Parkinson Disease

Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of intracellular alpha-synuclein protein aggregates called Lewy bodies. The SNpc projects to the striatum (caudate and putamen) via the nigrostriatal pathway, providing dopaminergic input essential for smooth, coordinated voluntary movement. Loss of approximately 60-80% of dopaminergic neurons occurs before motor symptoms manifest clinically, indicating a prolonged preclinical phase. Alpha-synuclein is a presynaptic protein that normally facilitates synaptic vesicle trafficking. In PD, misfolded alpha-synuclein aggregates into toxic oligomers and fibrils that propagate in a prion-like fashion from cell to cell, following the Braak staging hypothesis: beginning in the olfactory bulb and dorsal motor nucleus of the vagus (stages 1-2, explaining early hyposmia and constipation), ascending to the brainstem and midbrain (stages 3-4, motor symptoms), and eventually reaching the neocortex (stages 5-6, cognitive decline and dementia). The basal ganglia motor circuit involves a balance between the direct pathway (facilitating movement, mediated by D1 receptors) and the indirect pathway (inhibiting movement, mediated by D2 receptors). Dopamine depletion tips the...