Neurology >
Parkinson’s Disease
“Progressive neurodegenerative disease involving a depletion of dopaminergic neurons in the basal ganglia, particularly the substantia nigra“
Risk Factors
- Age > 60 years
- Familial history + various genes (α-synuclein gene) → in approximately 10–15% of cases
- Environmental factors (e.g., exposure to manganese and specific pesticides)
- Diet/metabolism (e.g., low levels of vitamin D, high iron intake, obesity)
- Structural damage (e.g., history of traumatic brain injury)
Classifications
- Earlier disease onset type: onset < 55 years
- Tremor dominant type: onset ≥ 55 years with tremor as a sole initial (or generally predominating) symptom
- Non-tremor dominant type: onset ≥ 55 years with predominating bradykinesia/rigidity
- Rapid disease progression without dementia type: rapid progression of motor symptoms and death within 10 years
Pathophysiology
- Reduced dopamine
- The basal ganglia → the direct and indirect pathway
- Basal ganglia = collection of nuclei and pathways that control movement
- Making movement – direct
- Not moving – indirect
- The direct pathway – ↑ motor cortex activity to ↑ movement
- The thalamus is inhibited at rest. In order to move, the thalamus needs to become excited
- Motor cortex recognises instruction to move → an excitatory message to the striatum
- Excitatory glutamate synapses with an inhibitory neuron → stimulates the striatum to release inhibitory GABA
- This inhibitory neurotransmitter ↓ activity of globus pallidus interna
- When inhibited, globus pallidus interna can no longer inhibit the thalamus → thalamus sends ↑ excitatory messages to the motor cortex → stimulated muscle movement
- The substantia nigra and subthalamic nucleus act to fine-tune these messages
- Substansia nigra has dopamine neuron communicating with striatum inhibitory neurons via the nigrostriatal pathway
- When DA is released, it binds to the D1 receptors on the inhibitory neuron → ↑ inhibitory action → ↑ thalamus activity → ↑ movement
- The subthalamic nucleus excites the substansia nigra → ↑ DA release → ↑ inhibition (↓ activity) of the globus pallidus interna → ↑ thalamic activity + movement
- The substansia nigra can feedback to the subthalamic nucleus to ↓ excitation → ↓ DA
- It helps to view the globus palidus interna as a “leash” on the thalamus, that can be tightened or loosened via excitatory or inhibitory messages to alter its communication with the motor cortex
- The indirect pathway – ↓ unwanted movements by ↑ inhibition of the thalamus via ↑ inhibitory activity of globus pallidus interna
- This pathway controls how excited the thalamus becomes → control movement size and changes
- Motor cortex recognises instruction to move → excitatory message to the striatum
- Excitatory glutamate synapses with an inhibitory neuron → stimulates the striatum to release inhibitory GABA
- In this pathway, inhibitory neurons synapse with the globus pallidus externa → synapse with subthalamic nucleus → ↓ activity and ↓ communication with the subthalamic nucleus
- This allows for an ↑ activity and excitation of the subthalamic nucleus
- ↑ Activity and excitation of the subthalamic nucleus → ↑ excitation of the globus pallidus interna → ↓ activity/ ↑ inhibition of the thalamus → ↓ communication with motor cortex
- The substantia nigra and subthalamic nucleus fine-tunes/adjusts the inhibitory message
- Substansia nigra has dopamine neurons communicating with striatum excitatory neurons via the nigrostriatal pathway
- The subthalamic nucleusexcites the substansia nigra → ↑ DA release → bind to D2 receptors on the striatum excitatory neuron
- This causes ↓ excitatory activity in the striatum → ↓ inhibition of globus pallidus externa → ↑ globus pallidus externa activity
- This also causes ↓ globus pallidus interna → ↑ activity of thalamus + movement
- The substansia nigra can feedback to the subthalamic nucleus to ↓ excitation → ↓ DA
- When a loss of dopamine neurons in the nigrostriatal pathway occurs, the “fine-tuning” is lost. This progressive dopaminergic neuron degeneration → dopamine deficiency at the respective receptors of the striatum with interrupted transmission to the thalamus and motor cortex → motor symptoms of Parkinson’s. As these neurons die, formation of Lewy bodies also occurs, a collection of abnormal proteins (specifically α-synuclein).
- When ~80% of these neurons die, motor symptoms and physical signs begin to manifest
Clinical Presentation
This presentation varies between patients and may progress, worsen and spread over time.
- Resting tremor – involuntary shaking at rest, inhibited during movement
- Cogwheel rigidity – inability to perform movements smoothly
- Bradykinesia – weakness and slowing down of movements
- Postural instability – unbalanced when standing/moving (¯ postural reflexes)
- Parkinsonian gait – shuffling gait with quickened and shortened steps
Patients may experience non-movement disorders: depression, apathy/ withdrawal, anxiety, dementia (in 10-15% patients), hyposomnia, forward leaning gait, micrographia
In later stages, they may also experience symptoms related to ¯ autonomic nervous system function such as constipation, hypotension, sexual dysfunction, and temperature/sweating
- Remember as TRAPS:
- Tremor
- Rigidity
- Akinesia
- Postural Instability
- Shuffling Gait
Investigations
- Clinical diagnosis based on symptoms, medical history and detailed examination
- Imaging: not used routinely for diagnosis but to rule out other disorders
- DAT scan: dopamine uptake scan
- Apomorphine test: observe whether symptoms improve after levodopa administration
Management
- Levodopa/carbidopa
- Crosses BBB → converted to dopamine via DOPA decarboxylase → carbidopa inhibits L-dopa in the body so that more of it can reach the brain
- → improves tremor + bradykinesia, dyskinesia is a common side effect long term
- Dopamine agonists (pergolide, ropinirole, pramipexole)
- Bind to D2 receptors à mimic dopamine
- → treats motor symptoms, used in early stage and in adjunct to L-dopa in patients exhibiting fluctuating motor responses and dyskinesias
- MAO-B inhibitors (selegiline, rasagiline)
- Block the effects of MAO-B on dopamine degradation → increased dopamine levels
- COMT inhibitors (entacapone, tolcapone, opicapone)
- Prevent breakdown of levodopa by catechol-O-methyltransferase
- Anticholinergics (benztropine, trihexyphenidyl)
- Block acetylcholine receptors → reduce the effect of acetylcholine → balance the effect of decreased amounts of dopamine → reduced tremor
- Glutamate antagonists (amantadine)
- Weak antagonist of the NMDA-type glutamate receptor, increases dopamine release, and blocks dopamine reuptake → decreasing, or smoothing out, fluctuations in movement
- Deep brain stimulation
- Implantation of electric current generator/ electrodes to stimulate areas of the basal ganglia
- Physiotherapy, occupational therapy, speech and language therapy, diet, support groups
Complications
- Worsen in the later stages of the disease
- Don’t die from Parkinson’s but die with it: severe falls and aspiration pneumonia