Baseline α–synuclein seeding activity and disease progression in sporadic and genetic Parkinson's disease in the PPMI cohort

Background α–Synuclein (α–syn) seed amplification assays (SAAs) have shown remarkable potential in diagnosing Parkinson's disease (PD). Using data from the Parkinson's Progression Markers Initiative (PPMI) cohort, we aimed to test whether baseline α–syn seeding activity was associated with disease progression in sporadic PD, LRRK2 –associated PD ( LRRK2 PD), and GBA –associated PD ( GBA PD). Methods We analyzed 7 years of motor, non-motor, and cognitive assessments and 5 years of dopamine transporter imaging along with baseline α–syn SAA results from 564 PPMI participants (n=332 sporadic PD, 162 LRRK2 PD, and 70 GBA PD) using linear mixed-effects models, adjusted for potential confounders, to test whether baseline α–syn SAA positivity (n=315 sporadic PD, 111 LRRK2 PD, and 66 GBA PD) was associated with PD progression. Results While non–statistically significant, there was a trend towards faster motor decline in participants with α–syn SAA positive LRRK2 PD compared to those with α–syn SAA negative LRRK2 PD (MDS-UPDRS III points per year: 2.39 (95% confidence interval: 1.86 — 2.92) vs. 1.76 (0.93 — 2.60); difference=0.63 (–0.29 — 1.55, p=0.18). There was no difference in motor decline between α–syn SAA positive and α–syn SAA negative participants with sporadic PD (2.46 (2.20 — 2.72) vs. 2.39 (1.36 — 3.42); difference=0.07 (–0.99 — 1.12), p=0.90) or GBA PD (2.67 (1.91 — 3.44) vs. 2.40 (–0.18 — 4.99); difference=0.27 (–2.42 — 2.96), p=0.84). No statistically significant differences were seen in the progression of non-motor symptoms, cognition, or DAT imaging. Conclusions We found no statistically significant associations between baseline α–syn seeding activity and PD progression among manifest patients in the PPMI cohort. Future studies are needed to further investigate relationships among baseline α–syn seeding activity, disease heterogeneity, disease stage, and PD progression.