## Pathological Hallmark of Parkinson Disease **Key Point:** The cardinal pathological finding in Parkinson disease is selective degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), with intracytoplasmic inclusions called Lewy bodies composed primarily of alpha-synuclein. ### Lewy Bodies - Eosinophilic, round intracytoplasmic inclusions - Composed of misfolded alpha-synuclein protein - Present in surviving nigral neurons - Also found in other brain regions (locus coeruleus, raphe nuclei, cortex) ### Neuronal Loss Pattern | Region | Loss Percentage | Clinical Correlation | |--------|-----------------|----------------------| | Substantia nigra pars compacta | 50–70% | Motor symptoms | | Locus coeruleus | 40–60% | Depression, cognitive changes | | Dorsal raphe | 40% | Sleep disturbance | | Ventral tegmental area | 20–30% | Motivation, reward | **High-Yield:** The 50–70% loss of SNpc dopaminergic neurons is required before motor symptoms (bradykinesia, rigidity, tremor) become clinically apparent. This explains the long preclinical phase. **Clinical Pearl:** Lewy bodies are not unique to Parkinson disease—they also occur in Lewy body dementia and Parkinson disease dementia, but the SNpc-predominant pattern with dopaminergic loss is pathognomonic for idiopathic PD. [cite:Harrison 21e Ch 296] 
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