Disease-specific patterns of glymphatic-related dysfunction between multiple sclerosis and neuromyelitis optica spectrum disorder

Abstract

Background Glymphatic dysfunction has been reported in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), yet disease-specific patterns of glymphatic-related impairment and their structural and cognitive consequences remain poorly characterized. Methods This study enrolled 196 MS patients, 88 NMOSD patients, and 108 healthy controls (HC). Glymphatic-related function was assessed using diffusion tensor image analysis along the perivascular space (DTI-ALPS) and periventricular diffusivity (PVeD). Between-group differences, partial correlations with structural and clinical outcomes, AQP4 subgroup comparisons, mediation analyses, and subcortical atrophy-based subgroup analyses were performed to characterize disease-specific glymphatic-related impairment patterns. Results MS showed more extensive glymphatic-related impairment than NMOSD, with significant reductions in both DTI-ALPS and PVeD compared to HC (all p<0.001). PVeD was significantly reduced in NMOSD compared to HC in both cohorts (p ≤ 0.008), whereas DTI-ALPS differences in NMOSD relative to HC were inconsistent across cohorts, reaching significance only in the GE replication cohort. In MS, PVeD showed widespread structural and cognitive associations; in NMOSD, associations were restricted to ventricular and choroid plexus volumes. A parallel multiple mediation model showed that subcortical gray matter atrophy, but not lesion volume, independently mediated the association between PVeD and Symbol Digit Modalities Test performance in MS, a pattern absent in NMOSD. Stratified subgroup analysis showed a pattern consistent with a glymphatic-cognitive association specific to patients with greater subcortical atrophy in MS, although formal interaction tests did not reach statistical significance; no such association was observed in either atrophy subgroup in NMOSD. AQP4-seropositive, but not seronegative, NMOSD patients showed significantly lower glymphatic-related metrics than HC (p<0.001); direct comparison between the two subgroups was not significant. Conclusion Glymphatic-related dysfunction exhibits distinct disease-specific patterns in MS and NMOSD, with PVeD showing broader sensitivity across both cohorts. These findings support PVeD as a promising complementary glymphatic-related diffusion marker in inflammatory demyelinating disease, though causal and disease-mechanistic interpretations await validation in longitudinal and mechanistic studies.