Block 4 Lecture 5 -- Dementia and AD Flashcards

1
Q

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

A

membrane protein; no further function known

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2
Q

How does a PrPC become pathogenic?

A

misfolding

    • insoluble and protease-resistant
    • induces more misfolding other membrane glycoproteins
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3
Q

What is scrapie:

A

neurodegenerative disease in sheep, goats

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4
Q

What is the usual cause of CJD?

A

90% due to spontaneous PrPC mutation, not prion consumption

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5
Q

What is kuru?

A

another neurodegenerative, prion disease in New Guinea

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6
Q

What is chronic wasting diseaes?

A

TSE in deer, elk, squirrel, and mink

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7
Q

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

A

AD

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8
Q

What are the types of AD?

A

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

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9
Q

What is MCI?

A

mild cognitive impairment

    • possible indicator of Pre-Alzheimer’s condition
    • “prodromal dementia”
    • reversible, or stable
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10
Q

What are the signs/symptoms of MCI?

A

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

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11
Q

What causes vascular dementia?

A

repeated mini-strokes or atherosclerosis

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12
Q

What is the prognosis for MCI?

A
stable or reversible
can progress to:
-- AD
-- other dementias
-- vascular dementias
-- mixed conditions
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13
Q

What are the risk factors for AD?

A

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

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14
Q

What symptoms in mild AD?

A

mood, memory, personality

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15
Q

What symptoms in moderate AD?

A

long-term memory

wandering, confusion, aggression

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16
Q

What symptoms in severe AD?

A

motor disturbances

bedridden

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17
Q

What are the stages of AD?

A

mild, moderate, severe

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18
Q

How is AD diagnosed?

A

dementia AND histological evaluation of POST-MORTEM brain

– need to r/o other possibilities first

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19
Q

What disease screening tests are used for AD?

A

MMSE, clock drawing

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

20
Q

What chromosome/gene abnormalities have been implicated in AD?

A

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

21
Q

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

A

mutations give

    • increased production of gamma secretase
    • insoluble forms of Ab-amyloid
22
Q

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

A

atherosclerosis yields vascular dementia

    • sxs difficult to differentiate from AD
    • risk factor for late-onset AD
23
Q

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

A

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

24
Q

What is the pathology associated with AD?

A

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

25
Q

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

A

decreased number of synapses

26
Q

What is the normal function of amyloid precursor protein?

A

membrane-associated glycoprotein (110-135 kDa)

– cell surface signaling

27
Q

What are the 2 hypothesis for the cause of AD?

A

1) amyloid hypothesis

2) hyperphosphorylated tau hypothesis

28
Q

What is the normal function of tau?

A

structural protein in microtubules

– microtubules for axonal transport of molecules in neuron

29
Q

Hyperphosphorylation of tau results in…

A

aggregation into paired helical filaments

    • intracellular neurofibrillary tangles
    • impaired axonal transport
30
Q

Intracellular neurofibrillary tangles are first seen in the…

A

HP, entorhinal cortex

31
Q

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

A

alpha, gamma
– yields soluble beta-amyloid

beta, gamma
– yields insoluble, toxic beta-amyloid

32
Q

What are neuritic plaques?

A

insoluble beta amyloid and other protein fragments

33
Q

What is the GoT for AD pharmacotherapy? Why?

A

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
34
Q

What are the AChE-Is?

A

donepezil
galantamine
rivastigmine

35
Q

What main drug classes are used to treat AD?

A

AChE-Is

NMDAr antagonist

36
Q

What is memantine?

A
    • an NMDAr antagonist
    • a7 nAChR antagonist
    • 5-HT3 antagonist
37
Q

What types of AD are the main drugs used for?

A

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

Memantine: mod-severe

38
Q

Which AChE-I has a slightly different MoA?

A

galantamine

    • weak cholinesterase inhibitor
    • APL of a7 nAChR
39
Q

How do AChE-Is affect AD?

A
    • improve memory
    • improve functional status
    • improve behavioral symptoms
    • delay admission to nursing home
40
Q

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

A
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
41
Q

What non-drug measures are used for AD?

A
structured exercise
environmental stimuli
social interaction
varied, intense novel stimuli
weight control
42
Q

What are the sxs of AD?

A

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
43
Q

What is apraxia?

A

loss of skilled motor movements

44
Q

How long until death after AD?

A

5-10 years after dx

– can be longer

45
Q

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

A

TH

vit. b12

46
Q

What things cause dementia?

A

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