cognitive motor disorders

Question 1

the direct basal nuclei pathway…thalamic output to the cortex

Answer 1

increases

Question 2

the indirect basal nuclei pathway…thalamic output to the cortex

Answer 2

decreases

Question 3

what does the nigral-striatal dopaminergic projection do?

Answer 3

decreases activity of indirect pathway
this balances the direct and indirect pathways and favours movement

Question 4

parkinsons diease overview

Answer 4

• 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

Question 5

what are the motor symptoms of parkinsons?

Answer 5

tremor
rigidity
slowness of movement (bradykinesia)
postural instability
(mainly shuffled gait and stooped posture)

Question 6

what are the neuropsychoatric symptoms of parkinsons?

Answer 6

cognitive impairement
mood and behavioural alterations
sleep disorders

Question 7

other symptoms of parkinsons?

Answer 7

olfactory and autosnomic dysfunction

Question 8

gross neuropathology of parkinsons

Answer 8

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

Question 9

PD and the loss of nigral-striatal dopaminergic projectiom

Answer 9

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)

Question 10

cellular neuropathology of PD

Answer 10

• loss of melanin containing dopaminergic neurons in SN
• lewy body inclusions in DAergic neurons of the SN (alpha-synuclein)

Question 11

where are lewy bodies found?

Answer 11

– cerebral cortex
– locus coeruleus
– raphe nuclei
– dorsal motor nucleus of vagus nerve
– sympathetic ganglia

Question 12

what are lewy bodies?

Answer 12

aggregations of alpha-synuclein

Question 13

what is alpha-synuclein?

Answer 13

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

Question 14

alpha-synuclein promotes SNARE complex formatiom

Answer 14

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

Question 15

alpha-synuclein aggreation pathway

Answer 15

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

Question 16

healthy vs unhealthy alpha synuclein

Answer 16

in healthy cells: α-synuclein is soluble and unfolded or loosely structured.
in disease: it misfolds → forms oligomers → aggregates into fibrils → accumulates as lewy bodies

Question 17

does aging make SNc neurons more vulnerable?

Answer 17

aging decreases L-type calcium channel currents and pacemaker (tonic) firing fidelity in SN dopaminergic neurons

Question 18

treatments for parkinsons disease

Answer 18

1. transmitter replacement
2. deep brain stimulation

Question 19

transmitter replacement- PD treatment

Answer 19

replacing dopamine that has been lost through L-DOPA in striatum
effectiveness is generally short-lived

Question 20

deep brain stimulation- PD treatment

Answer 20

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
reduced excitatory drive to GPi/SNr
→ less inhibition of the thalamus
→ increased thalamocortical output
→ improved motor function

Question 21

parkinsons and diabetes treatments

Answer 21

treatment with a type-II diabetes drug exanatide prevented disease progression in trials with 62
patients (lancet 2017)

Question 22

huntingtons disease overview

Answer 22

• 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)

Question 23

motor symptoms of HD

Answer 23

random, uncontrolled movements (chorea)
abnormal facial expressions
abnormal posture
difficulties chewing/swallowing

Question 24

cognitive symptoms of HD

Answer 24

executive functions
short- and long-term memory deficits
ultimately leads to dementia

Question 25

neuropsychiatric symptoms of HD

Answer 25

anxiety depression aggression reduced display of emotions

Question 26

HD- polyglutamine expansion disorder

Answer 26

long glutamine tract makes mHtt prone to misfolding and aggregation whihc forms intracellular protein aggregates overbalamce of glutamine leads to hydrogen bonding and protein aggregation this takes over (kidnaps) smaller proteins and blocks their function

Question 27

what is rhes?

Answer 27

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

Question 28

what is mHtt associated with?

Answer 28

mHTT gets ubiquitinated, especially when misfolded this tags it for destruction by the proteasome the result is toxic buildup of mHTT as the proteasome becomes overwhelmed

Question 29

what brain regions degenerate due to HD?

Answer 29

– most prominent is the caudate/putamen – cerebral cortex – hippocampus – purkinje cells of cerebellum – thalamic nuclei – hypothalamic nuclei

Question 30

neuropathology of HD

Answer 30

- 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

Question 31

medium spiny neurons and HD

Answer 31

in the caudate/putamen the medium spiny neurones projecting to GPe D2 receptor expressing (indirect pathway) are more vunerable than those projecting to GPi (output of basal nuclei)

Question 32

cellular pathophysiology of HD

Answer 32

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

Question 33

treatment of HD

Answer 33

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)