White Matter Tract Degeneration in Multiple Sclerosis Patients With Progression Independent of Relapse Activity.

Background and objectives: Progression independent of relapse activity (PIRA) is associated with worse outcomes in people with multiple sclerosis (pwMS). Although previous research has linked PIRA to accelerated brain and spinal cord atrophy and compartmentalized chronic inflammation, the role of white matter (WM) tract degeneration remains unclear. This study aimed to explore the relationship between PIRA and the integrity of major WM tracts using diffusion tensor imaging (DTI).

Methods: A cohort of 258 pwMS was stratified based on the presence or absence of PIRA over a 4-year follow-up period. At the end of follow-up, DTI metrics were compared between groups using propensity score-weighted linear regression models to account for potential confounders.

Results: PwMS with ≥1 PIRA event (n = 39) exhibited significant reductions in fractional anisotropy and increases in radial, axial, and mean diffusivity within the corpus callosum and motor tracts (false discovery rate-adjusted p ≤ 0.04) compared with those without PIRA, indicating more pronounced WM damage.

Discussion: Our findings highlight an association between PIRA and microstructural damage in key WM tracts. The observed DTI changes likely reflect processes such as Wallerian degeneration and contribute to the growing evidence linking PIRA to neurodegeneration.