Association of DTI-ALPS Glymphatic Index With Differential Phenoconversion in Isolated REM Sleep Behavior Disorder: A Multi-Cohort MRI Study

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: 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.

Figure 1. Processing Steps Involved in Deriving the Glymphatic Index

(A) Diffusion-weighted and T1-weighted MRI scans were processed using the TractoFlow-ABS pipeline. (B) Using the fractional anisotropy map template from the ICBM DTI-81 atlas, 4 masks were positioned on the associative and projection fibers at the level of the lateral ventricle body of each hemisphere and were warped to every participant's native space. Diffusivity measurements were extracted and harmonized for scanner effects using ComBat. The DTI-ALPS index was calculated for each participant as a proxy of glymphatic function. The flowchart is shared courtesy of the TractoFlow development team. ABS = atlas-based segmentation; ALPS = along the perivascular space; BIDS = Brain Imaging Data Structure; DTI = diffusion tensor imaging; DWI = diffusion-weighted imaging; fODF = fiber orientation distribution function; FRF = fiber response function; iRBD = isolated REM sleep behavior disorder; T1w = T1-weighted MRI scan.

Figure 2. Comparison of the DTI-ALPS Index Between Patients With iRBD and Controls

(A) Violin plots showing the distribution of DTI-ALPS indices (left and right) in healthy controls (blue) and patients with iRBD (orange). The left DTI-ALPS index is significantly lower in patients with iRBD compared with controls. (B) Violin plots showing the distribution of DTI-ALPS indices (left and right) in nonconverted iRBD (blue) and phenoconverted iRBD (orange) groups. The left DTI-ALPS index is significantly lower in the phenoconverted iRBD group compared with the nonconverted iRBD group. The plot includes boxplots within each violin, displaying the median (middle line) and interquartile range of DTI-ALPS indices. ALPS = along the perivascular space; DTI = diffusion tensor imaging; iRBD = isolated REM sleep behavior disorder.

Figure 3. Kaplan-Meier Survival Curves of Conversion Based on the DTI-ALPS Index

(A) Kaplan-Meier survival curves illustrating the relationship between low and high DTI-ALPS indices (based on the median) and conversion risk in iRBD. A lower left DTI-ALPS z-score is associated with a higher risk of conversion. (B) Kaplan-Meier survival curves illustrating the relationship between low and high DTI-ALPS indices (based on the median) and conversion risk to PD in the iRBD group. A lower left DTI-ALPS z-score is associated with a higher risk of conversion to PD. Shaded areas represent the 95% CIs. ALPS = along the perivascular space; DTI = diffusion tensor imaging; iRBD = isolated REM sleep behavior disorder; PD = Parkinson disease.