White Matter and Normal‐Appearing White Matter in Low‐Disability Patients With Multiple Sclerosis: A Diffusion Tensor MRI Study

BACKGROUND: Diffusion tensor imaging (DTI) is sensitive to white matter (WM) microstructural alterations in multiple sclerosis (MS), but duration-defined "early MS" cohorts may be clinically heterogeneous. PURPOSE: To investigate diffusion alterations in WM and normal-appearing white matter (NAWM) in low-disability MS versus healthy controls (HC). STUDY TYPE: Retrospective cross-sectional case-control study. POPULATION: 20 patients with MS (Expanded Disability Status Scale ≤ 3.5; ambulatory without assistance) and 20 age- and sex-matched HC. SEQUENCE: ) and nine b0 volumes. ASSESSMENT: Tract-Based Spatial Statistics (TBSS) assessed fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) in conventional WM and lesion-masked NAWM. DeepLesionBrain (volBrain) automatically segmented WM lesions; a neuroradiologist with 10 years of experience reviewed and corrected segmentations when necessary. STATISTICAL TEST: FMRIB Software Library (FSL) randomize using 10,000 permutations, threshold-free cluster enhancement, and family-wise error correction (p < 0.01). Permutation Analysis of Linear Models (PALM) used two-sided inference and FWE correction across diffusion metrics and directions. RESULTS: Standard TBSS showed lower FA in the right anterior corona radiata (ACR) and posterior thalamic radiation (PTR), and higher RD in the corpus callosum genu, in MS versus HC. NAWM-restricted TBSS showed lower FA in the corpus callosum genu, right PTR, and right tapetum, and higher RD in bilateral ACR, right posterior corona radiata, and an unclassified region. In randomized, AD and MD were nonsignificant (minimum corrected p = 0.0118 and 0.0103 in standard TBSS; p = 0.0103 and 0.0107 in NAWM, respectively). Under PALM across-metric correction, no metric remained significant: standard TBSS, FA p = 0.0861, AD p = 0.1273, RD p = 0.0271, MD p = 0.0177; NAWM, FA p = 0.0807, AD p = 0.1225, RD p = 0.0282, MD p = 0.0197. CONCLUSION: Functionally defined low-disability MS shows focal WM and NAWM microstructural alterations, predominantly reflected by reduced FA and increased RD. EVIDENCE LEVEL: 4. TECHNICAL EFFICACY: Stage 1.