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 
  1. Making movement – direct
  2. 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.

1. Resting tremor – involuntary shaking at rest, inhibited during movement
2. Cogwheel rigidity – inability to perform movements smoothly
3. Bradykinesia – weakness and slowing down of movements
4. Postural instability – unbalanced when standing/moving (¯ postural reflexes)
5. 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