Li Zhou, Yaping Liu, Bei Huang, Yi-Xiang Wang, Shi Tang, Yuhua Yang, Siyi Gong, Steven W H Chau, J T S Chan, M Y Yu, J W-H Tsang, S Li, Siu Ping Lam, Vincent C T Mok, Karen K Y Ma, Anne Y Y Chan, Jihui Zhang, Yun Kwok Wing
BACKGROUND: Although clinical markers (eg, motor and cognitive impairment) in isolated rapid eye movement sleep behavior disorder (iRBD) are associated with faster phenoconversion, their longitudinal trajectory patterns (linear or nonlinear) remain unclear. Additionally, evidence regarding the magnitude of neurodegenerative risk in iRBD compared to non-RBD individuals remains limited. OBJECTIVES: The aim was to investigate longitudinal changes in clinical markers and assess the magnitude of neurodegenerative risk in iRBD versus non-RBD subjects. METHODS: In this prospective matched cohort study, video-polysomnography-confirmed iRBD patients and age- and sex-matched non-RBD subjects were followed every 1.5-2 years to evaluate neurodegenerative outcomes and markers. Longitudinal marker changes and neurodegenerative risk between groups were compared. RESULTS: One-hundred thirty-three iRBD patients and 101 non-RBD subjects were followed for a mean of 6.9 ± 2.9 years. Parkinsonism-first converters were associated with motor dysfunction, whereas dementia-first converters were associated with cognitive, motor, olfactory, and color vision dysfunctions. Motor and global cognitive functions exhibited nonlinear progression in iRBD, with marked acceleration before parkinsonism or dementia diagnosis. Conversion rates in iRBD patients were 4.7% at 3 years, 30.1% at 7 years, and 79.5% at 13 years, exceeding those in non-RBD subjects (3% at 3 years and 16.1% at 13 years). iRBD patients had a higher neurodegeneration risk (hazard ratio [95% confidence interval [CI]: 9.6 [3.8, 23.8], P < 0.001). CONCLUSIONS: Motor and global cognition demonstrate nonlinear accelerating progressions during iRBD phenoconversion. iRBD carries a nearly 10-fold higher risk of future neurodegeneration than non-RBD subjects. These findings highlighted a critical window for risk stratification and early intervention before neurodegenerative disease onset in iRBD. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.