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We assessed WM changes in premanifest HD by exploiting ultra\u2010strong\u2010gradient magnetic resonance imaging (MRI). This allowed to separately quantify magnetization transfer ratio (MTR) and hindered and restricted diffusion\u2010weighted signal fractions, and assess how they drove WM microstructure differences between patients and controls. We used tractometry to investigate region\u2010specific alterations across callosal segments with well\u2010characterized early\u2010 and late\u2010myelinating axon populations, while brain\u2010wise differences were explored with tract\u2010based cluster analysis (TBCA). Behavioral measures were included to explore disease\u2010associated brain\u2010function relationships. We detected lower MTR in patients' callosal rostrum (tractometry:\n                    <jats:italic>p<\/jats:italic>\n                    \u00a0=\u00a0.03; TBCA:\n                    <jats:italic>p<\/jats:italic>\n                    \u00a0=\u00a0.03), but higher MTR in their splenium (tractometry:\n                    <jats:italic>p<\/jats:italic>\n                    \u00a0=\u00a0.02). Importantly, patients' mutation\u2010size and MTR were positively correlated (all\n                    <jats:italic>p<\/jats:italic>\n                    \u2010values\u2009&lt;\u2009.01), indicating that MTR alterations may directly result from the mutation. Further, MTR was higher in younger, but lower in older patients relative to controls (\n                    <jats:italic>p<\/jats:italic>\n                    \u00a0=\u00a0.003), suggesting that MTR increases are detrimental later in the disease. Finally, patients showed higher restricted diffusion signal fraction (FR) from the composite hindered and restricted model of diffusion (CHARMED) in the cortico\u2010spinal tract (\n                    <jats:italic>p<\/jats:italic>\n                    \u00a0=\u00a0.03), which correlated positively with MTR in the posterior callosum (\n                    <jats:italic>p<\/jats:italic>\n                    \u00a0=\u00a0.033), potentially reflecting compensatory mechanisms. In summary, this first comprehensive, ultra\u2010strong gradient MRI study in HD provides novel evidence of mutation\u2010driven MTR alterations at the premanifest disease stage which may reflect neurodevelopmental changes in iron, myelin, or a combination of these.\n                  <\/jats:p>","DOI":"10.1002\/hbm.25859","type":"journal-article","created":{"date-parts":[[2022,4,9]],"date-time":"2022-04-09T07:09:20Z","timestamp":1649488160000},"page":"3439-3460","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Mutation\u2010related magnetization\u2010transfer, not axon density, drives white matter differences in premanifest Huntington disease: Evidence from in vivo ultra\u2010strong gradient\n                    <scp>MRI<\/scp>"],"prefix":"10.1002","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0292-3330","authenticated-orcid":false,"given":"Chiara","family":"Casella","sequence":"first","affiliation":[{"name":"Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology Cardiff University  Cardiff UK"},{"name":"Department of Perinatal Imaging and Health, School of Biomedical Engineering &amp; Imaging Sciences King's College London, St Thomas' Hospital  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxime","family":"Chamberland","sequence":"additional","affiliation":[{"name":"Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology Cardiff University  Cardiff UK"},{"name":"Donders Institute for Brain, Cognition and Behavior Radboud University  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9191-7409","authenticated-orcid":false,"given":"Pedro L.","family":"Laguna","sequence":"additional","affiliation":[{"name":"Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology Cardiff University  Cardiff UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greg D.","family":"Parker","sequence":"additional","affiliation":[{"name":"Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology Cardiff University  Cardiff UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne E.","family":"Rosser","sequence":"additional","affiliation":[{"name":"Department of Neurology and Psychological Medicine Hayden Ellis Building  Cardiff UK"},{"name":"School of Biosciences Cardiff University  Cardiff UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Coulthard","sequence":"additional","affiliation":[{"name":"Bristol Medical School University of Bristol  Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugh","family":"Rickards","sequence":"additional","affiliation":[{"name":"Birmingham and Solihull Mental Health NHS Foundation Trust  Birmingham UK"},{"name":"Institute of Clinical Sciences, College of Medical and Dental Sciences University of Birmingham  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0628-7391","authenticated-orcid":false,"given":"Samuel C.","family":"Berry","sequence":"additional","affiliation":[{"name":"Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology Cardiff University  Cardiff UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek K.","family":"Jones","sequence":"additional","affiliation":[{"name":"Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology Cardiff University  Cardiff UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Metzler\u2010Baddeley","sequence":"additional","affiliation":[{"name":"Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology Cardiff University  Cardiff UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,4,9]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(92)90178-C"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1053-8119(03)00336-7"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2015.10.019"},{"key":"e_1_2_10_5_1","unstructured":"ArmonkN.IBM Corp. 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