Neurodegenerative
Diseases
Neurodegenerative
Diseases
These are diseases of gray matter
characterized:
• by the progressive loss of neurons
• with associated secondary changes in
white matter tracts.
Neurodegenerative
Diseases
• The pattern of neuronal loss is selective,
affecting one or more group of neurons.
• A common theme is the presence of
protein aggregates resistant to
degredation through the ubiquitinproteasome system.
Neurodegenerative
diseases
• Characterized by nerve cell loss and
gliosis, often in specific regions of the
brain which correlate with clinical
symptoms
– example: Huntington diseasecaudate nucleus
• Specific or non-specific inclusions are
common
• Gross atrophy of the affected regions
may be seen—
• Examples:
– Diffuse atrophy in Alzheimer disease,
– Caudate atrophy in Huntington disease.
Neurodegenerative disorders
• Degenerative diseases affecting the cerebral cortex
 Alzheimer disease

Frontotemporal dementias

Pick disease

Progressive supranuclear palsy

Corticobasal degeneration

Vascular dementia
• Degenerative diseases of basal ganglia and brain stem

Parkinson disease- Akinetic

Dementia with Lewy bodies

Huntington disease- Hyperkinetic
• Spinocerebellar degenerations

Spinocerebellar ataxia

Friedrich ataxia

Ataxia telengiectasia
• Degenerative diseases affecting motor neurons

ALS

Bulbospinal atrophy

Spinal muscular atrophy
Degenerative diseases
affecting the cerebral
cortex
Degenerative diseases affecting the
cerebral cortex
• Alzheimer disease
• Dementia of frontotemporal lobe type ;
DFLT)
• Pick disease
• Other
– Vascular dementia (serebrosclerosis)
– Dementia with hydrocephalus (NPH).
Dementia
• Neuropathologically
– Alzheimer disease 65%
– Vascular disease 15-20%
– Dementia with Lewy bodies 10%
– Others:
• Dementia of frontal lobe type
– Pick disease (<2%)
Alzheimer's Disease
• Degenerative;
• The major cause of dementia in the elderly;
• Main pathologic change is generalized
atrophy of brain with neurofibrillary
tangles, senile plaques and amyloid
angiopathy in many parts of the brain.
• Impairment of recent memory
• Aphasia (naming), apraxia (motor), agnosia
(object), executive functioning
• Progressive over time
• 47% of people over 85 years of age are
affected
• Familial cases with a defined inheritance
pattern account for only 5 to 10% of
Alzheimer's disease.
– Familial cases tend to have an earlier age at onset.
– Genetic defects in familial cases have been
identified on chromosomes 21, 19, 14, 12 and 1.
• Regardless of the cause, the diagnosis of AD is
made clinically by the finding of progressive
memory loss with increasing inability to
participate in activities of daily living.
– Late in the course of the disease, affected persons
are not able to recognize family members and may
not know who they are.
• The definitive diagnosis is made pathologically
by examination of the brain at autopsy.
• Grossly, there is cerebral atrophy, mainly in
frontal, temporal, and parietal regions.
• As a consequence, there is ex vacuo ventricular
dilation.
Alzheimer's disease leads to cerebral atrophy.
The external surface of the brain with widened sulci and narrowed
gyri, mostly over the frontal and parietal regions, gross.
Alzheimer's disease : the characteristic hydrocephalus ex
vacuo, or ventricular dilation resulting from loss of cortex.
In the neuropil of the cerebral cortex there is fragmentation
of neurites (neuronal processes) within gray matter producing
the characteristic "senile plaques“. These are degenerative
presynaptic endings. The plaques may also contain a few
astrocytes, and microglia. Bielschowsky silver stain.
The thioflavin
stain viewed with
fluorescence
microscopy
highlights the
neuritic plaques of
Alzheimer's
disease with
amyloid deposition
which fluoresces
bright green, as
shown here.
neurofibrillary tangle
Older plaques contain a
central amyloid core, seen
here with Congo red stain. A
small vessel demonstrates
amyloid angiopathy as well.
• The pathologic changes of Alzheimer
disease occur in nearly all Down syndrome
(trisomy 21) patients by the age of 45.
• Amyloid precursor protein (APP)
– Abnormal APP processing leads to deposits of
insoluble β-pleated amyloid protein resulting in
fibrillar aggregates of beta-amyloid that is
toxic to neurons.
• Normal aging
– Diffuse plaques and neuritic plaques:
uncommon (20% of those studied) in
6th decade, common (90%) in
centenarians
– Neurofibrillary degeneration:
uncommon in cortex in normal aging.
Alzheimer disease:
Summary
• Most common cause of dementia in the
elderly
• Degenerative cell loss leads to gross
atrophy of the entire brain with
“hydrocephalus ex vacuo”
• Neuritic plaques, neurofibrillary tangles,
cell loss and gliosis, granulovacuolar
degeneration, amyloid angiopathy, Hirano
bodies.
Pick disease
• Onset 45-65 years, rare after 75
• 80% are sporadic / 20% familial
• 5-10 year duration
• Frontal lobe symptoms (personality changes,
‘haphazard’ behavior, lack of planning, antisocial,
obsessive compulsive, language deficits, anomia and
echolalia),
• Anterior temporal lobe symptoms (aphasia,
semantic memory loss, Kluver-Bucy syndrome) and
pathology
– memory relatively retained.
• Gross appearance: severe localized atrophy
of frontal lobes and anterior temporal lobes
“knife-edge” atrophy
• Microscopic appearance: Pick cells (ballooned
neurons) and Pick bodies with cell loss and
gliosis
• Pick cells are seen in 1/2 of cases with typical
gross appearance and Pick bodies only 20%
Pick's disease with the gross appearance of lobar atrophy
is seen here involving the frontal lobe. Note the "knife
like" gyri.
Pick's disease is demonstrated grossly in this coronal section
in which there is marked atrophy with ex vacuo ventricular
dilation.
Multi-infarct dementia
(MID)
• Multi-infarct dementia (MID) can cause a
dementia similar to Alzheimer's disease
(AD).
• However, no pathologic findings are
present characteristic of AD.
• Instead, there are multiple ischemic
lesions in the cerebral cortex that
cumulatively result in loss of enough
neurons to produce dementia.
• Most patients with MID have an abrupt onset
of cognitive symptoms along with an
incremental loss of mental function.
• Focal neurologic deficits can be present,
depending upon the size and location of the
infarcts.
• In some cases, though, there is gradual loss
of mental function.
• Pathologically,
– marked cerebral arterial
atherosclerosis and/or
– thromboembolic disease
can account for the appearance of
many infarcts, typically small and
scattered.
Grossly, this
composite view of
the brain
demonstrates
multiple remote
cystic infarcts in
various locations.
This process took
several years.
Degenerative Diseases of
Basal Ganglia and Brainstem
Movement disorders
• Akinetic-rigid
– Parkinson disease (PD)
Postencephalitic parkinsonism (PEP)
– Multiple system atrophy (MSA)
Parkinson disease
• Idiopathic Parkinson disease (vs.
parkinsonism or parkinsonian syndrome)
• Tremor (rest)
• Rigidity (cogwheel rigidity)
• Bradykinesia (mask-like facies, loss of
arm-swing)
• Festinating gait (loss of righting reflexes)
• Gross: loss of pigment in the
substantia nigra
• Microscopic : Lewy bodies with
pigmented neuronal cell loss and gliosis
– cortical Lewy bodies present in 80% or
more of PD cases
• Most cases are sporadic.
• Mechanism: Loss of dopaminergic input
from substantia nigra to striatum
• This syndrome covers several diseases of
different etiologies which affect primarily
the pigmented neuronal groups including
the
–
–
–
–
substantia nigra,
locus ceruleus,
dorsal motor nucleus of cranial nerve X,
the substantia innominata.
• The pigmented neurons are slowly lost as
the disease progresses and melanin
pigment can be seen within the background
neuropil or within macrophages.
• Astrocytosis occurs secondary to neuronal
loss.
• Some patients with Parkinsonian symptoms
also have dementia, and in these patients
there are Lewy bodies in the cerebral
cortex, as well as the substantia nigra.
Pathology
• Lewy bodies in association with
Parkinson's disease are found within the
cytoplasm of pigmented neurons.
• For a diagnosis of DLB, the Lewy bodies
must be found in the neocortex.
– These are homogeneous pink bodies on H&E
stains with a surrounding halo.
– Immunohistochemical staining with antibody to
alpha-synuclein is positive in these Lewy
bodies.
A normally pigmented
substantia nigra 
The patient with
Parkinson's disease has
decreased neurons and
pigment as seen
microscopically at the
right 
Other parkinsonian
syndromes
• Differential diagnosis of parkinsonism
– Progressive supranuclear palsy (PSP)
– Corticobasal degeneration (CBD)
– Multiple system atrophy (MSA)
• striatonigral degeneration
• olivopontocerebellar atrophy
• Shy-Drager syndrome
– Dementia pugilistica
– Postencephalitic parkinsonism (PEP)
Parkinson disease summary
• Akinetic movement disorder
• Loss of dopaminergic input from substantia
nigra to striatum
• Pigmented (neuromelanin containing) nerve
cell loss with gliosis in the substantia nigra
pars compacta and locus ceruleus (pigment
loss is grossly apparent)
• Lewy body formation in brainstem and
cortex.
Parkinson disease and
dementia
• Relatively common disorder in the middleaged and elderly;
• The major pathologic changes are seen in
the pigmented neurons of the substantia
nigra in the midbrain;
– neurons in this area contain intracytoplasmic
inclusions called Lewy bodies.
• 40% of Parkinson Disease patients
develop dementia;
• demented PD patients have more
Alzheimer disease pathology than nondemented PD patients
– some demented PD patients have only Lewy
body pathology
Dementia with Lewy Body Diseases
(DLB)
Dementia with Lewy bodies is a
clinicopathological syndrome that may
account for up to 20% of all cases of
dementia in older patients, typically in
their seventh and eighth decades.
DLB
There are three major syndromes
associated with the appearance of Lewy
bodies. These are:
• (1) Parkinson disease,
• (2) autonomic nervous system failure,
• (3) dementia.
• The clinical presentation of Lewy body
disease varies according to the site of Lewy
body formation and associated neuronal loss.
• In Parkinson disease, the Lewy bodies are
found in the substantia nigra of the midbrain,
coupled with the loss of pigmented neurons.
• In persons with the dementia of diffuse
Lewy body disease, there are Lewy bodies in
the neocortex.
• Some persons have the Lewy bodies in both
locations.
• The basal ganglia and diencephalon may also
be involved in some cases.
Lewy bodies
• spherical, intraneuronal, cytoplasmic, eosinophilic
inclusions.
H&E stain demonstrates a rounded pink
cytoplasmic Lewy body in a neuron of the
cerebral cortex from a patient with diffuse
Lewy body disease, which can be a cause for
dementia.
Lewy bodies can also be seen in substantia
nigra with Parkinson's disease.
An immunoperoxidase stain for ubiquitin,
seen at the right, helps demonstrate the
Lewy bodies more readily by the brown
reaction product within them.
Multiple system atrophy
(MSA)
• Prevalence: 8% of parkinsonian cases in PD
brain banks
• Microscopic finding: oligodendroglial
cytoplasmic inclusions
• Clinical signs and symptoms
– Parkinsonism (striatonigral degeneration)
– Autonomic failure (Shy-Drager syndrome)
– Cerebellar findings (olivopontocerebellar
degeneration)
• Striatonigral degeneration
– parkinsonism with orthostatic hypotension
and cerebellar ataxia
– cell loss and gliosis in putamen
• Olivopontocerebellar atrophy (sporadic)
– neuronal loss and gliosis
• Shy-Drager syndromesympathetic ganglia
Movement disorders
• AkineticPD, other diseases with
parkinsonian features
• Hyperkinetic
– Huntington chorea
– Other
• Myoclonus
• Ballismus
• Dystonia
• Tic disorders
Huntington’s disease
• Choreiform movements, neuropsychiatric
disturbance and slowly progressive
dementia
– seizures or rigidity may occur initially
• Gross: atrophic, flattened caudate
• Microscopic: cell loss and gliosis in caudate
nucleus (dorsal putamen, globus pallidus
and nucleus accumbens affected later)
Huntington's
disease is
shown grossly
in this coronal
section of the
brain.
It
demonstrates
atrophy of
the caudate
with resultant
increase in
size of lateral
ventricles.
Microscopically, the
caudate nucleus in
Huntington's disease
demonstrates loss of
neurons along with
gliosis.
• Autosomal dominant genetic disorder,
(sporadic mutations not described)
• Characterized by chorieform movements,
cognitive deterioration, emotional
disturbances
• Huntingtin gene (HD gene), chromosome 4,
contains an unstable trinucleotide repeat
(CAG= 37-86 vs 19 in normals, codes for
glutamic acid)
• Complete dominance-- heterozygotes as
severely affected as homozygotes
• Children inheriting the gene from
their father have either juvenile
onset disease or onset approximately
3 years early (genomic imprinting)
• Onset is typically in 4-5 decade
Huntington Disease: Summary
• Hyperkinetic movement disorder
• Characterized by chorieform movements,
cognitive deterioration, emotional
disturbances
• Caudate atrophy
• Deep gray nuclei cell loss/gliosis
• Autosomal dominant
• Trinucleotide repeat disease
* *
*
*N. Caudatus
*Corpus callosum
*Thalamus
Basal ganglia
• Typical disorders of the basal
ganglia, (dyskinesias) include:
• Huntington chorea--striatum,
• ballismus--subthalamic nucleus and
• PD--substantia nigra
• .
• The functional definition of the basal
ganglia includes:
– the corpus striatum (lentiform and caudate
nuclei),
– subthalamic nucleus.
– substantia nigra.
SPINOCEREBELLAR
DEGENERATIONS
• Spinocerebellar Ataxias
• Friedreich Ataxia
• Ataxia-Telangiectasia
Spinocerebellar Ataxias
• This is a group of genetically distinct diseases
characterized by signs and symptoms referable
to the cerebellum (progressive ataxia),
brainstem, spinal cord, and peripheral nerves, as
well as other brain regions in different
subtypes.
• Pathologically, they are characterized by
neuronal loss from the affected areas with
secondary degeneration of white matter tracts.
Friedreich Ataxia
• This is an autosomal-recessive progressive ,
beginning in the first decade of life with gait
ataxia, followed by hand clumsiness and
dysarthria.
• Deep tendon reflexes are depressed or absent,
but an extensor plantar reflex is typically
present.
• Joint position and vibratory sense are impaired,
and there is sometimes loss of pain and
temperature sensation and light touch.
• Most patients develop pes cavus and
kyphoscoliosis.
• There is a high incidence of cardiac
disease with arrhythmias and congestive
heart failure.
• Concomitant diabetes is found in about
10% of patients.
• Most patients become wheelchair-bound
within about 5 years of onset; the cause
of death is intercurrent pulmonary
infections and cardiac disease.
Ataxia-Telangiectasia
• Ataxia-telangiectasia is an autosomal-recessive
disorder
• characterized by an ataxic-dyskinetic syndrome
• beginning in early childhood,
• caused by neuronal degeneration predominantly
in the cerebellum,
• the subsequent development of telangiectasias
in the conjunctiva and skin, and
immunodeficiency.
DEGENERATIVE DISEASES
AFFECTING MOTOR NEURONS
• Lower motor neurons in the anterior horns of
the spinal cord
• Lower motor neurons in certain cranial nerve
motor nuclei (V, VII, IX, XII) but not those
that control eye movements (III, IV, VI)
• Upper motor neurons (Betz cells) in the motor
cortex
DEGENERATIVE DISEASES
AFFECTING MOTOR NEURONS
• Amyotrophic Lateral Sclerosis (Motor
Neuron Disease)
• Bulbospinal Atrophy (Kennedy Syndrome)
• Spinal Muscular Atrophy
• Genetic Metabolic Diseases
Amyotrophic Lateral
Sclerosis ALS
• ALS
– (also known as Lou Gehrig's disease after the famous
Yankee first baseman who had this disease)
• results from loss of motor neurons which is most
striking in the anterior horn cells of spinal cord
but may involve cranial motor nuclei and Betz
cells(large pyramidal cells in the motor cortex of
the precentral gyrus).
• The loss of anterior horn cells leads to muscle
atrophy.
• Males are affected more commonly than
females.
• The patients present in middle age with
weakness of the extremities and may go on
to develop bulbar signs and symptoms.
• Astrocytosis is seen in response to the
loss of motor neurons.
• Because of the loss of upper motor
neurons, there is lateral column
degeneration with gliosis, the so-called
"sclerosis" of the lateral columns of spinal
cord.
• The course is usually 2 to 6 years after
diagnosis,
– but patients presenting with bulbar signs and
symptoms have a shorter life span because of
swallowing difficulties and aspiration.
• The etiology is unknown.
• Most cases occur sporadically,
– but 1 to 10% of cases may have an autosomal
dominant inheritance pattern.
There is lateral column degeneration of the
spinal cord microscopically in this case of
ALS, as seen with Luxol fast blue stain.
Bulbospinal Atrophy
(Kennedy Syndrome)
• This X-linked adult-onset disease is
characterized by distal limb amyotrophy and
bulbar signs such as atrophy and fasciculations
of the tongue and dysphagia.
• Affected individuals manifest androgen
insensitivity with gynecomastia, testicular
atrophy, and oligospermia.
Genetic Metabolic Diseases
• Neuronal storage diseases are mostly autosomalrecessive diseases caused by a deficiency of a
specific enzyme involved in the catabolism of
sphingolipids, mucopolysaccharides, or
mucolipids.
• Leukodystrophies show a selective involvement
of myelin (either abnormal synthesis or
turnover), and generally exhibit no neuronal
storage defects.
• Mitochondrial encephalomyopathies are a group
of disorders of oxidative phosphorylation,
usually resulting from mutations in the
mitochondrial genome
LEUKODYSTROPHIES
• Krabbe Disease This disease is an
autosomal-recessive leukodystrophy
resulting from a deficiency of
galactocerebroside β-galactosidase
(galactosylceramidase), the enzyme
required for the catabolism of
galactocerebroside to ceramide and
galactose
LEUKODYSTROPHIES
• Metachromatic Leukodystrophy
• This disorder is transmitted in an
autosomal-recessive pattern and results
from a deficiency of the lysosomal enzyme
arylsulfatase
LEUKODYSTROPHIES
• Adrenoleukodystrophy
• This disorder, which has several clinically and genetically
distinct forms, is a progressive disease with symptoms
referable to myelin loss from the CNS and peripheral
nerves as well as adrenal insufficiency.
• In general, forms with earlier onset have a more rapid
course.
• The X-linked form usually presents in the early school
years with neurologic symptoms and adrenal
insufficiency and is rapidly progressive and fatal
• Dementia
–
–
–
–
Summary
Prion disease
Alzheimer’s disease
Dementia with Lewy bodies
Pick’s lobar atrophy
• Movement disorders
– Akinetic rigid--Parkinson disease and
parkinsonian syndromes
– Hyperkinetic--Huntington disease
Prion disease
• Spongiform encephalopathy
– Kuru (New Guinea)
– Creutzfeldt-Jakob (sporadic, iatrogenic)
– Gerstmann-Sträussler-Scheinker
syndrome
• familial, ataxia prominent
– FFI (fatal, familial insomnia)
– Animals: BSE ( bovine spongiform
encephalopathy), scrapie
TRANSMISSIBLE AGENT (PRION)
DISEASES
SPONGIFORM ENCEPHALOPATHY
CREUTZFELDT-JACOB DISEASE
• 50-70 years old, rapidly evolving
dementia,
– myoclonus
– characteristic EEG pattern of repetitive sharp
waves.
Early symptoms include personality
changes, impaired judgement, gait
abnormalities, vertigo.
• In some patients cerebellar and visual
abnormalities predominate
• Majority die within 3-6 months.
Prion disease pathogenesis
• Transmissible but not “infectious”
• Prion protein, Prusiner--1997 Nobel
Prize, (not a “slow virus”, just a protein).
• PrPC  produced normally in most cells
amino acid sequence abnormal protein.
• Abnormal PrPC deposits in specific locations
causing specific clinical features (thalamus
in FFI-- fatal, familial insomnia),
• Localization correlates with clinical findings:
– cerebellar findings with cerebellar “Kuru
plaques” in Gerstmann-Sträussler-Scheinker
syndrome.
• Gross appearance
– may be normal due to short duration of
disease
• Microscopic appearance
– Vacuolation of neuropil*, within nerve cell
bodies and neuronal processes:
• Many round to oval vacuoles varying in size from one
to 50 microns in size in the neuropil of cortical gray
matter.
• These vacuoles may be single or multiloculated.
• The vacuoles may coalesce to microcysts.
*Neuropil: a dense network of neurons and glia in the central nervous
system; the brain tissue that lies between axons.
– Cell loss and gliosis may be prominent.
There are numerous gray
matter vacuoles, along
with gliosis and neuronal
loss, in a patient with
advanced CJD.
Prion disease: Summary
•
•
•
•
A rapidly progressive dementing disease
EEG characteristic
Gross brain often not atrophic
Spongiform changes on microscopic
examination (gliosis may be extensive)
• Caused by a abnormal protein (PrPC) not a
virus.