Regional IVIM-DWI Abnormalities in Normal-Appearing White Matter and Lesion Tissue in Relapsing–Remitting Multiple Sclerosis

Background/Objectives: Normal-appearing white matter (NAWM) in relapsing–remitting multiple sclerosis (RR-MS) may contain abnormalities not visible on conventional MRI. This study evaluated whether intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) detects regional NAWM abnormalities and differentiates non-lesional white matter from lesion tissue in RR-MS. Methods: This retrospective cross-sectional single-center study included 189 patients with RR-MS and 26 healthy controls. Apparent diffusion coefficient (ADC), true diffusion coefficient (D), pseudo-diffusion coefficient (D*), and perfusion fraction (f) were measured in the genu, splenium, frontal white matter, and posterior white matter. Regional MS NAWM was compared with the anatomically corresponding control white matter. Tissue-compartment analysis compared averaged control white matter, averaged MS NAWM, and lesion-averaged MS tissue. Results: Posterior white matter showed the strongest abnormalities, with lower ADC, D, D*, and f in RR-MS than in controls (all p < 0.001); ADC, D, and D* showed large effects (Cohen’s d: −0.81 to −1.07). In the splenium, ADC and D were higher, whereas D* was lower in RR-MS. After age and sex adjustment, posterior white matter ADC, D, and D* and splenial D* remained significant, whereas posterior f and splenial ADC/D were attenuated. No clear IVIM-DWI abnormality was detected in the sampled frontal white matter. Lesion-averaged MS tissue showed higher ADC, D, and D* than averaged MS NAWM and control white matter (all p < 0.001). Conclusions: Regional IVIM-DWI identified region-specific NAWM abnormalities in RR-MS, most robustly in posterior white matter, within an exploratory imaging framework. Larger matched longitudinal cohorts are required before clinical or prognostic utility can be established.