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

Le résumé fourni par la source

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.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.