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The D50 disease progression model is a framework to comprehensively dissect biomarker-signals towards their relevance regarding disease accumulation\/phase (rD50), or disease aggressiveness (D50). Based on previous findings using 1.5-Tesla Magnetic-Resonance-Imaging (MRI), this study hypothesized that high-resolution MRI markers of Grey-Matter (GM) structural integrity would enable quantification of disease accumulation, independent of aggressiveness.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A separate cohort of 75 patients with ALS and 73 Healthy Controls (HC) underwent T1-weighted 3-Tesla MRI. Voxel-Based-Morphometry measured GM and White-Matter (WM) density and Surface-Based-Morphometry assessed Cortical Thickness (CT). Non-parametric Threshold-Free-Cluster-Enhancement with 5000 permutations was applied for inter-group and regression contrasts, whilst correcting for possibly interfering co-variates and applying Family-Wise-Error-adjustment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Compared with HC, the ALS cohort showed widespread decreases of CT and GM\/WM density (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). These case\u2013control effects were driven by patients scanned during rD50-defined disease Phase 2 (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). Within the ALS-cohort, direct Phase 2 versus Phase 1 contrasts revealed spatially-distributed decreases, reflecting higher disease accumulation (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). These were independent of disease aggressiveness (and onset-region), as corrected for in the models. Accordingly, all contrasts assessing aggressiveness did not yield significant results.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These semi-automated analyses of T1-weighted-images captured disease accumulation related GM structural integrity-loss in this cohort scanned with 3-Tesla MRI, independent of the underlying disease aggressiveness. This principle was validated across different scanners and field strengths, supporting its application for objective and non-invasive staging of patients with ALS, whereby true longitudinal studies are necessary.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00415-026-13937-4","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T06:37:16Z","timestamp":1782715036000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Quantification of amyotrophic lateral sclerosis (ALS) disease accumulation with T1-weighted high-resolution magnetic resonance imaging: validation in an independent cohort"],"prefix":"10.1007","volume":"273","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-5566-2699","authenticated-orcid":false,"given":"Philip Alexander","family":"Gremmler","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0647-5923","authenticated-orcid":false,"given":"Janina","family":"von der Gablentz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3893-9427","authenticated-orcid":false,"given":"Julia","family":"Meyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2260-0803","authenticated-orcid":false,"given":"Benjamin","family":"Ilse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0137-9939","authenticated-orcid":false,"given":"Behnaz","family":"Farahi Ghasraboonasr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0339-4562","authenticated-orcid":false,"given":"Sophie","family":"Dalbert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0633-8832","authenticated-orcid":false,"given":"Isabelle Jana","family":"Buchholz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9525-1424","authenticated-orcid":false,"given":"Julian","family":"Grosskreutz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3936-6010","authenticated-orcid":false,"given":"Robert","family":"Steinbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"issue":"10107","key":"13937_CR1","doi-asserted-by":"publisher","first-page":"2084","DOI":"10.1016\/S0140-6736(17)31287-4","volume":"390","author":"MA van Es","year":"2017","unstructured":"van Es MA, Hardiman O, Chio A, Al-Chalabi A, Pasterkamp RJ, Veldink JH, van den Berg LH (2017) Amyotrophic lateral sclerosis. 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