cognitive motor disorders Flashcards
the direct basal nuclei pathway…thalamic output to the cortex
increases
the indirect basal nuclei pathway…thalamic output to the cortex
decreases
what does the nigral-striatal dopaminergic projection do?
decreases activity of indirect pathway
this balances the direct and indirect pathways and favours movement
parkinsons diease overview
- most cases are idiopathic
- leads to difficulty initiating movement
- incidence increases with age e.g 0.4% cases for people over 40 and 3-4% of those older than 85
- duration= 5-15 years
what are the motor symptoms of parkinsons?
tremor
rigidity
slowness of movement (bradykinesia)
postural instability
(mainly shuffled gait and stooped posture)
what are the neuropsychoatric symptoms of parkinsons?
cognitive impairement
mood and behavioural alterations
sleep disorders
other symptoms of parkinsons?
olfactory and autosnomic dysfunction
gross neuropathology of parkinsons
loss of dopaminergic cells in the substantia nigra compacta (nigral-striatal pathway)
you therefore lose ability to balance the direct and indircet pathways- indirect becomes dominant
loss of functionality
PD and the loss of nigral-striatal dopaminergic projectiom
reverts to default indirect state
stronger inhibition of
thalamic output to
supplementary
motor cortex
difficult to initiate
movement
in early stages of PD, only some motor plans will be lost (e.g can ride a bike but cannot walk)
cellular neuropathology of PD
- loss of melanin containing dopaminergic neurons in SN
- lewy body inclusions in DAergic neurons of the SN (alpha-synuclein)
where are lewy bodies found?
– cerebral cortex
– locus coeruleus
– raphe nuclei
– dorsal motor nucleus of vagus nerve
– sympathetic ganglia
what are lewy bodies?
aggregations of alpha-synuclein
what is alpha-synuclein?
pre-synaptic protein
soluble when unfolded but membrane bound in alpha-helical form
* involvement in vesicle trafficking
* action as a molecular chaperone in SNARE complexes
* interaction with microtubules in a similar fashion to tau
alpha-synuclein promotes SNARE complex formatiom
alpha-synuclein has an intrinsic ability to bind to lipid membranes, particularly in the synaptic vesicle membrane
this membrane-binding property helps in localizing alpha synuclein to the areas where neurotransmitter release occurs
alpha-synuclein aggreation pathway
in its membrane bound form, alpha-synuclein is normal
in its unbound form, it is more likely to intercact with itself and generate aggregates of itself and this forms beta-sheets
fibrils then bind and form the lewy bodies
all of the alpha-synuclein then cannot generate synaptic transmission as it is stuck in the lewy body
does aging make SNc neurons more vulnerable?
aging decreases L-type calcium channel currents and pacemaker (tonic) firing fidelity in SN dopaminergic neurons
treatments for parkinsons disease
- transmitter replacement
- deep brain stimulation
transmitter replacement- PD treatment
replacing dopamine that has been lost through L-DOPA in striatum
effectiveness is generally short-lived
deep brain stimulation- PD treatment
DBS in subthalamic nucleus- regulates excitability of whole network
stimulation leads to enhanced activity of GABAergic SNr/GPi = inhibition of thalamus which helps to regulate and balance the pathways
parkinsons and diabetes treatments
treatment with a type-II diabetes drug exanatide prevented disease progression in trials with 62
patients (lancet 2017)
huntingtons disease overview
- inherited in an autosomal dominant fashion
- onset usually in mid 30s
- caused by mutations to the huntingtin gene (HT) which codes for HTT
- HTT contains a trinucleotide repeat (CAG which codes for glutamine)
- in HD this is repeated an abnormal number of times (>35) resulting in mutant HTT (mHtt)
motor symptoms of HD
random, uncontrolled movements (chorea)
abnormal facial expressions
abnormal posture
difficulties chewing/swallowing
cognitive symptoms of HD
executive functions
short- and long-term memory deficits
ultimately leads to dementia
neuropsychiatric symptoms of HD
anxiety
depression
aggression
reduced display of emotions
HD- polyglutamine expansion disorder
overbalamce of glutamine leads to hydrogen bonding and protein aggregation
this takes over (kidnaps) smaller proteins and blocks their function
what is rhes?
selective protein to striatum
mHtt binds to the small GTP binding protein rhes which induces sumoylation of mHtt and this leads directly to cytotoxicity
this leads to cell death in the striatum
what is mHtt associated with?
ubiquitin and accumulates in the
nucleus of affected cells
what brain regions degenerate due to HD?
– most prominent is the caudate/putamen
– cerebral cortex
– hippocampus
– purkinje cells of cerebellum
– thalamic nuclei
– hypothalamic nuclei
neuropathology of HD
- huge loss of striatum material
- shrinking of rest of the cortex
- deep sulci
- very enlarged lateral ventricles as the caudate forms the wall of the verntricle
medium spiny neurons and HD
in the caudate/putamen the medium spiny neurones projecting to GPe (indirect pathway) are more vunerable than those projecting to GPi (output of basal nuclei)
cellular pathophysiology of HD
loss of striatal-pallidal inhibitory projection
lowers basal nuclei output
increases thalamic drive to cortex
losing dominance of indirect pathway but still have nigral-striatal pathway which is enhacning the dircet pathway and reducing the indirect
treatment of HD
if you have HD mutation you will develop HD so there is no treatment
currently in development is gene silencing technology which may reduce the expression of the mHtt protein (RNAi)
