{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T22:23:44Z","timestamp":1781735024535,"version":"3.54.5"},"reference-count":40,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2023,10,3]],"date-time":"2023-10-03T00:00:00Z","timestamp":1696291200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000272","name":"National Institute for Health and Care Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000848","name":"University of Edinburgh","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000848","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000765","name":"University College London","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000765","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012066","name":"Wings for Life","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012066","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Magnetic Resonance Imaging"],"published-print":{"date-parts":[[2024,6]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p><jats:sup>1<\/jats:sup>H\u2010magnetic resonance spectroscopy (<jats:sup>1<\/jats:sup>H\u2010MRS) may provide a direct index for the testing of medicines for neuroprotection and drug mechanisms in multiple sclerosis (MS) through measures of total <jats:italic>N<\/jats:italic>\u2010acetyl\u2010aspartate (tNAA), total creatine (tCr), myo\u2010inositol (mIns), total\u2010choline (tCho), and glutamate\u2009+\u2009glutamine (Glx). Neurometabolites may be associated with clinical disability with evidence that baseline neuroaxonal integrity is associated with upper limb function and processing speed in secondary progressive MS (SPMS).<\/jats:p><\/jats:sec><jats:sec><jats:title>Purpose<\/jats:title><jats:p>To assess the effect on neurometabolites from three candidate drugs after 96\u2010weeks as seen by <jats:sup>1<\/jats:sup>H\u2010MRS and their association with clinical disability in SPMS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Study\u2010Type<\/jats:title><jats:p>Longitudinal.<\/jats:p><\/jats:sec><jats:sec><jats:title>Population<\/jats:title><jats:p>108 participants with SPMS randomized to receive neuroprotective drugs amiloride [mean age 55.4 (SD 7.4), 61% female], fluoxetine [55.6 (6.6), 71%], riluzole [54.6 (6.3), 68%], or placebo [54.8 (7.9), 67%].<\/jats:p><\/jats:sec><jats:sec><jats:title>Field Strength\/Sequence<\/jats:title><jats:p>3\u2010Tesla. Chemical\u2010shift\u2010imaging 2D\u2010point\u2010resolved\u2010spectroscopy (PRESS), 3DT1.<\/jats:p><\/jats:sec><jats:sec><jats:title>Assessment<\/jats:title><jats:p>Brain metabolites in normal appearing white matter (NAWM) and gray matter (GM), brain volume, lesion load, nine\u2010hole peg test (9HPT), and paced auditory serial addition test were measured at baseline and at 96\u2010weeks.<\/jats:p><\/jats:sec><jats:sec><jats:title>Statistical Tests<\/jats:title><jats:p>Paired <jats:italic>t<\/jats:italic>\u2010test was used to analyze metabolite changes in the placebo arm over 96\u2010weeks. Metabolite differences between treatment arms and placebo; and associations between baseline metabolites and upper limb function\/information processing speed at 96\u2010weeks assessed using multiple linear regression models. <jats:italic>P<\/jats:italic>\u2010value&lt;0.05 was considered statistically significant.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In the placebo arm, tCho increased in GM (mean difference\u2009=\u2009\u22120.32\u2009IU) but decreased in NAWM (mean difference\u2009=\u20090.13\u2009IU). Compared to placebo, in the <jats:italic>fluoxetine arm<\/jats:italic>, mIns\/tCr was lower (<jats:italic>\u03b2<\/jats:italic>\u2009=\u2009\u22120.21); in the <jats:italic>riluzole arm<\/jats:italic>, GM Glx (<jats:italic>\u03b2<\/jats:italic>\u2009=\u2009\u22120.25) and Glx\/tCr (<jats:italic>\u03b2<\/jats:italic>\u2009=\u2009\u22120.29) were reduced. Baseline tNAA(<jats:italic>\u03b2<\/jats:italic>\u2009=\u20090.22) and tNAA\/tCr (<jats:italic>\u03b2<\/jats:italic>\u2009=\u20090.23) in NAWM were associated with 9HPT scores at 96\u2010weeks.<\/jats:p><\/jats:sec><jats:sec><jats:title>Data Conclusion<\/jats:title><jats:p><jats:sup>1<\/jats:sup>H\u2010MRS demonstrated altered membrane turnover over 96\u2010weeks in the placebo group. It also distinguished changes in neuro\u2010metabolites related to gliosis and glutaminergic transmission, due to fluoxetine and riluzole, respectively. Data show tNAA is a potential marker for upper limb function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Level of Evidence<\/jats:title><jats:p>1<\/jats:p><\/jats:sec><jats:sec><jats:title>Technical Efficacy<\/jats:title><jats:p>Stage 4<\/jats:p><\/jats:sec>","DOI":"10.1002\/jmri.29017","type":"journal-article","created":{"date-parts":[[2023,10,4]],"date-time":"2023-10-04T08:24:50Z","timestamp":1696407890000},"page":"2192-2201","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Longitudinal Metabolite Changes in Progressive Multiple Sclerosis: A Study of 3 Potential Neuroprotective Treatments"],"prefix":"10.1002","volume":"59","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9834-4498","authenticated-orcid":false,"given":"Nevin A.","family":"John","sequence":"first","affiliation":[{"name":"Department of Medicine, School of Clinical Sciences Monash University  Melbourne Australia"},{"name":"Department of Neurology Monash Health  Melbourne Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5946-7604","authenticated-orcid":false,"given":"Bhavana S.","family":"Solanky","sequence":"additional","affiliation":[{"name":"Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Institute of Neurology, Faculty of Brain Sciences University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Floriana","family":"De Angelis","sequence":"additional","affiliation":[{"name":"Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Institute of Neurology, Faculty of Brain Sciences University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Parker","sequence":"additional","affiliation":[{"name":"Edinburgh Clinical Trials Unit Usher Institute, University of Edinburgh  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Weir","sequence":"additional","affiliation":[{"name":"Edinburgh Clinical Trials Unit Usher Institute, University of Edinburgh  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Stutters","sequence":"additional","affiliation":[{"name":"Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Institute of Neurology, Faculty of Brain Sciences University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7872-0142","authenticated-orcid":false,"given":"Ferran Prados","family":"Carrasco","sequence":"additional","affiliation":[{"name":"Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Institute of Neurology, Faculty of Brain Sciences University College London  London UK"},{"name":"Centre for Medical Image Computing (CMIC) University College London  London UK"},{"name":"e\u2010Health Center, Universitat Oberta de Catalunya  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torben","family":"Schneider","sequence":"additional","affiliation":[{"name":"Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Institute of Neurology, Faculty of Brain Sciences University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anisha","family":"Doshi","sequence":"additional","affiliation":[{"name":"Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Institute of Neurology, Faculty of Brain Sciences University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Calvi","sequence":"additional","affiliation":[{"name":"Laboratory of Advanced Imaging in Neuroimmunological Diseases (imaginEM), Fundaci\u00f3 de Recerca Cl\u00ednic Barcelona\u2013Institut d'Investigacions Biom\u00e8diques August Pi I Sunyer (FRCB\u2010IDIBAPS)  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Williams","sequence":"additional","affiliation":[{"name":"Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Institute of Neurology, Faculty of Brain Sciences University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Plantone","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Neuroscience University of Siena  Siena Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Monteverdi","sequence":"additional","affiliation":[{"name":"Department of Brain and Behavioural Sciences University of Pavia  Pavia Italy"},{"name":"Brain Connectivity Center C. 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