Parkinson's Disease: Mechanism, Symptoms, and Treatment

Overview

• Parkinson's Disease: A neurodegenerative condition affecting dopaminergic neurons in the brain.
• Neurodegeneration: Progressive, irreversible loss of neurons, especially dopamine-producing neurons in the substantia nigra.

Brain Structures and Pathways

• Cerebral Cortex: Generates signals for movement.
• Motor Pathways: Transmit signals leading to muscle contraction and movement.
• Basal Ganglia: Group of nuclei in the brain regulating movement.
  • Components: Striatum (putamen and caudate nucleus), Globus pallidus, Subthalamic nucleus, and Substantia nigra.

Pathways of Movement

• Direct Pathway: Excitatory, facilitates movement.
  • Motor cortex sends excitatory signals (glutamate) to the striatum.
  • Striatum sends inhibitory signals (GABA) to the Globus pallidus internus and substantia nigra pars reticulata.
  • Results in overall increased thalamus activity, promoting movement.
• Indirect Pathway: Inhibitory, terminates movement.
  • Striatum sends inhibitory signals (GABA) to the Globus pallidus externus.
  • Globus pallidus externus normally inhibits the subthalamic nucleus.
  • Subthalamic nucleus stimulates Globus pallidus internus, increasing its inhibition of the thalamus and reducing movement.

Mechanism in Parkinson's Disease

• Degeneration of Neurons: Particularly in the substantia nigra pars compacta, which release dopamine.
  • D1 Receptors: Direct pathway neurons, excited by dopamine.
  • D2 Receptors: Indirect pathway neurons, inhibited by dopamine.
  • Loss of neurons leads to reduced direct pathway stimulation and less inhibition of the indirect pathway, decreasing overall movement.
• Alpha-synuclein Accumulation: Protein involved in synaptic vesicle regulation; linked to Lewy Body dementia.

Symptoms

• Bradykinesia: Slow movement.
• Rigidity: Stiff muscles; includes cogwheel rigidity (gear-like movements) and lead pipe rigidity (continuous resistance).
• Mask-like Face (Hypomimia): Combination of rigidity and bradykinesia.
• Tremors: Pill rolling tremor (index finger and thumb); resting tremors that disappear during movement.
• Gait Abnormalities: Shuffling gait, small steps, increased fall risk.
• Parkinsonism: Collective term for these symptoms; Parkinson's accounts for 80% of cases.
• Other Symptoms: Autonomic disturbances (hypersalivation, constipation, incontinence) and cognitive impairments.

Causes and Risk Factors

• Idiopathic: Most cases have no specific cause.
• Genetic Link: Higher risk among first-degree relatives; 10-15% of cases familial with autosomal dominant and recessive patterns.
• Environmental Factors: Rural living, exposure to chemicals, infections (encephalitis).
• Age: Major risk factor; mean onset 60 years, but 5-15% before 40 years.
• Gender: Slightly more common in males.

Diagnosis

• Clinical: No specific laboratory or imaging tests.
• Movement Disorder Society Criteria: Requires parkinsonism (bradykinesia + either resting tremor or rigidity), supportive criteria, no absolute exclusion criteria, and no red flags.
  • Supportive Criteria: Improvement with dopaminergic treatment, levodopa-induced dyskinesia.
  • Exclusion Criteria: Symptoms limited to lower limbs, dopamine receptor blocker treatment.
  • Red Flags: Rapid gait impairment progression, symmetrical parkinsonism, severe autonomic failure.
• DAT Scan: Radioactive isotope highlighting dopaminergic neuronal loss (not widely available).

Treatment

• Medications: Aim to improve quality of life but do not slow progression.

  • Levodopa: Precursor to dopamine (paired with Carbidopa to prevent breakdown).
  • Dopamine Agonists: Pramipexole, ropinirole.
  • MAO-B Inhibitors: Selegiline.
  • NMDA Receptor Antagonists: Amantadine (increases dopamine synthesis, reduces reuptake).
  • COMT Inhibitors: Tolcapone, entacapone (prolong levodopa effects, risk of liver toxicity).

• On-Off Phenomenon: Periods of controlled (on) and uncontrolled (off) symptoms, switching rapidly.

  • Dyskinesias: Involuntary movements, side effects of levodopa.
    • Diphasic Dyskinesia: Occurs during on-off switching.
    • Peak Dose Dyskinesia: Follows medication peak dopamine levels.

• Deep Brain Stimulation: Option for patients not benefitting from medication; electrodes stimulate basal ganglia areas to improve function.