Evolution of Motor and Nonmotor Characteristics in an Idiopathic/Isolated REM Sleep Behavior Disorder Cohort

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Abstract
Years before diagnosis of Parkinson disease (PD), dementia with Lewy bodies (DLB), or multiple system atrophy (MSA), mild prodromal manifestations can be detected. Longitudinal follow-up of people with prodromal synucleinopathy, particularly idiopathic/isolated REM sleep behavior disorder (iRBD), enables in-depth clinical phenotyping of early disease, which could facilitate stratification for clinical trials, provide the definition of appropriate end points, or predict phenoconversion more precisely. The aim of this study was to update and expand on previous studies assessing clinical evolution from iRBD to clinically diagnosed disease, up to 14 years before diagnosis. People with polysomnography-proven iRBD were included in this prospective cohort study (2004-2023) at Center for Advanced Research in Sleep Medicine (Montreal). Participants were followed annually with comprehensive motor and nonmotor assessments until they fulfilled clinical diagnostic criteria for PD, DLB, or MSA ("phenoconversion"). Tracing backward from phenoconversion, clinical trajectories in iRBD were compared with age-expected trajectories, as well as between PD and DLB phenoconverters, using mixed-effects models. A total of 95 people with iRBD were included in the analysis (69.0 ± 8.5 years, 26% female, RBD duration 7.1 ± 7.4 years, follow-up 1-15 years) and were eventually diagnosed with either PD (n = 46), DLB (n = 43), or MSA (n = 6). Among phenoconverters, Movement Disorders Society-Unified Parkinson's Disease Rating Scale Part III and quantitative motor testing showed slowly progressing changes from Y-10, followed by exponential increase approximately 4 years before phenoconversion (F(4,298) = 79.1, p < 0.001). From 4 to 5 years before phenoconversion, accelerated worsening was found in global cognition (F(3,278) = 33.7, p < 0.001) and color vision (F(3,646) = 15.9, p < 0.001). Hyposmia was evident from Y-14 and progressed linearly (F(1,37) = 15.0, p < 0.001). Autonomic manifestations were evident from Y-12. DLB phenoconverters showed faster decline in global cognition (F(3,95) = 21.0, p < 0.001) and color vision (F(3,235) = 3.5, p = 0.02) than PD phenoconverters. Participants with iRBD showed evolving motor and nonmotor impairment many years before diagnosis of manifest synucleinopathy compared with estimated age-expected references. Our results suggest that some clinical features emerge early and progress linearly while others develop gradually and progress more rapidly shortly before phenoconversion. Prodromal PD, MSA, and DLB phenoconverters showed overlapping but distinct clinical trajectories, mainly for motor testing, cognitive function, and color vision. Additional large multicenter studies including longitudinal follow-up of controls are needed.

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