Block 4 Lecture 5 -- Dementia and AD

Question 1

What is the function of the normal prion protein (PrPC)?

Answer 1

membrane protein; no further function known

Question 2

How does a PrPC become pathogenic?

Answer 2

misfolding

• • insoluble and protease-resistant
• • induces more misfolding other membrane glycoproteins

Question 3

What is scrapie:

Answer 3

neurodegenerative disease in sheep, goats

Question 4

What is the usual cause of CJD?

Answer 4

90% due to spontaneous PrPC mutation, not prion consumption

Question 5

What is kuru?

Answer 5

another neurodegenerative, prion disease in New Guinea

Question 6

What is chronic wasting diseaes?

Answer 6

TSE in deer, elk, squirrel, and mink

Question 7

What is the most common cause of dementia in people 65+?

Answer 7

AD

Question 8

What are the types of AD?

Answer 8

1) early onset (before 65)
- - most severe and rapidly progressing
2) late onset

Question 9

What is MCI?

Answer 9

mild cognitive impairment

• • possible indicator of Pre-Alzheimer’s condition
• • “prodromal dementia”
• • reversible, or stable

Question 10

What are the signs/symptoms of MCI?

Answer 10

1) measurable cognitive difficulties
- - does not adversely affect QoL, as some cognitive domains remain intact
- - not enough for dx of dementia
2) reduced number of synapses

Question 11

What causes vascular dementia?

Answer 11

repeated mini-strokes or atherosclerosis

Question 12

What is the prognosis for MCI?

Answer 12

stable or reversible
can progress to:
-- AD
-- other dementias
-- vascular dementias
-- mixed conditions

Question 13

What are the risk factors for AD?

Answer 13

1) age, female, small head circumference, low level of education
2) chronic traumatic encephalopathy (TBI)
3) down syndrome
4) genetics
- - 10% of cases
- - 50% of early-onset

Question 14

What symptoms in mild AD?

Answer 14

mood, memory, personality

Question 15

What symptoms in moderate AD?

Answer 15

long-term memory

wandering, confusion, aggression

Question 16

What symptoms in severe AD?

Answer 16

motor disturbances

bedridden

Question 17

What are the stages of AD?

Answer 17

mild, moderate, severe

Question 18

How is AD diagnosed?

Answer 18

dementia AND histological evaluation of POST-MORTEM brain

– need to r/o other possibilities first

Question 19

What disease screening tests are used for AD?

Answer 19

MMSE, clock drawing

mini-cog, time and change, 7-minute screen, montreal and SLU

Question 20

What chromosome/gene abnormalities have been implicated in AD?

Answer 20

1) chromosome 19, apoE4 gene
2) chromosome 1, presenilin 2; chromosome 14, presenilin 1
3) chromosome 21, APP gene

Question 21

Why have chromosome 1, presenilin 2 and chromosome 14, presenilin 1 been linked to AD?

Answer 21

mutations give

• • increased production of gamma secretase
• • insoluble forms of Ab-amyloid

Question 22

Why has chromsome 19, apoE4 gene been linked to AD?

Answer 22

atherosclerosis yields vascular dementia

• • sxs difficult to differentiate from AD
• • risk factor for late-onset AD

Question 23

Why has chromosome 21, APP gene been linked to AD?

Answer 23

down syndrome patients (trisomy 21) have an AD-like pathology
– but, absence of AD-like memory problems

Question 24

What is the pathology associated with AD?

Answer 24

1) enlarged sulci
- - mostly temporal
2) decreased number of synapses
3) reduction in cholinergic transmission
- - basal forebrain, cx, limbic
- - ACh, ChAT, nAChRs
- - mAChRs preserved
4) increased inflammation
- - microglial infiltration
5) BBB breakdown

Question 25

What pathology is best correlated to specific measures of cognitive decline in AD?

Answer 25

decreased number of synapses

Question 26

What is the normal function of amyloid precursor protein?

Answer 26

membrane-associated glycoprotein (110-135 kDa) | -- cell surface signaling

Question 27

What are the 2 hypothesis for the cause of AD?

Answer 27

1) amyloid hypothesis | 2) hyperphosphorylated tau hypothesis

Question 28

What is the normal function of tau?

Answer 28

structural protein in microtubules | -- microtubules for axonal transport of molecules in neuron

Question 29

Hyperphosphorylation of tau results in...

Answer 29

aggregation into paired helical filaments - - intracellular neurofibrillary tangles - - impaired axonal transport

Question 30

Intracellular neurofibrillary tangles are first seen in the...

Answer 30

HP, entorhinal cortex

Question 31

How does the normal APP cleavage process take place? What happens when it is defunct?

Answer 31

alpha, gamma -- yields soluble beta-amyloid beta, gamma -- yields insoluble, toxic beta-amyloid

Question 32

What are neuritic plaques?

Answer 32

insoluble beta amyloid and other protein fragments

Question 33

What is the GoT for AD pharmacotherapy? Why?

Answer 33

keep patient home as long as possible - - many pts become resistant to interventions for hygiene, nutrition, and safety - - no drugs cure or significantly alter progression

Question 34

What are the AChE-Is?

Answer 34

donepezil galantamine rivastigmine

Question 35

What main drug classes are used to treat AD?

Answer 35

AChE-Is | NMDAr antagonist

Question 36

What is memantine?

Answer 36

- - an NMDAr antagonist - - a7 nAChR antagonist - - 5-HT3 antagonist

Question 37

What types of AD are the main drugs used for?

Answer 37

Donepezil: mild-severe Galantamine: mild-mod Rivastigmine: mild-mod Memantine: mod-severe

Question 38

Which AChE-I has a slightly different MoA?

Answer 38

galantamine - - weak cholinesterase inhibitor - - APL of a7 nAChR

Question 39

How do AChE-Is affect AD?

Answer 39

- - improve memory - - improve functional status - - improve behavioral symptoms - - delay admission to nursing home

Question 40

What other medications may be useful for AD (currently existing)?

Answer 40

``` ACE-Is statins PPAR-gamma agonists omega-3 FAs anti-oxidants -- red wine melatonin (sleep) estrogen NSAIDs, lo-dose ASA hi-dose vit. B, folate, selenium ```

Question 41

What non-drug measures are used for AD?

Answer 41

``` structured exercise environmental stimuli social interaction varied, intense novel stimuli weight control ```

Question 42

What are the sxs of AD?

Answer 42

slow-onset, progressive - - memory loss - - inability to learn/retain new info - - loss of independence - - depression, psychosis, agitation, dysphoria, fear - - apathy, avoidance, aggression - - motor restlessness, wandering - - apraxia

Question 43

What is apraxia?

Answer 43

loss of skilled motor movements

Question 44

How long until death after AD?

Answer 44

5-10 years after dx | -- can be longer

Question 45

What nutritional/endocrine issues may be a cause of dementia?

Answer 45

TH | vit. b12

Question 46

What things cause dementia?

Answer 46

1) AD 2) vascular dementia 3) neurodegenerative disorders - - TSEs, HIV, MS, Huntingtons, PD, neurotrauma, alcoholism