitation

Exclusion  criteria  for  AD  diagnosis

Movement  disorders
Abrupt  onset
Delirium,  seizures,  focal  signs  (e.g.  paralysis)
 Risk  factors  for  Alzheimer’s  disease
Age
Genetics
Autosomal  dominant  mutations:  amyloid  precursor  protein  (APP),  presenilin 1  
presenilin 2  account  for  <1%  of  cases,  involved  in  production  of  amyloid  peptide
Normally-­occurring  isoform  of  the  apolipoprotein  ApoE4  (a  lipid  transporter)  associated  with  
increased  risk,  but  not  determinate

Diabetes  Type  II  (Stewart  1998)

Midlife hypertension  (Elias  et  al  1993)
Smoking  (Ott et  al  1998,  Launer et  al 1999) cardiovascular  
risk  factors
Atrial  fibrillation  (Stewart  et  al  1999)
Previous  stroke (Kalaria &  Skoog 2000)
High  cholesterol (Notkola et  al  1998,  Kivipelto et  al  2001)
Healthy  heart,  healthy  brain

Head  injury
Low  educational  attainment  (may  be  study  bias,  socioeconomic  factors)
Chr -­‐ chromosome
The  neuropathology  of  Alzheimer’s  
disease
‘On  certain  peculiar  diseases  of  old  age’
The  disease  that  has  Alzheimer’s  name

Perusini

Alois Alzheimer Auguste M Alzheimer’s  drawing  of  tangles  1907

Strange  and  Beautiful  Early  Illustrations  
of  Alzheimer’s  Disease

http://beckerrarebooks.tumblr.com/post/93809947259/strange-­‐and-­‐
beautiful-­‐early-­‐illustrations-­‐of
 Cortical  atrophy  in  AD
control Alzheimer’s  disease

No  ante-­mortem  biological  marker

Normal  brain

amygdala hippocampus/ER  cortex

 Summary  of  the  progression  of  AD  cognitive  
dysfunction/neuropathology  correlates
Alzheimer’s    disease  early  
Anterograde  memory  dysfuncton -­ no  NEW  memories  
What  was  that  conversation  about?  Where  did  I  leave  
my  car?  Did  we  just  have  tea?   AD
Atrophy  &  neuronal  pathology  (tangles)    in  
hippocampus/entorhinal cortex

Alzheimer’s  disease  later  

Retrograde  memory  dysfunction  -­ OLD  memories  lost  
Previously  consolidated  memories  erode
Who  are  you?  Where  am  I?  What  is  that  called?  What  
do  I  do  with  this?
Atrophy  &  neuronal  pathology  (tangles)  in  neocortex
 Alzheimer’s  disease  microscopic  neuropathology
senile  plaques  and  neurofibrillary  tangles  

Senile  plaque

II

IV

Intraneuronal
neurofibrillary
tangle  

50µm
1mm  
entorhinal  cortex

High  density  of  tangles  in  hippocampus  and  entorhinal cortex

Neurofibrillary  tangles  are  composed  of  a  disrupted  neuronal  cytoskeleton
4
1 2 3

1. Microtubule  associated  protein  tau becomes  hyper-­‐phosphorylated

2. Hyperphosphorylated tau  (Hp-­‐tau)  fills  the  neuron
3. Hp-­‐tau  forms  fibrils  that  collect  into  tangles  within  neurons
4. Neurons  eventually  die,  leaving  the  tangle  (‘ghost  tangle’)

What  causes  this  hyperphosphorylation?

Hundreds  of  hypotheses….
 The accumulation  of  neurofibrillary  tangles  as  Alzheimer’s  disease  
progresses  – whole  brain  map
Subtle  symptoms  appear Other  cognitive  symptoms,  
No  symptoms memory  affected  early clinical  diagnosis
stages  I-­‐II stages  III-­‐IV stages  V-­‐VI

lateral  view

mid  sagittal    view

Inferior  ½  brain  view

Nelson,  P.T.  &  al,  e.  (2010)    J    Neuropathol Exp Neurol,  71,  362-­381.
Post  mortem  stages  I-­VI Braak H,  Braak E.  Acta Neurologica Scandinavica Supplementum 165:3-­12.1996.
 The accumulation  of  neurofibrillary  tangles  as  Alzheimer’s  disease  
progresses  – medial  temporal  lobe
hippocampus
stage  I stage  IV
Dementia  symptoms  (clinical)  begin  to  be  
apparent  around  stage  III-­‐IV

=  Mild  cognitive  impairment

stage  II stage  V

Early  stage:  Tangles  are  seen  in  
hippocampus/entorhinal  cortex

Late  stage:    tangles  are  found  in  temporal  

stage  III stage  VI neocortex,  then  limbic  and  association  cortex

entorhinal
cortex  

Braak H,  Braak E    Evolution  of  the  neuropathology  of  Alzheimer's  

!  Tangles  also  found  in  hypothalamus,  amygdala,  brainstem disease.  Acta Neurologica Scand Supp 165:3-­12.1996.  
Disconnection  of  the  memory  trace  as  ‘nodes’  – neurons-­‐ in  
the  network  succumb  to  tangle  formation
 Amyloid-­beta  (Aß)  deposition
• Aß is  derived  from  abnormal  cleavage  of  the  
precursor  protein  (APP)
• Aß is  deposited  extra-­‐neuronally in  plaques
• Aß is  deposited  within  and  around  blood  vessels
• Not  well-­‐correlated  with  dementia  symptoms  
compared  to  tangles II-­‐III

Cortical  layers
V-­‐VI

Amyloid  distribution
 Amyloid  (Aß)  processing
(supplementary  background    information  only)  
Derived  from  the  amyloid  precursor  protein  (APP)
Secretase enzymes  cleave  the  precursor  protein  into  the  amyloidogenic peptide  Aß
Genetic  cases  (~1-­‐2%  of  cases)  relate  to  APP  mutations
Aß peptides  accumulate  in  
ß-secretase extracellular  plaques

Aß

Aß Aß Aß cell  membrane

γ-secretase

Most  drugs  in  development  focus  on  Aß blocking  or  

removal.    Will  it  pay  off?  
 Frontotemporal dementia  (FTD)

FTD  is  a  group of  disorders/syndromes  with  different  aetiologies*,  

frequencies,  progression,  symptoms  and  genetics.

They  have  in  common  atrophy  in  frontal  and  temporal  lobes:  strikingly  
specificity

FTD accounts  for  just    ~10-­‐15%  of  dementias  overall,  all  ages  considered

For  persons  under  50  years,  FTD  accounts  for  >50%  of  dementias!

*aetiology =  disease  origin,  trigger,  underlying  basis

 Frontotemporal  dementia
cortical  atrophy

Frontal  lobe  &  temporal  lobe  atrophy normal

http://www.neuroscience.cam.ac.uk/uploadedFiles/jxuereb_phpWjayhZ.jpg
and  the  University  of  Rochester    NY  USA
 gyrus rectus
parahippocampal gyrus
orbital  cortex

fusiform  gyrus
dorsolateral  
inferior   prefrontal  cortex
temporal    
gyrus

The  fusiform  gyrus is  also  called  the   gyrus rectus  is  also  the  
tempero-­occipital    gyrus ventromedial  prefrontal  cortex  
 Regions  of  reduced  activity  in  frontotemporal  dementia  

18FDG*  PET  

Blood  flow  is  a  proxy  measure    for  neuronal  

neuronal  activity

Red  areas  show  reduced  glucose  uptake,  reduced  

blood  flow

Indicative  of  regions  of  lower  activity  in  FTD

Frontal  lobes,  temporal  lobes,  cingulate,  language  areas *fluorodeoxyglucose18

Ishii,  K.  (2013)  PET  approaches  for  diagnosis  of  dementia.  American  Journal  of  Neuroradiology,  http://dx.doi.org/10.3174/ajnr.A3695.
Clinical  features  of  FTD  related  to  brain  regions
Behavioural abnormalities  related  to  prefrontal  areas
Decreased  initiative
Social  disinhibition
Poor  planning
Impulsivity,  loss  of  restraint  
Emotional  blunting,  difficulty  regulating  emotion
Stereotypical  behaviours
repetitive  behaviours,  mimicking  behaviours,  compulsive  behaviours
Aphasias
Some  forms  of  FTD  have  primarily  a  language  dysfunction,  less  behavioural or  memory
Related  to  temporal  lobe  areas  (Wernicke’s)  and  Broca’s area
Memory  dysfunction    -­‐ temporal  lobe  areas  &  DLPF  cortex
Usually  appears  later,  can  be  a  minor  feature  and  often  not  as  severe  as  in  AD
*Movement  disorders*  -­‐ some  subtypes  of  FTD  (e.g.  FTD  17,  a  tau  mutation)  show  parkinsonism
More  likely  to  have  an  early  age  of  onset  (midlife  – 40-­‐50  years)

2-­15  year  duration  of  symptoms

 Many  unanswered  questions  in  frontotemporal  dementia

Frontotemporal  dementia  was  once  called  Pick’s  disease  

Now  it  is  considered  a  minor  subset  of  all  FTDs

Microscopic  pathology  in  FTD  not  well  understood  compared  to  

AD
In  most  cases  see  no  distinct  neuronal  inclusions  (e.g.  Pick  
Arnold  Pick  1892
bodies)

Tau  is  a  component  in  some  cases

Inflammation  – gliosis  -­‐ is  common  (astrocyte  and  microglia  

reaction)

Pick  bodies  are  found  in  only  5%  of  FTD  patients,  forcing  rethink  
of  disease  classification  and  mechanisms

Pick  Bodies
Tau-­‐positive  structures  within  
neurons
 Genetics  of  FTD
Familial  cases  account  for  20-­50%  of  individuals  with  FTD,  2-­3%  
of  dementias

Some  of  the  putative  genes  in  FTD    -­‐ DON’T  MEMORISE  but  be  aware  of  the  variety  of  
candidates
MAPT  gene (  Chr17)  tau
GRN  gene (  Chr17)  progranulin protein
TARDBP  gene (Chr1)  trans-­‐active  response  DNA-­‐binding  protein  43-­‐kDa  (TDP-­‐43)
VCP  gene (Chr9)  valosin-­‐containing  protein
CHMP2B  (Chr3)    multivesicular body  protein  2B
 Summary  of  FTD
• Frontotemporal dementia  is  relatively  rare  compared  to  AD

• Large  proportion  of  patients  have  young  onset  (40s  &  50s  but  
may  be  as  young  as  20  years  !  

• Larger  proportion  of  patients  have  a  genetic  link  compared  to  AD

• Cortical  atrophy  seen  mainly  in  frontal  and  temporal  lobes

• Symptoms  related  to  behavioural/emotional  control  and  language  

appear  early  in  the  disease

• Memory  dysfunction  is  present,  but  not  the  prominent  feature  

early  on  (contrast  Alzheimer’s  disease)

• Disease  mechanisms  and  histopathology  is  still  puzzling  – some  

cases  have  Pick’s  bodies  in  neurons,  large  majority  do  not
Head  injury:    often  damages  medial  temporal  lobe,  prefrontal  areas
Chronic  traumatic  encephalopathy  CTE

Head  injury

Inferior  view  of  cranial  cavity