Pathology of Alzheimers

Question 1

Protein aggregates involved in neurodegenerative disease?

Answer 1

Tau
Amyloid
alpha-synuclein

Question 2

What part of the brain does Alzheimers affect first and associated clinical features?

Answer 2

Medial temporal lobes (hippocampus –> short term memory loss) and move outward

Question 3

Pathophysiology behind sporadic Alzheimers? Risk factors?

Answer 3

Normally, APP can be degraded by alpha-secretase to form Aalpha proteins that are solubilized.

However, in Alzheimers you get beta cleavage of APP to form insoluble Abeta that forms amyloids that aggregate to form fibrils.

Risk factors include age and epsilon4 of APOE, which is NOT a mutation but simply allelic variation.

Question 4

What are the risk factors for early onset Alzheimers?

Answer 4

For familial cases - presenilin 1 and 2

Down syndrome - APP is located on chromosome 21

Question 5

Histological features of Alzheimers disease?

Answer 5

Neurofibrillary tangles (intracellular)- flame or globoid shaped bundles of filaments composed of hyperphosphorylated tau.

Neuritic plaques (extracellular) - focal, spherical collections of neurites around central amyloid core (Abeta)

Cerebroamyloid angiopathy: amyloid deposition around vessels that increases risk for intraparenchymal hemorrhage

Question 6

What components make up Alzheimers staging?

Answer 6

Location/density of plaques

Location of tangles

Question 7

Clinical progression of multi-infarct vascular dementia?

Answer 7

“Stepwise” progression of cognitive decline

Question 8

What is the role of tau protein normally?

What are the genetics behind its ability to cause pathology?

Answer 8

Normally a microtubule associated protein.

Located on chromosome 17 with 6 isoforms. Isoform 3R and 4R are the “problematic” ones because of increased MT-binding sites that contributes to tau aggregation.

Hyperphosphorylation also changes tau solubility to contribute to filamentous intracellular aggregates.

Question 9

What part of the cortex does Pick disease affect and associated clinical features?

Gross changes?
Histological findings?

Answer 9

Pick disease is a degenerative disease of frontal and temporal lobes, resulting in EARLY onset (45-60) of behavioral and personality changes and language deficits.

Gross changes include “knife” like (thin) gyri.

Histological findings are round tau cytoplasmic inclusions called “Pick bodies.”

Question 10

Frontotemporal dementia with parkinsonism

Genetics
Pathophysiology
Associations
Gross and microscopic findings

Answer 10

Frontotemporal lobe degeneration is common cause. Can be associated with ALS because of shared TDP-43 protein.

Involves chromosome 17 mutations–TAU gene.

Frontotemporal atrophy
Mild to moderate atrophy of BG
Moderate pallor of SN

Globose TAU tangles and tufted astrocytes. Spongiosis.

Question 11

What clinical features must be present to diagnose dementia with Lewy Bodies?

Answer 11

At least two of the following:

1) Fluctuating cognition
2) Recurrent visual hallucinations
3) Spontaneous motor features of parkinsonism

R/O PD first!
Remember dementia with Lewy Bodies non-responsive to L-DOPA.

Question 12

Cause of Wernicke-Korsakoff syndrome?

Clinical features?
Macroscopic findings?
Microscopic findings?

Answer 12

Thiamine/vitamin B1 deficiency

Clinical features:

1) Acute gaze palsy and ataxia
2) Acute confusion/delirium
3) Psychosis with amnesia and confabulations

Would see petechial hemorrhage and atrophy of mammillary bodies.

Edema, demyelination of fibers with neuronal preservation