Reduced perivascular diffusion in multiple sclerosis is associated with aging, disease duration, and mobility...

The glymphatic system supports brain homeostasis by facilitating perivascular fluid transport and metabolic waste clearance. Diffusion-tensor imaging along the perivascular space (ALPS-index) provides a non-invasive surrogate marker of glymphatic activity. The objectives of this study were to: (1) compare the ALPS-index between individuals with relapsing-remitting MS (RRMS) and non-MS controls, (2) examine the role of age in the association between ALPS-index and disease duration, and (3) examine the relationship between ALPS-index and walking speed in RRMS.

Individuals with RRMS and age‑ and sex-matched controls underwent 3T MRI, including diffusion‑weighted imaging. ALPS‑index was calculated using standardized regions of interest. Walking function was assessed using a two‑minute walk test.

Individuals with RRMS have significantly lower ALPS‑index compared to controls (p = 0.001). Across participants, older age was associated with lower ALPS‑index (p < 0.001), with no evidence that age effects differed by group (group effect: p = 0.311, group x age: p = 0.954). In RRMS, a lower ALPS‑index was associated with longer disease duration (p = 0.028); however, mediation analyses showed that chronological age largely explained this relationship (p = 0.012). In a multivariable model, both lower ALPS‑index and slower gait speed were independently associated with longer disease duration, with an interaction effect (p = 0.032) suggesting functional compensation between perivascular diffusion and mobility.

These findings highlight the interconnected roles of aging, perivascular fluid transport, and mobility in MS and support the ALPS‑index as a feasible, non‑invasive imaging marker of age‑related vulnerability.