In a biomarker-defined cohort of PSG-confirmed iRBD participants positive for CSF α-synuclein seed amplification, investigators observed multi-domain prodromal Lewy body disease features (cognitive deficits, subthreshold parkinsonism, neuropsychiatric, autonomic, and sensory symptoms) at…

Defining prodromal synucleinopathy with CSF α-synuclein SAA provides a clinically and biologically specific cohort for early intervention trials, improving patient selection, stratification, and potential outcome measures for Parkinson's and DLB therapeutic development.

OBJECTIVE: Isolated rapid eye movement sleep behavior disorder (iRBD) is a prodromal state for Lewy body disorders and exhibits biological heterogeneity that may influence clinical expression and progression. We examined clinical features in individuals with iRBD and biomarker-defined synucleinopathy. METHODS: Parkinson's Progression Markers Initiative (PPMI) is a longitudinal, multi-center observational study. Participants included polysomnogram (PSG)-confirmed iRBD individuals who were cerebrospinal fluid (CSF) α-synuclein seed amplification assay positive with no clinical diagnosis of Parkinson's disease or dementia with Lewy bodies, along with robust healthy controls (HCs). Clinical and biological features of prodromal PD and DLB, including mild cognitive impairment (MCI), subthreshold parkinsonism, and a range of neuropsychiatric, autonomic, and sensory symptoms, were assessed. RESULTS: Compared with HCs (N = 136), iRBD participants (N = 197) demonstrated worse cognitive performance, including a lower cognitive summary score (p < 0.0003, effect size = 0.41), and higher odds of subthreshold parkinsonism (OR = 24.5), and neuropsychiatric (OR = 3.5), autonomic (OR = 7.2) and sensory symptoms (OR = 13.2). Common features included hyposmia (75%), pain (54%), urinary problems (52%), constipation (49%), lightheadedness (40%) and anxiety (36%), whereas rates of MCI (32%), subthreshold parkinsonism (27%) and psychosis (7%) were lower. iRBD participants with abnormal dopamine transporter imaging had higher anxiety scores and antidepressant use. Although only 10% met criteria for prodromal DLB due to the requirement for MCI, most exhibited multi-domain impairment. INTERPRETATION: iRBD with synucleinopathy is associated with multi-domain clinical impairment before clinical neurodegenerative disease diagnosis, supporting broad clinical assessment in early biomarker-defined synuclein disease.