CNS Pathology

Part 1. Degeneration and dementia

A. Alzheimer Disease
a. Degeneration of the cerebral cortex
b. Results in diffuse cortical atrophy
i. widening of sulci, narrowing of gyri, expansion of the ventricles
c. ACh neurotransmission by cholinergic neurons in the nucleus basalis of
Meynert
i. AChE inhibitors: donepezil, galantamine, rivastigmine
1. SE: D/V, dizziness, insomnia
ii. Block glutamate NMDA receptor: memantine
d. Most common cause in dementia in the elderly
e. Causes
i. majority of cases are sporadic
ii. allele variations of apolipoprotein E (APOE) on chromosome 19
determine risk
1. 4 is associated with increased risk
a. sporadic early-onset cases
2. 2 is associated with decreased risk
iii. familial early-onset cases can involve presenilin mutations (-
secretase)
1. presenilin-1 (chromosome 14)
2. presenilin-2 (chromosome 1)
f. Associated conditions
i. Down syndrome
1. risk of developing Alzheimer's because the APP gene is
located on chromosome 21
2. commonly presents before age 40
g. Presentation
i. Short-term memory losslong-term memory loss, etc.
h. Evaluation
i. Clinical diagnosis of exclusionconfirmation is autopsy histology
ii. Histology: plaques then tangles
1. senile/neuritic plaques = extracellular A-amyloid core
derived from amyloid precursor protein (APP)
a. APP normally degraded via -secretase cleavage,
followed by -secretase
b. -secretase (rather than -secretase) cleavage of APP
results in A-amyloid
2. neurofibrillary tangles
a. intracellular aggregations of hyper-
phosphorylated tau protein
b. tau is an insoluble cytoskeletal element (microtubule-
associated protein)
i. Complications
i. Amyloid angiopathy weakened vessels intracranial
hemorrhage
 Tangle plaque (silver)

B. Vascular dementia, 2nd most common cause of dementia in the elderly

a. result of multifocal infarctions
i. due to vasculitis, atherosclerosis, or hypertension

C. PicksDiseasefrontotemporal lobar degeneration

a. Dementia involving degeneration of the frontotemporal cortex
b. No treatment
c. Presentation
i. Early symptoms
1. behavior changes
2. aphasia
ii. Later symptoms
1. Dementia
2. parkinsonian aspects
d. Evaluation
i. Histologic findings Pick bodes
1. round intracellular aggregates of tau protein
2. same protein seen in Alzheimer's disease but results in
tangles NOT round aggregates
ii. Histologic findings abnormal TDP-43 stain (1/3 of the time)
in cortical neurons
1. Also seen ALS

Pick bodies TDP-43 stain

D. Creutzfeldt-Jakob disease a.k.a. spongiform encephalopathy

a. Degenerative brain disease as a result of prions
 i. prions are a normal neuronal protein with an -helix structure
1. a cascade is begun once a subset of these proteins
are converted to -sheets (PrPC PrPSC)
2. the conversion to -sheets can induce subsequent conversion
of -helices to -sheets
3. -sheets are resistant to proteases and are toxic to neurons
ii. Spongiform encephalopathy has several subclasses of disease
1. Creutzfeldt-Jakob disease (die in a year)
a. typically from unknown or sporadic causes
b. rarely a result of exposure to prion-infected tissue
i. e.g. corneal transplant and purified human
hormones
c. variant CJD = mad cow disease

b. familial fatal insomnia

i. inherited form of prion disease

1. severe insomnia

2. exaggerated startle response

c. Symptoms

i. Creutzfeldt-Jakob disease rapidly progressive dementia

1. occurs in weeks to months

ii. startle myoclonus (continuous startle-like movement)

iii. ataxia

E. Other causes of dementia

a. Infectious
i. Neurosyphilis
ii. HIV/AIDS
b. Metabolic
i. vitamin B12 deficiency
ii. Wilson's disease
iii. acute intermittent porphyria (AIP)
1. increased in PBG (porphobilinogen)

F. Parkinsonism
a. An idiopathic, slowly progressive, degenerative CNS disorder
b. Primary Parkinson's disease
i. pigmented neurons of the substantia nigra, locus ceruleus, and
other brain stem dopaminergic cell groups are lost
 ii. loss of substantia nigra neurons, which project to the caudate
nucleus and putamen, results in depletion of the neurotransmitter
dopamine in these areas

c. Secondary Parkinsonism

i. loss or interference with the action of dopamine in the basal ganglia

ii. due to idiopathic degenerative diseases, drugs, or exogenous toxins

1. most common cause is antipsychotic drugs

a. e.g.) reserpine and dopamine antagonists

2. classic toxin example is MPTP which is a contaminant

of illicit drugs

Normal vs. Parkinsonian SN nucleus Lewy body

d. presentation
i. motor involvement
1. begins insidiously with a resting pill-rolling tremor
2. movement becomes
a. slow (bradykinesia)
b. decreased (hypokinesia)
c. difficult to initiate (akinesia)
3. cogwheel rigidity
4. classic shuffling gait
5. postural instability
6. mask-like facies
ii. late onset dementia (more than 12 months post onset of
Parkinsonian)
1. due to loss of dopaminergic neurons in substantia nigra
2. if early consider Lewy body dementia
a. PD motor features w/ early-onset dementia and
hallucinations
b. Cortical Lewy bodies (vs. PDs Lewy bodies
found in BG)
iii. speech becomes hypo-phonic
 1. characteristic monotonous, stuttering dysarthria
e. evaluation
i. clinical diagnosis
ii. histology Lewy bodies
1. round eosinophilic inclusions of -synuclein (associated
w/ synapsis)

G. Huntington Disease
a. An autosomal dominant disorder characterized by
i. choreiform movements
ii. progressive intellectual deterioration
iii. exhibits genetic anticipation (especially from father)
b. Epidemiology
i. symptoms usually begin to appear in the 3rd-5th decade of life
ii. both sexes are affected equally
c. Genetic
i. Inheritance: autosomal dominant
ii. Mutation
1. CAG triplet repeat expansion in huntingtin gene
(chromosome 4)
2. mutation leads to atrophy of striatum (especially caudate
nucleus, as shown on MRI) with neuronal loss and gliosis
3. decrease in the levels of GABA and Ach
d. Pathophysiology
i. changes in neurotransmitters with Huntington's disease
1. dopamine and GABA and Ach
2. high dopamine can act on the nigrostriatal pathway to result
in hyperkinesis
3. high dopamine can act on the meso-limbic pathway to result
in psychotic symptoms
e. Symptoms: progressive
i. choreiform movements of all limbs, ataxic gait
ii. dementia, depression, grimacing

Atrophy of caudate nucleus (biopsy, MRI)

f. Treatment
 i. Pharmacologic
ii. medications used to treat Huntington's disease include
1. amine-depleting agents
a. reserpine
i. release of amines (dopamine)
b. Tetrabenazine
i. degradation of amines (dopamine)
2. Antipsychotics
a. Haloperidol
b. dopamine receptor antagonist
i. effect of excess dopamine resulting in
psychotic symptoms
3. Hypnotic
a. benzodiazepines

H. Friedreichs Ataxia
a. Congenital impairment of mitochondrial function leading to cerebellar and
spinal cord degeneration
i. due to a mutation in the frataxin gene which is essential for
mitochondrial iron regulation
ii. Presents in childhood
iii. Autosomal recessive: trinucleotide repeat disorder (GAA),
chromosome 9
b. Presentation
i. staggering gait
ii. frequent falling
c. Physical exam
i. nystagmus
ii. dysarthria
iii. decreased vibratory and proprioceptive senses
iv. muscle weakness
v. loss of deep tendon reflexes
d. Death in adolescence most commonly due to cardiac arrhythmia
i. Sequelae of hypertrophic cardiomyopathy

I. Lou Gehrig disease a.k.a. amyotrophic lateral sclerosis

a. A chronic progressive degenerative disease of unknown etiology
i. Possibly due to mutated SOD 1 neuron apoptosis
b. Characterized by
i. loss of upper and lower motor neurons
ii. in spinal cord, brainstem, and cortex
c. Presentation
i. asymmetric slowly progressive weakness affecting the arms, legs,
and cranial nerves
ii. fasciculations
iii. difficulty speaking
d. Physical exam
i. upper motor neuron signs
1. weakness, spasticity, and hyperreflexia
ii. and / or lower motor neuron signs
 1. weakness, atrophy, fasciculations, hypotonia, and areflexia
iii. lack of sensory impairment distinguishes ALS from
syringomyelia
e. Evaluation
i. Can have TDP-43 anomalies in the motor neurons of spinal cord
ii. Picks disease and ALS probably two extremes along a
spectrum

J. Werdnig-Hoffman Disease a.k.a. spinal muscular atrophy type I

a. Congenital degeneration of anterior motor horn
i. Same area is destroyed by polio virus
ii. Autosomal recessive
b. Presentation
i. LMN signs
ii. Decreased muscle tone at birth
iii. COD respiratory distress

K. Chronic traumatic encephalopathy (Football athletes, boxers, etc.)

a. Superficial layers of cortex
i. Neurofibrillary tau tangles and accumulation of TDP-43