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We sought to compare the ability of emerging plasma markers in distinguishing MSA from its mimics and healthy controls in early disease stages, and to evaluate their performance in detecting disease severity and brain atrophy. Plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), phosphorylated tau181, amyloid-\u03b2 (A\u03b2)42, and A\u03b240 were measured using ultrasensitive Simoa in early-stage patients with MSA (<jats:italic>n<\/jats:italic>\u2009=\u200973), spinocerebellar ataxia (SCA, <jats:italic>n<\/jats:italic>\u2009=\u200929), Parkinson\u2019s disease (PD, <jats:italic>n<\/jats:italic>\u2009=\u200928), and healthy controls (<jats:italic>n<\/jats:italic>\u2009=\u2009100). We observed that elevated NfL outperformed other biomarkers in distinguishing MSA and its subtypes (AUC\u2009=\u20090.9) versus controls. Intriguingly, when separating MSA from its mimics, increased GFAP (AUC\u2009=\u20090.717) in MSA-C and decreased A\u03b240 (AUC\u2009=\u20090.807) in MSA-P best discriminated from SCA and PD respectively. Plasma levels were comparable between MSA-C and MSA-P and the differentiation by plasma index alone was poor. Combining plasma markers noticeably improved the discriminatory efficacy. Of note, among MSA patients, higher GFAP and NfL were correlated with the atrophy of brain regions vulnerable to MSA (e.g., cerebellum, pons, or putamen). They could also aggravate the severity of MSA, and this association was partially mediated by cerebral volumes. In contrast, no obvious associations of phosphorylated tau and A\u03b2 with disease severity were observed. Collectively, plasma biomarkers, especially in combination, are useful to facilitate the discriminatory work-up of MSA at early stages. Moreover, NfL and GFAP may be promising biomarkers to monitor the disease severity of MSA.<\/jats:p>","DOI":"10.1038\/s41531-023-00481-5","type":"journal-article","created":{"date-parts":[[2023,3,26]],"date-time":"2023-03-26T19:51:48Z","timestamp":1679860308000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Head-to-head comparison of 6 plasma biomarkers in early multiple system atrophy"],"prefix":"10.1038","volume":"9","author":[{"given":"Yu","family":"Guo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue-Ning","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Yi","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Fen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Fu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya-Ru","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1118-1743","authenticated-orcid":false,"given":"Wei","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3874-0130","authenticated-orcid":false,"given":"Qiang","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2532-383X","authenticated-orcid":false,"given":"Jin-Tai","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,3,15]]},"reference":[{"key":"481_CR1","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/s41572-022-00382-6","volume":"8","author":"W Poewe","year":"2022","unstructured":"Poewe, W. et al. 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