Parkinson's

Question 1

Clinical presentation

Answer 1

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).

Question 2

Prevalence of PD

Answer 2

180/100,000

Question 3

Age of onset

Answer 3

60yrs average but 5% under 40 with some people getting age 20.

Question 4

Symptoms

Answer 4

Premotor: Olfactory impairment, REM sleep disorder, autonomic disturbance.

Motor: tremor, gait, rigidity, bradykinesia.

Non-motor: Pain, anxiety, depression, urinary dysfunction.

Question 5

Lewy Body progression in Parkinson’s disease

Answer 5

Olfactory bulb, brainstem (substantia nigra), cortex.

Question 6

Outline how Levodopa works

Answer 6

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.

Question 7

Name dopamine agonist

Answer 7

Mirapexin

Question 8

Treatment via enhancing drug action by enzymes

Answer 8

COMT inhibitor: prevents breakdown of dopamine
MAO B inhibitor: prevents breakdown of dopamine.

Question 9

Explain therapeutic window

Answer 9

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.

Question 10

What is peak dose dyskinesia

Answer 10

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.

Question 11

Rotigotine treatment

Answer 11

transdermal patches are used to treat the signs and symptoms of Parkinson’s disease: DA agonist

Question 12

DBS

Answer 12

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

Question 13

Apomorphine

Answer 13

Pen injection throughout day: more control of dose = more time in therapeutic window.
* DA agonist.

Side effects: hypotension, nausea, impulse control disorder, hallucinations.

Question 14

Outline role of basal ganglia

Answer 14

Motor control, motor learning, executive functions, behaviour and emotions.

Question 15

Define akinesia

Answer 15

Difficulty in initiating movement.

Question 16

Mean survival time after parkinson’s diagnosis

Answer 16

10 years (drug therapy improves clinical symptoms but does not alter disease progression).

Question 17

Pathology associated with parkinson’s

Answer 17

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

Question 18

What is MPTP?

Answer 18

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.

Question 19

Outline the basal ganglia

Answer 19

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)

Question 20

Outline and give roles of different types of dopaminergic pathways.

Answer 20

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).

Question 21

What is the hyperdirect pathway?

Answer 21

Excitatory: Cortex to subthalamic nucleus.

Question 22

How does parksinson’s arise in terms of direct and indirect pathways?

Answer 22

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.

Question 23

Define bradykinesia

Answer 23

slow movement

Question 24

Oscillations in Parkinson’s

Answer 24

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.

Question 25

State the different surgical options.

Answer 25

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.