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 
    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

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