PATHOLOGY
6.02c CNS Pathology III: Neurodegenerative &
Demyelinating Diseases
Maria Lourdes A. Tilbe, MD, FPSP | April 25, 2018
OUTLINE
I. Neurodegenerative Diseases
II. Degenerative diseases of the Cerebral Cortex
A. Alzheimer’s Disease
B. Frontotemporal Lobar Dementia
C. Pick’s Disease
III.Degenerative diseases of the Basal Ganglia and Brainstem
A. Parkinson’s Disease
B. Huntington’s Disease
C. Amyotrophic Lateral Sclerosis
IV. Demyelinating Diseases
A. Multiple Sclerosis
B. Acute Disseminated Leukoencephalitis
C. Acute Hemorrhagic Leukoencephalitis
D. Neomyelitis Optica
E. Central Pontine Myelinosis
F. Progressive Multiple Encephalopathy
IV. References
V. Quiz
OBJECTIVES:
At the end of the lecture, the student should be able to:
1. Demonstrate knowledge of the degenerative and demyelinating
diseases
2. Correctly identify gross and microscopic lesions
3. Correctly give the nature of injurious agent / mechanism of injury and
effect on neurons
4. Correctly give the likely underlying pathology given a set of clinical
data
5. Give the prognosis and predict outcome
Legend:
Supplementary Book
Audio Recording Emphasized Notes
Information
  ---------
I. NEURODEGENERATIVE DISEASES
Characterized by the progressive loss of neurons, typically
affecting groups of neurons with functional relationships even if they
are not immediately adjacent.
• Selective neuronal degeneration / loss of neurons in specific
defined area of the brain causing loss of neuronal function.
• Relentlessly progressive
• Most diseases are associated with accumulation of protein
aggregates that are resistant to degradation, which may be due to:
o Mutations that alter the protein’s conformation or disrupt the
pathways involved in processing or clearance of the proteins.
o Subtle imbalance between protein synthesis and clearance
that allows gradual accumulation of proteins.
Protein aggregates typically are resistant to degradation, show
aberrant localization within neurons, and elicit a stress response from
the cell; in addition, they are often directly toxic to neurons.
o As the abnormal proteins aggregate, there is often both an
associated toxic gain-of-function and a loss-of-function, as
more and more protein is shunted into the aggregates rather
than performing normal physiologic functions.
o These protein aggregates are recognized histologically as
inclusions, usually the diagnostic hallmark of the disease.
• Neurodegenerative diseases differ both with respect to the
anatomic localization of involved areas and in their specific cellular
abnormalities (e.g., tangles, plaques, Lewy bodies).
Basic Pathology: Deposition of abnormal proteins in the brain
→ Cellular degeneration and atrophy → Degenerative diseases
Neurodegenerative diseases are usually discussed using two
approaches:
1. Symptomatic/anatomic: based on the anatomic regions of the
CNS that are primarily affected, which is typically reflected in the
TRANSCRIBERS Tan, B., Tan, C., Tanganco, Tanjangco EDITOR
clinical symptoms (e.g., neocortical involvement resulting in
cognitive impairment and dementia)
2. Pathologic: based on the types of inclusions or abnormal
structures observed (e.g., diseases with inclusions containing tau
or containing synuclein)
Table 1. Degenerative Neurologic Diseases
Degeneration of the Degeneration of the
Cerebral Cortex → Basal Ganglia / Brainstem /
DEMENTIA Other portions of the brain →
IMPAIRED MOTOR FUNCTION &
Other abnormalities
Alzheimer’s Disease Parkinson’s Disease
Frontotemporal Dementia Huntington’s Disease
Pick’s Disease Amyotrophic Lateral Sclerosis
There are 2 systems responsible for protein recycling:
1. Ubiquitin – Proteasome System (UPS)
• Components:
o Proteasome – a multi-enzyme complex
o Ubiquitin – a small protein that tags proteins targeted for
proteasomal degradation.
• Normally, UPS degrades abnormal and damaged proteins.
• Abnormal forms of proteins (tau, huntingtin, & mutant
synuclein) form aggregates that cannot be digested in
proteasomes and accumulate in the cytoplasm or nucleus in
the form of inclusions that damage the UPS.
• Seen in
o Alzheimer’s disease
o Parkinson's disease
o Huntington's disease
o ALS
2. Lysosomal System
• Degrade long-lived proteins, thus protect cells from
accumulation of damaged organelles that could cause
apoptosis
• Abnormally folded proteins are processed through lysosomes
→ accumulation → impairs lysosomal function
II. DEGENERATIVE DISEASES OF THE CEREBRAL CORTEX
PRODUCING DEMENTIA
A. Alzheimer’s Disease
• Most common cause of dementia in older adults, with an
increasing incidence as a function of age.
• Characterized by dementia & cognitive impairment as main
neurologic manifestations
• Caused by degeneration / loss of neocortical neurons
o Usually becomes clinically apparent as insidious
impairment of higher cognitive functions – memory deficits,
visuo-spatial orientation, judgment, personality, and
language emerge as the disease progresses.
o There is loss of memory, inability to learn new things, loss
of language function, a deranged perception of space,
inability to do calculations, indifference, depression,
delusions
With preservation of consciousness and motor function
• Relentlessly progressive & fatal within 5-10 years
o Over a course of 5 to 10 years, the affected individual
becomes profoundly disabled, mute, and immobile
Rarely becomes symptomatic before 50 years of age, and
incidence increases with age
Understand Alzheimer’s Disease in 3 minutes
(https://www.youtube.com/watch?v=Eq_Er-tqPsA)
• Alzheimer’s is a slow, fatal disease of the brain affecting 1 in 10
people over the age of 65. No one is immune.
Tilbe (0925 545 2480) 1 of 12
• The disease comes on gradually as two abnormal protein
fragments called plaques and tangles accumulate in the brain
and kill brain cells
• They start in the hippocampus where memories are first
formed. Over many years’ time, the plaques and tangles slowly
destroy the hippocampus and it becomes harder and harder to
form new memories. Simple recollections from a few hours or
days ago that the rest of us might take for granted are just not
there.
• More plaques and tangles spread into different regions of the
brain, killing cells and compromising function wherever they go.
This spreading around is what causes the different stages of
Alzheimer’s.
• From the hippocampus, the disease spreads to the region
where language is processed. When that happens, it becomes
tougher and tougher to find the right word.
• Next, the disease creeps toward the front of the brain, where
logical thought takes place. Very gradually, a person begins to
lose the ability to solve problems, grasp concepts, and make
plans.
• Next, the plaques and tangles invade the part of the brain
where emotions are regulated. When this happens, the patient
gradually loses control over moods and feelings.
• After that, the disease moves to where the brain makes
sense of the things it sees, hears, and smells. In this stage,
Alzheimer’s wreaks havoc on a person’s senses and can spark
hallucinations
• Eventually, the plaques and tangles erase a person’s oldest
and most precious memories, which are stored in the back of
the brain.
• Near the end, the disease compromises the person’s balance
and coordination, and in the very last stage, it destroys the
part of the brain that regulates breathing and the heart.
• The progression from mild forgetting to death is slow and steady
and takes place over an average of 8-10 years. It is relentless
and, for now, incurable
Mechanisms & Secrets of Alzheimer's Disease: Exploring the
Brain (https://www.youtube.com/watch?v=dj3GGDuu15I)
• Described in 1907 by Alois Alzheimer by performing a
histopathologic study of the brain of his patient Auguste D. who
is suffering from dementia
• He found two types of lesion in the brain: senile plaques and
neurofibrillary tangles
• Brain is made up of neurons interconnected to form a vast
network. The connections known as synapses enable the
transmission of information from one neuron to another
• In AD, 10-15 years before the appearance of the symptoms,
2 main lesions form in the brain: senile plaques composed of
amyloid beta protein, and neurofibrillary tangles composed
of tau proteins
• How is the senile plaque formed? On the surface of the neuron
is a large protein called APP. Normally APP is sectioned by
enzymes on the surface of the neuron and frees a protein called
amyloid beta. The amyloid beta protein is then cleared in the
body
• In the case of AD, there is an imbalance: the amyloid beta
protein is no longer regulated and is found in too great
quantity. The proteins form indissoluble fibers and create senile
plaques
• How are neurofibrillary tangles formed? When a neuron
communicates with another, a signal goes from the soma to the
synapse to transfer information. It passes through the
microtubules which are stabilized by normal tau protein.
• In AD, tau protein becomes defective and detaches from the
microtubules; thus, the skeleton of the neuron dissociates as it
is no longer maintained.
• Defective tau protein assembles to form filaments in the
neuron. Without the skeleton, the neurons degenerate and
connections between the neurons are lost.
• The abnormal accumulation of tau protein creates
neurofibrillary tangles and eventually causes the death of the
neuron
• These 2 lesions do not follow the same pathway in the brain
6.02c CNS Pathology III: Neurodegenerative & Demyelinating Diseases
• Neurofibrillary tangles first develop in the hippocampus
which is essential to memory and learning. It disseminates in the
brain through centrifugal movement. The process causes
atrophy; thus, global dysfunction
• The progression of the lesion corresponds with the
symptoms of the disease which began with memory problems,
followed by problems of language, recognition, and incapacity to
perform gestures.
• Senile plaques develop differently. They are initially
observed in the cortex, secondly in the hippocampus, and
then the senile plaques reach the whole brain following
centripetal movements. Their progression does NOT
correspond to the progression of the disease.
• The presence of the two lesions is necessary to develop AD,
since one does not come without the other.
• Reducing senile plaques in the brain is not sufficient to eradicate
the disease. It is now suggested that long before the formation
of senile plaques, smaller forms of amyloid beta called
oligomers appear to be toxic for neurons, disturbing their
communication when they fix onto synapses. It would appear
that the toxic oligomers and their accumulation in senile plaques
are the origin of neurofibrillary tangles, which in their turn are
responsible for the symptoms.
• 2 main lesions in Alzheimer’s Disease 
o Senile plaques (SPs) (also called Alzheimer's plaques or
neuritic plaques) are deposits of aggregated Aβ peptides in
the neuropil
o Neurofibrillary tangles are aggregates of the microtubule
binding protein tau, which develop intracellularly and then
persist extracellularly after neuronal death.
Pathogenesis
• Deposition of abnormal, insoluble, extracellular beta
amyloid (Aß)
o Aß is the main component of senile plaques
o Aß deposition is specific for AD.
• Deposition of intracellular tau proteins.
o Tau is the component of neurofibrillary tangles (NFTs).
o NFTs are also seen in other degenerative diseases.
Role of Beta amyloid (Aß)
• Aß is a 40 to 42 amino acid peptide, which is part of a larger
protein, the Amyloid Precursor Protein (APP).
• APP is a transmembrane protein, made by neurons and other
brain cells.
• Aß is toxic to neurons: damages synapses; kills neurons.
Deposits of Aβ form the basis of:
o Diffuse plaques
o Senile plaques
o Cerebral amyloid angiopathy
• The Aß amyloid residue is derived by the successive cleavage
of APP by the enzymes beta-secretase and gamma-secretase.
• Aberrant cleavage of APP by secretases result in
accumulation of Aß
• Altered structure or increased amounts cause Aß peptides to
aggregate
Several lines of evidence suggest that Aß generation is the
critical initiating event for the development of AD.
o Multiple lines of genetic evidence point to the likely
importance of altered Aβ metabolism; mutations in the
protein from which Aβ is derived (APP) cause familial AD,
as does increased copy number (either from small
duplications or from trisomy 21) of the APP gene
o Point mutations in proteins that are part of the protease
complexes that generate Aβ from APP also give rise to AD
• Aß is also found in diffuse, non-fibrillar deposits known as
diffuse plaques -- they do not disrupt the neuropil
Diffuse plaques – deposition of Aß peptides with the
absence of surrounding neuritic processes
• Large numbers of Aß may sometimes be seen in in old, non-
demented persons
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Figure 1. Protein aggregation in Alzheimer’s disease. Amyloid
precursor protein cleavage by α-secretase and γ-secretase produces a
harmless soluble peptide, whereas amyloid precursor protein cleavage by
β-amyloid–converting enzyme (BACE) and γ-secretase releases Aβ
peptides, which form pathogenic aggregates and contribute to the
characteristic plaques and tangles of Alzheimer disease.
Figure 2. Neuritic plaque with a rim of dystrophic neurites
surrounding an amyloid core. Spherical lesion in the Cerebral cortex
composed of a central core of extracellular amyloid surrounded by
dystrophic neuronal processes with neurofibrillary degeneration.
The center would stain positive for Congo red. Senile Plaques
represent a focus of damage of the neuropil leading to severe
disconnection.
Role of Tau
• Tau is a microtubule associated protein, encoded by the MAPT
gene on 17q21.
• Normally, tau is phosphorylated and is present mainly in axons
where it binds and stabilizes microtubules.
• Tau is hyperphosphorylated → aggregates as pairs of
filaments that are twisted around one another (paired helical
filaments) → neuronal degeneration
• The aggregates of tau protein elicit a stress response and the
microtubule stabilizing function of tau protein is lost.
Figure 3. Neurofibrillary tangles as long pink filaments in the
cytoplasm, H&E (left) & Silver stain (right). Deposits are composed of
insoluble polymers of hyperphosphorylated microtubule-associated
protein tau in the neuronal body. These lesions may be better appreciated
by using Silver stain.
6.02c CNS Pathology III: Neurodegenerative & Demyelinating Diseases
Gross Features
• Senile Plaques and Neurofibrillary Tangles → Loss of neurons
and synapses → Brain Atrophy → Compensatory Dilatation of
the Lateral ventricles due to loss of brain tissue
(hydrocephalus ex vacuo)
• Hydrocephalus ex vacuo – dilated ventricles but with normal
CSF pressure
Figure 4. (Top) Advanced Alzheimer’s showing dilated ventricles and
atrophic gyri. (Bottom) Cortical Atrophy with compensatory
dilatation of the cerebral hemispheres.
Notes in the PPT but were not discussed in the lecture:
• In Alzheimer’s Disease, damage of the hippocampus → loss of
cholinergic neurons in the basal forebrain → decreased
acetylcholine levels → explains the impairment in memory
• Ach plays a crucial role in information processing and memory
• Cognitive impairment correlates best with the loss of Ach
• Damage of the association cortex correlates with the loss of
higher intellectual functions
Risk Factors
• Increasing age
You can also see senile plaques and neurofibrillary tangles in
elderly patients, but in patients with Alzheimer’s, they have
MORE of these lesions
• Genetics: the gene for APP is on chromosome 21; thus,
persons with Trisomy 21:
o Produce 1.5x as much APP as normal people
o Develop AD at a young age
Histologic findings appear in the second and third decades
followed by neurologic decline about 20 years later.
• Apolipoprotein E (ApoE) genotype is the most important
genetic factor
o ApoE is a protein that carries lipids in and out of cells
o It occurs in three isoforms: ApoE2, ApoE3, and ApoE4.
o The gene for ApoE is on chromosome 19
o Persons who are homozygous for the ApoE4 allele
develop AD at a mean age of 70.
o Persons with other ApoE phenotypes develop the disease
later
• Mutations in Presenilin 1 and 2
o PS1 on chromosome 14 & PS2 on chromosome 1
o Causes majority of early-onset familial AD
Presenilins are thought to affect secretase activity.
Mutations would result in a defect of processing of normal APP.
The gamma-secretase complex would generate increased
amount of beta amyloid
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Diagnosing Alzheimer’s Dementia
• There are no specific clinical findings in AD.
• Presumptive diagnosis:
o Progressive dementia evolving over a few years
without focal neurologic deficits or abnormal imaging
o Elevation of tau protein and decrease of Aß in the CSF
are useful biomarkers.
o Formation of SPs (senile plaques) and NFTs
(neurofibrillary tangles) is part of the aging process. Brains
of demented people contain more SPs and NFTs. The
more numerous and widespread the SPs and NFT, the
more severe the dementia.
• Definitive diagnosis can only be made by pathological
examination of brain tissue by counting the senile plaques and
Figure 5. Brain of Patient with AD. Note the atrophy on the right side of
the neurofibrillary tangles or finding large numbers in the the brain 
neocortex of deceased patient with clinical evidence of dementia.

Editor’s note: The ff. sections on Alzheimer’s are not included in

the lecture and are only found in Robbins. Gusto ko sanang
tanggalin kaso sayang naman effort ng trans group lol. The
pictures here will most likely not appear in the projection exam.
Roles of Inflammation 
• Both small aggregates and larger deposits of Aß elicit an
inflammatory response form microglia and astrocytes
Figure 6. Senile Plaque. Neuritic plaque with a rim of dystropic neurites
• This response probably assists in the clearance of the surrounding an amyloid core. Spherical lesion in the cerebral cortex
aggregated peptide, but may also stimulate the secretion of composed of a central core of extracellular amyloid surrounded by
mediators that cause damage dystrophic neuronal processes with neurofibrillary degeneration. Plaques
• Additional consequences of the activation of these inflammatory are found in the hippocampus, amygdala, and neocortex, although there
cascades may include alterations in tau phosphorylation, along is usually relative sparing of primary motor and sensory cortices (this also
with oxidative injury to the neurons. applies to neurofibrillary tangles). The amyloid core, which can be stained
Basis for Cognitive Impairment  by Congo red, contains several abnormal proteins. The dominant
• Presence of a large burden of plaques and tangles is highly component of the amyloid plaque core is Aβ. 
associated with severe cognitive dysfunction.
• The number of neurofibrillary tangles correlates better with
the degree of dementia than the number of neuritic plaques.
• Biochemical markers that have been correlated with the degree
of dementia include loss of choline acetyltransferase,
synaptophysin immunoreactivity, and amyloid burden.
Biomarkers 
• It is now possible to demonstrate Aβ deposition in the brain
through imaging methods that rely on F-labeled amyloid binding
compounds. This approach can identify asymptomatic patients
who are at high risk for developing AD. . Figure 7. Neurofibrillary tangles. Photo on right shows special staining
with silver stain, making the NFT stand out. In pyramidal neurons, they
• These biomarkers have allowed for the identification of
often have an elongated “flame” shape; in rounder cells, the basket weave
preclinical stages of AD, well in advance of the development of of fibers around the nucleus takes on a rounded contour (“globose”
dementia or other clinical signs and symptoms. tangles). Neurofibrillary tangles are visible as basophilic fibrillary
Clinical Features  structures with H & E staining (left photo) but are demonstrated much
• The progression of AD is slow but relentless, with a symptomatic more clearly by silver (Bielschowsky) staining (right photo) and with
course often running more than 10 years. immunohistochemistry directed against tau. 
• Initial symptoms: forgetfulness and other memory disturbances; Table 2. Summary of Senile Plaques vs Neurofibrillary Tangles
with progression of disease, other symptoms emerge including: Senile Plaques Neurofibrillary Tangles
language deficits, loss of mathematical skills, and loss of learned Extracellular Aβ Intracellular tau
motor skills. Aβ exclusive to AD Tau seen in other degen. dx
• In final stages of AD, affected individuals may become Due to aberrant cleavage of Due to hyperphosphorylation of
incontinent, mute and unable to walk. APP by secretases tau
• Intercurrent disease, often pneumonia, is usually the terminal Gene for APP is on Gene for tau encoded by MAPT
event. chromosome 21 gene on chromosome 17q21
• Current clinical trials are focused on treating subjects in early, Disseminates through Disseminates through
preclinical stages of the illness, using strategies that include centripetal movement centrifugal movement
clearing Aβ from the brain through immunologic approaches, Progression does NOT Progression corresponds to the
disruption of the generation of Aβ with pharmacologic correspond to the symptoms symptoms of the disease
agents that target either γ secretase or BACE (βsecretase of the disease
1), as well as approaches aimed at preventing alterations in Patient’s with trisomy 21 will Increased number correlates to the
tau. have 1.5x more APP; thus, degree of dementia
earlier onset of AD
Morphology 
Spherical lesion composed of Neurofibrillary tangles as long
• Gross: there is a variable degree of cortical atrophy marked by a central core of pink filaments in the cytoplasm,
widening of the cerebral sulci that is most pronounced in the extracellular amyloid Deposits are composed of insoluble
frontal, temporal and parietal lobes surrounded by dystrophic polymers of hyperphosphorylated
• Microscopically: The lesions in Alzheimer’s Disease are called neuronal processes with microtubule-associated protein tau in
Senile Plaques and Neurofibrillary Tangles neurofibrillary degeneration. the neuronal body.

6.02c CNS Pathology III: Neurodegenerative & Demyelinating Diseases 4 of 12

B. Frontotemporal Lobar Dementia
Frontotemporal Lobar Degeneration
• Clinical term that refers to a group of progressive
neurodegenerative disorders that affect the frontal and/or
temporal lobes (atrophy)
Distinguished from AD by the fact that alterations in personality,
behavior and language (aphasias) precede memory loss.
One of the more common causes of early-onset dementia
• Clinical manifestations:
o Personality changes (apathy, disinhibition, loss of insight &
emotional control)
o Language dysfunction
o Loss of the ability to recognize meaning of words and
objects
o Global cognitive decline
Few patients also develop extrapyramidal motor loss
• Microscropic findings:
o Neuronal loss and gliosis
o Ballooned neurons
• All show abnormal protein inclusions in neurons and glial cells
Two Groups of FTLDs
(Based on chemical nature of abnormal protein inclusions)
a) FTLDs with tau-positive inclusions
b) FTLDs with inclusions which contain the protein TDP-43
conjugated with ubiquitin
o TDP- 43 is a nuclear protein encoded by the TARDBP
gene on chromosome 1
o Abnormal hyperphosphorylated TDP-43, conjugated with
ubiquitin, is deposited in neurons and glial cells in the form
of intranuclear, cytoplasmic, & neuritic inclusions. These
inclusion deposits are responsible for neuronal
degeneration
C. Pick’s Disease
• Prototype of FTLDs
• Manifests between 45-65 y/o
• Progressive course lasting 2-5 years (sometimes more)
• With FTLD clinical manifestations
Pathologic Findings
Figure 8. Pick’s Disease. Marked atrophy produces “knife-like” thinning
of the gyri in the frontal and temporal lobes
• Atrophy of frontal and temporal lobes
• Pick bodies (tau-positive spherical cytoplasmic inclusions)
• Pick cells (ballooned neurons with dissolution of chromatin)
III. DEGENERATIVE DISEASES OF THE BASAL GANGLIA AND
BRAINSTEM CAUSING MOVEMENT DISORDERS
A. Parkinson’s Disease
• Characterized by hypokinetic movement disorder that is caused
by loss of dopaminergic neurons from the substantia nigra
• Parkinson’s is only one of the neurodegenerative conditions that
have parkinsonism as part of the clinical presentation.
• Clinical syndrome of parkinsonism reflects dysfunction of the
EPS, particularly the nigrostriatal projection.
6.02c CNS Pathology III: Neurodegenerative & Demyelinating Diseases
Other diseases may present with Parkinsonism as long as there is
dysfunction of the nigrostriatal system; however, PD is the principal
degenerative disease that affects the nigrostriatal system.
• Parkinsonism may present with any or all of the ff:
o Rigidity
o Involuntary tremor - “pill rolling” type (back-and-forth
rubbing of the thumb and forefinger as if rolling a pill)
o Bradykinesia
o Postural instability
o Stooped posture
o Expressionless face
o Slurred speech
o Gait disturbance
o Autonomic disturbance
o Depression
o Dementia
The presumptive diagnosis of PD can be based on the presence
of the central triad of parkinsonism: tremor, rigidity, & bradykinesia,
in the absence of a toxic or other known underlying etiology.
There is evidence that the degeneration of the substantia nigra
(which results in the motor symptoms) represents a mid-stage in a
progressive disease that begins lower in the brainstem and can
eventually progress to involve the cerebral cortex, leading to cognitive
impairment
Parkinson’s part 1 of 2 – Medical Animation by Watermark
(https://www.youtube.com/watch?v=zJ4H6ewXqCo)
• Movement in the human body is modulated by the
extrapyramidal system – the Substantia Nigra, Subthalamic
Nucleus, Basal Ganglia and Thalamus. The extrapyramidal
system can either promote or inhibit movement.
• The Basal Ganglia are two large group of nerve cells located
near the base of the brain consisting of the Caudate, Putamen
and Globus Pallidus. (Caudate + Putamen = Corpus Striatum)
• The Substantia Nigra is a tiny structure located deep within the
brain. Normal movement depends on adequate levels of the
neurotransmitter Dopamine, produced by the cells in the darkly
pigmented Zona Compacta of the Substantia Nigra, and
delivered in the striatum and different parts of the brain. It is
known as the Nigral Striatal Pathway.
• The synthesis of Dopamine begins with the amino acid
Tyrosine. Tyrosine is converted to Levodopa through Tyrosine
Hydroxylase. Levodopa is then converted into Dopamine via
Dopa-Decarboxylase. When signaled by an impulse travelling
down the axon to synapse, Dopamine is released into the
synaptic cleft. Some of the released Dopamine binds to
dopamine receptors, triggering a signal that is relayed through
the neurons to the motor center in the cerebral cortex of the
brain. This then travels to the spinal cord to modify activity in the
muscle cells.
• Free floating dopamine in the synaptic gap may be taken back
into the neuron that released it and stored for future use in a
process called reuptake. It may also be converted into other
substances through the action of enzymes MAO-B and COMT.
• Within the Striatum, there is a delicate balance within Dopamine
and Acetylcholine. In patients with PD, there is massive
degeneration of Dopamine-producing cells in the Substantia
Nigra, and the supply is then reduced. This disrupts the balance
resulting in a relative excess of Ach.
• When 60-80% of the dopamine-producing cells in the Substantia
Nigra are damaged, the extrapyramidal system loses the ability
to promote movement and the motor symptoms of PD begin to
appear. Therefore, the primary of objective of pharmacologic
therapy in PD is to increase dopamine levels in the brain.
Pathogenesis
• Multifactorial etiology – genetic and environmental factors play
a role in the disease progression
• Majority of cases are sporadic
• Autosomal dominant forms of PD are caused by
o Mutations of the synaptic protein, α-synuclein, encoded by
a gene on chromosome 4q21
o Mutations of parkin, a ubiquitin-related protein, and
other genes of the ubiquitin-proteasomal pathway (UPP).
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Histologic Features
• α-synuclein
o Lipid-binding protein associated with synapses
o Major component of the Lewy body
o Like Aβ in Alzheimer disease, α-synuclein has been
demonstrated to form aggregates
• Lewy body – HALLMARK of PD
o Round lamellated eosinophilic cytoplasmic inclusions
containing insoluble α-synuclein in the neuronal body
o Often have a dense core surrounded by a pale halo
o Been demonstrated to form aggregates that cause
neuronal degeneration and death specifically affecting the
dopamine-producing neurons of the substantia nigra (SN)
o This causes impairment of noradrenergic, serotoninergic,
and cholinergic neurotransmission
If you have tau: Neurofibrillary tangles in Alzheimer’s, you have
α-synuclein: Lewy body in PD.
Figure 9. Parkinson’s Disease – Lewy Bodies. Single or multiple,
cytoplasmic, eosinophilic, round to elongated inclusions that often have a
dense core surrounded by a pale halo
• Loss of Pigmented Neurons in Substantia Nigra
o Loss of the pigmented, catecholaminergic neurons in
substantia nigra associated with gliosis.
o Loss of pigment from remaining neurons which contain
Lewy bodies (neurofilaments, α-synuclein and ubiquitin)
Figure 10. Loss of pigmented neurons - stained in H and E stain; upper
left photo: normal; upper right and lower photo: decreased number of
pigmented dopaminergic neurons; orange arrow: rounded pink
cytoplasmic Lewy Body in remaining neuron of the cerebral cortex
Gross Features
• Depigmented Substantia Nigra & Locus Ceruleus– pallor
seen in advanced PD w/ loss of pigmented catecholaminergic
neurons
Figure 11. A. Normal Substantia Nigra B. Depigmented SN in idiopathic
PD – accumulation of LBs → neuronal damage → death of dopamine-
producing neurons of SN → impairment of neurotransmission
6.02c CNS Pathology III: Neurodegenerative & Demyelinating Diseases
• Loss of dopaminergic neurons in the pigmented nuclei →
disruption of normal function of the nigrostriatal system →
degeneration of dopaminergic nigrostriatal pathway + dopamine
depletion in striatum → triad: rigidity, bradykinesia, tremor at rest
Hypokinetic or Parkinsonian Gait
(https://www.youtube.com/watch?v=j86omOwx0Hk)
• Stooped posture, leaning forward
• Difficulty initiating gait
• Small steps, often with tremor
• Fenestrated gait – increase in speed of steps after initiation
• En bloc turning – like a statue turning around
B. Huntington’s Disease
In PD, you have hypokinetic gait; in Huntington’s, you have
hyperkinetic gait
• Fatal autosomal dominant condition
• Characterized by progressive movement disorders &
dementia, caused by degeneration of striatal neurons of the
extrapyramidal motor system
• Characterized by
o Behavioral changes
o Chorea (jerky, hyperkinetic, sometimes dystonic
movements involving all parts of the body)
o Extrapyramidal signs
o Progressive dementia
Motor symptoms often precede the cognitive impairment
• Begins usually in the 4th decade of life
• Relentlessly progressive and uniformly fatal, with an average
course of 15 years
Chorea / Choreiform / Hyperkinetic Gait
(https://www.youtube.com/watch?v=QORlwMeWOeU)
• Dancelike gait with increased and involuntarily jerky
movement of all parts of the body
• Orofacial dyskinesias + movements in the upper extremities +
fragments of semipurposeful type of movements or writhing type
of movements
• Superimposition of the movements that affects the gait but the
patient does not fall because balance is not affected
Genetic Defect
• The abnormal gene (HD) is located in the short arm of
chromosome 4, contains 67 exons, and encodes for the protein
huntingtin
• Huntingtin contains increased trinucleotide sequences (CAG
repeat). The more repeat sequences, the earlier the onset of the
disease
• Huntingtin is deposited as intranuclear and cytoplasmic
inclusions resulting in cellular degeneration and cell death
No sporadic form
Gross
• Atrophy of the caudate nucleus due to severe loss of striatal
neurons
Putamen may also atrophy in a lesser degree in the early
stages. Globus pallidus may atrophy secondarily.
• Boxlike dilatation of the anterior horns of the lateral ventricles
• Compensatory “ex vacuo” boxlike dilation of the anterior
horns of the lateral ventricles.
• Cortical atrophy is present in advanced cases
Atrophy is frequently seen in the frontal lobe, less often in
the parietal lobe, and occasionally throughout the entire cortex
Figure 12. A. Normal B. Shrunken head of the caudate is due to severe
loss of small neurons in the caudate and putamen.
6 of 12
 Dilatation of the ventricles / Hydrocephalus ex vacuo is also
present in what disease? Alzheimer’s disease
Histology
• Intranuclear and Cytoplasmic inclusions (protein aggregates
containing huntingtin) resulting in cellular degeneration and cell
death – striatal neurons are affected
• Loss of medium size spiny internuncial neurons in the
caudate nucleus and putamen
• Loss of cortical neurons
• Gliosis (usually more extensive than in the usual reaction
to neuronal loss)
Figure 13. Loss of internuncial neurons in CN and Putamen with
gliosis. 1) Loss of spiny internuncial neurons in the caudate nucleus and
putamen 2) Loss of cortical neurons. 3) Gliosis. In severe cases you
would only see your gliosis, since there are no more neurons.
Biochemical Defect
• Loss of gamma aminobutyric acid (GABA), acetylcholine,
and substance P → abnormal motor movements
C. Amyotrophic Lateral Sclerosis
• Also known as Motor Neuron Disease (MND) or Lou Gehrig
Disease
Named after the baseball legend who got the disease
• Most common motor disorder in adults
• There is loss of upper motor neurons in the cerebral cortex and
lower motor neurons in the spinal cord and brainstem.
Often in association with toxic protein accumulation
• Clinical Manifestations
o Signs and symptoms of both UMN and LMN damage
o UMN: spasticity, hyperreflexia, positive Babinski sign
o LMN: weakness, fasciculations, hypotonicity, muscle atrophy
• Gross features:
o Atrophy of the anterior / ventral spinal nerve roots
o Atrophy of precentral motor gyrus in severe cases
• Microscopic features:
o Loss of neurons in anterior horn cell
o Gliosis (seen in advanced cases )
o Residual neurons containing eosinophilic Bunina bodies
• Incidence:
o 5th decade or later
o More common in males
o Most are sporadic
o Familial forms in 5 – 10% are linked to mutation in
superoxide dismutase (SOD1) gene
▪ Mutated SOD1 protein misfolds and forms aggregates
• Death due to progressive respiratory failure usually 1–5 years
from diagnosis
Figure 14. Normal spinal nerve (Left) and ALS (right). Atrophy of
anterior spinal nerves can be noted in ALS.
6.02c CNS Pathology III: Neurodegenerative & Demyelinating Diseases
Figure 15 (Left). Amyotrophic lateral sclerosis. Spinal cord showing
loss of myelinated fibers (lack of stain) in corticospinal tracts as well as
degeneration of anterior roots. Photo from Robbins. (Right). Bunina
Bodies. Photo from internet. Both photos are not in the lecture.
Cases for Review
Case 1: A 35 y.o man has hx of behavioral & personality changes,
and unusual involuntary movements.
PE: + chorea and dystonia.
Family Hx: Patient’s mother and maternal grandfather have similar
clinical symptoms.
MRI: bilateral cerebral atrophy and enlargement of lateral ventricles.
1. Marked atrophy would also be expected in which regions of
patient’s brain?
2. Which of the following diseases has prominent hyperkinetic
movement disorder as clinical manifestation?
A. Multiple sclerosis
B. Amyotrophic lateral sclerosis
C. Huntington’s disease
D. Central pontine myelinosis
3. The following diseases will present with dementia as prominent
initial clinical manifestation, EXCEPT:
A. Pick’s disease
B. Multiple cerebral infarcts
C. Parkinson’s disease
D. Alzheimer’s disease
Case 2: A 75-year-old woman presents with progressive memory loss
and disorientation.
LP: shows clear and colorless CSF.
CT scan: Moderate atrophy of the brain.
4. The following findings are consistent with the diagnosis, EXCEPT
A. Neurofibrillary tangles
B. Senile plaques
C. Dilated ventricles and increased CSF pressure
D. Increased tau, decreased beta amyloid tumor markers in
CSF
Case 3: A 35 y/o man with Down’s syndrome dies of acute
lymphoblastic leukemia. At autopsy, the patient’s brain shows mild
microcephaly and underdevelopment of superior temporal lobes.
Histologic findings reveal numerous senile plaques in atrophic lobes.
5. Which of the following is/are compatible with the history:
A. If alive, the patient will have early onset of Alzheimer’s
disease
B. Extracellular amyloid noted in senile plaques
C. Both A & B
D. Neither A nor B
Case 4: A 45 y/o male presents with weakness and wasting of the
muscles of right hand for 8 months. PE shows fasciculation of the
hand. The patient’s speech is impaired and 6 years later, he dies of
respiratory insufficiency.
6. Which of the following findings is consistent with the diagnosis?
A. atrophy of ventral roots in the spinal cord
B. atrophy of dorsal roots in the spinal cord
C. atrophy of cerebral hemispheres
D. atrophy of the basal ganglia
Answers
1. Caudate nucleus, putamen, globus pallidus
Huntington’s disease is characterized by reduced
striatal neurons
2. C
3. B, the rest presents with dementia
4. C, should be normal CSF pressure
5. C
6. A
7 of 12
 IV. DEMYELINATING DISEASES
• Acquired conditions characterized by loss of myelin with variable
loss of axons
• Myelin loss → affect transmission of electrical impulses along the
axons → clinical deficits/symptoms
Figure 16. Normal Nerve vs. Damaged Nerve with damaged myelin.
There is relative preservation of axons.
• Causes of myelin damage
o Immune-mediated destruction of myelin
▪ Multiple sclerosis
▪ ADEM
o Damage to oligodendrocytes
▪ Viral infection: PML
▪ Central Pontine Myelinosis (CPN)
o Disorders in metabolism that affect synthesis or turnover
of myelin components (leukodystrophies)
A. Multiple Sclerosis
An autoimmune demyelinating disorder characterized by
distinct episodes of neurologic deficits, separated in time, attributable
to white matter lesions that are separated in space.
Incidence
• Most common of the demyelinating diseases; 2.5 million
people are affected by MS around the world
• Female > Male (2:1) 
 Microscopic Features
• More common in young adults
• More common in colder countries > warmer countries
• More common in high latitude zones > low latitude zones
• Philippines: 8,400 people suffer from MS yearly. 
 lymphocytes, & macrophages
• United States: 388,000 people affected yearly 
 o
• Europe and North America: most common cause of
neurological disability in young adults, affecting 1 in 800 of
the population.
• Rare in Asian countries
Etio-pathogenesis
• Autoimmune reaction against components of self’s myelin sheath
• Probably triggered by a viral infection.
• Genetic susceptibility and environmental factors play important
roles.
• MS is initiated by TH1 and TH17 T-cells that react against
myelin antigens and secrete cytokines.
o TH1 cells secrete IFN-γ, which activates macrophages, and
TH17 cells promote the recruitment of leukocytes.
• Activated leukocytes and cytokines are responsible for
demyelination.
Multiple Sclerosis – Polygon Medical Animation
(https://www.youtube.com/watch?v=o4YkqRUErPY)
• Multiple Sclerosis (MS) affects the ability of the brain and the
spinal cord to communicate with each other effectively.
• Nerve cells communicate by sending electrical signals down long
fibers called Axons which are contained within an insulating
substance called Myelin.
• Evidence suggests that MS results from an autoimmune reaction
in which a malfunctioning immune system produces T cells that
react with and damage the body’s own cells.
• In MS, an unknown trigger activates Helper T cells. This enables
the T cells to adhere to and cross over the Blood Brain Barrier
which normally prohibits the flow of substances to the brain.
6.02c CNS Pathology III: Neurodegenerative & Demyelinating Diseases
• Antigen specific receptors on the surface of T cells recognize
CNS myelin as an antigen. The T cells attack the myelin that
surrounds the axons. This causes the CNS to lose some of its
ability to send signals around the body, causing the debilitating
symptoms of MS.
• Almost any neurological symptom can appear with the disease
and often progresses to physical and cognitive disability.
Permanent neurological problems often occur especially as the
disease advances.
• After injury, the CNS can repair itself. However, after repeated
inflammatory attacks, this repair mechanism can become less
successful.
• Current treatments currently target inflammatory elements of the
disease and are somewhat effective. Innovative treatments are
required that can directly target the CNS not only reducing
inflammation but also inducing repair of the damaged tissue.
Genetic Susceptibility
• Risk of MS in relatives of patients is 7x higher (15x in Robbins)
• Monozygotic twins are 25.9% concordant for MS
• Dizygotic twins are only 2.3% concordant.
• Genetic susceptibility is probably conferred by MHC molecules
that modulate the immune response (particularly
autoimmunity) and cell-cell interactions.
Gross Features
• Irregular, sharply demarcated gray white areas in the white
matter referred to as plaques
• Usually multiple and randomly distributed in brain and spinal
cord
• Long standing plaques are firm (sclerotic) because of gliosis
Plaques commonly occur adjacent to the lateral ventricles and
are also frequent in the optic nerves and chiasm, brainstem,
ascending and descending fiber tracts, cerebellum, and spinal cord.
Plaques can also extend into gray matter, since myelinated fibers are
present there as well.
• Acute phase: Activated mononuclear cells destroy, phagocytose
and degrade myelin
o Inflammatory cells present in plaques are microglia, T-
Plaques may also contain components of humoral immunity
(B-lymphocytes, plasma cells, immunoglobulins, and
complement)
There is ongoing myelin breakdown associated with
abundant macrophages. Lymphocytes and monocytes are also
present, mostly as perivascular cuffs, especially at the outer edge
of the lesion. Active lesions are often centered on small veins.
Within a plaque there is relative preservation of axons and
depletion of oligodendrocytes.
• Inactive phase: Plaques almost devoid of myelin; inflammation
is replaced by astrocytosis and gliosis
• Chronic phase: Gliosis and demyelinated axons
• Partial remyelination by remaining oligodendrocytes may occur
if inflammatory process is arrested in the early phase.
• In severe, acute lesions: axonal necrosis, cavitation and axonal
loss may develop
• Myelin is preferentially affected
Figure 17. Multiple Sclerosis. Presence of multiple plaques of
demyelination can be noted.
8 of 12

Figure 18. Active Plaque in Multiple Sclerosis. Active lesions contain
inflammatory cells: (1) microglia, (2) T-lymphocytes, and (3)
Macrophages. May also contain B-lymphocytes, plasma cells,
immunoglobulins, and complement factors
Figure 19. MS Plaques. Predilection for the periventricular white matter,
optic nerves, and spinal cord. Optic neuritis causes visual loss;
transverse myelitis causes paralysis and sensory loss. Do NOT mistake
these for infarcts. 
Symptoms
• The neurological deficit from an acute MS plaque is caused by:
o Loss of myelin and axons
o Inflammation and edema
▪ Axon loss: permanent disability
• Symptoms depend on the location of the plaques
• May involve upper and lower motor neurons
• Common symptoms and highly suggestive of MS:
o Unilateral optic neuritis (eye pain with acute change in
visual acuity), due to involvement of the optic nerve
o Transverse myelitis
• Other symptoms:
o Diplopia
o Spasticity
o Ataxia
Involvement of the brainstem produces cranial nerve signs,
ataxia, nystagmus, and internuclear ophthalmoplegia from
interruption of the fibers of the medial longitudinal fasciculus.
Spinal cord lesions give rise to motor and sensory impairment of
trunk and limbs, spasticity, and difficulties with the voluntary control of
bladder function.
Clinical course 
• In most cases, the clinical course takes the form of relapsing
and remitting episodes of variable duration (weeks to months
to years) marked by neurologic defects, followed by gradual,
partial recovery of neurologic function.
• The frequency of relapses tends to decrease during the course
of time, but there is a steady neurologic deterioration in most
affected individuals.
Diagnosis
• History and thorough neurological exam
o The distribution and the on and off pattern of symptoms:
integral clue in suspecting a diagnosis of MS
• Diagnostic tests:
o MRI (best diagnostic test)
▪ MRI can reveal “silent” plaques – usually around the
lateral ventricles
▪ Advanced MS causes brain atrophy.
▪ Extensive periventricular plaques cause dilatation of
the lateral ventricles.
o CSF analysis
o Immunoglobulin G test
6.02c CNS Pathology III: Neurodegenerative & Demyelinating Diseases
• CSF Findings
o CSF protein is moderately elevated
o Mild mononuclear pleocytosis.
o IgG/albumin index in CSF is elevated in 90% of patients
o Oligoclonal IgG bands are detected on electrophoresis in
90% of patients.
Figure 20. MRI of MS. MRI can reveal “silent” plaques-usually around the
lateral ventricles
B. Acute Disseminated Encephalomyelitis (ADEM)
• Also known as:
o Post-infectious encephalomyelitis
o Postvaccinal encephalomyelitis
o Allergic encephalomyelitis
• Acute diffuse monophasic (all lesions have similar appearance)
demyelinating disease
• Children are most commonly affected
• Develops a few days to 4 weeks after an Upper Respiratory
Tract Infection (URTI) or rarely after a viral immunization
Pathogenesis
• Due to acute autoimmune reaction to myelin
o Probably due to T-cell mediated immune response
triggered by the preceding viral infection or vaccination.
o Sensitized T-cell attack not only the virus but also neural
tissues having similar proteins
Morphological Features
• Perivenous inflammation (T-lymphocytes and macrophages):
demyelination and axonal loss
Grossly, cut sections of the brain show only grayish discoloration
around white-matter vessels. On microscopic examination, myelin
loss with relative preservation of axons can be found throughout the
white matter. In the early stages, neutrophils are found within the
lesions; later, mononuclear infiltrates predominate.
Clinical Presentation
• Initial phase of URTI is followed by multifocal deficits
(hemiplegia, ataxia, sensory abnormalities, visual loss)
appearing within hours or a few days.
• Symptoms: headache, lethargy, coma
• Rapid course, 20% may die. The rest recover completely
C. Acute Hemorrhagic Leukoencephalitis
• Also known as Acute Necrotizing Hemorrhagic
Encephalomyelitis
• A hyperacute variant of ADEM
• Fulminant syndrome of perivascular distribution of CNS
demyelination
• Usually affects children and young adults
• Almost invariably preceded by a recent episode of upper
respiratory infection, most often of unknown cause.
• Forms excessive, confluent white matter lesions characterized
by vascular necrosis, acute inflammation, and edema
• Damage is similar to ADEM but more severe:
o Destruction of small blood vessels
o Disseminated necrosis of white and gray matter with acute
hemorrhage
o Fibrin deposition
o Abundant neutrophils
• Prognosis: Frequently fatal and survivors present with deficits
9 of 12
D. Neomyelitis Optica Case 5: A 30-year-old woman presents because of a 1-week history
• Synchronous bilateral optic neuritis and spinal of mild tremor in her arm and impaired balance when walking.
demyelination Symptoms disappear the following week. A year later, the patient’s
• Rapidly progressive course symptoms recur.
• More likely to affect women Neuro exam: ataxia, dysarthria and decreased vibratory sense in her
• It is characterized by presence of antibodies against legs, (-) abdominal reflexes, increased DTRs and Babinski sign on
aquaporin-4, which is a major water channel of astrocytes the left. 15 years after the onset of symptoms, the patient becomes
bedridden and dies. Which of the following is expected pathologic
• Antibodies injure astrocyte by complement dependent
findings?
mechanism A. Senile plaques
• Demyelinated white matter lesions show: B. Periventricular plaques
o Absence of aquaporin 4 protein C. Neurofibrillary tangles
o Necrosis D. Lacunar infarcts
o Inflammatory infiltrate by neutrophils Answer: B, this is MS
o Ig and complement deposits
• Prognosis: Poor recovery from first attack Take home messages:
• Treatment: Reduce antibody burden by plasmapheresis and • Intracellular and extracellular accumulation of abnormal pr-
depletion of B cells with anti-CD20 antibody molecules cause cellular degeneration and atrophy and
responsible for the manifestations of the degenerative
E. Central Pontine Myelinosis diseases.
• Also known as Osmotic Demyelination Disorder o AD: dementia: tau & beta amyloid
• Acute disorder characterized by loss of myelin in the basis o PD: hypokinetic motor disorder: alpha-synuclein
pontis and portions of pontine tegmentum in a roughly o HD: hyperkinetic motor disorder: huntingtin
symmetric pattern o ALS: UMN and LMN disorder: mutated SOD1
• A complication resulting from damage to oligodendrocytes • Demyelinating diseases result from damage to myelin
brought about by rapid correction of hyponatremia / sheath from various injurious agents and of various
electrolyte imbalance (commonly arise 2-6 days after correction mechanisms.
of osmolar imbalance) • MS is the most common demyelinating disease and has an
Hyponatremia should be corrected slowly and carefully in underlying autoimmune mechanism as cause
order to prevent this complication • It is imperative for hyponatremia to be corrected slowly to
Morphological Features prevent tragic complications (Central Pontine Myelinosis)
• Loss of myelin in the basis pontis and portions of pontine • Demyelination may follow viral infection or vaccination.
tegmentum
• Neurons and axons are well-preserved REFERENCES
• No inflammation in lesions 1. Robbin’s Pathology 9th Ed.
2. Recordings
Clinical Presentation
3. Neurodegenerative & Demyelinating PPT– Dra. Tilbe
• Rapidly evolving quadriplegia, may be fatal or lead to severe 4. Youtube videos
long-term deficits QUIZ
• “Locked in” syndrome – patients fully conscious but
1. Demyelinating diseases may result from:
unresponsive A. Immunologic injury directed at myelin sheath
F. Progressive Multifocal Leukoencephalopathy (PML) B. Viral infection of oligodendrocytes
• A fatal demyelinating disease due to infection of C. Both A & B
D. Neither A nor B
oligodendrocytes by the polyoma virus JC (JCV)
2. System/s responsible for recycling of proteins:
• JCV (after primary infection) remains latent in the kidneys and A. Ubiquitin-proteosomal system
lymphoid tissues for life but is reactivated when B. Lysosomal system
immunosuppressed (ex: AIDS and cancer) C. Both A & B
• Characterized by a variety of neurologic deficits such as D. Neither A nor B
visual loss, paralysis, and dementia 3. A 72-year-old woman presents with a 5-year history of progressive
• Neurologic deficits evolve rapidly and cause death in a few motor functioning degeneration and memory loss. No other
months neurologic deficits noted. What is the LEAST likely diagnosis?
• CSF is either normal or shows a few lymphocytes A. Alzheimer’s disease
• Key Feature: Oligodendrocytes infected by JC Virus B. Parkinson’s disease
C. Huntington’s disease
D. Multiple sclerosis
4. A patient with Huntington’s disease has:
A. Atrophy of cerebral cortex
B. Loss of GABA
C. Both A & B
D. Neither A nor B
5. Damage in Multiple Sclerosis is seen in:
A. Myelin sheath
B. Axons
C. Both A & B
D. Neither A nor B
6. A 75-year-old woman presents to the hospital with progressive
memory loss and disorientation. Lumbar puncture done shows clear
and colorless CSF. CSF pressure is normal. CT scan shows dilated
Figure 21. Key features of PML. Infected oligodendrocytes with enlarged
ventricles. Clinical impression is Alzheimer’s disease. The ff.
nuclei and have a ground glass appearance due to viral particles.
finding/s is/are consistent with the diagnosis:
Demyelinate lesions may be initially small but may later become large
A. Neurofibrillary tangles & senile plaques
irregular white matter lesions. Myelin is destroyed but axons are relatively
B. Bradykinesia & pill rolling tremor
spared.

6.02c CNS Pathology III: Neurodegenerative & Demyelinating Diseases 10 of 12

 C. Atrophic caudate nucleus & putamen B. Apolipoprotein E3 genotype
D. All of the above C. Apolipoprotein E4 genotype
7. Which of the ff. is the histologic hallmark in #6? D. None of the above
A. Beta amyloid 17. Which of the ff. diseases in INCORRECTLY paired with the type of
B. Abnormal tau neuron affected?
C. Alpha synuclein A. Parkinson’s disease: pigmented neuron in the substantia nigra
D. TDP-43 B. Pick’s disease: cholinergic neurons in the hippocampus
8. What are the expected CSF findings in #6? C. Huntington’s disease: internuncial striatal neurons
A. Increased tau D. Amyotrophic lateral sclerosis: upper and lower motor neurons
B. Decreased beta amyloid 18. A 35-year-old man has history of behavioral and personality changes
C. Both A & B and unusual involuntary movements. PE reveals chorea and
D. Neither A nor B dystonia. Patient’s mother and maternal grandfather has similar
9. A 30-year-old woman presents because of a 1-week history of mild clinical symptoms. MRI shows enlargement of lateral ventricles.
tremor in her arm and impaired balance when walking. Symptoms Marked atrophy would also be expected in which of the following
disappear the following week. A year later, the patient’s symptoms regions of patient’s brain?
recur. Neurologic examination reveals ataxia, dysarthria, and A. Caudate & putamen
decreased vibratory sense in her legs, absent abdominal reflexes, B. Frontal lobes
increased deep tendon reflexes and Babinski sign on the left. C. Hippocampus
Fifteen years after the onset of symptoms, the patient becomes D. All of the above
bedridden and dies. Autopsy shows multiple active and inactive 19. Which of the ff. diseases is INCORRECTLY matched with its
lesions. Which of the ff. is LEAST likely to be seen? proposed pathogenesis?
A. Periventricular plaques containing perivenous neutrophilic A. Parkinson’s disease: dopamine depletion
infiltrates B. Huntington’s disease: decreased GABA
B. Periventricular sclerotic plaques C. Both A & B
C. Periventricular plaques containing perivenous infiltrates of D. Neither A nor B
macrophages, microglia, and lymphocytes 20. Which of the ff. is INCORRECTLY matched?
D. Periventricular plaques containing CD4 Th1 cells and CD8 T- A. Mutation of gene encoding for SOD1 in chromosome 21:
cells Amyotrophic lateral sclerosis
10. The ff. are expected CSF findings in #9, EXCEPT: B. Mutation of gene encoding for alpha-synuclein in chromosome
A. Increased protein 4: Parkinson’s disease
B. Neutrophilic pleocytosis C. Both A & B
C. Increased IgG/albumin index D. Neither A nor B
D. IgG oligoclonal bands on electrophoresis 21. Which of the ff. diseases is INCORRECTLY matched with the
11. A 45-year-old male presents with weakness and wasting of the proposed mechanism of cell/tissue injury?
muscles of right hand for 8 months. PE shows fasciculations of the A. Damage to myelin due to T-cell mediated immune response:
hand. The patient’s speech is impaired and 6 years later, he dies of Acute Disseminated Encephalomyelitis
respiratory insufficiency. Which of the following findings is consistent B. Damage to oligodendrocytes due to rise in osmolality: Central
with the history of the patient? Pontine Myelinosis
A. Residual atrophic neurons with residual Bunina bodies in C. Damage to oligodendrocytes due to infection by JC virus:
ventral roots of the spinal cord Progressive Multiple Leukoencephalopathy
B. Residual atrophic neurons with residual Lewy bodies in D. Damage to myelin due to attack of antibodies by complement
substantia nigra dependent mechanism: Multiple Sclerosis
C. Residual atrophic neurons with residual Pick bodies in frontal & 22. TRUE regarding the lesion shown:
temporal lobes
D. Residual neurons with neurofibrillary tangles in the
hippocampus
12. Insoluble Aß is derived from the cleavage of APP by:
A. Alpha-secretase followed by gamma-secretase
B. Beta-secretase followed by gamma-secretase
C. Gamma-secretase followed by beta-secretase
D. Alpha-secretase followed by beta-secretase followed by
gamma-secretase
E. Beta-amyloid converting enzyme (BACE) only A. Disseminates in the brain centrifugally
13. Lesions in Pick’s disease include: B. Center stains with Congo Red
A. Ballooned neurons with dissolution of chromatin C. Central core consists of intracellular amyloid
B. Tau-positive spherical cytoplasmic inclusions D. A & B only
C. Knife-like thinning of temporal gyri E. B & C only
D. All of the above 23. TRUE regarding the lesion shown:
E. B & C only
14. Huntington’s disease is associated with which protein: trinucleotide
pair?
A. Huntingtan: CGG
B. Huntingten: CCA
C. Huntingtin: CAG
D. Huntingtun: CGA
15. A 35-year-old man with Down’s syndrome dies of acute
lymphoblastic leukemia. CT scan of the patient’s brain shows
atrophic superior temporal lobes. The ff. is/are compatible with the A. May be due to mutations in ubiquitin related protein
patient’s prolife and clinical presentation: B. Clinically characterized by hyperkinetic gait
A. Pick bodies in superior temporal lobes C. May progress to dementia
B. Extracellular beta amyloid noted in senile plaques D. A & B only
C. Periventricular plaques E. A & C only
D. None of the above 18A 19D 20D 21D 22B 23E
16. Most important genetic risk factor for Alzheimer’s disease: 1C 2C 3A 4B 5C 6A 7A 8C 9A 10B 11A 12B 13D 14C 15B 16C 17B
A. Apolipoprotein E2 genotype

6.02c CNS Pathology III: Neurodegenerative & Demyelinating Diseases 11 of 12

 Appendix. Neurodegenerative Diseases
Disease Clinical Features Pathogenesis Genetics Gross Histo
Alzheimer’s Progressive dementia, Degeneration of neurons Homozygous for Brain atrophy, Senile plaques
Disease cognitive impairment w/o by aberrantly cleaved Aß ApoE4: develop at hydrocephalus ex and neurofibrillary
focal neurologic deficits or & hyperphosphorylated mean age of 70; vacuo tangles
abnormal imaging tau APP in ch21;
PS1 in ch14 & PS2 in
ch1
Frontotemporal Personality changes, Degeneration of neurons TARDBP gene on ch1 Frontal and temporal Neuronal loss and
Lobar Language dysfunction, Loss by hyperphosphorylated (TDP-43 variant) lobe atrophy gliosis
Degeneration of the ability to recognize tau or Ballooned neurons
(FTLD) meaning of words and hyperphosphorylated All show abnormal
objects, Global cognitive TDP-43 conjugated with protein inclusions
decline ubiquitin
Pick’s Disease Manifests between 45-65 Most likely same as FTLD None mentioned Frontal and temporal Pick bodies, pick
y/o, lasting 2-5 years, with lobe atrophy, knife like cells
FTLD clinical mx thinning of the gyi
Parkinson’s Hypokinetic movement Loss of dopaminergic Mutation of alpha- Depigmented Lewy bodies with
Disease disorder, Parkinsonism neurons in the substantia synuclein in ch4q21, substantia nigra and alpha synuclein
(Tremor, rigidity, nigra Mutation of parkin locus ceruleus
bradykinesia)
Huntington’s Hyperkinetic movement Loss of gamma Mutation of gene Atrophy of caudate Inclusions
Disease disorder (chorea), EPS, aminobutyric acid (GABA), coding for huntingitin nucleus and putamen, containing
progressive dementia acetylcholine, and in ch4, containing hydrocephalus ex huntingtin, Loss of
substance P → abnormal increased CAG repeat vacuo internuncial striatal
motor movements sequences neurons with
gliosis
Amyotrophic UMN: spasticity, Loss of upper motor Mutation in superoxide Atrophy of the anterior Loss of neurons in
Lateral hyperreflexia, (+) Babinski neurons in the cerebral dismutase (SOD1) / ventral spinal nerve anterior horn cell
Sclerosis sign cortex and lower motor gene roots Gliosis
LMN: weakness, neurons in the spinal cord Bunina bodies
fasciculations, hypotonicity, and brainstem.
muscle atrophy

Appendix. Demyelinating Diseases

Disease Clinical Features Pathogenesis Gross Histo
Multiple Sclerosis Relapsing and remitting TH1 and TH17 T-cells that Irregular, sharply Acute phase: Activated
episodes of variable duration react against myelin demarcated gray white mononuclear cells
(weeks to months to years) antigens and secrete areas in the white matter Inactive phase: Plaques almost
marked by neurologic defects, cytokines. referred to as plaques devoid of myelin; inflammation is
followed by gradual, partial replaced by astrocytosis and
recovery of neurologic function. gliosis
Chronic phase: Gliosis and
demyelinated axons
Acute Initial phase of URTI is Acute autoimmune Grayish discoloration Perivenous inflammation (T-
Disseminated followed by multifocal deficits reaction to myelin due to around white-matter lymphocytes and macrophages):
Encephalomyelitis (hemiplegia, ataxia, sensory T-cell mediated immune vessels. demyelination and axonal loss
(ADEM) abnormalities, visual loss) response triggered by
appearing within hours or a few preceding viral infection
days.
Acute Hyperacute, fulminant variant Almost invariably White matter lesions Fibrin deposition
Hemorrhagic of ADEM preceded by a recent characterized by vascular Abundant neutrophils
Leukoencephalitis episode of upper necrosis, acute
respiratory infection inflammation, and edema
Neomyelitis Synchronous bilateral optic Antibodies against Necrosis Neutrophilic infiltrates, Ig and
Optica neuritis and spinal aquaporin-4, which injure complement deposits
demyelination astrocyte by complement
dependent mechanism

Central Pontine Rapidly evolving quadriplegia, Damage to Loss of myelin in the basis No inflammation in lesions
Myelinosis may be fatal or lead to severe oligodendrocytes brought pontis and portions of
long-term deficits; about by rapid correction pontine tegmentum
“Locked in” syndrome of hyponatremia
Progressive Variety of neurologic deficits Iinfection of Oligodendrocytes with enlarged
Multifocal such as visual loss, paralysis, oligodendrocytes by the nuclei and have a ground glass
Leukoence- and dementia polyoma virus JC (JCV) appearance due to viral particles.
phalopathy

6.02c CNS Pathology III: Neurodegenerative & Demyelinating Diseases 12 of 12