Pathology of Alzheimer & Other Neurodegenerative Diseases

Question 1

What are the common features of neurodegenerative diseases?

Answer 1

Progressive - gradual progressive loss of neurologic function

Symmetrical, and involving a particular cell population in CNS / PNS -> will not be regional or focal damage on one side, as would be with a vascular cause.

Associated with neuronal loss and gliosis in the area affected

Question 2

What degeneration is seen in Fredreich ataxia and what causes it?

Answer 2

Caused by GAA(it) expansion in frataxin gene on chromosome 9 which is an iron binding protein in mitochondria -> free radial damage of neurons

Causes degeneration of cerebellum -> ataxia

Degeneration of dorsal root ganglia -> loss of vibratory sense and proprioception

degeneration of spinal cord in general -> frequent falling

Question 3

What does Fredreich ataxia present and what is the cause of death?

Answer 3

Presents in childhood with kyphoscoliosis

Cause of death is hypertrophic cardiomyopathy

Question 4

What are the Tauopathies?

Answer 4

Disorders of tau protein accumulation

Alzheimer’s, Pick disease, progressive supranuclear palsy

Question 5

What are the synucleinopathies?

Answer 5

Disorders of alpha-synuclein accumulation

Parkinson, diffuse Lewy body disease

Question 6

What are the two forms of Alzheimer’s and its major risk factors (outside of genetics)?

Answer 6

Presenile dementia
Senile dementia

Risk factors: Risk factors for atherosclerosis + cerebrovascular disease (statins are protective)

Others: History of depression, low education levels, hypothyroidism

Question 7

What diseases are associated with Alzheimer’s disease?

Answer 7

Trisomy 21 - most get it after age 50

Parkinson and DLBD - 50% have AD

Cerebral amyloid angiopathy - amyloid plaques in blood vessels

Question 8

What are the early and late changes seen in Alzheimer’s disease?

Answer 8

Early - memory changes with difficulty finding words and impaired visuospatial memory

Late changes - nonfluent speech, agitation / aggression, severe rigidity

Question 9

How does the course of vascular dementia vs diffuse Lewy body disease vs Alzheimer’s differ?

Answer 9

Alzheimer’s - steady decline

Vascular dementia - Stepwise decline

Lewy body disease - waxes and wanes on its way down

Question 10

What does MRI of Alzheimer’s show ? Where are neurons lost?

Answer 10

Cortical atrophy (with loss of brain weight) with narrowing of gyri and widening of sulci

• > medial temporal lobe (affects hippocampus)
• > loss of neurons in frontal cortex (nucleus basalis in basal forebrain)
• > loss of neurons in limbic system -> especially posterior cingulate gyrus

Hydrocephalus ex vacuo

Question 11

What are neurofibrillary tangles? How do they appear on electron microscopy? Does this cause the cell death?

Answer 11

Intracellular, hyperphosphorylated tau protein (a microtubule-associated protein) in association with other neurofilaments in the cytoplasm of neurons.

Appear as paired helical filaments on EM

Unclear if this causes cell death or is just associated with it.

Question 12

What are neuritic plaques?

Answer 12

Also called senile plaques, they are extracellular zones of disrupted neuropil containing axons and dendrites with a Beta-amyloid core.

Question 13

How is diagnosis of Alzheimer disease made?

Answer 13

Can only be done pathologically post-mortem
-> assess numbers of neurofibrillary tangles and senile plaques in affected brain areas, comparing it to the standard at that age (always increases with age)

-> patient must also have a clinical history of dementia

Question 14

What are three other common changes seen in elderly patients with or without diagnosis of Alzheimer’s disease?

Answer 14

1. Hirano bodies - crystalloid, rod-like structures made of actin alongside hippocampal neurons
2. Granulovacuolar degeneration - intracytoplasmic vesicles with tau core
3. Amyloid angiopathy - deposition of beta-amyloid in walls of leptomeningeal and intracortical blood vessels

Question 15

How is A-beta amyloid formed? How is it usually cleared?

Answer 15

APP is normally cut by alpha-secretases

If APP is cut by beta-secretases -> Amyloid-beta fragments stay in the cell membrane and can form aggregates. This can be further processes by gamma secretases.

It is neurotoxic and usually degraded and cleared by proteosomes of astrocytes

Question 16

What are the familial forms of Alzheimer’s caused by? What are the inherited risk factors for the sporadic form?

Answer 16

Risk modifiers for sporadic form: ApoE4 increased risk, ApoE2 decreased risk

Familial forms:
Presenilin-1, presenilin-2 mutations which are part of gamma-secretase

Question 17

What is the normal function of tau protein? What form is seen in Pick disease vs AD?

Answer 17

Microtubule-associated protein with multiple phosphorylation sites

Pick disease - 3 repeat isoform (3R)

AD - 3R or 4R, associated with amyloid-beta.

Question 18

What is Pick disease? What are the symptoms?

Answer 18

Frontotemporal dementia

Frontal lobe effects - behavioral symptoms, especially disinhibition

Temporal lobe - aphasia (language effects)

Question 19

What is seen pathologically in Pick disease?

Answer 19

Frontotemporal atrophy “knife-blade atrophy”

Microscopic - “Pick bodies” - round aggregates of tau protein in neurons of the cortex

Question 20

What drives amyloid formation in sporadic vs familial forms of Alzheimer’s?

Answer 20

Sporadic - environmental factors such as metal ions, free radicals, and oxidative stress
-> antioxidants may be of some benefit

Familial - mutations induce misfolding of amyloid

Question 21

What is the function of prion protein and how does it lead to CJD / other dysfunction?

Answer 21

Signal transducer and regulator of cleavage of amyloid precursor protein

• > PrPsc is resistant to protease cleavage
• > toxic to neurons when it accumulates
• > can form fibrils and amyloid aggregates as well as causing other prion proteins to assume B-pleated sheet conformation

Question 22

What are the causes of iatrogenic CJD?

Answer 22

Patients receiving human pituitary-derived growth hormone supplements, dural / corneal grafts, and contaminated neurosurgery instruments

Question 23

What is variant CJD?

Answer 23

Bovine spongiform encephalopathy

-> as opposed to sporadic CJD, which is the most common form

Question 24

What are the characteristic physical exam findings and EEG findings of CJD?

Answer 24

Physical exam - rapidly progressive dementia with startle myoclonus

EEG findings - periodic sharp waves

Question 25

What are the characteristic MRI findings and CSF findings of CJD?

Answer 25

MRI - enhancement in basal ganglia (represents cause of startle myoclonus)

CSF - 14-3-3 protein in CSF
-> protein released from normal damaged neurons which is a phosphoserine-binding protein with many functions

Question 26

What does the pathology of CJD look like?

Answer 26

1. Spongiform degeneration -
   Represents intracellular vacuoles filled with abnormal PrPsc protein -> tends to be in gray matter areas where there its lots of neuropil (vacuolated cytoplasmic processes)
2. Gliosis - extensive astrocyte hyperplasia and activation of microglial cells (beyond what would be normally expecting)
3. Neuronal loss - apoptosis with activation of microglial cells, but minimal inflammation and minimal atrophy (since so rapid)
4. Amyloid plaques - in various places depending on exact type of CJD

Question 27

What codon controls susceptibility to CJD?

Answer 27

Codon 129 of PRNP on chromosome 20

Valine/Valine is most protective
Methionine / Methionine is most susceptible

Variations in these codons alter susceptibility and generally anyone can get it