Elevated plasma neurofilament light chain in isolated REM sleep behavior disorder: Associations with neurogenic orthostatic hypotension and implications for phenoconversion

Background Isolated REM sleep behavior disorder (iRBD) is a prodromal stage of alpha-synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Evaluating trajectories of phenoconversion is crucial in this population. Plasma neurofilament light chain (NfL), a marker of axonal injury, has emerged as a promising candidate for tracking disease progression.Objectives To assess plasma NfL levels in iRBD patients, examine their associations with clinical features, particularly neurogenic orthostatic hypotension (nOH), and explore their potential role in predicting phenoconversion.Methods Plasma NfL was measured in 54 iRBD subjects, 54 PD, 54 healthy controls and 16 MSA. Participants underwent motor, cognitive, and non-motor symptoms assessments. Longitudinal follow-up data have been collected for iRBD subjects. NfL was quantified using the Ella platform; analyses were performed with Prism 9.Results NfL levels were significantly higher in iRBD compared to controls and similar to PD. iRBD-nOH+ patients had significantly higher NfL than nOH- counterparts, with values overlapping PD and MSA. nOH was inversely associated with hyposmia, supporting phenotypic divergence. NfL correlated positively with SCOPA-AUT and BDI scores. At follow-up, all four MSA converters had nOH at baseline.Conclusions Plasma NfL elevation in iRBD supports its role as a marker of early neurodegeneration. Its association with nOH suggests that this autonomic feature may identify a biologically more severe iRBD phenotype, possibly on a trajectory toward MSA. These findings warrant extended longitudinal validation and support the integration of clinical and biological markers, including NfL, for stratifying conversion risk.