Alzheimer's Disease

Question 1

what type of cognitive change happens with age

Answer 1

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

Question 2

describe working memory and ageing

Answer 2

active manipulation of info is currently being maintained in focal attention
= brief, 7+/- 2 pieces of info, need rehearsal
marked decline in older adults

Question 3

what is working memory reliant on

Answer 3

prefrontal cortex
region undergoes cell shrinkage and cell loss w/age

Question 4

describe long term memory

Answer 4

retrieval of info no longer maintained in active state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

Question 5

what is episodic memory + ageing

Answer 5

personal experiences and events
gradual decline/longitudinal shift w/age

Question 6

how is hippocampus involved with LTM

Answer 6

less activity in hippo when older adults are learning pictures than young adults
maybe connected to inefficient storage of info in older adults

Question 7

what happens to remote memory and ageing

Answer 7

over time, mem no longer depend on hippo
cortical regions can support mem = more resilient, less affected by brain damage + initial AD

Question 8

describe dementia stats

Answer 8

3rd leading cod + disability burden in aus
worldwide 46.8 people with dementia
131.5 predicted by 2050

Question 9

dementia is an umbrella term for what

Answer 9

distrubance sin cog function, mem, behaviour, impairement in daily living activities
alzheimers = most common cause of dementia = 75%

Question 10

describe alzheimers

Answer 10

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

Question 11

diagnosis alzheimers

Answer 11

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

Question 12

what are macroscopic changes in AD

Answer 12

atrophy
widening of sulci + enlargement ventricles
pronounces in frontal, temporal, parietal lobes
subcortical structures, brainstem + occipital lobe = spared

Question 13

describe preclinical AD

Answer 13

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

Question 14

describe mild-mod AD

Answer 14

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

Question 15

what is sundowning behaviour

Answer 15

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

Question 16

describe severe AD

Answer 16

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

Question 17

what is the cholinergic hypothesis of AD

Answer 17

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

Question 18

pathology = Ab and NFT

Answer 18

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

Question 19

what is Ab

Answer 19

B-APP = amyloid precursor protein
expressed my most tissues, esp neurons
reaches axon terminals + dendrites
neuronal growth, survival, repair

Question 20

describe the pathology with Ab cleaving

Answer 20

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

Question 21

describe ab toxicity

Answer 21

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

Question 22

describe tau and de/phosphorylated

Answer 22

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

Question 23

describe NFTs

Answer 23

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

Question 24

braak staging of ad

Answer 24

nft
locuc coeruleus -> transentorhinal & entorhinal layer pre-a -> hippo neocortical association areas -> neocortex inc primary cortices

Question 25

prion-like propagation of tau

Answer 25

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

Question 26

describe genetics and AD

Answer 26

sporadic = 75%, late onset
familial = 5%, early onset, single gene inheritance, 15-25 late onset w/complex inheritance

Question 27

describe the genes associated with familial ealy-onset AD

Answer 27

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

Question 28

describe genes associated with late onset AD

Answer 28

ApoE = e4 dec age onset
A2M = A2M-2 inc risk dev AD

Question 29

describe neuroinflammation and AD

Answer 29

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?)

Question 30

treatment of AD

Answer 30

mild-mod = dnoepezil, rivastigmine, galatntamine = cholinesterase inhibitors to dc breakdown ACh, support com b/neurons
mod-sev= memantine = prevent reabsorption of glut into neurons