Review of iRBD biomarker-positive participants shows higher rates of cognitive and autonomic symptoms compared to healthy controls.

Isolated rapid eye movement sleep behavior disorder (iRBD) is a prodromal state for Lewy body disorders, with the highest likelihood of long-term conversion to a clinical diagnosis of either Parkinson disease (PD) or dementia with Lewy bodies (DLB). There is heterogeneity in the neuropathophysiology of iRBD that may have prognostic significance regarding the ultimate clinical features, and previous research has not focused on iRBD biologically defined as having neuronal synuclein disease (NSD) present. Parkinsons Progression Markers Initiative (PPMI) is a longitudinal, observational, multi-center natural history study. PPMI participants with recently-diagnosed, polysomnogram-confirmed iRBD and who were cerebrospinal fluid neuronal alpha-synuclein seed amplification assay positive without a clinical diagnosis of PD or DLB, were examined for the clinical characteristics of prodromal PD and DLB, including mild cognitive impairment (MCI), subthreshold parkinsonism, and a range of neuropsychiatric, autonomic and sensory symptoms, and compared with a group of internal, robust healthy controls (HCs). iRBD participants (N=197) performed worse cognitively than the HC group (N=136), including on a cognitive summary score (p<0.0003, effect size = 0.41). In addition, the iRBD group was more likely to have subthreshold parkinsonism (odds ratio = 24.5, p<0.0001), neuropsychiatric symptoms (odds ratio = 3.5, p<0.0001), autonomic symptoms (odds ratio = 7.2, p<0.0001) and sensory symptoms (odds ratio = 13.2, p<0.0001) compared with the HCs. In the iRBD group, the most common symptoms or features were hyposmia (75%), pain (54%), urinary problems (52%), constipation (49%), lightheadedness (40%) and anxiety (36%). In contrast, rates of mild cognitive impairment (MCI; 32%), subthreshold parkinsonism (27%) and psychosis (7%) were lower. iRBD participants with an abnormal dopamine transporter SPECT scan (DaTscan) had higher anxiety scores and more frequent antidepressant use than those with a normal DaTscan. Only 10% of iRBD participants met diagnostic criteria for prodromal DLB criteria due to the requirement for MCI as a defining feature. However, treating MCI as just one of five possible clinical domains, multi-domain impairment in wide-ranging combinations affected the majority of iRBD participants. In summary, persons with iRBD and positive CSF neuronal alpha-synuclein testing, but without a clinically-diagnosed neurodegenerative disorder, have cognitive deficits of moderate effect size, and also have elevated rates of subthreshold parkinsonism and symptoms across neuropsychiatric, autonomic, and sensory domains, compared with healthy controls. These findings highlight the importance of assessing multiple clinical domains and symptoms in early biologically-defined synuclein disease without a formal neurodegenerative disease diagnosis, and not anchoring diagnostic criteria solely to motor symptoms or cognitive impairment.