38. Parkinson's disease - etiology, pathogenesis, clinical manifestations.

Parkinson's disease – etiology, pathogenesis, and clinical manifestations.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra pars compacta, leading to motor and non- motor symptoms.

Etiology (Causes)

1. 1 Idiopathic (most common form)

• Exact cause unknown.
• Likely multifactorial — combination of genetic susceptibility and environmental factors.

1. 2 Genetic factors

• ~10% of cases are familial.
• Mutations in genes:
• SNCA (α- synuclein gene).
• LRRK2, PARK2 (parkin), PINK1, DJ-1.

1. 3 Environmental factors

• Exposure to certain toxins:
• MPTP (synthetic opioid contaminant).
• Pesticides, herbicides.
• Rural living, well water exposure (epidemiological associations).

1. 4 Secondary (Parkinsonism syndromes)

• Post- encephalitic parkinsonism.
• Drug- induced (e.g., antipsychotics blocking dopamine receptors).
• Vascular parkinsonism (multiple small infarcts in basal ganglia).

Pathogenesis

1. 1 Degeneration of dopaminergic neurons

• Progressive loss of dopaminergic neurons in substantia nigra pars compacta.
• Reduced dopamine levels in striatum (caudate nucleus and putamen).

1. 2 Lewy body formation

• Lewy bodies: intracytoplasmic eosinophilic inclusions containing α-synuclein and ubiquitin.
• Seen in surviving neurons —thought to reflect abnormal protein aggregation.

1. 3 Basal ganglia circuit dysfunction

• Decreased dopamine → reduced activation of direct (facilitatory) pathway and excess activity in indirect (inhibitory) pathway.

Net effect: excess inhibition of the thalamus, leading to decreased cortical motor activity.

Clinical Manifestations

Motor symptoms (classic tetrad)

Other motor features

• Mask-like facies (hypomimia).
• Micrographia (small handwriting).
• Shuffling gait ("festinating gait").
• Hypophonia (soft, monotonous speech).

Non-motor symptoms

• Autonomic dysfunction:
• Orthostatic hypotension.
• Constipation.
• Urinary incontinence.
• Neuropsychiatric:
• Depression, anxiety.
• Cognitive impairment, dementia (later stages).
• Sleep disturbances (REM sleep behavior disorder, insomnia).
• Anosmia (loss of smell) —early sign.

Disease progression

• Gradual worsening over years.
• Initially asymmetric (often starts on one side).