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Previous proteomics and metabolomics studies conducted in blood samples collected from FMR1 premutation carriers with FXTAS reported abnormalities in energy metabolism, and precursors of gluconeogenesis showed significant changes in plasma expression levels in FMR1 premutation carriers who developed FXTAS. We conducted an analysis of postmortem human brain tissues from 44 donors, 25 brains with FXTAS, and 19 matched controls. We quantified the metabolite relative abundance in the inferior temporal gyrus and the cerebellum using untargeted mass spectrometry (MS)-based metabolomics. We investigated how the metabolite type and abundance relate to the number of cytosine-guanine-guanine (CGG) repeats, to markers of neurodegeneration, and to the symptoms of FXTAS. A metabolomic analysis identified 191 primary metabolites, the data were log-transformed and normalized prior to the analysis, and the relative abundance was compared between the groups. The changes in the relative abundance of a set of metabolites were region-specific with some overlapping results; 22 metabolites showed alterations in the inferior temporal gyrus, while 21 showed differences in the cerebellum. The relative abundance of cytidine was decreased in the inferior temporal gyrus, and a lower abundance was found in the cases with larger CGG expansions; oleamide was significantly decreased in the cerebellum. The abundance of 11 metabolites was influenced by changes in the CGG repeat number. A histological evaluation found an association between the presence of microhemorrhages in the inferior temporal gyrus and a lower abundance of 2,5-dihydroxypyrazine. Our study identified alterations in the metabolites involved in the oxidative-stress response and bioenergetics in the brains of individuals with FXTAS. Significant changes in the abundance of cytidine and oleamide suggest their potential as biomarkers and therapeutic targets for FXTAS.<\/jats:p>","DOI":"10.3390\/cells12172132","type":"journal-article","created":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T10:09:53Z","timestamp":1692871793000},"page":"2132","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Brain Metabolomics in Fragile X-Associated Tremor\/Ataxia Syndrome (FXTAS)"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2412-9146","authenticated-orcid":false,"given":"Maria Jimena","family":"Salcedo-Arellano","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA"},{"name":"Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis, Sacramento, CA 95616, USA"},{"name":"Institute for Pediatric Regenerative Medicine at Shriners Hospitals for Children Northern California, Sacramento, CA 95817, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael D.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA"},{"name":"Institute for Pediatric Regenerative Medicine at Shriners Hospitals for Children Northern California, Sacramento, CA 95817, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8272-2012","authenticated-orcid":false,"given":"Yingratana A.","family":"McLennan","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA"},{"name":"Institute for Pediatric Regenerative Medicine at Shriners Hospitals for Children Northern California, Sacramento, CA 95817, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ye Hyun","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pablo","family":"Juarez","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA"},{"name":"Institute for Pediatric Regenerative Medicine at Shriners Hospitals for Children Northern California, Sacramento, CA 95817, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erin Lucille","family":"McBride","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA"},{"name":"Institute for Pediatric Regenerative Medicine at Shriners Hospitals for Children Northern California, Sacramento, CA 95817, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adriana P.","family":"Pantoja","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA"},{"name":"Institute for Pediatric Regenerative Medicine at Shriners Hospitals for Children Northern California, Sacramento, CA 95817, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Blythe","family":"Durbin-Johnson","sequence":"additional","affiliation":[{"name":"Division of Biostatistics, Department of Public Health Sciences, UC Davis School of Medicine, Sacramento, CA 95817, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Flora","family":"Tassone","sequence":"additional","affiliation":[{"name":"Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis, Sacramento, CA 95616, USA"},{"name":"Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Randi J.","family":"Hagerman","sequence":"additional","affiliation":[{"name":"Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis, Sacramento, CA 95616, USA"},{"name":"Department of Pediatrics, UC Davis School of Medicine, Sacramento, CA 95817, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ver\u00f3nica","family":"Mart\u00ednez-Cerde\u00f1o","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA"},{"name":"Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis, Sacramento, CA 95616, USA"},{"name":"Institute for Pediatric Regenerative Medicine at Shriners Hospitals for Children Northern California, Sacramento, CA 95817, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1111\/nyas.12693","article-title":"Fragile X-associated tremor\/ataxia syndrome","volume":"1338","author":"Hagerman","year":"2015","journal-title":"Ann. 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