Patho of dementia/alzheimer's Flashcards
AD epidemiology
-major cause of dementia
-more females
->85yo
-mean survival 8 years after dx
AD sx
-memory loss (esp shortterm)
-impaired ability to learn/reason
-impaired ability to carry out ADLs, confusion, untidiness
-anxiety, suspicion, hallucination
-motor dysfunction can also occur late stage
Environmental risk factors of AD
-age
-low education level
-reduced mental/physical activity in late life
-risk for vasc disease
-head injury
AD neuropathology
-loss of brain volume
-amyloid plaques and neurofibrillary tangles
-synapse loss
Amyloid plaques
-extracellular
-consist of amyloid-B peptide (AB)
neurofibrillary tangles
-intracellular
-consist of hyper-phosphorylated tau
Progression of neuropathology
-plaques and tangles spread through cortex
-entorhinal cortex (memory formation/consolidation)
-hippocampus (‘’)
-basal forebrain cholinergic systems (learning)
-neocortex (memory, learning, cognition)
-nucleus basalis (memory, attention, arousal, perception)
synapse loss
-destruction of synapses in neurons w tangles and near amyloid plaques
=dec levels of NT, esp ACh but also serotonin, NE, DA
-also = dysregulated glutamate = xs excitotoxicity and neurotoxicity
Which is key pathogenic molecule: AB or tau?
-genetic evidence suggests AB
-mutations in gene encoding AB precursor protein APP are linked to early onset AD
-trisomy 21 (down’s) associated w AD-like phenotype at 40 yo and APP gene is located on chromo 21!!
-mutations in gene encoding presenilin protein involved in cleaving AB from APP are linked to early onset AD
Production of AB peptide from APP
-AB peptide released from transmembrane amyloid precursor protein (APP) by activity of B-secretase (BACE) and y-secretase
-cleavage of APP by a-secretase in middle of AB segment releases non-amyloidogenic (non-toxic) fragment
-AB generally 40-42 aa
-AB42 forms amyloid fibrils more readily than AB40
Mutations in APP gene
-favor cleavage of APP by B or y secretase
=more AB42 than AB40 (more plaques)
mutations in presenilin-1 or 2 (PSEN1 or 2) genes
-PSEN1 and 2 are components of y-secretase complex
-alter APP cleavage by y-secretase
=more AB42 to AB40
Effects of AB aggregation on tau pathoology
=kinase activation
=tau hyperphosphorylation
=tangles
=disruption of axonal trafficking
Accumulation of tangles
-cytoskeletal mincrotubule tracks are disrupted and disorganized
=defects in axonal transport
=synaptic dysfunction
Effects of AB aggregation of microglial activation
-neuroinflammation and oxidative stress
-microglial activation probably trying to clear amyloid
-activated microglia release proinflammatory cytokines (prostaglandins, IL, TNFa)
-also release reactive nitrogen species (nitric oxide and peroxynitrite) and ROS (superoxide, hydrogen peroxide) that cause oxidative stress
ApoE
-transport LSL in brain
-altered function can affect AB aggregation or clearance
Impact of ApoE genetics on AD risk
-three isoforms (ApoE2,3,4)
-ApoE4 inc risk of AD
-ApoE2 dec AD risk
slide 17 summary
slide 17 summary
Which of the following statements is TRUE?
(A) Aβ accumulation results in an inhibition of kinases that
phosphorylate tau.
(B) Interleukins contribute to synaptic loss in AD.
(C) The presence of one or two ApoE2 alleles increases the risk
of AD.
(D) Synaptic degeneration in AD triggers a loss of acetylcholine
but not dopamine.
Interleukins contribute to synaptic loss in AD
Current AD therapies
-cholinesterase inhibitors
-anti-glutamaterfic therapy
-new, anti-amyloid antibodies
Cholinesterase inhibitor drugs
-Donepezil
-Rivastigmine
-Galantamine
cholinesterase inhibitor MOA
-block enzymatic reaction shown on slide 20
-compensate for loss of ACh that results from degeneration of cholinergic nerve terminals in AD
cholinesterase
Donepezil (Ariceppt_
-specific
-REVERSIBLE inhibitor of ACETYLcholinesterase
Rivastigmine
-inhibts ACETYL and BUTYRYL cholinesterase
-oral or patch
Galantamine
-selective
-REVERSIBLE inhibitor of ACETYLcholinesterase
-enhances action of ACh on nicotinic receptors
=inc ACh release from neurons
slide 21
slide 21
slide 21
Antiglutamatergic therapy drug
-Memantine
Memantine
-NMDA ANTAgonist
-blocks glutamatergic transmission
-noncompetitive
-dec excitotoxicity
-can combo w donezepil = namzaric
Glutamate
-excitatory NT for learning and memory
-xc leads to excitotoxicity = neuronal death
Namzaric
-memantine ER + donepezil
AD imaging
-FlorBETApir (18F)
-radiolabeled agent
-binds B-amyloid
-PET scan
-might help see role of amyloid in disease
-for tau: 18F-FlorTAUcipir
AD blood test
-immunoprecipitation w mass spectrometry or Ab based detection
-measure plasma levels of AB isoforms
-AB levels detected in plasma correlate well w AB PET scan
-indicates that AB precedes tau in disease progression
Anti-amyloid antibodies (new) drugs
-Lecanemab
-Donanemab
Anti-amyloid antibodies (new)
-Lecanemab and Donanemab
-induce dec in AB levels
-ARIA side effect
Donanemab
-anti-amyloid Abs
-dec AB levels
-slows cognitice decline esp in early stage w lower tau
ARIA
-amyloid-related imaging abnormalities
-brain swelling and microhemorrhages
-MRI monitoring necessary during tx
-esp in individuals w 2 ApoE4 alleles
Non-AD dementias
-Vascular dementia
-Dementia w Lewy Bodies
-Frontotemporal dementia (FTD): Pick’s Disease
-can have mixed dementia
Vascular dementia
-impaired judgement or executive function more common than memory loss
-result of brain injury w vasc disease or stroke
-defects determined by location of brain injury
Dementia w Lewy Bodies (DLB)
-combo cognitive decline and parkinsonian sx
-decline more prevalent ar disease onset than for PD
-visual hallucinations are a core diagnostic feature
-presence of corticol Lewy bodies
Frontotemporal dementia (FTD)
-Pick’s Disease
-disinhibited behavior, poor impulse control, antisocial
-disturbances in executive function
-tau accumulations
-Pick’s bodies in pick’s disease
Which of the following statements is FALSE?
(A) Donepezil is a more specific acetylcholinesterase inhibitor
than rivastigmine.
(B) Memantine interferes with Ca2+ accumulation in neurons
exposed to glutamate.
(C) Lewy bodies are a pathological hallmark of PD and DLB.
(D) Small molecules that activate tau kinases are drug candidates
for AD
-small molecules that activate tau kinases are drug candidates for AD
