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Target analyte levels were studied longitudinally in 37 ALS cases. Participants were stratified according to the rate of disease progression estimated before and after baseline and <jats:italic>C9orf72<\/jats:italic> genetic status. Survival and longitudinal analyses were undertaken with reference to matched neurofilament protein expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Compared to healthy controls, total neurofilament proteins and antibodies, neurofilament light immune complexes (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001), and neurofilament heavy antibodies (<jats:italic>p<\/jats:italic>\u2009=\u20090.0061) were significantly elevated in ALS, patients with faster progressing disease (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001) and in ALS cases with a <jats:italic>C9orf72<\/jats:italic> mutation (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0003). Blood neurofilament light protein discriminated better ALS from healthy controls (AUC: 0.92; <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001) and faster from slower progressing ALS (AUC: 0.86; <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001) compared to heavy\u2010chain antibodies and light\u2010chain immune complexes (AUC: 0.79; <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001 and AUC: 0.74; <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001). Lower neurofilament heavy antibodies were associated with longer survival (Log\u2010rank Chi\u2010square: 7.39; <jats:italic>p<\/jats:italic>\u2009=\u20090.0065). Increasing levels of antibodies and immune complexes between time points were observed in faster progressing ALS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We report a distinctive humoral response characterized by raising antibodies against neurofilaments and dipeptide repeats in faster progressing and <jats:italic>C9orf72<\/jats:italic> genetic mutation carriers ALS patients. We confirm the significance of plasma neurofilament proteins in the clinical stratification of ALS.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51428","type":"journal-article","created":{"date-parts":[[2021,7,28]],"date-time":"2021-07-28T06:45:43Z","timestamp":1627454743000},"page":"1831-1844","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Humoral response to neurofilaments and dipeptide repeats in ALS progression"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3697-4726","authenticated-orcid":false,"given":"Fabiola","family":"Puentes","sequence":"first","affiliation":[{"name":"Neurodegeneration Group Blizard Institute, Barts and the London School of Medicine and Dentistry Queen Mary University of London London E1 2AT United Kingdom"},{"name":"Department of Neuromuscular Diseases UCL Queen Square Institute of Neurology University College London London WC1N 3BG United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vittoria","family":"Lombardi","sequence":"additional","affiliation":[{"name":"Neurodegeneration Group Blizard Institute, Barts and the London School of Medicine and Dentistry Queen Mary University of London London E1 2AT United Kingdom"},{"name":"Department of Neuromuscular Diseases UCL Queen Square Institute of Neurology University College London London WC1N 3BG United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ching\u2010Hua","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases UCL Queen Square Institute of Neurology University College London London WC1N 3BG United Kingdom"},{"name":"School of Medicine China Medical University 91 Xueshi Road North District Taichung City 404 Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ozlem","family":"Yildiz","sequence":"additional","affiliation":[{"name":"Neurodegeneration Group Blizard Institute, Barts and the London School of Medicine and Dentistry Queen Mary University of London London E1 2AT United Kingdom"},{"name":"Department of Neuromuscular Diseases UCL Queen Square Institute of Neurology University College London London WC1N 3BG United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pietro","family":"Fratta","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases UCL Queen Square Institute of Neurology University College London London WC1N 3BG United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adrian","family":"Isaacs","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases UCL Queen Square Institute of Neurology University College London London WC1N 3BG United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoana","family":"Bobeva","sequence":"additional","affiliation":[{"name":"Neurodegeneration Group Blizard Institute, Barts and the London School of Medicine and Dentistry Queen Mary University of London London E1 2AT United Kingdom"},{"name":"Department of Neuromuscular Diseases UCL Queen Square Institute of Neurology University College London London WC1N 3BG United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanne","family":"Wuu","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Miami Miami Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"ALS Biomarker Consortium","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"CReATe Consortium","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Benatar","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Miami Miami Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Malaspina","sequence":"additional","affiliation":[{"name":"Neurodegeneration Group Blizard Institute, Barts and the London School of Medicine and Dentistry Queen Mary University of London London E1 2AT United Kingdom"},{"name":"Department of Neuromuscular Diseases UCL Queen Square Institute of Neurology University College London London WC1N 3BG United 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