Parkinson Disease

Parkinson disease involves progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), with hallmark alpha-synuclein aggregation forming Lewy bodies and Lewy neurites. Dopamine loss disrupts the basal ganglia circuit: normally, dopamine from the SNpc facilitates the direct pathway (D1 receptors → movement initiation) and inhibits the indirect pathway (D2 receptors → movement suppression). In PD, dopamine deficiency causes relative overactivity of the indirect pathway, leading to excessive thalamic inhibition and hypokinesia. Motor symptoms appear after ~60-80% of dopaminergic neurons are lost. The pathology spreads in a caudal-to-rostral pattern (Braak staging): stage 1-2 involves olfactory bulb and brainstem (explaining prodromal anosmia, REM sleep behavior disorder, constipation), stage 3-4 involves the substantia nigra (motor symptoms), and stage 5-6 involves the cortex (cognitive decline, dementia). Non-motor symptoms (depression, autonomic dysfunction, pain) result from alpha-synuclein pathology in non-dopaminergic systems (serotonergic, noradrenergic, cholinergic).