Neurodegenerative disorders Flashcards
what characterizes the deficits in Alzheimer’s disease?
loss of hippocampal and cortical neurons resulting in impaired memory formation and cognitive deficits
what characterizes the deficits in parkinson’s disease and huntington’s disease?
loss of dopaminergic neurons in basal ganglia leading to altered movement control
what characterizes the deficits in amyotrophic lateral sclerosis?
degeneration of cortical and spinal motor neurons resulting in muscular weakness
what are the protein accumulations associated with AD?
extracellular beta amyloid and intracytoplasmic neurofibrillary tangles
what are the protein accumulations associated with ALS and parkinsons?
intracytoplasmic aggregates
PD - alpha synuclein
what are the protein accumulations associated with huntingtons?
intranuclear inclusions of huntingtin protein
what are the cognitive symptoms associated with AD?
loss of short term memory aphasia apraxia (inability to carry out motor activities) agnosia disorientation
what are the noncognitive symptoms associated with AD?
depression, psychotic
what is the cholinergic hypothesis of AD?
deficiency in Ach due to degeneration of subcortical cholinergic neurons (memory formation areas - hippocampus)
PRIMARY PATHOGENESIS HYPOTHESIS
what is the amyloid hypothesis of AD?
extracellular accumulations of beta amyloid peptides (BA) are toxic to neurons
does deposition of BA plaques correlate with neuronal loss?
no
early onset AD is associated with mutations in what genes? what is the result?
APP, PSEN1, PSEN2
overproduction of AB
what is the role of PSEN1 and PSEN2?
encode for membrane proteins involved in cleaving APP
what is the role of APP?
encodes amyloid B precursor peptides
what is the tau hypothesis in AD?
hyperphosphorylation of tau forms aggregates and neurofibrillary tangles
what is the result of tau hyperphosphorylation?
microtubular disintegration and instability
collapse of neuronal transport system
altered NT release and synaptic function
cell death
what is the first line therapy for symptomatic treatment of cognitive impairments in mild to moderate AD? does it modify the progression?
cholinesterase inhibitors
no
what is the MOA of the cholinesterase inhibitors?
reduce breakdown of endogenously released Ach, resulting in greater activation of postsynaptic Ach receptors
what are the cholinesterase inhibitor agents for AD?
tacrine
donepezil
rivastigmine
galantamine
donepezil inhibits primarily what enzyme?
AchE
what is the MOA of rivastigmine?
inhibits AchE and BchE
which AD agent appears selective for hippocampus and prefrontal cortex?
rivastigmine
what is the route for rivastigmine?
transdermal pouch
what are the cholinergic side effects of cholinesterase inhibitors?
SLUDGE
salivation lacrimation urinary incontinence diarrhea GI cramps emesis
what is the main side effect associated with donepezil?
bradycardia
what is the glutamate antagonist agent for AD?
memantine
what is the MOA of memantine?
non-competitive antagonist of the NMDA glutamate receptor with long half life
provides neuroprotection by reducing intracellular calcium influx and glutamate induced neurotoxicity
which hormone is used as replacement therapy in women with AD?
estrogen
what is the main treatment options for the psychotic symptoms associated with AD?
atypical antipsychotics
risperidone, olanzapine, quetiapine
what is the main treatment options for the depression symptoms associated with AD?
SSRIs
sertraline, citalopram
which drugs should be avoided in treating the depression associated with AD? why?
TCAs
side effects - anticholinergic affects, orthostatic hypotension
