α-Synuclein seeding activity and progression in sporadic and genetic forms of Parkinson's disease in the Parkinson's Progression Markers Initiative cohort

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). 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. 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. 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.