14 - AD

Question 1

AD: definition?

Answer 1

age dependent GLOBAL deterioration of intellectual + cognitive function

Question 2

AD: symptoms + signs

Answer 2

impaired: memory, attention, language, communication, abstract thinking, judgement, personality, depression, visuo-spatial disorientation. motor + gait disturbances, extrapyramidal signs, bladder/bowel control problems.

Question 3

4 things to diagnose AD?

Answer 3

history of symptoms + exam. tests to exclude other causes of dementia. brain imaging with CT, MRI. other brain tests like MRI diffusion tensor imaging, PET scans, detection of amyloid

Question 4

AD: % cause of dementia? % cost?

Answer 4

most common cause, 70 - 80% of dementia. 40% total health care cost associated with neuological diseases

Question 5

AD: % people? # people?

Answer 5

7 - 9% canadian population over 65 and 35.5% over 85 have AD. 4.5 million people in can/US, will be 14 million by 2050

Question 6

2 main types of AD? associated genes?

Answer 6

early onset: APP, Presenilin 1 and 2. late (over 65) Apo E

Question 7

PS1 and PS2: what? KO mice?

Answer 7

integral membrane proteins with 8 TM domains. double KO of PS1 = decrease in protein Notch important for embryogenesis and neural development, also decreased AB 1 - 40 and 1 - 42 development

Question 8

presenilin 1 and 2: implicated as?

Answer 8

the enzyme responsible for Y-secretase cleavage of APP

Question 9

4 Apo E functions in CNS

Answer 9

transport of cholesterol, phospholipids, fatty acids + anti-oxidant vitamins in serum/CSF. synaptic remodelling and regeneration. interacts with amyloid metabolism. interacts with cytoskeleton

Question 10

number of apo E 4 copies affects (4)?

Answer 10

risk of developing AD. age of onset. accumulation of brain markers of AD like amyloid plaque and NFT load. neuronal cell number/density in hippocampus.

Question 11

apo E 4 and age on onset?

Answer 11

decreases age of onset of AD. no apoe E 4 = late onset. 2 alleles = earlier onset

Question 12

apo E 4 and response to ChEI?

Answer 12

cortical cholinergic dysfunction: ApoE4 positive has worst cholinomimetic drug response, ApoE 4 negative has best response

Question 13

cholinergic basal forebrain nuclei project to? lesions? AD?

Answer 13

CFB nuclei project to hippocampus + limbic areas. lesions in CBF = impairs learning and memory. degeneration of these neurons important in AD.

Question 14

memantine: does what?

Answer 14

treats symptoms at all stages of AD, not a cure. interferes with release of too much glutamate.

Question 15

4 neuropathological features of AD

Answer 15

cortical atrophy, especially of temporal + parietal cortices. NFTs. senile amyloid plaques. granulovacuolar degeneration and hirano bodies.

Question 16

processing of APP

Answer 16

a secretase = soluble APP, good guy. B + Y secretase = aggregated AB and CT fragment = bad, neurotoxic

Question 17

glutamate cell death and amyloid?

Answer 17

glutamate induced cell death potentiated by amyloid; potentiates toxic effect

Question 18

apoE4 knock IN mice show? AD patients? concl about ApoE4 and AD?

Answer 18

decrease in GABA interneurons. learning/memory deficits. AD pts: decreased GABA = apoE4 contributes to AD partially by causing impairments of GABA interneurons.

Question 19

3 potential therapeutic strategies for AB?

Answer 19

lower AB production w/ secretase inhibitors, enhance AB clearance w/ antibodies or enzymes. block interaction of AB with cell surface receptors. modulate downstream pathways.

Question 20

AB binds to what receptors?

Answer 20

nAChRs : a7 and a4b2 subtypes. may have multiple receptor targets

Question 21

6 protective factors for AD

Answer 21

high education. NSAIDs. statins (lower cholesterol). red wine. intellectual leisure activities and socialization. post menopausal hormone replacement therapy

Question 22

possible AD treatments

Answer 22

ACh: inhibit esterases, muscarinic/nitotinic bifunitonals. beta-amyloid: APP-releasers, anti-aggregation agents. also: estrogen, anti-oxidants, anti inflammatories, free radical scavengers