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 and α-syn SAA kinetic parameters are associated with disease progression in sporadic PD, *LRRK2*-associated PD (*LRRK2* PD), and *GBA*-associated PD (*GBA* PD). ### Methods We analysed 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) and α-syn SAA kinetic parameters are associated with PD progression. ### Findings 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 to 1.55, p = 0.18). This trend appeared to be driven by R1441C/G + M1646T carriers (3.89 (1.22–6.55) vs. 0.31 (−1.32 to 1.93); difference = 3.58 (0.56–6.60, p = 0.02) and excluding them eliminated any trend (2.33 (1.79–2.86) vs. 2.26 (1.34–3.18); difference = 0.07 (−0.93 to 1.07, p = 0.89). Based on a clinically meaningful difference of 4.63 points we found no statistically significant or clinically meaningful 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 to 1.12), p = 0.90) or *GBA* PD (2.67 (1.91–3.44) vs. 2.40 (−0.18 to 4.99); difference = 0.27 (−2.42 to 2.96), p = 0.84). No statistically significant or clinically meaningful differences were seen in the progression of non-motor symptoms, cognition, or DAT imaging. Additionally, we found no clinically meaningful association between α-syn SAA kinetic parameters and PD progression. ### Interpretation We found no statistically significant associations between baseline α-syn seeding activity, α-syn SAA kinetic parameters, and PD progression among manifest patients in the PPMI cohort. Future studies are needed to further investigate relationships among α-syn seeding activity, disease heterogeneity, disease stage, and PD progression. ### Funding This research was funded by Aligning Science Across Parkinson's grant ASAP-237603 through the Michael J. Fox Foundation for Parkinson's Research and by the National Institutes of Health through the National Institute of Neurological Disorders and Stroke grants R01NS102735 and 5R01NS126260.