Phosphorylated Neurofilament Heavy Chain: A Biomarker of Survival for C9ORF72-Associated Amyotrophic Lateral Sclerosis

• Type of Material: Article
• Authors: Tania F. Gendron, Mayo Clinic; Lillian M. Daughrity, Mayo Clinic; Michael G. Heckman, Mayo Clinic; Nancy N. Diehl, Mayo Clinic; Joanne Wuu, University of Miami; Timothy M. Miller, Washington University; Pau Pastor, University of Barcelona; John Q. Trojanowski, University of Pennsylvania; Murray Grossman, University of Pennsylvania; James D. Berry, Massachusetts General Hospital; William Hu, Emory University; Antonia Ratti, IRCCS Istituto Auxologico Italiano; Michael Benatar, University of Miami; Vincenzo Silani, IRCCS Istituto Auxologico Italiano; Jonathan D Glass, Emory University; Mary Kay Floeter, National Institute of Neurological Disorders and Stroke; Andreas Jeromin, Iron Horse Diagnostics, Inc.; Kevin B. Boylan, Mayo Clinic; Leonard Petrucelli, Mayo Clinic
• Language: English
• Date: 2017-07-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association
• Final Published Version (URL): http://dx.doi.org/10.1002/ana.24980
• Title of Journal or Parent Work: Annals of Neurology
• ISSN: 0364-5134
• Volume: 82
• Issue: 1
• Start Page: 139
• End Page: 146
• Grant/Funding Information: This work was supported in part by the National Institutes of Health (NIH)/National Institute on Aging [P01AG017586 (M.G., J.Q.T.), K23AG042856 (W.T.H.), P30AG10124 (J.Q.T., M.G.)]; NIH/National Institute of Neurological Disorders and Stroke [R21NS089979 (K.B.B., T.F.G.), R01NS078398 (T.M.M.), R35NS097273 (L.P.), R21NS084528 (L.P.), P01NS084974 (L.P., K.B.B.), R01NS088689 (L.P.), R01NS093865 (L.P.)]; Intramural NIH/National Institute of Neurological Disorders and Stroke [Z01NS003146 (M.K.F.)]; Department of Defense [ALSRP AL130125 (L.P.)]; Mayo Clinic Foundation (L.P.); Mayo Clinic Center for Individualized Medicine (K.B.B., T.F.G., L.P.); Amyotrophic Lateral Sclerosis Association (K.B.B., M.B, J.D.G., T.F.G., L.P., J.W.); Robert Packard Center for ALS Research at Johns Hopkins (L.P.); Target ALS (L.P.); Association for Frontotemporal Degeneration (L.P.); ALS Therapy Alliance (J.D.B., J.D.G); ALS Finding A Cure Foundation (J.D.B.); Muscular Dystrophy Association (#416137, T.F.G.; #4365 and #172123, M.B., J.W.); Italian Ministry of Health (RF-2013-02355764, A.R., V.S.) and STRENGTH project funded by EU Joint Programme – Neurodegenerative (A.R., V.S.); and CReATe (U54-NS-092091, M.B, J.W.), which is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), NCATS.; CReATe is funded through collaboration between NCATS and NINDS
• Keywords: C9ORF72; EXPANSION; SUBUNIT PNF-H; Life Sciences & Biomedicine; CONSENSUS; TOXICITY; DIAGNOSTIC-CRITERIA; Neurosciences; POPULATION; Clinical Neurology; CSF; ALS; Science & Technology; Neurosciences & Neurology; HEXANUCLEOTIDE REPEAT
• Research Categories: Biology, Neuroscience; Health Sciences, Pathology

Abstract

As potential treatments for C9ORF72-associated amyotrophic lateral sclerosis (c9ALS) approach clinical trials, the identification of prognostic biomarkers for c9ALS becomes a priority. We show that levels of phosphorylated neurofilament heavy chain (pNFH) in cerebrospinal fluid (CSF) predict disease status and survival in c9ALS patients, and are largely stable over time. Moreover, c9ALS patients exhibit higher pNFH levels, more rapid disease progression, and shorter survival after disease onset than ALS patients without C9ORF72 expansions. These data support the use of CSF pNFH as a prognostic biomarker for clinical trials, which will increase the likelihood of successfully developing a treatment for c9ALS. Ann Neurol 2017;82:139–146.