Parkinson's Flashcards
Clinical presentation
Blank face (little blinking), tremors in hand at rest that get worse when distracted by something such as mental maths, lack of arm swinging when walking, shuffling gait, visual-spatial issues that cause them to pause at door or when something passes in front of them.
Hypokinetic disorder (akinesia and rigidty observed and associated with tremor).
Prevalence of PD
180/100,000
Age of onset
60yrs average but 5% under 40 with some people getting age 20.
Symptoms
Premotor: Olfactory impairment, REM sleep disorder, autonomic disturbance.
Motor: tremor, gait, rigidity, bradykinesia.
Non-motor: Pain, anxiety, depression, urinary dysfunction.
Lewy Body progression in Parkinson’s disease
Olfactory bulb, brainstem (substantia nigra), cortex.
Outline how Levodopa works
Levodopa taken orally is converted into dopamine in the body with dopa decarboxylase inhibitor.
The inhibitor of peripheral DOPA decarboxylase reduces the conversion of L-DOPA to dopamine in the systemic circulation, allowing for greater L-DOPA distribution into the central nervous system.
Name dopamine agonist
Mirapexin
Treatment via enhancing drug action by enzymes
COMT inhibitor: prevents breakdown of dopamine
MAO B inhibitor: prevents breakdown of dopamine.
Explain therapeutic window
Too much dopamine and too little bad.
* too little: cannot move
* too much: move too much
There is a narrow window where movement is in good boundaries and patients can control movements well.
As disease progresses therapeutic window narrows (more specific conc needed): use of Da drugs alter DA receptor sensitivity and less endogenous DA.
What is peak dose dyskinesia
Writhing movements that can occur when peak PD dopaminergic drugs are given.
Patients prefer exaggerated movement to not being able to move.
If patient takes 8 separate doses a day they can be in this state on 8 separate occasions.
Rotigotine treatment
transdermal patches are used to treat the signs and symptoms of Parkinson’s disease: DA agonist
DBS
Subthalamic nucleus is aim (above substantia nigra): DBS applied has overall inhibitory effect.
Side effects: weight gain, apraxia of eyelid opening, depression.
Ideal: young, no comorbid, good levodopa response, no freezing gait.
Lesion of stn = less excitation onto GPI and less inhib of thalamus
Apomorphine
Pen injection throughout day: more control of dose = more time in therapeutic window.
* DA agonist.
Side effects: hypotension, nausea, impulse control disorder, hallucinations.
Outline role of basal ganglia
Motor control, motor learning, executive functions, behaviour and emotions.
Define akinesia
Difficulty in initiating movement.
Mean survival time after parkinson’s diagnosis
10 years (drug therapy improves clinical symptoms but does not alter disease progression).
Pathology associated with parkinson’s
Specific loss of dopamine cells in substantia nigra pas compacta.
Loss of dopaminergic nigro-striatal pathway.
Black structure is completely lost so only white seen in patients with Parkinson’s
What is MPTP?
1-methyl 4-phenyl1,2,3,6-tetrahydropyridine: irreversible selective destruction of nigro-striatal neurons - leads to frozen addict syndrome.
Neurotoxic side product formed in the chemical synthesis of desmethylprodine opioid analgesic… results in permant parkinson’s symptoms.
Converted to MPP+ by MAO B and uptake by specific DA transporter system.
Inhibits mitochondrial oxidation reactions- oxidative stress.
Useful experimental tool.
Outline the basal ganglia
Six interconnected nuclei: striatum, GPi, STN, SNr, SNc.
integrates motor and sensory information from the cortex before relaying it back to cortex via the thalamus.
many parallel loop circuits, not all strictly ‘motor’ (also ‘sensory’ even ‘emotional’ (limbic) loops)
= ‘parallel processing’ hypothesis
Output from the BG is controlled by two parallel but opposing pathways which are modulated by dopamine (keeps balance)
Outline and give roles of different types of dopaminergic pathways.
1) Indirect pathway = inhibits motor activity, post-synaptic D2 (inhibited by da)
The dorsal striatal neurons expressing the D2-family of dopamine receptors are inhibited by dopamine from the SN. These D2R neurons send inhibitory GABAergic connections to the GPe. The GPe inhibits the subthalamic nucleus, which excites the GPi/SNpr, completing the “Indirect pathway.” As mentioned above, the GPi sends inhibitory GABAergic signals to the VA and VL of the thalamus. In this way, the activation of the “Indirect pathway” results in stimulation of the GPi which then inhibits the VA/VL of the thalamus, ultimately inhibiting movement.
Da reduces inhibition of thalamus
2) Direct pathway: thalamocortical loop inhibited by BG output.
Type: Excitatory
Pathway: cortex -> striatum -> globus pallidus, pars interna -> thalamus -> motor cortex -> spinal cord / brainstem
Function: movement initiation
DA: modulates via released in striatum and act on postsynaptic D1 receptors that facilitate release of transmitter (are excitatory and increase cAMP).
What is the hyperdirect pathway?
Excitatory: Cortex to subthalamic nucleus.
How does parksinson’s arise in terms of direct and indirect pathways?
Imbalance between direct and indirect pathway due to loss of dopamine.
= excessive inhib of thalamocortical pathway.
Direct: less excitation onto striatum = less inhibition of output stations of BG and therefore thalamus is excessively inhibited.
Indirect: less inhibition onto striatum = more inhib of GPe = less inhib of STN (disinhibition) and fire faster = output stations more excited = more inhibition of thalamus.
Hyperdirect: excitatory inputs from cortex to STN cause excessive inhibition of thalamus.
Define bradykinesia
slow movement
Oscillations in Parkinson’s
DA depletion = bursting and synchronisation of BG neuronal firing.
Beta frequency of 15-30Hz correlates to bradykinesia (exaggerated) = this is pathological and spreads throughout basal ganglia into cortex.
State the different surgical options.
1) pallidotomy and subthalamotomy: irreversible lesioning (deep in brain and close to blood vessel) = BG underbalance again.
2) thalamotomy: irreversible lesioning to relieve tremor.
3) DBS: of subthalamic nucleus (glutamatergic). High frequency, gets rid of bursting stim.
4) non-invasive stim: aim at the hyperdirect pathway, this is future research.
NB: 1 and 2 are not carried out now.
