Glymphatic defect in isolated REM sleep behavior disorder is associated with phenoconversion to Parkinson’s disease

Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is characterized by the loss of muscle atonia and abnormal, often violent, movements and vocalizations during REM sleep. It is the strongest prodromal marker for progression to synucleinopathies such as dementia with Lewy bodies (DLB) and Parkinson’s disease (PD). iRBD individuals already show brain changes consistent with manifest synucleinopathies, but their mechanisms remain poorly understood. The glymphatic system is involved in the brain clearance of waste products and its defect has been associated with a higher likelihood of pathological burden and neurodegeneration. The presence of glymphatic system dysfunction revealed by neuroimaging in iRBD and its association with disease progression remain uninvestigated, including its potential to predict conversion toward distinct trajectories of synucleinopathies.

We analyzed diffusion-weighted imaging data from a large international multicentric cohort of polysomnography-confirmed iRBD individuals and healthy controls. We used diffusion tensor imaging along the perivascular space to assess glymphatic function and derived a glymphatic index based on the diffusivity occurring within masks placed on associative and projection fibers adjacent to the lateral ventricles. The index was compared between groups and correlated with motor and cognitive features. Cox regression models assessed the relationship between glymphatic index and the likelihood of conversion to PD, DLB or remaining disease-free.

Our analyses included 250 polysomnography-confirmed iRBD participants (mean age 66.5 ± 6.8 years; 87% men) and 178 controls (65.7 ± 6.8 years; 81% men). There was a significantly reduced glymphatic index in iRBD individuals compared to controls. Among the 224 iRBD individuals followed longitudinally (6.1 years, 1-16 years), 65 developed a neurodegenerative disease. iRBD converters exhibited lower glymphatic index compared to non-converters. Lower glymphatic index was associated with a higher risk of phenoconversion towards PD over time compared to remaining disease-free (hazard ratio = 2.43, 95% CI = 1.13-5.25, P = 0.012).

This study reports glymphatic dysfunction in iRBD and its potential for predicting conversion to PD, underscoring its utility in identifying at-risk iRBD individuals.