Parkinson's disease

Question 1

How is dopamine synthesised and metabolised?

Answer 1

Synthesis
L-tyrosine (i) L-DOPA  (ii)  Dopamine (DA)
This process utilises the enzymes:
Tyrosine hydroxylase (rate limiting)
DOPA decarboxylase
Metabolism
DA removed from synaptic cleft by dopamine transporter (DAT) & noradrenaline transporter (NET)
Three enzymes metabolise DA:
Monoamine oxidase A (MAO-A): metabolises DA, NE & 5-HT
MAO-B: metabolises DA
Catechol-O-methyl transferase (COMT): wide distribution, metabolises all catecholamines

Question 2

What are the dopaminergic pathways?

Answer 2

Major locations
Nigrostriatal pathway - susbstantia nigra pars compacta (SNc) to the striatum. Inhibition results in movement disorders

Mesolimbic pathway - ventral tegmental area (VTA) to the Nucleus Accumbens (NAcc). Brain reward pathway.

Mesocortical pathway - VTA to the cerebrum. Important in executive functions & complex behavioural patterns.

Tuberoinfundibular pathway - arcuate nucleus to the median eminence. Inhibition results in hyperprolactinaemia

Question 3

Define

Answer 3

•	Neurodegenerative disease of the dopaminergic neurones of the substantia nigra, characterised by:
o	Bradykinesia
o	Rigidity
o	Resting tremor 
o	Postural instability

Question 4

What is the pathophysiology?

Answer 4

o Degeneration of dopaminergic neurones projecting from the substantia nigra to the striatum

• Lewy bodies & neurites  Found respectively within neuronal cell bodies & axons
• Consist of abnormally phosphorylated neurofilaments, ubiquitin & -synuclein

o Patients are only symptomatic after the loss of > 70% of dopaminergic neurones

Question 5

Explain the aetiology

Answer 5

• Sporadic/Idiopathic Parkinson’s Disease
o Most COMMON
o Aetiology UNKNOWN
o May be related to environmental toxins and oxidative stress
• Secondary Parkinson’s Disease
o Neuroleptic therapy (e.g. for schizophrenia)
o Vascular insults (e.g. in the basal ganglia)
o MPTP toxin from illicit drug contamination
o Post-encephalitis
o Repeated head injury
• There are some familial forms of Parkinson’s disease

Question 6

Epidemiology

Answer 6

• Very COMMON
• Prevalence: 1-2% of > 60 yrs
• Mean age of onset: 57 yrs
- Around 5% of cases are due to mutations in certain genes (e.g. SNCA, LRRK2)

Question 7

What are the key risk factors?

Answer 7

Age
Familial PD
MPTP exposure
Mutation in glucocerebrosidase (GBA) (enzyme that is deficient in Gaucher’s disease, x5 increased risk of PD)

Question 8

What are the presenting symptoms?

Answer 8

• INSIDIOUS onset
• Resting tremor (mainly in hands)
• Stiffness and slowness of movements
• Difficulty initiating movements
• Frequent falls
• Smaller hand writing (micrographia)
• Insomnia
• Mental slowness (bradyphenia)

Question 9

What are the signs?

Answer 9

•	Tremor 
o	Pill rolling rest tremor 
o	4-6 Hz 
o	Decreased on action 
o	Usually asymmetrical
•	Rigidity
o	Lead pipe rigidity of muscle tone 
o	Superimposed tremor can cause cogwheel rigidity
o	Rigidity can be enhanced by distraction
•	Gait
o	Stooped 
o	Shuffling 
o	Small-stepped gait
o	Reduced arm swing 
o	Difficulty initiating walking 
•	Postural Instability
o	Falls easily with little pressure from the back or the front 
•	Other features
o	Frontalis overactivation (leads to furrowing of the brow)
o	Hypomimic face 
o	Soft monotonous voice (hypophonia)
o	Impaired olfaction 
o	Tendency to drool
o	Mild impairment of up-gaze 
•	Psychiatric
o	Depression
o	Cognitive problems and dementia (in later stages)

Question 10

What is the 1st line investigation?

Answer 10

CLINICAL DIAGNOSIS

if unsure - dopminergic agent trial

• Levodopa Trial
o Timed walking and clinical assessment after administration of levodopa

Question 11

What are some investigations to consider?

Answer 11

• Bloods
o Serum caeruloplasmin - rule out Wilson’s disease as a cause of Parkinson’s disease in younger patients
• CT or MRI Brain
o To exclude other causes of gait decline (e.g. hydrocephalus)
• Dopamine Transporter Scintigraphy
o Reduction in striatum and putamen

Question 12

What drugs used to treat PD by dopamine replacement?

Answer 12

Levodopa (L-DOPA)
Rapidly converted to DA by DOPA decarboxylase (DOPA-D)
Can cross blood-brain barrier (BBB)
Peripheral breakdown by DOPA-D  Leads to nausea & vomiting
Long-term side-effects: dyskinesias & ‘on-off’ effects. NOT disease-modifying

Adjuncts:
DOPA decarboxylase inhibitors: Carbidopa & Benserazide
*Do not cross BBB  prevent peripheral breakdown of levodopa
Reduce required levodopa dosage
COMT inhibitors: Entacapone & Tolcapone
 amount of levodopa in the brain

Question 13

What are the other drugs used?

Answer 13

Dopamine receptor agonists:

Ergot derivatives: Bromocriptine & Pergolide
Act as potent agonists of D2 receptors
Associated with cardiac fibrosis

Non-ergot derivatives: Ropinirole & Rotigotine
Ropinirole also available as extended-release formulation
Rotigotine also available as a patch

Monoamine oxidase B (MAOB) inhibitors:
Selegiline (deprenyl) & Rasagiline

Reduce the dosage of L-DOPA required
Can increase the amount of time before levodopa treatment is required