{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T12:15:14Z","timestamp":1790252114890,"version":"4.1.0"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2022,3,7]],"date-time":"2022-03-07T00:00:00Z","timestamp":1646611200000},"content-version":"vor","delay-in-days":27,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Cambridge British Heart Foundation Centre of Research Excellence","award":["RE\/18\/1\/34212"],"award-info":[{"award-number":["RE\/18\/1\/34212"]}]},{"name":"Medical Research Council"},{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"crossref","award":["MC-PC-12025"],"award-info":[{"award-number":["MC-PC-12025"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"crossref"}]},{"name":"European Union\u2019s Horizon 2020","award":["667375"],"award-info":[{"award-number":["667375"]}]},{"DOI":"10.13039\/501100002926","name":"Cambridge University Hospitals","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002926","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NIHR Biomedical Research Centre","award":["BRC-1215-20014"],"award-info":[{"award-number":["BRC-1215-20014"]}]},{"DOI":"10.13039\/501100002996","name":"Dutch Heart Foundation","doi-asserted-by":"crossref","award":["2016 T044"],"award-info":[{"award-number":["2016 T044"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,7,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Cerebral small vessel disease is a major cause of vascular cognitive impairment and dementia. There are few treatments, largely reflecting limited understanding of the underlying pathophysiology. Metabolomics can be used to identify novel risk factors to better understand pathogenesis and to predict disease progression and severity.<\/jats:p>\n                  <jats:p>We analysed data from 624 patients with symptomatic cerebral small vessel disease from two prospective cohort studies. Serum samples were collected at baseline and patients underwent MRI scans and cognitive testing at regular intervals with up to 14 years of follow-up. Using ultra-performance liquid chromatography\u2013mass spectrometry and nuclear magnetic resonance spectroscopy, we obtained metabolic and lipidomic profiles from 369 annotated metabolites and 54\u2009764 unannotated features and examined their association with respect to disease severity, assessed using MRI small vessel disease markers, cognition and future risk of all-cause dementia.<\/jats:p>\n                  <jats:p>Our analysis identified 28 metabolites that were significantly associated with small vessel disease imaging markers and cognition. Decreased levels of multiple glycerophospholipids and sphingolipids were associated with increased small vessel disease load as evidenced by higher white matter hyperintensity volume, lower mean diffusivity normalized peak height, greater brain atrophy and impaired cognition. Higher levels of creatine, FA(18:2(OH)) and SM(d18:2\/24:1) were associated with increased lacune count, higher white matter hyperintensity volume and impaired cognition. Lower baseline levels of carnitines and creatinine were associated with higher annualized change in peak width of skeletonized mean diffusivity, and 25 metabolites, including lipoprotein subclasses, amino acids and xenobiotics, were associated with future dementia incidence.<\/jats:p>\n                  <jats:p>Our results show multiple distinct metabolic signatures that are associated with imaging markers of small vessel disease, cognition and conversion to dementia. Further research should assess causality and the use of metabolomic screening to improve the ability to predict future disease severity and dementia risk in small vessel disease. The metabolomic profiles may also provide novel insights into disease pathogenesis and help identify novel treatment approaches.<\/jats:p>","DOI":"10.1093\/brain\/awac041","type":"journal-article","created":{"date-parts":[[2022,2,2]],"date-time":"2022-02-02T15:18:01Z","timestamp":1643815081000},"page":"2461-2471","source":"Crossref","is-referenced-by-count":53,"title":["Metabolomic profiling in small vessel disease identifies multiple associations with disease severity"],"prefix":"10.1093","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8767-0928","authenticated-orcid":false,"given":"Eric L","family":"Harshfield","sequence":"first","affiliation":[{"name":"Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge , Cambridge CB2 0QQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline J","family":"Sands","sequence":"additional","affiliation":[{"name":"National Phenome Centre, Department of Metabolism, Digestion and Reproduction, Imperial College London , London SW7 2AZ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anil M","family":"Tuladhar","sequence":"additional","affiliation":[{"name":"Department of Neurology, Donders Center for Medical Neuroscience, Radboud University Nijmegen Medical Center , 6500 HB Nijmegen , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank Erik","family":"de Leeuw","sequence":"additional","affiliation":[{"name":"Department of Neurology, Donders Center for Medical Neuroscience, Radboud University Nijmegen Medical Center , 6500 HB Nijmegen , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew R","family":"Lewis","sequence":"additional","affiliation":[{"name":"National Phenome Centre, Department of Metabolism, Digestion and Reproduction, Imperial College London , London SW7 2AZ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugh S","family":"Markus","sequence":"additional","affiliation":[{"name":"Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge , Cambridge CB2 0QQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,2,8]]},"reference":[{"issue":"7","key":"2022072919093436900_awac041-B1","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/S1474-4422(10)70104-6","article-title":"Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges","volume":"9","author":"Pantoni","year":"2010","journal-title":"Lancet Neurol"},{"issue":"18","key":"2022072919093436900_awac041-B2","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.1212\/WNL.0000000000004594","article-title":"Change in multimodal MRI markers predicts dementia risk in cerebral small vessel 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