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It remains unclear whether microstructural injury in normal\u2010appearing white matter (NAWM) and lesions manifests identically across these distinct anatomical environments or if advanced biophysical models offer diagnostic advantages over standard diffusion techniques. We performed a comprehensive 3T MRI protocol with same\u2010session brain and cervical SC imaging on 34 persons with relapsing\u2013remitting MS (pwRRMS) and 36 healthy controls (HCs). We focused on diffusion frameworks (diffusion tensor imaging [DTI], standard model imaging with free water [SMIfw]) to quantify and compare microstructural integrity between the brain and cervical SC for the first time. Specifically, we assessed the feasibility of SMI for clinical implementation in terms of sensitivity (contrast between lesions and NAWM in pwRRMS) and reliability (HC reproducibility). Our findings indicate that both simple (DTI) and advanced (SMI) models are sensitive to MS\u2010related microstructural changes, but the utility varied by region: notably, SMI\u2010derived neurite density fraction (\n                    <jats:italic>f<\/jats:italic>\n                    ) emerged as a robust marker of MS pathology in both the brain and SC, while DTI metrics like fractional anisotropy (FA) and radial diffusivity (RD) showed comparable sensitivity exclusively in the brain. Though axonal loss appears to be a global feature detectable even in early\u2010stage disease, the inflammatory or edematous environment of lesions differs fundamentally between the brain and SC. Taken together, these findings demonstrate the utility of SMI for comprehensive CNS assessment and support its potential for future usage in clinical trials and improved disease monitoring.\n                  <\/jats:p>","DOI":"10.1002\/nbm.70354","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T03:00:18Z","timestamp":1783566018000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Standard Model Imaging in the Brain and Spinal Cord of MS Patients: Initial Assessment and Comparison to Diffusion Tensor Imaging"],"prefix":"10.1002","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2939-263X","authenticated-orcid":false,"given":"Atlee","family":"Witt","sequence":"first","affiliation":[{"name":"Vanderbilt University Institute of Imaging Science  Nashville Tennessee USA"},{"name":"Vanderbilt University School of Medicine  Nashville Tennessee 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