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

作者：Jackson G. Schumacher, Xinyuan Zhang, Eric A. Macklin, Jian Wang, Armin Bayati, Johannes M. Dijkstra, Hirohisa Watanabe, Michael A. Schwarzschild, Marianna Cortese, Xuehong Zhang, Xiqun Chen · 发表于：EBioMedicine · 年份：2025 · DOI：10.1016/j.ebiom.2025.105866 · 被引用次数：8 · 研究领域：Parkinson's Disease Mechanisms and Treatments、Neurological disorders and treatments、Voice and Speech Disorders

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....