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We evaluated blood-based prognostic indicators using an array of pathological markers. Plasma samples were collected as part of a large, phase III clinical trial (Mitotarget\/TRO19622) at months 1, 6, 12 and 18. The ALSFRS-r score was used as a proxy of disease progression to assess the predictive value of candidate biological indicators. First, established clinical predictors were evaluated in all 512 patients. Subsequently, pathologic markers, such as proxies of neuronal integrity (Neurofilament light chain and phosphorylated heavy chain), DNA oxidation (8-oxo-2\u2032-desoxyguanosine), lipid peroxidation (4-hydroxy-2-nonenal, isoprostane), inflammation (interleukin-6) and iron status (ferritin, hepcidin, transferrin) were assessed in a subset of 109 patients that represented the whole cohort. Markers of neuronal integrity, DNA and lipid oxidation, as well as iron status at baseline are accurate predictors of disability at 18-month follow-up. The composite scores of these markers in association with established clinical predictors enable the accurate forecasting of functional decline. The identified four biomarkers are all closely associated with \u2018ferroptosis\u2019, a recently discovered form of programmed cell death with promising therapeutic targets. The predictive potential of these pathophysiology-based indicators may offer superior patient stratification for future trials, individualised patient care and resource allocation.<\/jats:p>","DOI":"10.1038\/s41598-019-39739-5","type":"journal-article","created":{"date-parts":[[2019,2,27]],"date-time":"2019-02-27T11:27:43Z","timestamp":1551266863000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":127,"title":["A ferroptosis\u2013based panel of prognostic biomarkers for Amyotrophic Lateral Sclerosis"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2417-799X","authenticated-orcid":false,"given":"David","family":"Devos","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Moreau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maeva","family":"Kyheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillaume","family":"Gar\u00e7on","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne Sophie","family":"Rolland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9l\u00e8ne","family":"Blasco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Gel\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"Timoth\u00e9e Lenglet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Veyrat-Durebex","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Corcia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Dutheil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Bede","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Jeromin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Oeckl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4273-4267","authenticated-orcid":false,"given":"Markus","family":"Otto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Meininger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00e9ronique","family":"Danel-Brunaud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-christophe","family":"Devedjian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A.","family":"Duce","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre Fran\u00e7ois","family":"Pradat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,2,27]]},"reference":[{"key":"39739_CR1","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1016\/S1474-4422(18)30089-9","volume":"17","author":"HJ Westeneng","year":"2018","unstructured":"Westeneng, H. 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The indicated authors take responsibility for data collection and analysis. The principal investigator (DD), who had full access to all the study data, takes full responsibility for submitting the final work for publication. Caroline Moreau has received grants from the France Parkinson charity as well as various honoraria from pharmaceutical companies for consultancy and lectures on Parkinson\u2019s disease. Anne Sophie Rolland, V\u00e9ronique Danel-Brunaud, Jean-Christophe Devedjian, Mary Dutheil, Charlotte Veyrat-Durebex, Alain Duhamel, Maeva Kyheng, H\u00e9l\u00e8ne Blasco, Guillaume Gar\u00e7on, Patrick Gel\u00e9, Timoth\u00e9e Lenglet, Patrick Oeckl, R\u00e9gis Bordet, Vincent Meininger and James Duce have nothing to declare. Philippe Corcia served on the advisory board and received honoraria from Roche for consultancy and grants from the ARSLA charity. Pierre Fran\u00e7ois Pradat has received grants from the ARSLA charity, the <i>Association Fran\u00e7aise contre les Myopathies-T\u00e9l\u00e9thon<\/i> (AFM-T\u00e9l\u00e9thon), the <i>Institut pour la Recherche sur la Moelle \u00e9pini\u00e8re et l\u2019Enc\u00e9phale<\/i> (IRME), the Thierry Latran Fondation and the Target ALS Fondation. Markus Otto received grants from the EU (Fairpark-II), German Ministry of Science and Technology (KNDD-FTLDc), Thierry Latran foundation, ALS foundation, Foundation of the state Baden-Wuerttemberg and the German science foundation. He has served as advisor for Axon, Biogen and given lectures for Lilly, Fujirebio and Teva. Andreas Jeromin is employed by Quanterix, Lexington, Massachusetts, USA Peter Bede is supported by the Health Research Board (HRB \u2013 Ireland; HRB EIA-2017\u2013019), the Irish Institute of Clinical Neuroscience IICN \u2212 Novartis Ireland Research Grant, and the Iris O\u2019Brien Foundation Ireland. David Devos has received grants from the French Ministry of Health (PHRC), the French Ministry of Research (ANR), the European Commission (H2020), the ARSLA charity and the France Parkinson charity. He served on advisory boards, as a consultant and given lectures on behalf of pharmaceutical companies such as Orkyn, Boston Scientific, Abbvie and ApoPharma.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"2918"}}