Alzheimer and Neurodegenerative Diseases

Question 1

Alzheimers disease

incidence

Answer 1

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%

Question 2

Alzheimers disease

Early sx

Answer 2

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

Question 3

Alzheimers disease

Late changes

Answer 3

Increasingly impaired remote memory

Non confluent speech

Agitation, aggression

Question 4

Alzheimers disease

Final stages

Answer 4

Recent and remote memory obliterated

Mute

Severe rigidity

Question 5

Alzheimers disease

Clinical course

Answer 5

Relentless progression over 5-10 years

Question 6

Alzheimers disease

imaging

Answer 6

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).

Question 7

Alzheimers disease

Differential diagnosis

Answer 7

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

Question 8

Disorders commonly assoc with AD

Answer 8

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)

Question 9

AD

Pathology

How is definitive dx made

Answer 9

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

Question 10

AD

Key pathological markers

Answer 10

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).

Question 11

AD

Associated pathological changes

Answer 11

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.

Question 12

AD

pathological changes

list

Answer 12

Senile plaques

Neurofibrillary tangles

Hirano-bodies

Granulo-vacuolar degeneration

Congophilic angiopathy

Neuronal loss and gliosis

Question 13

AD

Hirano-bodies

Answer 13

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

Question 14

AD

Granulo-vacuolar degeneration

Answer 14

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

Question 15

AD

Congophilic angiopathy

Answer 15

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

Question 16

AD

Neuronal loss and gliosis

Answer 16

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.

Question 17

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

Answer 17

Hirano bodies

Granulo-vacuolar degeneration

Congophilic angiopathy

Neuronal loss and gliosis

Question 18

AD

Pathologic-clinical correlations

Pathologic changes that correlate most closely with cognitive function

Answer 18

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

Question 19

AD

Definitive pathologic dx

How is it made

Answer 19

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.

Question 20

Pathogenesis of AD

genetics

Answer 20

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.

Question 21

Amyloid Hypothesis Diagram

Answer 21

239

Question 22

AD therapy

Answer 22

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

Question 23

AD

Therapy

Future developments

Answer 23

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

Question 24

Tauopathies

examples

Answer 24

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