What is the pathophysiology of Parkinson's disease?

Pathophysiology of Parkinson's Disease

Parkinson's disease (PD) is primarily characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta, leading to dopamine deficiency in the striatum and disruption of the basal ganglia-thalamo-cortical circuit. 1, 2

Core Pathological Features

Neuronal Loss and Dopamine Deficiency

• Selective degeneration of dopaminergic neurons in the substantia nigra pars compacta 1
• Approximately 40-50% of dopaminergic neurons are lost before clinical symptoms appear 1
• Estimated 5-year interval between initial neuronal loss and symptom manifestation 1
• Dopamine deficiency disrupts normal function of the basal ganglia-thalamo-cortical circuit 1

Alpha-Synuclein Pathology

• Abnormal intraneuronal (Lewy bodies) and intraneuritic (Lewy neurites) deposits of fibrillary aggregates 3
• Alpha-synuclein is the primary component of these protein aggregates 3, 4
• Majority of alpha-synuclein aggregates are located at presynapses, causing synaptic dysfunction 3
• Lewy pathology progresses in a stereotypical pattern throughout the brain 3

Molecular Mechanisms

• PRRT2 mutations affect the SNARE complex and calcium sensitivity 1
• Abnormal regulation of Nav1.2 and Nav1.6 channels contributes to neuronal dysfunction 1
• Post-translational modifications of proteins affect signaling networks and protein function 4
• Impaired axonal trafficking due to alpha-synuclein deposition 3

Progression and Spread

• Initial Lewy body deposition occurs in the medulla oblongata, pontine tegmentum, and olfactory system 1
• Later involvement of the substantia nigra and other deep gray nuclei corresponds with onset of clinical motor symptoms 1
• Final stage involves deposition of Lewy bodies in the cortex 1
• Functional connectivity changes correlate with disease progression 3

Clinical Manifestations Related to Pathophysiology

Motor Symptoms

• Resting tremor, bradykinesia, and rigidity result from dopamine deficiency in the striatum 2
• Postural instability and gait abnormalities occur in more advanced disease 2
• Motor symptoms typically appear after 60-80% loss of nigral dopaminergic neurons 5

Non-Motor Symptoms

• Result from widespread involvement of other CNS structures and neurotransmitter systems beyond dopamine 6
• May precede motor symptoms by years or decades 5, 6
• Include autonomic dysfunction, behavioral changes, and cognitive impairment 1
• Reflect the extensive pathology beyond the nigrostriatal system 6

Distinguishing Features from Other Parkinsonian Syndromes

• PD differs from Progressive Supranuclear Palsy (PSP), which shows more axial rigidity and vertical gaze palsy 7
• Multiple System Atrophy (MSA) involves additional autonomic dysfunction and cerebellar symptoms 1
• Corticobasal Degeneration (CBD) has distinct clinical features beyond typical parkinsonian symptoms 1

Nutritional and Metabolic Considerations

• Weight changes are common during disease progression 1
• Weight loss may be present at diagnosis and associated with disease progression 1
• Increased energy expenditure due to dyskinesias and rigidity is not fully compensated by increased energy intake 1
• Gastrointestinal dysfunction (dysphagia, sialorrhea, constipation) may contribute to nutritional challenges 1

Clinical Implications

• Early diagnosis remains challenging due to the long prodromal phase 5
• Current treatments address symptoms by replacing or boosting dopamine but do not modify disease progression 2, 5
• No definitive biomarkers exist for early diagnosis or monitoring disease progression 5
• Understanding the complex pathophysiology is crucial for developing disease-modifying therapies 6

The pathophysiology of Parkinson's disease extends beyond simple dopamine deficiency to include complex protein aggregation, synaptic dysfunction, and widespread neuronal involvement, explaining the diverse motor and non-motor manifestations of this neurodegenerative disorder.