Evaluating the Role of α‐Synuclein Seed Amplification as a Disease Progression Marker: Evidence and Uncertainties

Background α‐synuclein seeding amplification assay (α‐synuclein SAA) development as a diagnostic biomarker for Parkinson's disease (PD) has shown promising results over the past decade. However, the utility of these assays in the prediction of disease progression is unclear. Objectives To assess the relationship between α‐synuclein SAA and PD‐specific clinical outcome measures. Methods We extracted longitudinal data on individuals with sporadic PD from the Parkinson's Progression Markers Initiative at baseline and 5 years follow‐up. Primary outcome measures included MDS‐UPDRS Part III, Montreal Cognitive Assessment (MoCA) and L‐dopa equivalent daily dose (LEDD). Secondary outcome measures included REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ) question‐6 and other non‐motor assessments. α‐synuclein SAA kinetic parameters were added to linear regression models to assess their impact on model fit. Results We included 279 participants in the final analysis. There was no consistent evidence that α‐synuclein SAA parameters at baseline improved our prediction models for MDS‐UPDRS Part III, MoCA or LEDD at 5 years. α‐synuclein SAA kinetic parameters improved model fit for RBDSQ question‐6 and indicated that fast seeding profiles were associated with higher scores. Conclusions We did not find evidence of a relationship between α‐synuclein SAA and disease progression however α‐synuclein SAA was associated with RBDSQ. Further work is needed to understand the factors influencing α‐synuclein aggregation kinetics and the role of α‐synuclein SAA in disease prognosis.