## Pathological Hallmark of Parkinson's Disease **Key Point:** Lewy bodies, composed primarily of alpha-synuclein, are the pathognomonic intracellular inclusions of Parkinson's disease (PD). ### Lewy Body Characteristics - **Composition:** Alpha-synuclein (misfolded protein) with ubiquitin and other proteins - **Morphology:** Eosinophilic, round intracytoplasmic inclusions with a hyaline core and pale halo - **Location in PD:** Substantia nigra pars compacta (most prominent), locus coeruleus, dorsal raphe nucleus, and other brainstem nuclei - **Significance:** Loss of dopaminergic neurons in substantia nigra correlates with motor symptoms ### Protein Pathology Comparison | Disease | Pathological Protein | Location | |---------|----------------------|----------| | Parkinson's disease | Alpha-synuclein (Lewy bodies) | Substantia nigra, locus coeruleus | | Alzheimer's disease | Tau (tangles) + Amyloid-beta (plaques) | Hippocampus, cortex | | Frontotemporal dementia | TDP-43 or tau | Frontal/temporal lobes | | ALS | TDP-43 inclusions | Motor cortex, spinal cord | **High-Yield:** Lewy body pathology is NOT exclusive to PD—it can also be found in Lewy body dementia and Parkinson's disease dementia, but the substantia nigra involvement is most characteristic of idiopathic PD. **Clinical Pearl:** The Braak staging system for PD describes the rostrocaudal progression of Lewy pathology from the dorsal motor nucleus of the vagus (Stage 1) to the neocortex (Stage 6), which may correlate with disease progression and non-motor symptoms. [cite:Robbins 10e Ch 28] 
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