NEUROPATHOLOGY OF AGING

AND DEMENTIA
Normal young adult Non-demented elderly
Macroscopic changes in aging brain
• Brain volume and weight
• maximum in early teens
• reduces, esp after 50 yrs
• weight loss 2-3% per decade over
the next 4 decades
• Ventricular volume increases,
male>female
• Volume of grey reduces more than
white matter before 50 yrs but after
that white matter loss is greater
Microscopic changes in aging brain
• Reduction in neuronal number and
size
• Depends on neuronal populations
in various sites
• Neuronal loss: hippocampus,
cerebral cortex, substantia nigra,
locus ceruleus, nucleus basalis,
striatum
• Neuronal shrinkage: cerebral
cortex
• No loss or shrinkage: cranial
Microscopic changes in aging brain
• Reduction in synapses
• Amyloid plaques:
• 20% in 6th decade; 90-100% in
10th decade
• mostly non neuritic type
• occasionally in non demented
elderly large numbers of plaques
are found
• Neurofibrillary tangles
• frontal, temporal cortex,
hippocampus etc
 Definition of Dementia

An impairment of previously attained

occupational or social functioning
due to an acquired and persistent
impairment of memory associated
with an impairment of intellectual
function in one or more of the
following domains - language,
visuospatial skills, emotion,
personality or cognition - in the
presence of normal consciousness.
 Causes of Dementia
• Neurodegenerative diseases
• Cerebrovascular disease
• Toxic, metabolic, nutritional
disorders
• Hydrocephalus
• Mitochondrial encephalopathy
• Demyelinating and dysmyelinating
diseases
• Head injury
• Prion disease
• Infective disorders
 Causes of Dementia
• Neurodegenerative diseases
• Common
• Alzheimer’s disease
• dementia with Lewy bodies
• Less common
• dementia with MND inclusions
• Huntington’s disease
• progressive supranuclear palsy
• corticobasal degeneration
• Uncommon
• Pick’s disease
• multiple system atrophy
 Causes of Dementia
• Neurodegenerative diseases
• Cerebrovascular disease
• Toxic, metabolic, nutritional
disorders
• Hydrocephalus
• Mitochondrial encephalopathy
• Demyelinating and dysmyelinating
diseases
• Head injury
• Prion disease
• Infective disorders
 Causes of Dementia
• Cerebrovascular disease

Multi-infarct dementia, ischaemic

white matter degeneration or
hippocampal sclerosis etc, resulting
in loss of neurons leading to
dementia (vascular dementia)
 Causes of Dementia
• Neurodegenerative diseases
• Cerebrovascular disease
• Toxic, metabolic, nutritional
disorders
• Hydrocephalus
• Mitochondrial encephalopathy
• Demyelinating and dysmyelinating
diseases
• Head injury
• Prion disease
• Infective disorders
 Causes of Dementia
• Toxic, metabolic, nutritional
disorders
• drug-induced
• chronic alcoholism
• chronic hepatic encephalopathy
• vitamin B12, thiamine
deficiencies
• hypothyroidism
• neurometabolic storage diseases
• hypoglycaemia
• hypocalcaemia
 Causes of Dementia
• Neurodegenerative diseases
• Cerebrovascular disease
• Toxic, metabolic, nutritional
disorders
• Hydrocephalus
• Mitochondrial encephalopathy
• Demyelinating and dysmyelinating
diseases
• Head injury
• Prion disease
• Infective disorders
 Alzheimer’s disease
• 50-75% of dementia in western
populations
• Incidence increasing with age
• 5 main groups of AD
• Sporadic late onset (commonest)
• Familial late onset (uncommon)
• Familial early onset (rare)
• Associated with Downs’
syndrome
• Associated with other
neurodegenerative disease
 Alzheimer’s disease
• Several genes play a central role in
AD
• APP gene mutations
(chromosome 21)
• Apolipoprotein 4 allele
(chromosome 19)
• presenilin-1 gene mutations
(chromosome 14)
• presenilin-2 gene mutations
(chromosome 1)
 Alzheimer’s disease
• Macroscopic features (non specific)
• Brain atrophied (900-1200g;
normal about 1400 g)
• Medial temporal, frontal and
parietal regions affected
• Occipital lobe, motor cortex
normal
• Secondary hydrocephalus
• Substantia nigra normal
pigmentation
• Locus ceruleus pale
 Alzheimer’s disease
• Microscopic features (non-specific)
• Amyloid plaques (senile, neuritic
plaques)
• Neurofibrillary tangles
• Dystrophic neurites, neuropil
threads
• Neuronal and synapse loss
 Alzheimer’s Disease

Normal AD

Motor cortex
 Congo red
IHC: A
H&E
 H&E Tau IHC

Silver stains
 Neurofibrillar
y
tangles are
mainly
composed of
hyperphosph
ory
-lated tau
protein
(microtubule
Paired binding
helical
filaments proteins)
 Alzheimer’s disease
• Microscopic features (non-specific)
• Amyloid plaques (senile, neuritic
plaques)
• Neurofibrillary tangles
• Dystrophic neurites, neuropil
threads
• Neuronal and synapse loss
• Amyloid deposition in vessels
• Granulovacuolar degeneration
• Hirano bodies
 Granulovacuolar
Amyloid deposit in vessel degeneration

Hirano body
 Alzheimer’s disease
• Microscopic features (non-specific)
• Amyloid plaques (senile, neuritic
plaques)
• Neurofibrillary tangles
• Dystrophic neurites, neuropil
threads
• Neuronal and synapse loss
• Amyloid deposition in vessels
• Granulovacuolar degeneration
• Hirano bodies
NFT severity
correlates much
better with clinical
severity of AD
than with neuritic
plaques
Link between A
generation and
NFT formation is
unknown
 Alzheimer’s disease

• Amyloid cascade hypothesis

• Central role of A amyloid in the
pathogenesis of AD
• Evidence for:
• APP gene mutations
• Downs’ syndrome
• Evidence against:
• Non-demented elderly may have
large numbers of plaques
• Correlation between plaque
density and dementia severity is
weak
Amyloid cascade model of AD
 Alzheimer’s disease
• Pathologic diagnostic criteria for AD
• Histologic changes not entirely
pathognomonic and overlap with
cognitively normal elderly
• Diagnosis restricted to cases with
BOTH plaques and NFTs in the
hippocampus and neocortex, and a
history of dementia
• Criteria used, based on plaque density
include:
• National Institutes of Ageing
(Khatchaturian) criteria
• CERAD guidelines
 Causes of Dementia
• Neurodegenerative diseases
• Common
• Alzheimer’s disease
• dementia with Lewy bodies
• Less common
• dementia with MND inclusions
• Huntington’s disease
• progressive supranuclear palsy
• corticobasal degeneration
• Uncommon
• Pick’s disease
• multiple system atrophy
 Dementia with Lewy bodies
(Diffuse Lewy body disease, Lewy body variant of AD etc)

• 10-25% of dementia in western

populations
• Macroscopic features
• Mild to moderate involvement of
frontal, temporal and parietal
cortex; occipital lobe spared
• Pallor of substantia nigra and
locus ceruleus
 Dementia with Lewy bodies

• Microscopic features
• Lewy bodies in substantia nigra
and locus ceruleus, cerebral
cortex, amygdala
• AD changes commonly found:
• Numerous plaques in about
80% of patients
• NFT in entorhinal cortex; rare
in neocortex
• Rarer, pure form of DLB has no
AD changes
Ubiquitin IHC
 Frontotemporal Dementias
• 12-20% of all dementias
• Includes Pick’s disease, MND-
inclusion dementia, dementia with
changes of corticobasal
degeneration, dementia of frontal
type etc.
 Pick’s disease
• Macroscopic features
• Severe involvement of frontal,
temporal lobes
• Sparing of posterior part of
superior temporal gyrus
• “knife-edge” gyri
Pick’s Disease
Pick bodies
(cerebral cortex)

Swollen neuron

Pick bodies
(dentate fascia)
 Vascular Dementia
• Small vessel disease (arteriolosclerosis,
arteriosclerosis)
• ischaemic white matter
degeneration
• lacunar infarction
• Large vessel disease
• multi-infarct dementia
• Hypoperfusion lesions
• hippocampal sclerosis
• ischaemic encephalopathy
• Rare causes: CADASIL, vasculitis,
amyloid angiopathy
Lacunar infarction due to small
vessel disease of the brain
Ischaemic white matter
degeneration due to
small vessel
disease
Hyaline arteriosclerosis and
arteriolosclerosis (small
vessel disease)

Dilated perivascular spaces

with surrounding gliosis in
small vessel disease
 CA1 region

Bilateral hippocampal sclerosis

due to global cerebral hypoperfusion
(ischaemic encephalopathy)
Terima Kasih