Association of DTI-ALPS Glymphatic Index With Differential Phenoconversion in Isolated REM Sleep Behavior Disorder
Violette Ayral, Alexandre Pastor‐Bernier, Véronique Daneault, Christina Tremblay, Marie Filiatrault, Celine Haddad, Jean-François Gagnon, Ronald B. Postuma, Petr Dušek, Stanislav Mareček, Zsoka Varga, Johannes Klein, Michele T. Hu, Stéphane Lehéricy, Isabelle Arnulf, Marie Vidailhet, Jean‐Christophe Corvol, for the ICEBERG Study Group, Shady Rahayel, Violette Ayral, Alexandre Pastor‐Bernier, Véronique Daneault, Christina Tremblay, Marie Filiatrault, Celine Haddad, Jean-François Gagnon, Ronald B. Postuma, Petr Dusek, Stanislav Mareček, Zsoka Varga, Johannes Klein, Michele Hu, Stéphane Lehéricy, Isabelle Arnulf, Marie Vidaillhet, Jean‐Christophe Corvol, Shady Rahayel
Abstract
BACKGROUND AND OBJECTIVES: Isolated REM sleep behavior disorder (iRBD) is the strongest prodromal marker of synucleinopathies, including Parkinson disease (PD) and dementia with Lewy bodies (DLB). Identifying brain biomarkers that predict progression and distinguish phenoconversion trajectories remains a challenge. The glymphatic system is involved in interstitial waste clearance, and its dysfunction has been associated with pathologic protein accumulation and neurodegeneration. Diffusion tensor imaging along the perivascular space (DTI-ALPS) has been proposed as a noninvasive proxy for glymphatic function. The aim of this study was to determine whether patients with iRBD show a reduced DTI-ALPS index compared with controls and whether a lower DTI-ALPS index predicts future phenoconversion to PD or DLB. METHODS: We conducted a longitudinal, multicenter cohort study using brain MRI scans from patients with polysomnography-confirmed iRBD and healthy controls recruited across 5 international centers. All participants underwent T1-weighted and diffusion-weighted MRI. DTI-ALPS indices were computed from diffusivity along projection and associative fibers adjacent to the lateral ventricles. The primary outcome was time to phenoconversion to synucleinopathy. Linear models assessed baseline group differences and clinical correlates, and Cox proportional hazard models assessed the predictive value of DTI-ALPS for time to phenoconversion. RESULTS: = 0.012). Other diffusion metrics inside periventricular masks, namely fractional anisotropy, diffusivity metrics, and free water, did not differ between groups. DISCUSSION: Patients with iRBD exhibit a reduced DTI-ALPS index, suggesting altered glymphatic function. This reduction was associated with future phenoconversion to PD, supporting the DTI-ALPS index as a potential prognostic MRI biomarker of progression in prodromal synucleinopathies.