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?
- Nucleus basalis to the cortex
2. Pedunculopontine nucleus to thalamus
what role does acetyl choline play in the Nucleus basalis to the cortex pathway?
learning and memory 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 acetyl choline synthesis
- this then causes impaired memory in AD patients
what do we give to tackle the depletion of acetyl choline levels in AD?
-acetylycholine esterase inhibitors
give examples of acetylycholine esterase inhibitors?
- donepezil
- rivastigmine
- galantamine
- tacrine
what are side effects to taking acetylycholine esterase inhibitors?
Bradycardia, GI complaints, Sleep disturbance
why do we no longer use Tacrine as an acetylycholine esterase inhibitor?
because of its hepatotoxicity profile
acetylycholine esterase inhibitors don’t treat alzheimes disease. So why do we give them to patients?
because they are efficacious in treating cognitive symptoms in Alzheimer’s
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
what are the adverse effects of rivastigmine?
nausea, vomiting, diarrhoea, headache, dizzy
what are the adverse effects of Galantamine?
nausea, vomiting, agitation, sleep disturbances
what is given as an adjunct to cholinesterase inhibitors?
memantine which blocks glutamate excitotoxicity -NMDA antagonist
