THE NEUROPATHOLOGY OF
NEURODEGENERATIVE
DISEASES:
AN INTRODUCTION
Ronald L. Hamilton, M.D.
Assistant Professor of Neuropathology,
University of Pittsburgh
NP of neurodegenerative diseases
Alzheimers Disease (AD)
Parkinsons Disease
Dementia with Lewy Bodies (DLB)
Picks Disease
Progressive Supranuclear Palsy (PSP)
Huntingtons Disease
Amyotrophic Lateral Sclerosis (ALS)
Prion Encephalopathies (CJD)
HIV encephalitis (AIDS dementia)
Alzheimers Disease
Gross
Cortical atrophy
Frontal, parietal and temporal lobes
Mesial temporal lobe atrophy
Amygdala, hippocampus, entorhinal cortex
AD: gross
AD gross
amygdala
hippocampus
AD: Plaques and tangles
Neuritic
plaques
NFT
Bielschowsky stains have been used for almost
100 years to diagnose Alzheimers Disease
(NFT = neurofibrillary tangle)
AD: beta-A4 amyloid plaques
Plaques: diffuse or neuritic
Senile plaques are seen with Bielschowsky
stain and have been divided into diffuse and
neuritic subtypes. from CERAD handbook
Neuritic plaques
CERAD (Consortium to Establish a Registry for Alzheimers
Disease) criteria for the neuropathological diagnosis of
AD is based on a clinical history of dementia and agerelated numbers of neuritic plaques
CERAD criteria and NIA-RI criteria
CERAD criteria (1991) requires frequent neuritic
plaques and a clinical diagnosis of dementia in
a patient older than 75 years to make a
diagnosis of Definite AD. CERAD criteria do
not require any particular degree of tangle
formation.
NIA-RI criteria was developed in 1997 and
combines CERAD criteria and ALSO includes
the degree of tangle formation (as evaluated
by Braak stage (vide infra) to arrive at a
diagnosis.
Neurofibrillary tangles
NFTs are also
detected with
the
Bielschowsky
silver stain.
Neurofibrillary tangles
NFTs are composed of fibrillar
aggregates (above) made of
paired helical filaments.
They are very insoluble and
remain as ghost tangles
(right, arrows) after the death
of the host neuron.
Tau accumulation in AD
NFTs are made of abnormal accumulations of
hyerphosphorylated tau protein.
In the late stages of AD, NFTs are frequent in neocortical areas
and accompanied by numerous neuropil threads as
demonstrated with these tau immunostains
Braak staging
The severity of NFT
changes
correlates well
with the degree
of clinical
dementia.
NFTs changes are
evaluated
according to the
Braak staging
system
(NFT)
AD: Beta-A4 Amyloid and Tau
AD is characterized by extracellular accumulation of betaA4 amyloid (plaques) and intracellular accumulation of
tau (neurofibrillary tangles and neuropil threads)
Parkinsons Disease
Parkinsons Disease is characterized by loss of
pigment in the substantia nigra and locus
ceruleus
Parkinsons Disease
Neuronal loss in the substantia nigra is
accompanied by numerous pigment-laden
macrophages (melanophages, arrow) and gliosis
Lewy Bodies
Lewy bodies in the substantia nigra are relatively easy to
see with standard H&E stains and are essential for the
diagnosis of Parkinsons Disease.
Lewy Bodies
Multiple Lewy bodies in nigral neurons are not
uncommon.
Lewy Bodies
Lewy bodies are
abnormal
aggregates of
alpha-synuclein.
Immunostaining
for alphasynuclein
strongly labels
both Lewy
Bodies and Lewy
neurites in the
substantia nigra.
Both are also
ubiquitinpositive.
Alpha-synucleinopathies
Several neurodegenerative diseases are
characterized by abnormal intracellular
aggregation of alpha-synuclein:
Parkinsons Disease
Dementia with Lewy Bodies
Lewy Body Variant of AD
Multiple System Atrophies
OPCA
SND
Shy-Drager Syndrome
Dementia with Lewy Bodies
Diagnostic terminology:
Diffuse Lewy body disease
Lewy body variant of AD
Lewy body dementia
Senile dementia of Lewy body type
AD with incidental Lewy bodies
AD plus Parkinsons disease
CORTICAL LEWY BODIES
With standard H&E stain, Lewy bodies in cortical
neurons maybe difficult to appreciate.
Lewy Body Scoring
Five areas of the brain are used in the current LB scoring
system.
The entire area indicated in red is examined for Lewy bodies
by H&E or ubiquitin IHC.
Each area is then given a score of 0, 1 (1-5 LB), or 2
(6+ LB).
Lewy threads
AD
LBVAD
AD
LBVAD
Proteolysis pre-treatment reveals numerous neocortical alpha-synuclein-positive thread-like
processes
Lewy threads
Lewy threads are both abundant and widespread
in Dementia with Lewy bodies
Lewy bodies in AD
Using alpha-synuclein to detect
Lewy bodies, we found that 60% of
AD cases have Lewy bodies
Picks Disease
Picks Disease
shows severe
atrophy of the
frontal and
temporal lobes
(lobar atrophy),
often with knifeedge atrophy of
the gyri.
Picks Disease
Severe neuronal
loss with
intense gliosis
is seen in the
affected
cortical regions
Similar changes
are seen in
non-Pick
Frontotemporal
dementia (FTD)
as well.
Picks Disease
Tau
PICK CELL
Variable numbers of Pick bodies can be seen by H&E,
Bielschowsky and tau immunostains. Pick cells (balloon
cells) are often present.
Progressive Supranuclear Palsy
PSP typically shows severe depigmentation of
the substantia nigra and locus ceruleus
PSP
The most common areas
affected in PSP:
SN, GP, hippocampus,
entorhinal cortex,
subthalamic nuclei,
dentate nuclei, red
nuclei, periaqueductal
gray matter, colliculi,
as well as CN III, IV, X
and XII nuclei.
Putamen, pontine nuclei,
olivary nuclei, and
cortex may also show
globose tangles.
PSP
Globose NFTs
characterize PSP
and can be seen
with silver stains
(Gallyas).
The globose NFTs are
tau-positive.
Many glial cells also
contain abnormal
accumulations of
tau.
Huntingtons Disease
HD shows mild cortical atrophy and severe
atrophy of basal ganglia
Huntingtons Disease
Normal brain
(left) compared
to HD case
(right) showing
severe atrophy
of caudate
Huntingtons Disease
The caudate shows neuronal loss and severe gliosis. Loss
of aspiny (small, ACh+) neurons > than spiny (large,
GABA+) neurons.
Huntingtons Disease
Caudate atrophy is
assessed using
the Vonsattel
grading system
Amyotrophic Lateral Sclerosis
ALS is characterized by loss of upper and
lower motor neurons.
The spinal cord often shows atrophy of the
cervical and lumbar enlargements as well
as of the anterior spinal roots.
In some cases, atrophy of the pre-central
gyrus can be observed.
Amyotrophic Lateral Sclerosis
In cervical and lumbar regions, the anterior horns have
numerous large lower motor neurons (left) which are
lost in ALS (right).
Amyotrophic Lateral Sclerosis
In remaining LMN, there may be Bunina bodies (left)
and large hyaline inclusions (right)
Amyotrophic Lateral Sclerosis
Ubiquitin immunostains reveal some LMN with
ubiquitin skeins.
Amyotrophic Lateral Sclerosis
Loss of UMN leads to
degeneration of
motor axons, resulting
in pallor of the
cerebral peduncles,
pyramids (right,
upper) and both
lateral and anterior
corticospinal tracts in
the spinal cord (right,
lower) (myelin stain)
Amyotrophic Lateral Sclerosis
Loss of neurons in the motor cortex is
accompanied by gliosis, which is lacking in the
adjacent sensory cortex
Prion encephalopathies
Prion protein is a normal abundant protein in the brain.
The function is unknown. It has a normal secondary
structure dominated by alpha-helical formations and is
easily digested by proteases
Abnormal prion protein (the cause of the prion diseases)
is the same protein, but has a secondary structure
dominated by beta-pleated sheets, which makes it more
prone to aggregate and resitant to protease digestion.
Know one knows how the initial event that causes the
protein to change its secondary structure.
Abnormal prion protein somehow recruits the normal
prion to the abnormal shape thus allowing for
propagation and accounting for transmissability of an
agent that lacks RNA and DNA
Prion encephalopathies
Kuru (historical)
Creutzfeldt-Jakob
Sporadic
Transmitted
Familial
New variant (vCJD)
Gerstmann-Straussler-Scheinker
Fatal familial insomnia
CJD
Most cases
of CJD
show little
or no
cerebral
atrophy
CJD
Spongiform
changes of both
cortical and deep
gray matter,
neuronal loss and
gliosis characterize
the CJD brain.
CJD - prion plaques
In 15% of CJD cases kuru (prion) plaques can
be found in the cerebellum
GSS
GSS has numerous prion plaques primarily in the cerebellum.
There is little spongiform change.
There are several clinical and pathological variants of GSS, but all
are familial and due to mutations in the prion gene.
vCJD
vCJD has distinctive
pathology consisting of
numerous cortical and
cerebellar florid plaques
and moderate spongiform
change.
HIV ENCEPHALITIS
HIVE is characterized by multinucleated giant
cells and perivascular accumulations of
macrophages, most of which are HIV+
