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In Huntington\u2019s disease, altered proton magnetic resonance spectroscopy-determined concentrations of several metabolites have been described; however, findings are often discrepant and longitudinal studies are lacking. Proton magnetic resonance spectroscopy metabolites may represent a source of biomarkers, thus their relationship with established markers of disease progression require further exploration to assess prognostic value and elucidate pathways associated with neurodegeneration. In a prospective single-site controlled cohort study with standardized collection of CSF, blood, phenotypic and volumetric imaging data, we used 3\u2005T proton magnetic resonance spectroscopy in conjunction with the linear combination of model spectra method to quantify seven metabolites (total n-acetylaspartate, total creatine, total choline, myo-inositol, GABA, glutamate and glutathione) in the putamen of 59 participants at baseline (15 healthy controls, 15 premanifest and 29 manifest Huntington\u2019s disease gene expansion carriers) and 48 participants at 2-year follow-up (12 healthy controls, 13 premanifest and 23 manifest Huntington\u2019s disease gene expansion carriers). Intergroup differences in concentration and associations with CSF and plasma biomarkers; including neurofilament light chain and mutant Huntingtin, volumetric imaging markers; namely whole brain, caudate, grey matter and white matter volume, measures of disease progression and cognitive decline, were assessed cross-sectionally using generalized linear models and partial correlation. We report no significant groupwise differences in metabolite concentration at baseline but found total creatine and total n-acetylaspartate to be significantly reduced in manifest compared with premanifest participants at follow-up. Additionally, total creatine and myo-inositol displayed significant associations with reduced caudate volume across both time points in gene expansion carriers. Although relationships were observed between proton magnetic resonance spectroscopy metabolites and biofluid measures, these were not consistent across time points. To further assess prognostic value, we examined whether baseline proton magnetic resonance spectroscopy values, or rate of change, predicted subsequent change in established measures of disease progression. Several associations were found but were inconsistent across known indicators of disease progression. Finally, longitudinal mixed-effects models revealed glutamine + glutamate to display a slow linear decrease over time in gene expansion carriers. Altogether, our findings show some evidence of reduced total n-acetylaspartate and total creatine as the disease progresses and cross-sectional associations between select metabolites, namely total creatine and myo-inositol, and markers of disease progression, potentially highlighting the proposed roles of neuroinflammation and metabolic dysfunction in disease pathogenesis. However, the absence of consistent group differences, inconsistency between baseline and follow-up, and lack of clear longitudinal change suggests that proton magnetic resonance spectroscopy metabolites have limited potential as Huntington\u2019s disease biomarkers.<\/jats:p>","DOI":"10.1093\/braincomms\/fcac258","type":"journal-article","created":{"date-parts":[[2022,10,12]],"date-time":"2022-10-12T14:24:33Z","timestamp":1665584673000},"source":"Crossref","is-referenced-by-count":12,"title":["Longitudinal evaluation of proton magnetic resonance spectroscopy metabolites as biomarkers in Huntington\u2019s disease"],"prefix":"10.1093","volume":"4","author":[{"given":"Alexander J","family":"Lowe","sequence":"first","affiliation":[{"name":"UCL Huntington\u2019s Disease Centre, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Filipe B","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"UCL Huntington\u2019s Disease Centre, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marzena","family":"Arridge","sequence":"additional","affiliation":[{"name":"Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery , London WC1N 3BG , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enrico","family":"De Vita","sequence":"additional","affiliation":[{"name":"Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery , London WC1N 3BG , UK"},{"name":"Department of Radiology, Great Ormond Street Hospital , London WC1N 3JH , UK"},{"name":"Department of Biomedical Engineering, School of Biomedical Engineering & Imaging Sciences, King\u2019s College London, King\u2019s Health Partners, St Thomas\u2019 Hospital , London SE1 7EH , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eileanoir B","family":"Johnson","sequence":"additional","affiliation":[{"name":"UCL Huntington\u2019s Disease Centre, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachael I","family":"Scahill","sequence":"additional","affiliation":[{"name":"UCL Huntington\u2019s Disease Centre, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren M","family":"Byrne","sequence":"additional","affiliation":[{"name":"UCL Huntington\u2019s Disease Centre, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosanna","family":"Tortelli","sequence":"additional","affiliation":[{"name":"UCL Huntington\u2019s Disease Centre, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda","family":"Heslegrave","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute at University College London, Fluid Biomarker Laboratory , London WC1E 6BT , UK"},{"name":"Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute at University College London, Fluid Biomarker Laboratory , London WC1E 6BT , UK"},{"name":"Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK"},{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg , M\u00f6lndal SE-413 45 , Sweden"},{"name":"Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital , M\u00f6lndal SE-413 45 , Sweden"},{"name":"Hong Kong Center for Neurodegenerative Diseases, Fluid Biomarker Laboratory , 17 Science and Technology W Ave, Science Park, Hong Kong , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward J","family":"Wild","sequence":"additional","affiliation":[{"name":"UCL Huntington\u2019s Disease Centre, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,10,12]]},"reference":[{"issue":"4","key":"2022111516485417800_fcac258-B1","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/nrneurol.2014.24","article-title":"Huntington disease: Natural history, biomarkers and prospects for 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