lecture 44 Flashcards
rochet - alzheimer's disease and other dementias: pathophysiology and pharmacology
what is the gender ratio of alzheimer’s disease?
2:1 female:male
what are cardinal signs of AD?
brain shrinkage
senile plaques
neurofibrillary tangles
what are the core symptoms of AD?
memory loss (especially recent memories)
impaired ability to learn, reason
impaired ability to carry out daily activities (confusion, untidiness)
anxiety, suspicion, hallucinations
motor dysfunction can also occur in late-stage disease
what are the characteristics of amyloid plaques?
extracellular
consist of amyloid-B peptide (AB)
what are the characteristics of neurofibrillary tangles?
intracellular
consist of hyper-phosphorylated tau
what areas are primarily affect in AD?
entorhinal cortex
hippocampus
basal forebrain cholinergic system
neocortex
nucleus basalis
what areas of the brain deal with memory formation/consolidation and associated with loss in AD?
entorhinal cortex
hippocampus
what area of the brain deals with learning and associated with loss in AD?
basal forebrain cholinergic systems
what area of the brain deals with memory/learning/cognition and associated with loss in AD?
neocortex
what area of the brain deals with memory/attention/arousal/perception and associated with loss in aD?
nucleus basalis
what are the effects of synapse loss?
reduced levels of neurotransmitters, especially acetylcholine, but also serotonin, norepinephrine, and DA
what protein is linked to early onset AD?
AB precursor protein, APP, located on chromosome 21 is linked when cleaving AB from APP
what is the difference between AB42 and AB40?
amount of amino acid residues attached
42 forms amyloid fibrils more readily than 40
when is the production of more AB42 favored?
in mutations in the APP gene through favoring cleave by B or y-secretase
in mutations in the gene encoding PSEN1/PSEN2 alter APP cleavage by y-secretase
what is PSEN1/PSEN2?
presenilin-1 or presenilin-2
components of the y-secretase complex
alters APP cleavage by y-secretase
what is the process of AB aggregation related to tau pathology?
kinase activation (and AB aggregation) –> tau hyper-phosphorylation –> neurofibrillary tangles –> disruption of cytoskeleton, axonal trafficking
how do tangles associate with synaptic dysfunction?
tangles accumulation –> disruption/disorganization of cytoskeletal tracks –> defects in axonal transport –> synaptic dysfunction
how is neuroinflammation caused in AD?
activated microglia release pro-inflammatory cytokines (prostaglandins, interleukins, tumor necrosis factor-a)
how is oxidative stress caused?
activated microglia also release reactive nitrogen species (nitric oxide, peroxynitrite) and reactive oxygen species (superoxide, hydrogen peroxide) that cause stress
how does ApoE decrease or increase risk of AD?
individuals with one to or two ApoE 4 –> increase
inheritance of ApoE 2 –> decrease
what drugs are cholinesterase inhibitors?
donepezil (aricept)
rivastigamine
galantamine
what is the moa of donepezil (aricpet)?
specific, reversible inhibitor of acetylcholinesterase
what is the moa of rivastigmine?
inhibits acetylcholinesterase and butyrylcholinesterase
delivered orally or with a patch
what is the moa of galantamine?
selective, reversible inhibitor of acetylcholinesterase and enhances the action of acetylcholine on nicotinic receptors
increases acetylcholine release from cholinergic neurons
what is moa of memantine?
NMDA antagonist that blocks glutamatergic neurotransmission via a noncompetitive mechanism, reduces excitotoxicity
what is florbetapir?
18F
radiolabeled agent that binds B-amyloid, visualized by PET scanning
what is the radiolabeled agent specific for tau?
18F=Flortaucipir
what is moa of donanemab?
induces a decrease in AB levels in the brains of AD patients
slows cognitive decline, especially in early stage disease with low/medium tau pathology
what is a major SE of donanemab?
ARIA (amyloid-related imaging abnormalities)
brain swelling or microhemorrhages
MRI monitoring is necessary during treatment, especially in individuals with 2 ApoE4 alleles
what are the three types of non-AD dementia?
vascular dementia
dementia with lewy bodies (DLB)
frontotemporal dementia (FTD) – Picks’ disease
what are the key characteristics of vascular dementia?
symptom – impaired judgment or executive function
cause - result of brain injury associated with vascular disease or stroke
what are the key characteristics of dementia with Lewy bodies (DLB)?
symptoms - combination of cognitive decline and parkinsonian symptoms, visual hallucinations
cause - presence of cortical Lewy bodies
what are the key characteristics of frontotemporal demential (FTD)?
symptoms - disinhibited behavior
cause - presence of tau accumulation (presence of Pick’s bodies in Pick’s disease)
