Alzheimer and Neurodegenerative Diseases Flashcards

1
Q

Alzheimers disease

incidence

A

Alzheimer’s disease (AD) is the most common type of senile dementia and accounts for 50-60% of all dementias.

Most cases of AD are sporadic (90%) and 10% are familial.

Prevalence increases with age:
People over 65 years of age 10%
People over 85 years of age 50%

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2
Q

Alzheimers disease

Early sx

A

 Difficulty in finding words (dysnomia)
 Impaired visuospatial memory (misplace things, not finding their way home)
 Impaired recent memory
 Delusions, insomnia, depression

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3
Q

Alzheimers disease

Late changes

A

Increasingly impaired remote memory

Non confluent speech

Agitation, aggression

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4
Q

Alzheimers disease

Final stages

A

Recent and remote memory obliterated

Mute

Severe rigidity

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5
Q

Alzheimers disease

Clinical course

A

Relentless progression over 5-10 years

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6
Q

Alzheimers disease

imaging

A
  1. MRI:
    Marked reduction in brain volume Cortical atrophy, frontal, parietal Ventricular dilatation (hydroceplus ex vacuo)
  2. Positron emission tomography (PET): (fluorodeoxyglucose study) Early changes: impaired glucose utilization in posterior cingulate gyrus and parietal cortex (cf. DLBD: anterior cingulate gyrus).
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7
Q

Alzheimers disease

Differential diagnosis

A

Multiple infarct dementia: Intermittent step-wise progression. Imaging.

Diffuse Lewy Body Disease: 30% of all dementia. Fluctuation in cognitive function day to day but progressive course. Often associated with extrapyramidal symptoms. PET scan: anterior cingulate gyrus affected

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8
Q

Disorders commonly assoc with AD

A

a. Down syndrome (trisomy 21): chromosome 21 includes amyloid precursor protein (APP) gene
b. Cerebrovascular disease (2xAD)
c. DLBD (60% incidence of AD)
d. ALS (2 xAD)
e. Idiopathic Parkinson’s disease (PD) (50% incidence of AD)
f. Diabetes (2.5 times higher incidence of AD)

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9
Q

AD

Pathology

How is definitive dx made

A

Definitive diagnosis of AD is a post-mortem pathological diagnosis.

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10
Q

AD

Key pathological markers

A

Neurofibrillary tangles: Flame-shaped or globose structures of hyperphosphorylated neurofilament + tau + -amyloid. Found in neuronal cytoplasm: hippocampus, cerebral cortex, basal nucleus of Meynert, amygdala. Ultrastructurally paired-helical filaments.

Senile plaques (neuritic plaques): These evolve from diffuse plaques which consist of focal deposits of -amyloid in the neuropil to primitive plaques which show neurite degeneration to mature plaques with neurite degeneration and a central -amyloid core to finally burnt-out plaques, which consist of an amyloid core only (the previously degenerated neurites have died-back).

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11
Q

AD

Associated pathological changes

A

AD can be regarded as a progressive dying-back degenerative process which affects at least initially the cholinergic system. Hence the earliest changes are synaptic degeneration which progresses to neurite degeneration to neuronal degeneration.

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12
Q

AD

pathological changes

list

A

Senile plaques

Neurofibrillary tangles

Hirano-bodies

Granulo-vacuolar degeneration

Congophilic angiopathy

Neuronal loss and gliosis

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13
Q

AD

Hirano-bodies

A

Crystalloid cytoplasmic inclusions which consist of 10 nm filaments. Seen in hippocampus mainly.

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14
Q

AD

Granulo-vacuolar degeneration

A

Granulo-vacuolar degeneration: Small vacuoles with dense argyrophilic material in the center, which consist of tau protein. Seen in hippocampus and entorhinal cortex.

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15
Q

AD

Congophilic angiopathy

A

Congophilic angiopathy: (also called amyloid angiopathy). Deposition of -amyloid in meningeal and intra-parenchymal arteries and arterioles. Seen particularly in occipital and parietal lobes.

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16
Q

AD

Neuronal loss and gliosis

A

Neuronal loss and gliosis. The ultimate fate of the degenerative dying back process is neuronal loss with gliosis. This is most pronounced in CA1 and subiculum of hippocampus and in entorhinal, temporal and parietal cortices. It also involves key limbic and deep gray structures such as nucleus basalis of Meynert, amygdala, and anterior and dorsomedial thalamus.

17
Q

Histopathological changes in AD that can also be seen in normal aging

A

Hirano bodies

Granulo-vacuolar degeneration

Congophilic angiopathy

Neuronal loss and gliosis

18
Q

AD

Pathologic-clinical correlations

Pathologic changes that correlate most closely with cognitive function

A

The pathologic changes that correlate most closely with cognitive function are 1) synaptic density, 2) senile plaques; and 3) neurofibrillary tangles, in that order.

19
Q

AD

Definitive pathologic dx

How is it made

A

Therefore based on the density of senile plaques, criteria have been set-up for the definitive pathologic diagnosis of AD. These differ with age and are based on evaluation of the four most severely affected areas of the brain (usually entorhinal, parietal and insular cortices and amygdala)

For the positive diagnosis of AD at age 50 years or less, 5 or more senile plaques per x200 field are required; for 50-65 years of age, 8 or more; for 66-75 years, 10 or more; and for individuals older than 75 years, 15 or more senile plaques per x200 field are required.

20
Q

Pathogenesis of AD

genetics

A

APP gene is located on chromosome 21. Almost all patients with Down’s Syndrome (who harbor three copies of APP) develop AD pathology at an early age.

Mutations of the APP gene are associated with familial AD.

Mutations or polymorphisms of apoE (chromosome 19); presenilin 1 (chromosome 14); and presenilin 2 (chromosome 1), which induce increased production of amyloid A, have been implicated in AD.

21
Q

Amyloid Hypothesis Diagram

A

239

22
Q

AD therapy

A

AD is primarily a disorder affecting the cholinergic systems believed to be responsible for several of the cognitive symptoms.

*Several controlled trials have been performed using cholinesterase inhibitors. Meta-analysis of these studies shows a modest beneficial impact on functional outcomes.
*Limited trials using glutamate receptor inhibitors or acetyl-L-
carnitine have shown small effects in patients with early AD.
*Untested therapies: Antioxidants. Cholesterol lowering agents

23
Q

AD

Therapy

Future developments

A

Proteins or chaperones are being developed to block to transformation of the physiological conformer of the amyloid-β peptide to the pathological β-sheet conformer, so called “β-sheet breaker peptides”. One such peptide “peptide-X” has shown promising results in rats and mice

24
Q

Tauopathies

examples

A
AD
Diffuse lewy body disease
Transient cerebral ischemia 
Pick's disease 
Cortico-basoganglionic degeneration 
Amyotrophic lateral sclerosis 
Progressive supranuclear palsy 
Chromosome 17-linked dementia 
Multiple system atrophy