Alzheimer's Disease Flashcards
what type of cognitive change happens with age
from least change to most change:
reading, vocab, long term factual memory, immediate memory span, sustained attention, serial learning, delayed recall, motor speed, visuo-spatial skills
describe working memory and ageing
active manipulation of info is currently being maintained in focal attention
= brief, 7+/- 2 pieces of info, need rehearsal
marked decline in older adults
what is working memory reliant on
prefrontal cortex
region undergoes cell shrinkage and cell loss w/age
describe long term memory
retrieval of info no longer maintained in active state
once we remember somethig = LTM -> working memory
essentially limitless capacity
can remember up to a lifetime
what is episodic memory + ageing
personal experiences and events
gradual decline/longitudinal shift w/age
how is hippocampus involved with LTM
less activity in hippo when older adults are learning pictures than young adults
maybe connected to inefficient storage of info in older adults
what happens to remote memory and ageing
over time, mem no longer depend on hippo
cortical regions can support mem = more resilient, less affected by brain damage + initial AD
describe dementia stats
3rd leading cod + disability burden in aus
worldwide 46.8 people with dementia
131.5 predicted by 2050
dementia is an umbrella term for what
distrubance sin cog function, mem, behaviour, impairement in daily living activities
alzheimers = most common cause of dementia = 75%
describe alzheimers
cause unknown
predominant risk factor = age
rare symptoms <50yrs
life expectancy after diagnosis = approx 8 yrs
95% cases = sporadic
5% familal bc autosomal dominant mutations in app, presenilin 1, presenilin 2
diagnosis alzheimers
patient history
cognitive assessment = mini-mental state exam, neuropsychological testing for progressive decline mem loss
neuro assessment
medication review, blood tests, ct/mro scans to rule out other pathologie s
biomarker analysis in plasma/csf
what are macroscopic changes in AD
atrophy
widening of sulci + enlargement ventricles
pronounces in frontal, temporal, parietal lobes
subcortical structures, brainstem + occipital lobe = spared
describe preclinical AD
signs notices in entorhinal cortex, then hippo
affected regions = shrink = nerve cells die
changes can occur 10-20 yrs before symptoms
1st symptom = mem loss
describe mild-mod AD
cerebral cortex shrink, more neurons die
mild = mem loss, confusion, trouble with money, poor judgemmet, mood changes, inc anxiety
mod = inc mem loss + confusion, problems recognising people, difficulty w/language + thought, restlessness, agitation, wandering, repetitive statements
what is sundowning behaviour
behavioural problems begin/worsen in afternoon/evening
inc confusion, agitation, mood swings, disorientation, restlessness leading to pacing + wandering
hypothesised to be related to alteration in circadian rhythm
describe severe AD
extreme shrinkage w/large ventricles
completely dependent on others for care
weight loss, seixures, skin infect, groaning, moaning, grunting, inc sleep, loss bladder + bowel control
death occurs from aspiration pneumonia/infections
what is the cholinergic hypothesis of AD
degeneration of cholinergic neurons in basal forebrain -> cog deficits
deficits in choline acetyltransferase (ach creation), choline uptake, ach release, cholinergic neurons from basal forebrain
acetylcholinesterase inhibitors currently predominant treatment
pathology = Ab and NFT
characterised by:
-primary hallmark = amyloid-b peptide, deposited extracellularly in diffuse + neuritic plaques
-inc hyperphosphorylated tau (p-tau) which is mictrotubule assembly protein that accumulates IC as neurofibrillary tangles (NFTs)
- widespread loss neurons + synapses
- amyloid cascade hypothesis
what is Ab
B-APP = amyloid precursor protein
expressed my most tissues, esp neurons
reaches axon terminals + dendrites
neuronal growth, survival, repair
describe the pathology with Ab cleaving
APP = transmembrane protein, undergoes proteolytic cleavage by secretase enzymes
cleaved by b and a is non path pathway
cleaved by b and y secretase enzymes => neurotoxic Ab peptides releases, accumulate into oligomore aggregates
small size = diffuse synapse => impair synaptic functions b/neurons
aggregate into insoluble b-sheet amyloid fibrils
trigger cascade -> dev plaques -> death neurons
describe ab toxicity
accumulation => axonal + synaptic damage, excitotoxicity, mito dysf, lysosomal failure, inc neuroinflam, damage to signalling pathway
amount ab does not correlate to lvl cog impairment
levels of tau better correlates
describe tau and de/phosphorylated
when phosph, lower affinity to bind to microtubulues
=> free mvm of cargo up/down axon
de/phosph = affinity to bind
ab plaques = shift equil = too much phosph (kinase act inc) => hyperphosph = remain in cyt for longer period of time, not bound to axon
=> self-aggregates
describe NFTs
found in entorhinal cortex, hippo pyramidal cells, amygdala, basal forebarin (ach) raphe nuclei (5-ht)
anatomical dist of tangle tau path is better correlated with AD
braak staging of ad
nft
locuc coeruleus -> transentorhinal & entorhinal layer pre-a -> hippo neocortical association areas -> neocortex inc primary cortices
prion-like propagation of tau
tauopathy = consequences of neighbouring anatomical areas vulnerable to tau aggregation from dying neurons
BUT
tau spread along anatomical regions similar to prion proteins = misfoldef one enters neurons and attaches to healthy tau = conformation changes = domino effect
describe genetics and AD
sporadic = 75%, late onset
familial = 5%, early onset, single gene inheritance, 15-25 late onset w/complex inheritance
describe the genes associated with familial ealy-onset AD
app = early 50s onset, 5%
presenilin1 = 28-65 onset, 50%
presenilin2 = 40-85, rare
presenilin mut inc cleavage APP -> AB + targets for cleavage by caspases involoved in y
describe genes associated with late onset AD
ApoE = e4 dec age onset
A2M = A2M-2 inc risk dev AD
describe neuroinflammation and AD
first evidence for innate inflam responsewas 20 yrs ago
AD inc exp pro-inflam markers eg cytokines + acute phase proteins
Ab plaques and tau oligomoers can attract + act microglia + astrocytes (microglia + astrocytes may also secrete… prion-like propagation?)
treatment of AD
mild-mod = dnoepezil, rivastigmine, galatntamine = cholinesterase inhibitors to dc breakdown ACh, support com b/neurons
mod-sev= memantine = prevent reabsorption of glut into neurons
