Neurodegeneration

Question 1

Alzheimer’s Disease: molecular composition of neurofibrillary tangles + stages

Answer 1

• intracellular in neurons
• helical filaments of abnormally phosphorylated Tau = microtubule associated protein (binds/stabilizes)
• Tau also forms neuritic threads
• Starts in the transentorhinal & entorhinal regions of hippocampus –> Occipito-temporal gyrus & insular cortex –> superior temporal gyrus –> toward frontal lobe

Question 2

Alzheimer’s Disease: molecular composition of plaques

Answer 2

• Senile plaques
• extracellular
• A-beta peptides (from B-amyloid precursor)
• can deposit around blood vessels –> weakening them –> predispositon to hemorrhagic stroke

Question 3

AD: Genetics

Answer 3

• Early onset - mutations in:
  
  • PS1 & 2 = enzymatic proteins cleaving amyloid protein –> majority
  • A-BetaPP = amyloid precursor protein
• Late onset - mutations in:
  
  • APOE –> majority

Question 4

Vascular dementia

Answer 4

• Stepwise neurologic decline
• Clinical phenotype depending on vascular territory

Question 5

Parkinson’s Disease: molecular

Answer 5

• Lewy Body
• Pigmented neuron in substantia nigra
• Cytoplasmic inclusions of straight filaments
• a-synuclein = synaptic ptorein enriched at presynaptic terminals
  
  • regulate synpatic vesicles and reserve vesicles (possible functions)
  • Self-aggregate –> toxic to cell

Question 6

Diseases w/ a-synuclein (Lewy body) pathology (4)

Answer 6

1. Parkinson’s Disease (stays in brainstem)
2. Dementia w/ Lewy bodies (spreads into cortex)
3. Lewy body variant of Alzheimer’s
4. Multiple systems atrophy

(+Other less common neurodegenerative diseases)

Question 7

Frontotemporal degeneration: phenotypes + molecular

Answer 7

1. Behavioral variant (disinhibition)
2. Semantic dementia
3. Primary non-fluent aphasia

Molecular:

1. Tau – neurofibrillary tangles
2. TDP-43 –> RNA bindign protein –> if present it is the major cytoplasmic inclusion (no Tau) –> can progress to ALS

TDP-43 + Tau = FTD

TDP-43 only = progress to ALS

Question 8

Tauopathies – diseases w/ tau pathology (7)

Answer 8

1. Alzheimer’s
2. ALS w/ parkinsonism-dementia
3. Creutzfeldt-Jakob disease
4. FTD w/ parkinsonism
5. Pick’s disease
6. Progressive supranuclear palsy (parkinsonism disease)
7. Chronic Traumatic Encephalopathy

+ others…

Question 9

Chronic Traumatic Encephalopathy

Answer 9

• head trauma linked to neurodegenerative disease
• Tau clusters (neurofibrillary tangles) around blood vessels and depths of gyri
  
  • unlike AD
• some cases even have amyloid plaques, or TDP proteinopathy
• Cerebral atrophy of fronto-temporal lobes
• ventricular dilation
• cavum septum pellucidum

Question 10

Amyotrophic Lateral Sclerosis: molecular, genetic

Answer 10

• 90% of cases have TDP pathology
• LMN and UMN degeneration –> MOTOR
• RNA dysfunction (mutated TDP, RNA binding protein),
• Abnormal proteostasis (handling of protein turnover)