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.

• MeSH
• Lewy Body Disease diagnostic imaging   MeSH
• Glymphatic System * diagnostic imaging   MeSH
• Cohort Studies MeSH
• Middle Aged MeSH
• Humans MeSH
• Longitudinal Studies MeSH
• Magnetic Resonance Imaging MeSH
• Brain * diagnostic imaging   MeSH
• Parkinson Disease diagnostic imaging   MeSH
• Polysomnography MeSH
• REM Sleep Behavior Disorder * diagnostic imaging   MeSH
• Prodromal Symptoms MeSH
• Disease Progression MeSH
• Aged MeSH
• Synucleinopathies diagnostic imaging   MeSH
• Diffusion Tensor Imaging * methods   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH

INTRODUCTION: Most individuals with isolated rapid eye movement sleep behavior disorder (iRBD) develop dementia with Lewy bodies (DLB) or Parkinson's disease (PD). Brain biomarkers predicting specific phenoconversion trajectories are lacking. METHODS: In this multicenter diffusion magnetic resonance imaging study (261 iRBD, 177 controls), free water (FW) was measured in the nucleus basalis of Meynert (NBM) and posterior substantia nigra (SN). Among 230 iRBD patients with follow-up, 64 converted (16 DLB, 38 PD). Time-to-event analyses were performed to assess differential phenoconversion. RESULTS: Phenoconverters had higher FW in the NBM and posterior SN. Only FW in the NBM predicted conversion to DLB over PD. NBM volume predicted DLB conversion, but only FW remained significant when both were modeled. FW in the NBM correlated with lower MoCA scores in iRBD. DISCUSSION: FW in the NBM is a sensitive biomarker of cognitive decline and DLB progression in iRBD, outperforming volume and supporting its use in early stratification. HIGHLIGHTS: FW in the NBM specifically identifies conversion to DLB. Increased FW in the NBM is associated with lower global cognition in iRBD. FW in the SN in iRBD does not relate more to DLB than PD. FW in the NBM is a biomarker of differential phenoconversion in iRBD.

• Keywords
• Parkinson's disease, REM sleep behavior disorder, biomarker, dementia with Lewy bodies, diffusion magnetic resonance imaging, free water, prognosis,
• MeSH
• Biomarkers MeSH
• Lewy Body Disease * diagnostic imaging   diagnosis   MeSH
• Diffusion Magnetic Resonance Imaging MeSH
• Middle Aged MeSH
• Humans MeSH
• Parkinson Disease diagnostic imaging   MeSH
• REM Sleep Behavior Disorder * complications   diagnostic imaging   MeSH
• Disease Progression MeSH
• Aged MeSH
• Water * MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Names of Substances
• Biomarkers MeSH
• Water * MeSH

INTRODUCTION: Isolated rapid eye movement (REM) sleep behavior disorder (iRBD), characterized by abnormal movements during REM sleep, is a prodromal stage of dementia with Lewy bodies (DLB) and Parkinson's disease (PD). While iRBD shows emerging brain changes, their impact on structural connectivity and network efficiency, and their predictive value, remain poorly characterized. METHODS: In this international prospective study, 198 polysomnography-confirmed iRBD patients and 174 controls underwent diffusion magnetic resonance imaging and were analyzed. Cutting-edge diffusion tractography and network-based statistics were applied to reconstruct individual connectomes and assess network properties predicting DLB or PD. RESULTS: Structural architecture was already disrupted in iRBD, with both reduced and compensatory increased connections. Global efficiency was decreased. Local efficiency in motor regions was altered and associated with early clinical symptoms. Altered local efficiency in the supramarginal gyrus predicted DLB only. DISCUSSION: Early disruption of brain architecture in iRBD predicts progression to synucleinopathy-related dementia, offering a novel potential prognostic biomarker. HIGHLIGHTS: Isolated rapid eye movement sleep behavior disorder (iRBD) patients show significant alterations in inter-regional structural connectivity. Global efficiency is reduced in iRBD compared to controls. Areas with increased local efficiency contribute to decreased global efficiency. Altered network efficiency is associated with emerging Parkinsonian features. Higher supramarginal efficiency predicts dementia with Lewy bodies in iRBD.

• Keywords
• dementia with Lewy bodies, diffusion magnetic resonance imaging, graph theory, parasomnias, sleep, structural connectivity, synucleinopathies,
• MeSH
• Lewy Body Disease * diagnostic imaging   physiopathology   MeSH
• Diffusion Magnetic Resonance Imaging MeSH
• Connectome MeSH
• Middle Aged MeSH
• Humans MeSH
• Brain * diagnostic imaging   pathology   MeSH
• Nerve Net * diagnostic imaging   MeSH
• Parkinson Disease diagnostic imaging   physiopathology   MeSH
• Polysomnography MeSH
• REM Sleep Behavior Disorder * diagnostic imaging   physiopathology   pathology   MeSH
• Prospective Studies MeSH
• Aged MeSH
• Diffusion Tensor Imaging MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH