L4 - Parkinsons

Introduction to Parkinson's Disease

• Overview

  • Parkinson's disease is a chronic progressive disorder of the central nervous system impacting movement.

  • It is the second most common neurodegenerative disease after dementia, affecting approximately 200,000 people in Australia and around 10 million globally.

Pathophysiology of Parkinson's Disease

• Dopamine Neuron Degeneration

  • Characterized by progressive degeneration of dopaminergic neurons in the substantia nigra, a critical area for movement control.

  • Declining dopamine levels impair the ability to initiate and control movement, leading to hallmark symptoms.

• Motor Symptoms

  • Key symptoms include muscle tremors (often starting in the hands), bradykinesia (slowness of movement), muscle weakness, rigidity, and altered posture.

  • Symptoms worsen over time, making daily activities challenging.

• Cellular Changes

  • Misfolding and aggregation of the protein alpha-synuclein lead to the formation of Lewy bodies, contributing to neuronal dysfunction and cell death.

  • Initially found in the substantia nigra, Lewy bodies can spread to cortical regions, subsequently affecting cognition, mood, and autonomic function.

Changes in Motor Circuits

• Dopaminergic Pathways

  • The loss of dopaminergic neurons results in decreased dopamine activity in the basal ganglia, disrupting normal motor control.

  • The direct pathway (promotes movement) becomes underactive, while the indirect pathway (suppresses unwanted movement) becomes overactive, leading to rigidity and bradykinesia.

Pharmacological Treatments for Parkinson's Disease

• L-DOPA Therapy

  • The most effective treatment, L-DOPA is a dopamine precursor that crosses the blood-brain barrier and is converted into dopamine in the brain.

  • Long-term use can cause side effects like motor fluctuations, nausea, and involuntary movements.

• Dopamine Agonists

  • These mimic dopamine effects and stimulate dopamine receptors.

  • They are used alone or in combination with L-DOPA, with potential side effects including hallucinations and cardiovascular issues.

• Monoamine Oxidase B Inhibitors

  • Prevent dopamine breakdown, increasing its availability.

  • Side effects may include postural hypotension and motor fluctuations.

• NMDA Receptor Antagonists

  • Originally antiviral drugs, these may indirectly enhance dopamine release and are used as adjunct therapy with L-DOPA.

  • Side effects include postural hypotension and hallucinations.

• Muscarinic Acetylcholine Receptor Antagonists

  • Block acetylcholine to restore dopamine-acetylcholine balance, but have significant side effects that limit their use.

• COMT Inhibitors

  • Enhance L-DOPA's effects by preventing its breakdown in the peripheral system, though they can cause nausea and dyskinesia.

Emerging Therapies

• Current Approaches

  • Ongoing research seeks to develop disease-modifying therapies to target neurodegeneration rather than just symptom management.

  • Precision Approaches focus on specific organelles and molecular pathways unique to individual patients.

  • Broad Approaches aim to address common neuronal abnormalities across the patient population.

Conclusion

• Parkinson's disease is a major neurodegenerative disorder with significant impacts on motor function and quality of life.

• Current treatments, while improving symptoms, do not prevent disease progression, underlining the need for further research and development of more targeted therapies.