α-Synuclein seeding activity and progression in sporadic and genetic forms of Parkinson’s disease in the Parkinson’s Progression Markers Initiative cohort
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Background
α-Synuclein (α-syn) seed amplification assays (SAAs) have shown remarkable potential as a diagnostic tool for Parkinson’s disease (PD). Using data from the Parkinson’s Progression Markers Initiative (PPMI) cohort, we aimed to assess whether baseline α-syn seeding and seed concentration are associated with progression in sporadic PD, LRRK2 -associated PD ( LRRK2 PD), and GBA -associated PD ( GBA PD).
Methods
Using a linear mixed-effects model adjusted for potential confounding factors, we analyzed 14 years of motor and cognitive assessments and five years of dopamine transporter imaging data from 878 PPMI participants to establish comprehensive progression profiles for sporadic PD (n=473), LRRK2 PD (n=275), and GBA PD (n=130). By introducing α-syn SAA results from 586 participants (n=351 sporadic PD, 163 LRRK2 PD, and 72 GBA PD), we determined whether baseline α-syn seeding positivity (95% sporadic PD, 69% LRRK2 PD, and 94% GBA PD) and the time to 50% of the maximum fluorescence (T50), an indicator of seed concentration, are associated with progression in PD.
Findings
Participants with sporadic PD (yearly change in MDS-UPDRS III: 1.50 points; 95% confidence interval 1.41–1.58) and GBA PD (1.52; 1.31–1.72)(p=0.873) progressed similarly while those with LRRK2 PD progressed slower (1.05; 0.89–1.20)(p<0.001). There was no significant difference between α-syn SAA+ sporadic PD (1.48; 1.03–1.92) and LRRK2 PD (1.09; 0.76–1.44) participants and their negative counterparts (1.25; 0.81–1.70)(p=0.347)(0.80; 0.50–1.10)(P=0.087). Similarly, α-syn seeding activity was not significantly associated with progression in GBA PD. Furthermore, there was no statistically significant difference in progression between sporadic PD participants with high (1.46; 1.33–1.59), medium (1.45; 1.30–1.61)(p=0.948), and low seed concentration (1.42; 1.11–1.73)(p=0.804). Similarly, seed concentration was not significantly associated with progression in LRRK2 or GBA PD.
Interpretation
Baseline α-syn seeding activity and seed concentration were not statistically significantly associated with PD progression in the PPMI cohort. More longitudinal investigations into the relationship between α-syn seeding activity, seed concentration, and progression are needed before concretely establishing α-syn aggregation as the primary driver of PD.
Funding
This study was funded in part by Aligning Science Across Parkinson’s No. ASAP-237603 through the Michael J. Fox Foundation for Parkinson’s Research and the National Institute of Health through the National Institute of Neurological Disorders and Stroke grant R01NS102735.
