Block 4 Lecture 5 -- Dementia and AD Flashcards
What is the function of the normal prion protein (PrPC)?
membrane protein; no further function known
How does a PrPC become pathogenic?
misfolding
- insoluble and protease-resistant
- induces more misfolding other membrane glycoproteins
What is scrapie:
neurodegenerative disease in sheep, goats
What is the usual cause of CJD?
90% due to spontaneous PrPC mutation, not prion consumption
What is kuru?
another neurodegenerative, prion disease in New Guinea
What is chronic wasting diseaes?
TSE in deer, elk, squirrel, and mink
What is the most common cause of dementia in people 65+?
AD
What are the types of AD?
1) early onset (before 65)
- - most severe and rapidly progressing
2) late onset
What is MCI?
mild cognitive impairment
- possible indicator of Pre-Alzheimer’s condition
- “prodromal dementia”
- reversible, or stable
What are the signs/symptoms of MCI?
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
What causes vascular dementia?
repeated mini-strokes or atherosclerosis
What is the prognosis for MCI?
stable or reversible can progress to: -- AD -- other dementias -- vascular dementias -- mixed conditions
What are the risk factors for AD?
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
What symptoms in mild AD?
mood, memory, personality
What symptoms in moderate AD?
long-term memory
wandering, confusion, aggression
What symptoms in severe AD?
motor disturbances
bedridden
What are the stages of AD?
mild, moderate, severe
How is AD diagnosed?
dementia AND histological evaluation of POST-MORTEM brain
– need to r/o other possibilities first
What disease screening tests are used for AD?
MMSE, clock drawing
mini-cog, time and change, 7-minute screen, montreal and SLU
What chromosome/gene abnormalities have been implicated in AD?
1) chromosome 19, apoE4 gene
2) chromosome 1, presenilin 2; chromosome 14, presenilin 1
3) chromosome 21, APP gene
Why have chromosome 1, presenilin 2 and chromosome 14, presenilin 1 been linked to AD?
mutations give
- increased production of gamma secretase
- insoluble forms of Ab-amyloid
Why has chromsome 19, apoE4 gene been linked to AD?
atherosclerosis yields vascular dementia
- sxs difficult to differentiate from AD
- risk factor for late-onset AD
Why has chromosome 21, APP gene been linked to AD?
down syndrome patients (trisomy 21) have an AD-like pathology
– but, absence of AD-like memory problems
What is the pathology associated with AD?
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
What pathology is best correlated to specific measures of cognitive decline in AD?
decreased number of synapses
What is the normal function of amyloid precursor protein?
membrane-associated glycoprotein (110-135 kDa)
– cell surface signaling
What are the 2 hypothesis for the cause of AD?
1) amyloid hypothesis
2) hyperphosphorylated tau hypothesis
What is the normal function of tau?
structural protein in microtubules
– microtubules for axonal transport of molecules in neuron
Hyperphosphorylation of tau results in…
aggregation into paired helical filaments
- intracellular neurofibrillary tangles
- impaired axonal transport
Intracellular neurofibrillary tangles are first seen in the…
HP, entorhinal cortex
How does the normal APP cleavage process take place? What happens when it is defunct?
alpha, gamma
– yields soluble beta-amyloid
beta, gamma
– yields insoluble, toxic beta-amyloid
What are neuritic plaques?
insoluble beta amyloid and other protein fragments
What is the GoT for AD pharmacotherapy? Why?
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
What are the AChE-Is?
donepezil
galantamine
rivastigmine
What main drug classes are used to treat AD?
AChE-Is
NMDAr antagonist
What is memantine?
- an NMDAr antagonist
- a7 nAChR antagonist
- 5-HT3 antagonist
What types of AD are the main drugs used for?
Donepezil: mild-severe
Galantamine: mild-mod
Rivastigmine: mild-mod
Memantine: mod-severe
Which AChE-I has a slightly different MoA?
galantamine
- weak cholinesterase inhibitor
- APL of a7 nAChR
How do AChE-Is affect AD?
- improve memory
- improve functional status
- improve behavioral symptoms
- delay admission to nursing home
What other medications may be useful for AD (currently existing)?
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
What non-drug measures are used for AD?
structured exercise environmental stimuli social interaction varied, intense novel stimuli weight control
What are the sxs of AD?
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
What is apraxia?
loss of skilled motor movements
How long until death after AD?
5-10 years after dx
– can be longer
What nutritional/endocrine issues may be a cause of dementia?
TH
vit. b12
What things cause dementia?
1) AD
2) vascular dementia
3) neurodegenerative disorders
- - TSEs, HIV, MS, Huntingtons, PD, neurotrauma, alcoholism
