Neurodegenerative disorders 2 Flashcards
what neurotransmitters are affected in HD?
decrease in GABA and GAD
decrease in ACh and acetyltransferase
dopamine remains unchanged or slightly increases
what are the general facts about huntingtons disease ?
gradual onset
progressive development
main symptoms= chorea and dementia
selective cell loss in cerebral cortex, corpus straitum
it is a mirror image of parkinsons disease but it does have some similarities
what pathways are lost in HD?
loss of GABAergic pathways
- pathway from globus pallidus & substantia nigra pars reticulata to the thalamus
- pathway from globus pallidus external segment to the subthalamic nucleus
what is the treatment for HD ?
no cure- death is inevitable
no symptomatic relief - drugs to increase GABA and ACh you would expect to work but it doesnt because GABA is the ubiquitous inhibitory neurotransmitter so increasing it would cause worse effects
what can be used to control the movement disorders in HD?
dopamine-2 antagonists such as haloperidol and chlorpromazine- important to get dose right to prevent PD symptoms occurring
dopamine depletion such as reserpine and tetrabenzine
what are the adverse effects of dopamine antagonists and dopamine depletion ?
dopamine 2 antagonists- parkinsonism and restlessness
da depletion- hypotension, depression, sedation and GI disturbances
what are some general characteristics of progressive supranuclear palsy ?
idiopathic
affects subcortical grey matter
progressive dementia
motor symptoms= opthalmoplegia (inhibits eye movements, first vertically then horizontally), balance/posture impaired, pseudobulbar palsy, exaggerated, bradykinesia/rigidity
what neurotransmitters are affected in progressive supranuclear palsy ?
decrease in dopamine in the caudate nucleus and cerebellum
what are the treatments for PSP?
dopaminergic preps for rigidity/bradykinesia e,g,L-DOPA
anticholinergics for gait, speech, pathologic laughing/crying- help to treat inappropriate emotional responses
methysergide for dysphagia
dementia is untreatable
ONLY TREATMENT FOR SYMPTOMATIC RELIEF - treatment depends on what patients respond to
what are the general facts about CBGD?
rare bradykinesia/rigidity like in PD apraxia and clumsiness postural instability myoclonus - chronic contraction of skeletal muscle atrophy of frontal and parietal cortex
what are the treatments for CBGD?
NO TREATMENT
PD treatments are ineffective - no symptomatic treatments
what are the general facts about amyotrophic lateral sclerosis?
starts at about 30-60 years
degeneration of the anterior horn cells
muscle denervation- loss of lower motor neurons
90-95% is sporadic and 5-10% is due to familial mutations in SOD
what could the sporadic form of ALS be due to ?
glutamate excitotoxicity - too much activity at NMDA and AMPA and kainate receptors
- causes too much calcium in cells and this can lead to apoptosis and necrosis when the concentrations are too high
what are the treatments for motor neurones disease ?
anticholinergics - atropine and aytriptyline- for drooling because it decreases salivary secretions
RILUZOLE
- inhibits glutamate release
- increases glutamate uptake into glial cells and neurons
- prolongs survival by about 3 months
- may slow progression- prolong time before patient has to have mechanical ventilation which makes you completely house bound
- no attenuation of motor effects - still have muscle paralysis
what are the adverse effects of treatment for motor neurons disease ?
fatigue dizziness GI disorders reduced pulmonary function increases liver enzymes- need to be careful if patient is taking other drugs
what are the general facts about picks disease ?
frontotemporal dementia
2-3% of all dementia
20-25% of all frontotemporal dementias
no known genetic factor but 45% of patients have a first degree relative with frontotemporal dementia
- personality changes, emotional changes, speech - it is typified by the personality changes
what neurotransmitters change in picks disease ?
decreases in serotonin receptors and serotonin levels
ChAT is unchanged
CSF and brain dopamine is unchanged
CSF and brain somatostatin decreased
what are the treatments for Picks disease ?
NONE
acetylcholineesterase inhibitorss are largely ineffective
what are the general facts about Alzheimer’s disease ?
most common causes of dementia
senile dementia (>65yrs) and presenile dementia (60 years
death is normally within 5-10 years
what are generally the causes of death from AD?
infection
inanition- inability to eat
stroke- amyloid beta protein has adverse effects on cerebrovasculature leading to haemorrhagic stroke
what is the seriously worrying fact about AD?
the number of sufferers will double in the next 20 years
- this is a serious problem with our ageing population
what is the link between nictonic receptors and AD?
there is an age related decrease in nicotinic receptors however this reduction is much larger in AD patients
- younger AD patients have much less nicotinic receptors, it is even less than the age related decrease
what is the most common treatment in AD ?
AChE inhibitors
- tacrine and donepezil
- inhibit AChE reversibly
- increases acetylcholine levels
- may slow progression but only by about 6 months
- may improve cognition in some individuals
DONT WORK IN EVERYONE
when was tacrine first used ?
used in america in 1996 but it was hepatotoxic
when was donepezil first used ?
first used in 1997
it was more selective for acetylcholinesterase compared to butyrylcholinesterase - this meant there were fewer peripheral effects
less systemic effects
drug of choice
what AD drug was released in 1999?
rivastigmine - reversible non-competitive inhibitor
- works for longer because its non-competitive
what AD drug was released in 2001?
galantamine - reversible competitive inhibitor, nicotinic agonist properties - the agonist activity confers it with slight advantage
originally only licensed for moderate AD then licensed for moderate to severe but changed in 2009 to mild to moderate
what are the adverse effects of AChE inhibitors ?
cholinergic effects - cardiodepressant effects= systemic effects such as reduced HR and this will potentiate any underlying hypotension - gastric acid secretion - bronchial constriction anorexia fatigue diarrhoea nausea and vomiting drowsiness blurred vision realisation state- sometimes cognition can improve and this can cause the patient to realise how ill they are and lead to depression
what is memantine ?
used to treat AD
glutamate receptor antagonist- voltage dependent and uncompetitive - this indicates that glutamate is involved in AD
used for moderately severe to severe
recommended for patient intolerant to AChE inhibitors
used for patients with MMSE<14
what are the side effects of memantine ?
dizziness
headache
constipation
somnolence
what are the 3 main future developments for AD ?
Beta breakers
antibody therapy
secretase inhibitors
what are beta breakers ?
small molecules that prevent the formation of beta-pleated structures preventing aggregability
what is antibody therapy ?
passive and active immunisation
active involves injecting a small sequence of amyloid peptide
this has worked in transgenic mouse models and produces antibodies against the plaques and then the plaques are removed by macrophages
in patients it causes an abnormal immune response causing encephalitis and then deth
what are secretase inhibitors ?
amyloid beta proteins are produced by secretase proteins
so far none have worked in clinical trials
what anti-inflammatories are being considered for AD treatment and why ?
rofecoxib and naproxen - shown no efficacy in clinical trials
sulindac, ibuprofen and indomethacin- improve risk ratio to 0.62 - some evidence that it may improve chances of individuals developing AD
thought to work because there is evidence of inflammation in AD
what antioxidants were used to treat AD and were they effective ?
vitamin E
melatonin
gingko-biloba
no positive effects
what is the link between HRT and AD?
postmenopausal women with HRT decrease risk of AD
this was apparent in phase 3 trials
normally trying them out on patients already with the disorder therefore they could only be effective for patients that havent already developed the disease
which sex has a slightly higher risk of developing AD ?
women
