Parkinson's Disease

Question 1

What pathological changes result in Parkinson’s Disease? [3]

Answer 1

1. Loss of dopaminergic neurons within substantia nigra
2. Surviving neurons contain Lewy bodies
3. Parkinson’s Disease manifests clinically after loss of approximately 50% of dopaminergic neurons

Question 2

What are the 2 types of Lewy bodies? [2]

Answer 2

1. α-synuclein
2. ubiquitin

Question 3

What are the possible mechanisms that result in Lewy body formation? [10]

Answer 3

1. Oxidative stress
2. Mitochondrial failure
3. Excitotoxicity
4. Protein aggregation
5. Interference with DNA transcription
6. Nitric oxide
7. Inflammation
8. Apoptosis
9. Trophin deficiency
10. Infection

Question 4

Describe the pathological progression of Parkinson’s disease including which neurological areas are affected and what clinical signs are present at each stage:

1. Stage 1-2? [5]
2. Stage 3-4? [3]
3. Stage 5-6? [2]

Answer 4

1. Stage 1-2 = medulla/pons and olfactory nucleus
   
   • pre-symptomatic or pre-motor
   • e.g. loss of smell
2. Stage 3-4 = midbrain: substantia nigra pars compacta
   
   • Parkinsonism only becomes evident after extensive nigral damage
3. Stage 5-6 = neocortex involvement
   
   • development of PD dementia

Question 5

What clinical signs define Parkinson’s disease? [4]

Answer 5

1. Bradykinesia
2. And at least one of the following:
   
   • Muscular rigidity
   • 4-6 Hz rest tremor
   • Postural instability

Question 6

What is bradykinesia? [1]

Answer 6

slowness in initiation of voluntary movement with progressive reduction in speed and amplitude of repetitive actions

Question 7

What are the non-motor symptoms of Parkinson’s disease:

1. neuropsychiatric? [3]
2. sleep? [3]
3. autonomic? [7]
4. other? [3]

Answer 7

1. Neuropsychiatric:
   
   • dementia
   • depression
   • anxiety
2. Sleep:
   
   • REM sleep behaviour disorder
   • restless legs syndrome
   • daytime somnolence
3. Autonomic:
   
   • constipation
   • urinary urgency/nocturia
   • erectile dysfunction
   • excessive salivation/sweating
   • postural hypotension
4. Other:
   
   • reduced olfactory function
   • fatigue
   • pain and sensory symptoms

Question 8

What are the differential diagnoses of Parkinson’s disease? [5]

Answer 8

1. Benign tremor disorders (e.g. essential tremor)
2. Dementia with Lewy bodies
3. Vascular parkinsonism
4. Parkinson plus disorders (e.g. progressive supranuclear palsy, multiple system atrophy)
5. Drug-induced parkinsonism/tremor

Question 9

What investigations would you carry out on a patient with suspected Parkinson’s disease? [3]

Answer 9

1. Bloods
   
   • if tremor present:
     
     • thyroid function tests,
     • copper/caeruloplasmin
2. Structural imaging
   
   • CT/MRI brain normal in PD,
     
     • abnormal in vascular parkinsonism and Parkinson plus disorders;
3. Functional imaging
   
   • imaging of presynaptic dopaminergic function using DAT SPECT is abnormal in degenerative parkinsonism

Question 10

Name the drugs classes used for the management of Parkinson’s disease [5]

Answer 10

1. L-dopa
2. dopa-decarboxylase inhibitor (carbidopa)
3. dopamine agonists
4. MAO-B inhibitors
5. COMB inhibitors

Question 11

Describe L-dopa under the following headings:

1. what is it and how is it prescribed? [2]
2. mechanism of action? [2]
3. adverse effects? [3]

Answer 11

1. Dopamine precursor, given combined with a dopa-decarboxylase inhibitor
   
   • L-dopa + carbidopa = Sinemet
   • L-dopa + benserazide = Madopar
2. Mechanism of action:
   
   • taken up by dopaminergic neurons and decarboxylated to dopamine within pre-synaptic terminals
3. Adverse effects:
   
   • Peripheral: Nausea, vomiting, postural hypotension
   • Central: confusion, hallucinations
   • Longer term: Approx. 50% of patients develop motor complications after 5 years of L-dopa

Question 12

Describe dopamine agonists under the following headings:

1. drug names? [4]
2. mechanism of action? [1]
3. side effects? [4]

Answer 12

1. Examples:
   
   • ropinirole,
   • pramipexole,
   • rotigotine,
   • apomorphine
2. Mechanism of action:
   
   • acts directly on post-synaptic striatal dopamine receptors (D2 subtype)
3. Side effects:
   
   • dopaminergic side effects
   • somnolence,
   • impulse control disorders (e.g. pathological gambling, hypersexuality)
   • nightmares

Question 13

Describe MAO-B inhibitors under the following headings:

1. examples? [2]
2. mechanism of action? [2]

Answer 13

1. Examples:
   
   • selegiline,
   • rasagiline
2. Mechanism of action:
   
   • prevents dopamine breakdown by binding irreversibly to monoamine oxidase

Question 14

Describe COMT inhibitors under the following headings:

1. drug names? [2]
2. mechanism of action? [2]
3. side effects? [2]

Answer 14

1. Examples:
   
   • entacapone
   • tolcapone
2. Mechanism of action:
   
   • inhibits catechol-o-methyltransferase results in longer L-dopa half-life/duration of action
   • hence co-prescribed with L-dopa
3. Side effects:
   
   • dopaminergic
   • diarrhoea

Question 15

What are the degenerative causes of Parkinsonism? [4]

Answer 15

1. Dementia with Lewy bodies
2. Progressive supranuclear palsy
3. Multiple system atrophy
4. Corticobasal degeneration

Question 16

What are the secondary causes of Parkinsonism? [4]

Answer 16

1. Drug-induced: chronic use of dopamine antagonists
2. Cerebrovascular disease
3. Toxins (e.g. carbon monoxide, organophosphates, MPTP)
4. Post-infectious