Brain Communications · Nov 2, 2026
White matter microstructure and hyperintensity burden in isolated REM sleep behavior disorder
By Mak E, Przybelski SA, Reid RI et al.
Isolated rapid eye movement sleep behavior disorder represents a prodromal phase of α-synucleinopathy. Diffusion MRI provides in vivo markers of white matter microstructural properties, while white matter hyperintensities reflect cerebrovascular injury. However, their relative contributions to cognitive and clinical dysfunctions in patients with isolated rapid eye movement sleep behavior disorder remain unclear. We analysed 168 polysomnography-confirmed isolated rapid eye movement sleep behavior disorder participants from the North American Prodromal Synucleinopathy Consortium. Multi-shell diffusion MRI was used to derive metrics from diffusion tensor imaging (fractional anisotropy and mean diffusivity) and Neurite Orientation Dispersion and Density Imaging (tissue-weighted neurite density index and orientation dispersion index) across 39 white matter regions using a modified Johns Hopkins University white matter atlas. White matter hyperintensity burden was quantified from fluid-attenuated inversion recovery MRI. Using linear regression adjusted for age and sex, we compared white matter microstructure and hyperintensity burden between clinically impaired and unimpaired participants and examined associations with multiple cognitive and clinical domains, including global cognition, working memory, motor severity, manual dexterity, autonomic dysfunction, olfactory function, prodromal disease severity, and daytime sleepiness. False discovery rate correction was applied to account for multiple comparisons. In our sample (n=168), participants with clinical impairment (n=57) demonstrated higher white matter hyperintensity burden than unimpaired participants (n=111) and showed limited microstructural differences, including lower fractional anisotropy in the superior fronto-occipital fasciculus and inferior occipital white matter and higher orientation dispersion index in inferior occipital white matter. After adjusting for white matter hyperintensity burden, only increased occipital orientation dispersion index remained statistically significant. Diffusion metrics showed widespread associations with digit span forward performance and autonomic dysfunction. In contrast, increased white matter hyperintensity burden demonstrated broader associations with poorer Montreal Cognitive Assessment scores, poorer digit span forward performance, lower Purdue Pegboard performance, and higher Prodromal Synucleinopathy Rating Scale scores, indicating greater prodromal disease severity. Our findings highlight cerebrovascular white matter burden as an important correlate of clinical dysfunction in isolated rapid eye movement sleep behavior disorder and underscore the need to consider cerebrovascular lesions when interpreting diffusion imaging markers in prodromal synucleinopathy.