Alpha-Synuclein Aggregation Triggers — Sporadic PD Initiation Mechanisms

SUMMARY

# Alpha-Synuclein Aggregation Triggers — Sporadic PD Initiation Mechanisms ## Background and Rationale Sporadic Parkinson's disease represents 90% of all PD cases, yet the initiating triggers remain largely unknown, hampering primary prevention efforts. This ambitious longitudinal study addresses this critical knowledge gap by prospectively following a large at-risk population to identify the environmental and biological factors that precipitate alpha-synuclein pathology in previously healthy in

METHODOLOGY NOTES

**Phase 1: Cohort Establishment and Environmental Exposure Assessment (Months 1-12)** Establish a prospective cohort of 2,000 individuals aged 50-70 without Parkinson's disease, recruited from primary care and community settings. Comprehensive baseline assessment including: detailed environmental exposure questionnaire (pesticides, metals, solvents, head trauma), occupational history, DaTscan imaging, olfactory testing (UPSIT), REM sleep behavior disorder screening (RBD-SQ), and blood collection for alpha-synuclein measurements (RT-QuIC, ELISA for oligomeric species). Genotype participants for known PD risk variants (SNCA, GBA, LRRK2) and apolipoprotein E status. **Phase 2: Longitudinal Biomarker Monitoring (Months 13-72)** Conduct annual follow-up visits with repeat clinical assessments, motor examination (UPDRS-III), cognitive testing (MoCA, specific executive function battery), and biomarker collection. Implement novel alpha-synuclein seed amplification assays (SAA) on CSF sample