Association of α-synuclein seed-amplification kinetics with cognitive decline in idiopathic Parkinson's disease.

INTRODUCTION

Neurodegeneration and α-synuclein aggregates are pathological hallmarks of Parkinson's disease (PD). The α-synuclein seed-amplification assay (SAA) is a robust diagnostic tool for synucleinopathies. However, its binary readout limits its utility, and associations between semi-quantitative parameters and clinical outcomes remain inconsistent. This cohort study investigated whether baseline CSF α-synuclein SAA kinetic parameters are associated with longitudinal clinical trajectories in PD.

METHODS

A total of 898 participants with idiopathic PD and positive α-synuclein SAA (24-h protocol) from the Parkinson's Progression Markers Initiative (PPMI) cohort were included.

RESULTS

Linear mixed-effects models showed that higher maximum fluorescence, area under the fluorescence curve, and maximum slope at baseline visit were significantly associated with slower cognitive decline, both globally and across specific cognitive domains. In exploratory analyses, a similar, though less consistent, pattern was observed for motor progression. Results were consistent in sensitivity analyses restricted to participants with at least five years of follow-up (n = 309).

CONCLUSION

The main findings of this study suggest that higher baseline amplitude-related parameters on CSF α-synuclein SAA are associated with less pronounced long-term cognitive decline in a subset of PD patients. These results should be interpreted with caution, and further studies are needed to determine whether these observations reflect methodological limitations of the assay or biologically meaningful differences in α-synuclein aggregation.