Normal appearing white matter and disability in multiple sclerosis

Background and ObjectivesMultiple sclerosis (MS) is characterized by lesions and atrophy on conventional MRI, yet these often fail to explain disability. Diffusion MRI (dMRI) detects microstructural injury with diffusion tensor (DTI) and kurtosis imaging (DKI) offering sensitivity, and Standard Model Imaging (SMI) providing biologically interpretable parameters. We evaluated whether these clinically feasible dMRI metrics are associated with disability beyond volumetric and lesion measures, and whether effects arise from normal-appearing white matter (NAWM). MethodsThis cross-sectional study included MS patients who underwent 3T MRI including T1- and T2-weighted and a [~]7-minute multi-shell dMRI protocol. Brain volumes (gray matter, white matter, thalamus) and lesion load were derived using FreeSurfer and Icobrain. Diffusion metrics included radial diffusivity (RD) from DTI, radial kurtosis (RK) from DKI, intra-axonal water fraction (f) and fiber dispersion (p2) from SMI. Clinical outcomes were the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), 9-Hole Peg Test (9HPT), Symbol Digit Modalities Test (SDMT), and disease duration. Voxelwise and tract-based regions of interest analyses were adjusted for sex and age at onset and repeated after excluding lesions. ResultsNinety-two patients (68 women; mean age 48, range 24-73; median disease duration 14 years; EDSS 3.0, range 0-8.5) were included. dMRI revealed widespread associations with all clinical measures that persisted after lesion exclusion, implicating NAWM. Functional outcomes were tract-specific: 9HPT correlated with corticospinal tract and optic radiations (RD {rho}=0.45; RK {rho}=-0.44; f {rho}=-0.42); MSFC with brainstem and optic radiations (RD {rho}=-0.52; RK {rho}=0.40; f {rho}=0.39). SDMT showed widespread correlation with diffusion and atrophy (white matter {rho}=0.49; thalamus {rho}=0.47). EDSS showed weaker diffusion highlighting commissural disorganization (forceps major/minor {rho} {approx}- 0.30 to -0.32) and was most strongly associated to infratentorial lesion load ({rho}=0.42). Disease duration was dominated by gray-matter atrophy ({rho}=-0.54) with commissural p2 reductions ({approx}-0.45). DiscussiondMRI detects NAWM injury underlying functional impairment beyond atrophy and lesions. SMI adds specificity (f for axonal loss/demyelination; p2 for inflammation). Structural measures capture the effect of cumulative burden in terms of disease duration and EDSS. Together, diffusion, volumetric, and lesion metrics offer complementary insights, supporting multimodal imaging for MS monitoring and stratification.