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: A total of 250 patients with iRBD (mean age: 66.5 ± 6.8 years; 87% male) and 178 controls (65.7 ± 6.8 years; 81% male) were included. Patients with iRBD showed a lower left DTI-ALPS index compared with controls (mean difference = -0.034, 95% CI -0.067 to -0.001; p = 0.043). Of 224 patients with iRBD followed for a mean of 6.1 ± 3.5 years, 65 phenoconverted to a synucleinopathy. Converters had a lower left DTI-ALPS index than nonconverters (mean difference = -0.050, 95% CI -0.098 to -0.003; p = 0.038). Lower left DTI-ALPS index was associated with an increased risk of conversion to PD over time (hazard ratio = 2.43, 95% CI 1.13-5.25; p = 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.

Centre for Advanced Research in Sleep Medicine Hôpital du Sacré Cœur de Montréal CIUSSS du Nord de l'Île de Montréal Quebec Canada

Department of Medicine University of Montreal Quebec Canada

Department of Neurology and Centre of Clinical Neurosciences 1st Faculty of Medicine Charles University and General University Hospital Prague Czechia

Department of Neurology Montreal General Hospital Quebec Canada

Department of Neuroscience University of Montreal Quebec Canada

Department of Psychology Université du Québec à Montréal Quebec Canada

Department of Psychology University of Montreal Quebec Canada

Oxford Parkinson's Disease Centre and Division of Neurology Nuffield Department of Clinical Neurosciences University of Oxford United Kingdom

Research Centre Institut Universitaire de Gériatrie de Montréal Quebec Canada

Sorbonne Université Institut du Cerveau Paris Brain Institute ICM Assistance Publique Hôpitaux de Paris INSERM 1127 CNRS 7225 France; and

The Neuro McGill University Quebec Canada

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doi: 10.1212/WNL.0000000000214130 PubMed

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Neurology. 105:e214130. PubMed

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