{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T13:55:13Z","timestamp":1783691713106,"version":"3.55.0"},"reference-count":48,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 NS080816"],"award-info":[{"award-number":["R01 NS080816"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000070","name":"National Institute of Biomedical Imaging and Bioengineering","doi-asserted-by":"publisher","award":["P41 EB027061"],"award-info":[{"award-number":["P41 EB027061"]}],"id":[{"id":"10.13039\/100000070","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016958","name":"Office of Research Infrastructure Programs","doi-asserted-by":"publisher","award":["S10 OD017974"],"award-info":[{"award-number":["S10 OD017974"]}],"id":[{"id":"10.13039\/100016958","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"abstract":"ABSTRACT<\/jats:title>\n \n Objective<\/jats:title>\n Neurochemical levels measured by brain MR spectroscopy (MRS) have been proposed as endpoints for clinical trials in early\u2010stage spinocerebellar ataxia (SCA) trials. We tested their trial\u2010readiness by quantifying neurochemicals in three affected brain regions in early\u2010stage cohorts of SCA2 and SCA3, examining their reproducibility in both patients and controls in a multisite\/multivendor setting, and determining if the same neurochemical outcomes can be used as endpoints for different SCA genotypes.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n Seventy\u2010two participants (18 SCA2, mean Scale for the Assessment and Rating of Ataxia (SARA)\u2009=\u20099 +\/\u2212 5; 25 SCA3, mean SARA\u2009=\u200910 +\/\u2212 6; 29 controls) underwent 3\u2009T scans at four sites using scanners from two vendors and a harmonized MRS protocol. Scans were performed twice with a maximum 2\u2010week interval. We measured neurochemical concentrations in the cerebellum, pons, and putamen, and assessed their within\u2010 and between\u2010site reproducibility and associations with clinician\u2010 and patient\u2010reported outcomes.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Test\u2013retest coefficients of variance were comparable across sites and vendors, but concentration estimates had to be adjusted for sites to account for small vendor\u2010based biases. Total\n N<\/jats:italic>\n \u2010acetylaspartate (tNAA) and glutamate were lower, and\n myo<\/jats:italic>\n \u2010inositol (mI) and total creatine (tCr) were higher in the cerebellum and pons in both SCAs vs. controls. Pontine tNAA and mI, and cerebellar tNAA, mI, and glutamate levels were significantly different between SCA2 and SCA3, with strong effect sizes (|Cohen's\n d<\/jats:italic>\n |\u2009=\u20091.1\u20132.1). The tNAA\/tCr ratio had the strongest associations with clinical outcomes (|r|\u2009\u2265\u20090.5), with stronger associations in the cerebellum for SCA2 and in the pons for SCA3.\n <\/jats:p>\n <\/jats:sec>\n \n Interpretation<\/jats:title>\n These data support the use of tNAA and its ratios in a genotype\u2010specific manner in early\u2010stage SCA2 and SCA3 trials in the multisite\/multivendor setting.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/acn3.70443","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T04:12:46Z","timestamp":1780978366000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Neurochemical Endpoints to Inform Early\u2010Stage Trials of Spinocerebellar Ataxia 2 and 3 in a Multisite Setting"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8444-2185","authenticated-orcid":false,"given":"James M.","family":"Joers","sequence":"first","affiliation":[{"name":"Center for Magnetic Resonance Research, Department of Radiology University of Minnesota Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaqiao","family":"Wei","sequence":"additional","affiliation":[{"name":"Division of Biostatistics University of Minnesota Minneapolis Minnesota USA"},{"name":"Graduate Program in the Department of Biostatistics Georgetown University Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4266-4780","authenticated-orcid":false,"given":"Dinesh K.","family":"Deelchand","sequence":"additional","affiliation":[{"name":"Center for Magnetic Resonance Research, Department of Radiology University of Minnesota Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1207-8193","authenticated-orcid":false,"given":"Adam","family":"Berrington","sequence":"additional","affiliation":[{"name":"Russell H. Morgan Department of Radiology and Radiological Science the Johns Hopkins University School of Medicine Baltimore Maryland USA"},{"name":"Sir Peter Mansfield Imaging Centre, School of Physics and Astronomy University of Nottingham Nottingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8737-6278","authenticated-orcid":false,"given":"Young Woo","family":"Park","sequence":"additional","affiliation":[{"name":"Center for Magnetic Resonance Research, Department of Radiology University of Minnesota Minneapolis Minnesota USA"},{"name":"Uniformed Services University of the Health Sciences Bethesda Maryland USA"},{"name":"Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guita","family":"Banan","sequence":"additional","affiliation":[{"name":"Department of Physics University of Florida Gainesville Florida USA"},{"name":"Graduate Program in Science and Technology Studies York University Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5498-5162","authenticated-orcid":false,"given":"Michal","family":"Povazan","sequence":"additional","affiliation":[{"name":"Russell H. Morgan Department of Radiology and Radiological Science the Johns Hopkins University School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5957-0313","authenticated-orcid":false,"given":"Jens T.","family":"Rosenberg","sequence":"additional","affiliation":[{"name":"Advanced Magnetic Resonance Imaging and Spectroscopy Facility, McKnight Brain Institute University of Florida Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2754-6594","authenticated-orcid":false,"given":"Andr\u00e9 J. W.","family":"van der Kouwe","sequence":"additional","affiliation":[{"name":"Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology Massachusetts General Hospital Charlestown Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7180-2869","authenticated-orcid":false,"given":"Tetsuo","family":"Ashizawa","sequence":"additional","affiliation":[{"name":"Stanley H. Appel Department of Neurology Houston Methodist Academic Institute Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khalaf O.","family":"Bushara","sequence":"additional","affiliation":[{"name":"Department of Neurology and the Bob Allison Ataxia Clinic University of Minnesota Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2255-4437","authenticated-orcid":false,"given":"Chiadi U.","family":"Onyike","sequence":"additional","affiliation":[{"name":"Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry and Behavioral Sciences Johns Hopkins University School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8052-9240","authenticated-orcid":false,"given":"Sub H.","family":"Subramony","sequence":"additional","affiliation":[{"name":"Department of Neurology and Fixel Institute for Neurological Disorders Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0706-5125","authenticated-orcid":false,"given":"Jeremy D.","family":"Schmahmann","sequence":"additional","affiliation":[{"name":"Ataxia Center, Division of Behavioral Neurology, Department of Neurology Massachusetts General Hospital and Harvard Medical School Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2750-7277","authenticated-orcid":false,"given":"Brian J.","family":"Soher","sequence":"additional","affiliation":[{"name":"Center for Advanced MR Research, Department of Radiology Duke University Medical Center Durham USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6410-7793","authenticated-orcid":false,"given":"Peter B.","family":"Barker","sequence":"additional","affiliation":[{"name":"Russell H. 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