Accurate Detection of α-Synuclein Seeds in Cerebrospinal Fluid from Isolated Rapid Eye Movement Sleep Behavior Disorder and Patients with Parkinson's Disease in the DeNovo Parkinson (DeNoPa) Cohort

Background: Misfolded alpha-synuclein (alpha Syn) aggregates (alpha Syn-seeds) in cerebrospinal fluid (CSF) are biomarkers for synucleinopathies such as Parkinson's disease (PD). alpha Syn-seeds have been detected in prodromal cases with isolated rapid eye movement sleep behavior disorder (iRBD).Objectives: The objective of this study was to determine the accuracy of the alpha Syn-seed amplification assay (alpha S-SAA) in a comprehensively characterized cohort with a high proportion of PD and iRBD CSF samples collected at baseline.Methods: We used a high-throughput alpha S-SAA to analyze 233 blinded CSF samples from 206 participants of the DeNovo Parkinson Cohort (DeNoPa) (113 de novo PD, 64 healthy controls, 29 iRBD confirmed by video polysomnography). Results were compared with the final diagnosis, which was determined after up to 10 years of longitudinal clinical evaluations, including dopamine-transporter-single-photon emission computed tomography (DAT-SPECT) at baseline, CSF proteins, Movement Disorder Society-Unified Parkinson's Disease Rating Scale, and various cognitive and nonmotor scales.Results: alpha S-SAA detected alpha Syn-seeds in baseline PD-CSF with 98% accuracy. alpha Syn-seeds were detected in 93% of the iRBD cases. alpha S-SAA results showed higher agreement with the final than the initial diagnosis, as 14 patients were rediagnosed as non-alpha Syn aggregation disorder. For synucleinopathies, alpha S-SAA showed higher concordance with the final diagnosis than DAT-SPECT. Statistically significant correlations were found between assay parameters and disease progression.Conclusions: Our results confirm alpha S-SAA accuracy at the first clinical evaluation when a definite diagnosis is most consequential. alpha S-SAA conditions reported here are highly sensitive, enabling the detection of alpha Syn-seeds in CSF from iRBD just months after the first symptoms, suggesting that alpha Syn-seeds are present in the very early prodromal phase of synucleinopathies. Therefore, alpha Syn-seeds are clear risk markers for synuclein-related disorders, but not for time of phenoconversion.(c) 2023 International Parkinson and Movement Disorder Society.