Alzheimer's

Question 1

Dementia classification

Answer 1

Decline in cognition sufficient to cause impairment of occupational or social functioning.

Question 2

Causes of dementia

Answer 2

AD
vascular diseases
Drugs (ethanol)
depression
medical/metabolic
endocrine
neurologic
tumor/toxin/trauma
immunologic
amnesia, autimmune, age associated

Question 3

AD classification

Answer 3

senile dementia

progressive deterioration of cognition without prexisting cause.
life expectancy 5-8 years from diagnosis

autopsy is needed for positive diagnosis

Question 4

progression of AD

Answer 4

initially just cognitive symptoms, then loss of activities of daily living. later stage, behavioural problems. death soon after

Question 5

Neuropathy: protein inclusions in the brain

Answer 5

EC amyloid plaques are the main marker of AD. they are neurotoxic.

Intraneuornal neurofibrillary tangles also occur (but not only found in AD). they are phyperphosphorylated tau proteins. these are disorganised bundles of filament in cytoplasm. known as tau immunohistochemistry

This causes disruption of neurotransmission.

Question 6

Structural changes at beginning

Answer 6

Brain atrophy.

Initially, loss of synapses and enlargement of the ventricles.

In early AD, degeneration of hippocampal cells. Causes mild forgetfulness and worsens problem solving

Question 7

Structural changes in moderate AD

Answer 7

Cerebral cortex atrophy.
causes unclear thinking, and decline in judgement language, and can cause emotional outbursts

Question 8

Structural changes in late AD

Answer 8

Death of more nerve cells.

Aggitation, wandering, cannot recognise faces and poor communication

Question 9

Neurotransmitter pathways affected

Answer 9

ACh, NA, and 5-HT, also cortical interneurones. Loss of these in cortex and hippocampus

Selective loss of nAChRs in hippocampus and cortex (forebrain). reduced choline acetyltransferase -> reduced ACh synthesis.

Question 10

AChE treatment

Answer 10

E.g., donepezil, rivastigmine

may improve, maintain or slow progression of disease state.

earlier the intervention the better

Question 11

Amyloid precursor protein and its metabolism

Answer 11

Single TM domain, ubiquitous. short half-life

When metabolised can be cleaved at alpha, beta, or gamma sites.

when metabolised by alpha-secretase and gamma-secretase it is turned into a non-amyloidogenic free peptide. this is a protective compound, has essential roles in cells.

When metabolised by beta-secretase and gamma-secretase, it forms a beta-amyloid (Amyloidogenic). disrupts Ca homeostasis, excitbtoxic, increases cytokines -> neuroinflammation

Question 12

Genetics

Answer 12

5-10% of cases are caused by autosomal dominant loci

APP gene, PS1 gene, and PS2 gene all alter APP processing, favouring the production of a more aggregative form of beta-amyloid (42AA long instead of 40AA)

Sporadic forms of AD have increased risk with APOE and TREM2 genes. these alter the clearance of the 42AA long beta-amyloids.

Question 13

Other pharmacological treatments.

Answer 13

Muscarinic agonists (animal models only)

Memantine to prevent excess excitation from gluatamate. (used instead of AChE when not effective)

Question 14

Amyloid cascade (accumulation) hypothesis

Answer 14

in dominant inherited forms, there is increased Abeta42 production throughout life, and it gradually accumulates and aggregates and then negative effects occur. microglia and astrocytes activate when amyloid aggregates, causes neuroinflamamtion.

similar mechanism for non-dominant forms, but the rising levels are more gradual, usually later onset.