• Maria Caranova, Júlia F Soares, Daniela Jardim Pereira, Ana Cláudia Lima, Lívia Sousa, Sónia Batista, Miguel Castelo-Branco, and João V Duarte.
• Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT), Institute for Nuclear Sciences Applied to Health (ICNAS), University of Coimbra, Coimbra, Portugal.
• J Neuroimaging. 2025 Jan 1; 35 (1): e70022e70022.

Background And PurposeStructural MRI (sMRI) is used in monitoring multiple sclerosis (MS) but lacks sensitivity in detecting clinically relevant damage to normal-appearing white matter (NAWM), that is, pre-lesional tissue, and specificity for identifying the underlying substrate of injury. In this longitudinal study, we identified pre-lesional tissue in MS patients and investigated its microstructure by modeling diffusion-weighted imaging (DWI) data using diffusion tensor imaging and neurite orientation dispersion and density imaging (NODDI).MethodsWe enrolled 18 patients with relapsing-remitting MS (10 females, 31.92 ± 8.09 years, disease duration 0.91 ± 1.81 years) and 18 healthy controls (10 females, 31.89 ± 8.15 years). Participants underwent two sMRI and DWI sessions (baseline and follow-up) with the same protocols. Average apparent diffusion coefficient (ADC), fractional anisotropy (FA), orientation dispersion index (ODI), and neurite density index (NDI) were estimated in data-driven regions of interest: nonpersistent lesional tissue (lesional tissue at baseline, resolved at follow-up), lesions that only existed at follow-up (pre-lesional tissue at baseline, lesions at follow-up), persistent lesional tissue (lesions at baseline and follow-up), and NAWM.ResultsCompared to NAWM, pre-lesional tissue showed lower ODI, and resolved lesional tissue showed higher FA and ADC and lower ODI and NDI. Over time, persistent lesional tissue showed a decrease in FA and ODI and an increase in NDI. Compared to nonpersistent lesional tissue, persistent lesional tissue showed higher ADC and lower NDI.ConclusionsDWI and, more particularly, NODDI, can reveal the unique microstructure of persistent, resolved, and pre-lesional tissue in MS.© 2025 American Society of Neuroimaging.

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