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In this study, we explored metabolic changes in normal-appearing white matter (NAWM) in patients with relapsing\u2013remitting MS (pwRRMS) using 7\u00a0T MRSI. 20 pwRRMS were scanned annually with 2D-MRSI, with follow-up ranging up to three years. Metabolic ratios were calculated within NAWM for each measurement and assessed cross-sectionally and longitudinally with established and emerging MRI measures of disease burden, including paramagnetic rim lesions (PRLs), brain atrophy, and T2 lesion load. At baseline, pwRRMS showed higher mI\/tNAA (\u03b2\u2009=\u20090.058;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.047) and lower tNAA\/total creatine (tCr) (\u03b2\u2009=\u2009\u2212\u20090.106;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.029) compared to controls. tNAA\/tCr was further reduced in pwRRMS with PRLs (\u03b2\u2009=\u2009\u2212\u20090.138;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.022). mI\/tNAA was associated negatively with cerebral WM volume (\u03b2\u2009=\u2009\u2212\u20090.001,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.015) and positively with T2 lesion volume (\u03b2\u2009=\u20090.009;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.044). mI\/tNAA increased longitudinally in pwRRMS (\u03b2\u2009=\u20090.014;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.022), especially with higher PRL count (\u03b2\n                    <jats:sub>timepoint:PRLcount<\/jats:sub>\n                    \u2009=\u20090.016;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.045). An association between tNAA\/tCr and the interaction of time with total GM volume was observed but did not survive FDR-correction (\u03b2\u2009=\u20090.001;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.078). These findings further support the clinical relevance of mI and tNAA alterations as imaging biomarkers of underlying pathology in MS. They highlight the value of 7\u00a0T MRSI in capturing subclinical disease burden and underscore the association of PRLs with overall widespread WM damage.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-45342-2","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T06:38:52Z","timestamp":1774334332000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Metabolic changes in normal-appearing white matter associate with MRI measures of disease burden in relapsing-remitting multiple sclerosis over three years"],"prefix":"10.1038","volume":"16","author":[{"given":"Anna","family":"Z\u00f6chner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Bogner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Assunta","family":"Dal-Bianco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard","family":"Strasser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilbert","family":"Hangel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulus Stefan","family":"Rommer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Niess","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,24]]},"reference":[{"key":"45342_CR1","volume":"6","author":"L Klotz","year":"2025","unstructured":"Klotz, L., Saraste, M., Airas, L. & Kuhlmann, T. 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