dementia pathophysiology and pharmacology Flashcards
what is dementia?
A disorder associated with impairment of memory, speech and language, comprehension, motor skills, judgement and orientation
what is the pathology of dementia characterised by?
cell death in areas of the brain
what age group are mainly affected by dementia?
over 65years
what is the most common form of dementia?
Alzheimer’s disease
what is Alzheimer’s disease?
an irreversible progressive disease that slowly destroys memory and thinking skills
what are the senile plaques found in the cerebral cortex of alzheimers patients made of?
- extracellular - accumulation of insoluble fragments of beta-amyloid
- intracellular - accumulation of hyperphosphorylated tau strands
what is the macro characteristic pathology of Alzheimer disease?
Ventricular enlargement, & hippocampal entorhinal and temporal cortex atrophy
what is the micro characteristic pathology of Alzheimer disease?
Amyloid plaques, neurofibrillary tangles, neuronal loss in the hippocampus, Locus Coerulus, and raphe nuclei
what is the molecular characteristic pathology of Alzheimer disease?
β-amyloid deposition (plaques), abnormal tau (tangles), synaptophysin (a synaptic vesicle protein) loss
what is the neurochemical characteristic pathology of Alzheimer disease?
Cortical cholinergic loss (correlates with dementia), also see loss of 5-HT, NA
what are β-amyloid plaques?
Dense deposits of protein and cellular material that accumulate outside the neurone
what are neurofibrillary tangles?
Twisted fibers that build up inside the neurone
what is the precursor to amyloid plaques?
amyloid precursor protein (APP)
how does APP cause plaque formation?
- APP sticks through the neuron membrane
- enzymes cut the APP into fragments of protein including beta-amyloid
- this leads to extracellular deposition of β-pleated assemblies of Aβ-peptides hence forming plaques
- plaques in the hippocampus and cerebral cortex inhibit neuronal activity
what is the role of tau
to stabilise the microtubules of neurones
what happens to tau in alzheimers disease?
- it is abnormally phosphorylated and assembles into paired helical filaments.
- this causes the microtubles to collapse and the tau proteins aggregate into neurofibrillary tangles
what are the 2 main acetyl choline pathways?
nucelus basalisis to the cortex
pedunculopontine nucleus to thalamus
what role does acetylcholine play in the nucelus basalis to the cortex pathway
learning and memor and is impaired in Alzheimer’s
what role does acetyl choline play in the Pedunculopontine nucleus to thalamus pathway?
sleep wake and sensory filtering
what happens to acetyl choline (ACh) in alzheimers disease (AD)?
atrophy of the nucleus basalis of meynert causes reduced activity of the choline acetyltransferase enzyme
resulting in reduced acetylcholine synthesis
this then causes impaired memory in AD patients
what do we give to tackle the depletion of acetylcholine levels in AD
acetylcholine esterase inhbiitors
give examples of acetycholine esterase inhibitors
donepezil
rivastigmine
galantamine
tacrine
what are side effects to taking acetylcholine esterase inhibitors
bradycardia, GI, compliants, sleep disturbance
why do we no longer use Tacrine as an acetylcholine esterase inhibtor
because of its hepatotoxicity profile
acetylcholine esterase inhibitors don’t treat alzheimers disease. so why do we give them to patients
becayse they are efficacious in treating cognitive symptoms in alzheimers
where are donepezil and galantamine metabolised
in the liver
what hydrolyses rivastigmine
cholinesterase (which is found in the synapse of ACh neurones)
what are the adverse effects of donepezil
nausea vomiting diarrhoea muscle cramps
adverse effects of rivastigmine
nausea vomiting diarrhoea headache dizzy
what are the adverse effects of galantamine
nausea vomit agitation sleep distrubance
what si given as an adjunct to cholinesterase inhibitors
memantine which block glutamate excitotoxicit-NMDA antagonist
