Parkinson's disease (PD) diagnosis relies primarily on clinical evaluation due to lack of validated tests and biomarkers. DaTscan imaging has been used to distinguish psychogenic and drug-induced parkinsonism from idiopathic PD. Some clinically diagnosed PD patients show scans without evidence of dopaminergic deficit (SWEDD), including some that respond to dopaminergic treatment. Some SWEDD patients present abnormal scans consistent with PD many years later and it is unknown if these patients developed PD in between scans or presented PD with low dopaminergic degeneration.

α-Synuclein seed amplification assays (αS-SAAs) detect α-synuclein (αSyn) aggregates in the cerebrospinal fluid (CSF) of PD, dementia with Lewy bodies (DLB), and isolated rapid eye movement (REM) sleep behavior disorder (iRBD) patients with high sensitivity and specificity. We used an optimized high-throughput αS-SAA (based on a previously described α-Syn protein misfolding cyclic amplification (PMCA) assay) that detects αSyn aggregates in CSF, to evaluate 140 blinded samples from the Parkinson's Progression Markers Initiative (PPMI). Samples included baseline (BL) and 3-year follow-up (V08) from 30 PD and 30 healthy controls (HC), and BL samples from 20 SWEDD patients. PD-BL samples were collected within 2 years from diagnosis and presented abnormal DaTscans, while SWEDD patients presented normal DaTscans. PPMI classified enrollees as PD or SWEDD based on visual inspection of their baseline DaTscans.