In patients with isolated REM sleep behavior disorder, higher DTI-ALPS indices—indicative of better glymphatic function—were associated with longer prodromal symptom duration and substantially delayed phenoconversion to alpha-synucleinopathy.

Points to glymphatic function as a noninvasive biomarker to stratify prodromal PD risk and a plausible, potentially modifiable target (e.g., sleep optimization, AQP4/vascular approaches) for interventions to delay conversion, while noting that causality and therapeutic efficacy remain to be proven.

Isolated rapid eye movement sleep behavior disorder (iRBD) is recognized as a prodromal stage of alpha-synucleinopathies. While glymphatic dysfunction has been investigated in Parkinson's disease, its role in iRBD remains incompletely understood. This study evaluated the association between glymphatic function and the speed-modulating effect to alpha-synucleionpathy conversion. Fifty-six patients (67.2 ± 7.1 [mean age ± SD]) with an iRBD and 48 control subjects (61.5 ± 10.0) underwent brain magnetic resonance imaging. Glymphatic function was evaluated using the diffusion tensor imaging along the perivascular space (DTI-ALPS) method with manual acquisition of the ALPS-index. The mean time from symptom onset to MRI acquisition (T1) was 7.05 ± 5.08 years, while among converters the mean time from symptom onset to phenoconversion (T2) was 11.07 ± 5.68 years. Higher ALPS-index was positively correlated with longer iRBD symptom duration (rho = 0.409, p = 0.002). Although the ALPS-index did not predict phenoconversion in the entire cohort, post-hoc analysis of converters revealed that patients with higher ALPS-index exhibited more than nine years longer time to conversion than patients with lower ALPS-index (χ² = 13.075, p < 0.001). These findings suggest that preserved glymphatic function may be associated with prolonged prodromal stability in iRBD.