Neurodegeneration Flashcards
what are the symptoms of Parkinson’s disease?
resting tremor, rigidity, bradykinesia, flexed posture, postural instability, loss of dopaminergic neurones, presence of Lewy bodies
why is Parkinson’s misdiagnosed?
mistaken for an essential tremor, Alzheimers, drug induced conditions
what are the risk factors of parkinsons?
age, twice as common in men, potential genetic cause, environmental factors
what is bradykinesia?
difficulty with everyday activities such as writing, shaving, using a knife and fork, opening buttons, decreasing blinking and slowed eating
what is rigidity?
muscle tone increase in flexor and extensor muscles providing constant resistance to passive movements
what autonomic functions are affected by parkinsons?
impotence, slower bowel motility, orthostatic hypotension
what effect does parkinsons have on cognition and mood?
slow executive functions, depression, apathy, frustration
what is caused by dysfunction of autonomic nervous system?
impaired GI motility, bladder dysfunction, excessive sweating
what are lewy bodies?
eosinophilic intracytoplasmic inclusions
where are Lewy bodies mainly found?
substantia nigra
how are Lewy bodies formed?
deposition of Alpha synuclein
what type of cells are affected by Lewy bodies?
neurons, rarely glial cells
what is the substantial nigra?
the major origin of the dopaminergic innervation of the striatum
what is the major function the striatum?
regulation of posture and muscle tone
how does depleting levels of dopamine correlate with PD?
symptoms begin when around 50-60% of DA containing neurones are lost
how is dopamine started?
tyrosine to L-DOPA to dopamine
what receptors does dopamine act on?
D 1-5 receptors
what effects take place in a cell after dopamine binds?
excitability, metabolism and gene expression of the cell
what is the nigrostriatal pathway?
pathway connecting substantially nigra and the striatum in the forebrain
what is the purpose of the nigrostriatal pathway?
for dopamine transport
how is movement regulated by signals to the spinal cord regulated in normal people using acetylcholine?
acetylcholine has a damoing effect on dopamine release in the basal ganglia, meaning signals to spinal cord are regulated
how is the acetylcholine damping effect on the spinal cord signals effected in someone with PD?
a lack of dopamine means that the signal to the spinal cord is larger meaning there is a constant on/off causing tremors
what is stage I of PD?
unilateral involvement
what is stage II of PD?
bilateral involvement but no postural abnormalities
what is stage III of PD?
bilateral involvement with mild postural imbalance on examination, leads independent life
what is stage IV of PD?
bilateral involvement with postural instability, requires substantial help
what is stage V of PD?
severe, fully developed disease, restricted to bed or wheelchair
how does L-DOPA treat PD?
is a precursor to dopamine and so crosses the BBB to restore DA levels in the brain
what are the issues with L-DOPA?
some converted before it reaches the brain
how can issues with L-DOPA be resolved?
issued with an inhibitor of decarboxylase so it does not get broken down before the BBB
how can half life of L-DOPA be increased?
COMT inhibitor prevents the breakdown
what other drugs can be used to treat PD?
oral dopamine agonists to mimic the dopamine, MAO-B inhibitor to reduce breakdown, anticholinergics to restore DA/ACh balance
what do MAO-B inhibitors do?
reduce metabolism of dopamine in the brain
what are the side effects of anticholinergics?
dry mouth, constipation, sedation
what is dyskinesia?
uncontrollable writhing and choreiform movements
what are the non-drug options of treating PD?
deep brain stimulation and ablative surgery
what is deep brain stimulation?
implantation of wire and high frequency stimulation to create a functional lesion
what is ablative surgery?
create a lesion on one or both sides of the brain which addresses the motor symptoms
what is the pathogenic cascade in PD?
protein aggregation, oxidative stress and mitochondrial impairment
what is the synaptic dysfunction in Alzheimers?
decreased neurotransmitters
what are the abnormal protein deposits in alzheimers?
neurofibrillary tangles and amyloid plaques
what is the very mild stage of alzheimers?
incidents go unnoticed and taken as a sign of getting old
what is the mild stage of alzheimers?
more frequent memory loss, unable to concentrate, difficulty remembering people or objects, misplacing things
what is the moderate stage of alzheimers?
failure to recall events, cannot plan or organise, become withdrawn
what is the moderately severe stage of alzheimers?
unknown address, date, season, still remembers own name and family members
what is the severe stage of alzheimers?
may forget spouse, need help dressing or personal hygiene, tendency to wander
what is the very severe stage of alzheimers?
speech lost, help needed for all aspects of life, unable to walk or sit without help, muscles rigid
what are the visual effects of alzheimers on the brain?
ventricles enlarged, loss in memory region, smaller gyri and areas missing
what are the amyloid plaques made up of?
amyloid beta
what are the enzymes involved in amyloid beta production?
alpha/beta/gamma secretases
what is the function of alpha secretases?
cleave secretes at a particular point
what is the function of beta secretases?
cleaves at the end terminus of the beta amyloid
what is the function of gamma secretases?
cleaves beta amyloid at the C- terminus
what are the 5 proteins that make up gamma secretase?
presinillin, nicastrin, APH-1, PEN-2, CD147
what mutations can cause early onset alzheimers?
mutations in chromosome 1 and 14 cause abnormal presenilins, mutation in chromosome 21 leads to abnormal amyloid precursor protein
where are precursor mutations found?
in certain residues close to alpha and gamma secretase which affect how amyloid beta is processed and can make it more likely to aggregate
where Is amylin or islet polypeptides found?
in type II diabetic pancreas
why are amyloid beta proteins made?
they are useful in small doses as they can protect from cell toxicity and prevent brain damage
what things can diagnose alzheimers?
blood tests for macro globulin and amyloid beta structures or mini-mental state exams
how can PET scans be used to investigate alzheimers?
use radioactive materials to track aspects of brain function
what radioactive materials can be used for PET scans? how does this work?
radioactive water or glucose and attach to amyloid plaques
why are PET scans important?
potential to diagnose at the preclinical stage and used to track changes
what things are assessed in a brain ageing index?
Brain stress, neurones function, brain amyloid, genetic risk, memory scores and shrinkage level
where is infected with amyloid beta aggregation less?
cerebellum and the pons
what is ApoE?
involved in the breakdown and uptake of amyloid beta
what are cholinergic defects?
reduced cholineacetyltransferase, acetylcholine release and choline uptake in the neocortex
what changes occur in terms of receptors in cholinergic defects?
reduced muscarinic M2 and nicotinic receptors
what are the current drugs used to treat alzheimers?
donezepil, galantamine, rivastigmine and memantine
what is donezepil?
acetylcholinesterase inhibitor
what is galantamine?
acetylcholinesterase inhibitor and nicotinic agonist
what is rivastigmine?
acetylcholinesterase and butyrylcholinesterase inhibitor
what is memantine?
NDMA receptor agonist
what is antiamyloid immunotherapy?
immunising against A beta peptide
what is a prion?
type of protein that can trigger normal proteins in the brain to fold abnormally
when do prion diseases occur?
when normal prion proteins becomes abnormal and clumps in the brain causing damage
what is sporadic CJD?
most common and occurs when the brain undergoes a spontaneous change to the abnormal form which results in disease
what is iatrogenic CJD?
accidentally transmitted during the course of medical or surgical treatment
what is familial CJD?
inherited abnormal gene
what is new variant CJD?
caused by ingestion of infected meat which causes conversion of normal prion to pathogenic form
what is fatal familial insomnia?
autosomal dominant disorder that is characterised by degeneration of thalamus and progressive insomnia
what are the symptoms of fatal familial insomnia?
vegetative state of sleep, inability to produce tears and well as poor reflexes and dementia
what is the cause of prions becoming infectious?
conformational change so a soluble protease sensitive form to an insoluble resistant form accumulates in the brain
what are the acquired forms of human prion diseases?
kuru, variant CJD and iatrogenic CJD
