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Block 4 PATH Exam -- Neurodegenerative diseases


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What are the two major classes of symptoms in ND diseases?
Movement disorders
What two diseases account for the vast majority of dementia?
Alzheimer's disease
Dementia w/ Lewy bodies
2 dementias w/ temporoparietal & frontotempororparietal involvement
Alzheimer's disease
Dementia w/ Lewy bodies
Diseases that entail fronotemporal and lobar atrophy (4)
Pick's disease
MND-inclusion dementia
Dementias of frontal type (DFT)
Chromosome 17-linked dementia
5 main groups of Alzheimer's disease

Also, which one is the most common?
Sporadic late onset AD
Familial late onset
Familial early onset
AD assoc. w/ Down's syndrome
AD assoc. w/ other ND disease

Sporadic late onset AD is the most common
% of cases of AD that have a strong family history
What is the AD1 gene due to?
APP gene mutations on chromosome 21
What is the AD2 gene assoc. w/?
ApoE epsilon4 allele on chromosome 19
What is the AD3 gene assoc. w/?
Mutations in the presenilin-1 gene on chromosome 14
What is the AD4 gene assoc. w/?
Mutations in the presenilin-2 gene on chromosome 1
Typically, how long do Alzheimer's pts. survive after onset of the disease?
Typically, 5-7 years
(range is from 6 months - 15 years)
Proteins implicated in cytoskeletal alterations in AD (NFTs & NPs)
Abnormal hyperphosphorylated MAP Tau

Ultimately, beta-amyloid is deposited
Type of stain that highlights NPs and NFTs in AD
Bielschowsky silver
How does AD atrophy in different brain lobes compare?
Frontal = Temporal > Parietal > Occipital
CERAD and B&B score combo for high probability of AD causing dementia
CERAD frequent + B&B V/VI
CERAD and B&B score combo for intermediate probability of AD causing dementia
CERAD moderate + B&B III/IV
CERAD and B&B score combo for low probability of AD causing dementia
CERAD infrequent + B&B I/II
Where in a neuron are Marinesco bodies found?
In the nucleus
Clinical manifestations of Dementia w/ Lewy bodies (4)
Prog. cog. decline w/ persistent memory impairment
FLUCTUATING cognition w/ VARIATION in attention/alertness
Recurrent visual hallucinations
Spontaneous motor features of Parkinsonism
Brain locations in which pallor is seen in dementia w/ Lewy bodies
Substantia nigra & locus ceruleus
Proteins that Lewy bodies contain that are useful to stain for
What neurochemical deficits are assoc. w/ Dementia w/ Lewy bodies?
Dopaminergic deficit in cortical & subcortical areas

Severe cortical cholinergic deficit
One of the main features that distinguishes frontotemporal dementias
Deterioration in PERSONALITY and social function
Histological features seen in Pick's Disease (2)
Pick's bodies
Spongiform cortical degeneration (NOT due to CJD)
What are the gyri described as in Pick's disease?
"Blade-like" or "knife-edge"
What stains do Pick's bodies stain positive for?
Silver positive
Tau, Ubiquitin positive
What areas of the brain are Pick's bodies primarily found in (2)?
Hippocampus (pyramidal neurons & dentate gyrus)
Cortical layers II & III
Mutation in what is the problem in chromosome-17 related dementia?
The codon region of the Tau gene

NOTE: there are Tau-immunoreactive inclusions
Where are inclusions most often found in FTD w/ ubiquitin inclusions?
Dentate gyrus
Entorhinal cortex
Layer II of the cortex
What does Tau protein do?
Binds to microtubles, promoting assembly
What differentiates different Tau protein isoforms?
The microtubule-binding repeats
Diseases in the Sporadic category of prion diseases (2)
Creutzfeldt-Jakob disease
Fatal insomnia
Diseases in the Dominantly Inherited category of prion diseases (3)
Familial CJD
Gerstmann-Straussler-Scheinker Syndrome
Familial fatal insomnia
Diseases in the Acquired category of prion diseases (3)
Iatrogenic CJD
New variant CJD
Hallmark histological change in prion diseases
Microvacuolation (spongiform change)
What is PrP(c)?
Prion protein
Normally expressed, membrane-assoc. protein (unknown function)
When PrP accumulates, what does it form?
PrP(c), which is normal, becomes PrP(p), abnormal
How is PrP(p) different from PrP(c)?
Conformationally different
Protease resistant

NOTE: PrP(p) induces further conversions of PrP(c) to PrP(p)
Point mutation/insertion assoc. w/ susceptibility to GSS?
PRO(102) --> LEU
What is the importance of polymorphism at codon 129?
Susceptibility factor for prion diseases

Over 90% of sCJD are homozygous for either M or V at 129
Diseases within the category Synucleopathies
Diseases within the category Tauopathies
Progressive Supranuclear Palsy (PSP)
Corticobasal Degeneration (CBD)
Clinical triad of PD
Rigidity and postural abnormalities
Reting tremor
When is the typical onset of PD?
Later in life (5th decade)
What does MPTP do?
Depletes dopamine stores
Destroys dopaminergic neurons
Areas where neurodegeneration selectively happens in PD
Pars compacta of the substantia nigra
Retrorubral and ventrotegmental areas of midbrain
% of neurons that have to be depleted before PD symptoms appear
80-85% of nigral neurons
(80% of striatal dopamine content)
Gross findings in MSA (4)
Atrophy of cerebellum, middle cerebellar peduncles, and pons
Pallor of SN and LC
Atrophy & gray/brown discoloration of putamen
Inclusions in MSA are positive for what?
Silver, Tau, Ubiquitin, alpha-synuclein, TUBULIN
Where are large numbers of inclusions present in MSA (2)?
Pons and putamen
Gross findings in PSP (2)
Depigmentation of SN and LC
Atrophy of midbrain, pons, GP
Microscopic findings in PSP
GLOBOSE TANGLES (basophilic, rounded tangles)
[silver +, tau immunoreactive]

Abnormal Tau accumulation in neurons and glia
Neuronal loss & astrogliosis
Other NDD that can present w/ PSP-like symptoms (3)
Lewy body diseases
Diseases w/ a course and pathology similar to PSP (3)
Postencephalitic Parkinsonism
Alzheimer's disease
Microscopic findings in CBD (4)
Swollen cortical neurons (neuronal achromasia)
Neuronal loss and microvacuolation in the cortex
Abnormal Tau accumulation in neurons and glia (like in PSP)
Diseases that entail large numbers of swollen neurons (3)
CBD, Pick's disease, CJD
Diseases that entail small numbers of swollen neurons (3)
Lewy body dementia, Alzheimer's, MND-inclusion dementia
Diseases that entail basal/cortical Tau-related pathology (2)
(remember, there are abnormal Tau accumulations in neurons and glia)
Trinucleotide repeat seen in Friedreich's ataxia
Type of inheritance seen in Huntington's disease
Autosomal Dominant
Number of CAG repeats seen in Huntington's disease
37 - 100 (or more)

NOTE: # of repeats inversely correlates to age of disease onset
What is genetic anticipation?

Which neurodegenerative disease covered displays it?
Later generations being affected earlier and more severely

Huntington's disease demonstrates anticipation
What type of transmission is most common in Juvenile onset HD?
What type of transmission is most common in Late Onset HD?
What form of HD is the most common?

What are some of the features of it?
(Mid-life and late-onset)

Choreiform movements, EARLY psych disease
Slow progression (17 yr duration)
What types of HD are assoc. w/ the akinetic-rigid form?
Juvenile and early onset

NOTE: this disease progresses rapidly
Types of HD and their corresponding age ranges
Juvenile onset (4-19 yo)
Early onset (20-34 yo)
Mid-life onset (35-49 yo)
Late onset (> 49 yo)
What areas are usually sig. atrophied in HD?
Caudate, putamen, and pallidus
(variable cerebral atrophy is seen)
Abnormal neuritis in HD is positive for what?
3 Inherited MNDs and their types of inheritance
(motor neuron diseases)
Spinal Muscular atrophy (aut. recessive)
Kennedy's syndrome (X-linked)
Familial ALS (aut. dominant)
What types of neurons are affected in ALS?
MOTOR neurons
(BOTH upper and lower)

Results in muscle atrophy and hyper-reflexia
When does ALS usually have its onset?

What group of people is more prone to get it?
5th-6th decade

Male predominance (2:1)
In familial ALS, what is mutated?
Gene coding for Cu/Zn superoxide dismutase 1
What 3 major groups of neurons are involved in ALS?
Anterior horn neurons of SC
Motor nuclei of brain stem (particularly the HYPOGLOSSAL)
UMNs of the cerebral cortex
How is intellectual capacity affected by ALS?
It is not

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