{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T18:45:19Z","timestamp":1789152319475,"version":"build-2803163510"},"reference-count":70,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2021,4,27]],"date-time":"2021-04-27T00:00:00Z","timestamp":1619481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007802","name":"Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica","doi-asserted-by":"publisher","award":["FGCR 01\/2013"],"award-info":[{"award-number":["FGCR 01\/2013"]}],"id":[{"id":"10.13039\/501100007802","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007802","name":"Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica","doi-asserted-by":"publisher","award":["2014\u2013005367-32"],"award-info":[{"award-number":["2014\u2013005367-32"]}],"id":[{"id":"10.13039\/501100007802","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ricerca Corrente of the Ministry of Health to the Fondazione IRCCS Istituto Neurologico \u201cCarlo Besta\u201d of Milan"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,10,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Strong evidence suggests that endoplasmic reticulum stress plays a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through altered regulation of proteostasis. Robust preclinical findings demonstrated that guanabenz selectively inhibits endoplasmic reticulum stress-induced eIF2\u03b1-phosphatase, allowing misfolded protein clearance, reduces neuronal death and prolongs survival in in vitro and in vivo models. However, its safety and efficacy in patients with ALS are unknown.<\/jats:p>\n               <jats:p>To address these issues, we conducted a multicentre, randomized, double-blind trial with a futility design. Patients with ALS who had displayed an onset of symptoms within the previous 18\u2009months were randomly assigned in a 1:1:1:1 ratio to receive 64\u2009mg, 32\u2009mg or 16\u2009mg of guanabenz or placebo daily for 6\u2009months as an add-on therapy to riluzole. The purpose of the placebo group blinding was to determine safety but not efficacy. The primary outcome was the proportion of patients progressing to higher stages of disease within 6\u2009months as measured using the ALS Milano-Torino staging system, compared with a historical cohort of 200 patients with ALS. The secondary outcomes were the rate of decline in the total revised ALS functional rating scale score, slow vital capacity change, time to death, tracheotomy or permanent ventilation and serum light neurofilament level at 6\u2009months.<\/jats:p>\n               <jats:p>The primary assessment of efficacy was performed using intention-to-treat analysis. The treatment arms using 64\u2009mg and 32\u2009mg guanabenz, both alone and combined, reached the primary hypothesis of non-futility, with the proportions of patients who progressed to higher stages of disease at 6\u2009months being significantly lower than that expected under the hypothesis of non-futility and a significantly lower difference in the median rate of change in the total revised ALS functional rating scale score.<\/jats:p>\n               <jats:p>This effect was driven by patients with bulbar onset, none of whom (0\/18) progressed to a higher stage of disease at 6\u2009months compared with those on 16\u2009mg guanabenz (4\/8; 50%), the historical cohort alone (21\/49; 43%; P\u2009=\u20090.001) or plus placebo (25\/60; 42%; P\u2009=\u20090.001). The proportion of patients who experienced at least one adverse event was higher in any guanabenz arm than in the placebo arm, with higher dosing arms having a significantly higher proportion of drug-related side effects and the 64\u2009mg arm a significantly higher drop-out rate. The number of serious adverse events did not significantly differ between the guanabenz arms and the placebo. Our findings indicate that a larger trial with a molecule targeting the unfolded protein response pathway without the alpha-2 adrenergic related side-effect profile of guanabenz is warranted.<\/jats:p>","DOI":"10.1093\/brain\/awab167","type":"journal-article","created":{"date-parts":[[2021,4,23]],"date-time":"2021-04-23T00:38:58Z","timestamp":1619138338000},"page":"2635-2647","source":"Crossref","is-referenced-by-count":59,"title":["The unfolded protein response in amyotrophic later sclerosis: results of a phase 2 trial"],"prefix":"10.1093","volume":"144","author":[{"given":"Eleonora","family":"Dalla Bella","sequence":"first","affiliation":[{"name":"3rd Neurology Unit and Motor Neuron Disease Centre, Fondazione IRCCS Istituto Neurologico \u201cCarlo Besta\u201d, Milan 20133, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrica","family":"Bersano","sequence":"additional","affiliation":[{"name":"3rd Neurology Unit and Motor Neuron Disease Centre, Fondazione IRCCS Istituto Neurologico \u201cCarlo Besta\u201d, Milan 20133, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Antonini","sequence":"additional","affiliation":[{"name":"NESMOS Department, Neuromuscolar Disease Unit, Sant'Andrea Hospital and University of Rome \u201cSapienza\u201d, Rome 00189, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Borghero","sequence":"additional","affiliation":[{"name":"Neurologic Unit, Monserrato University Hospital, Cagliari 09042, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margherita","family":"Capasso","sequence":"additional","affiliation":[{"name":"Neurologic Clinic, SS. Annunziata Hospital, Chieti 66100, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Caponnetto","sequence":"additional","affiliation":[{"name":"San Martino Polyclinic Hospital, Genoa 16132, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriano","family":"Chi\u00f2","sequence":"additional","affiliation":[{"name":"ALS Centre \u201cRita Levi Montalcini\u201d, Department of Neuroscience, University of Turin, Turin, Italy"},{"name":"Azienda Ospedaliero-Universitaria Citt\u00e0 della Salute e della Scienza, Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Corbo","sequence":"additional","affiliation":[{"name":"Department of Neurorehabilitaton, Casa Cura Policlinico, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2852-7512","authenticated-orcid":false,"given":"Massimiliano","family":"Filosto","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Sciences, University of Brescia, ASST Spedali Civili Brescia and NeMO-Brescia Clinical Centre for Neuromuscular Diseases, Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Giannini","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgery Sciences and Neurosciences, University of Siena, Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8910-3131","authenticated-orcid":false,"given":"Rossella","family":"Spataro","sequence":"additional","affiliation":[{"name":"ALS Research Centre, BioNeC, University of Palermo, Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4788-1875","authenticated-orcid":false,"given":"Christian","family":"Lunetta","sequence":"additional","affiliation":[{"name":"NEuroMuscular Omnicentre of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Mandrioli","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Azienda Ospedaliero Universitaria di Modena, Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Messina","sequence":"additional","affiliation":[{"name":"Unit of Neurology and Neuromuscular Disorders, Department of Clinical and Experimental Medicine and University of Messina, AOU Policlinico \u201cG. Martino\u201d, Messina, Italy"},{"name":"NEuroMuscular Omnicentre of Messina, University Hospital \u201cG. Martino\u201d, Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Rosaria","family":"Monsurr\u00f2","sequence":"additional","affiliation":[{"name":"\u201cLuigi Vanvitelli\u201d Campania University Naples, Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Mora","sequence":"additional","affiliation":[{"name":"ICS Maugeri IRCCS, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0513-9517","authenticated-orcid":false,"given":"Nilo","family":"Riva","sequence":"additional","affiliation":[{"name":"Department of Neurology IRCCS \u201cSan Raffaele\u201d Hospital, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romana","family":"Rizzi","sequence":"additional","affiliation":[{"name":"Neurology Unit, Department of Neuro-Motor Diseases, Azienda Unit\u00e0 Sanitaria Locale, IRCCS of Reggio Emilia, Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Siciliano","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Neurology Unit, University of Pisa, Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Silani","sequence":"additional","affiliation":[{"name":"Department of Neurology-Stroke Unit and Laboratory of Neuroscience, Istituto Auxologico Italiano IRCCS, Milan, Italy"},{"name":"Department of Pathophysiology and Transplantation, \u201cDino Ferrari\u201d Centre and Centre for Neurotechnology and Brain Therapeutics, University of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Simone","sequence":"additional","affiliation":[{"name":"Department of Neurology and Psychiatry, University of Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianni","family":"Sorar\u00f9","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, University of Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Tugnoli","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Rehabilitation, Division of Neurology, University Hospital of Ferrara, Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Verriello","sequence":"additional","affiliation":[{"name":"Neurology Unit, S. Maria della Misericordia University Hospital, Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Volanti","sequence":"additional","affiliation":[{"name":"Intensive Neurorehabilitation Unit, ICS Maugeri IRCCS, Mistretta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Furlan","sequence":"additional","affiliation":[{"name":"Clinical Neuroimmunology Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1234-0304","authenticated-orcid":false,"given":"John M","family":"Nolan","sequence":"additional","affiliation":[{"name":"Drew University, Caspersen School of Graduate Studies, Madison, NJ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuelle","family":"Abgueguen","sequence":"additional","affiliation":[{"name":"InFlectis BioScience, Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Tramacere","sequence":"additional","affiliation":[{"name":"Scientific Directorate, Fondazione IRCCS Istituto Neurologico \u201cCarlo Besta\u201d, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9773-020X","authenticated-orcid":false,"given":"Giuseppe","family":"Lauria","sequence":"additional","affiliation":[{"name":"3rd Neurology Unit and Motor Neuron Disease Centre, Fondazione IRCCS Istituto Neurologico \u201cCarlo Besta\u201d, Milan 20133, Italy"},{"name":"Department of Biomedical and Clinical Sciences \u201cLuigi Sacco\u201d, University of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,4,27]]},"reference":[{"issue":"6","key":"2021103110133989800_awab167-B1","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1111\/neup.12119","article-title":"Basophilic inclusions and neuronal intermediate filament inclusions in amyotrophic lateral sclerosis and frontotemporal lobar degeneration","volume":"34","author":"Ito","year":"2014","journal-title":"Neuropathology"},{"issue":"3","key":"2021103110133989800_awab167-B2","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1113\/JP270213","article-title":"New perspectives on amyotrophic lateral sclerosis: The role of glial cells at the neuromuscular junction","volume":"595","author":"Arbour","year":"2017","journal-title":"J Physiol"},{"issue":"Pt B","key":"2021103110133989800_awab167-B3","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.expneurol.2014.05.015","article-title":"Glial cells in amyotrophic lateral sclerosis","volume":"262","author":"Philips","year":"2014","journal-title":"Exp Neurol"},{"issue":"10","key":"2021103110133989800_awab167-B4","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1590\/0004-282X20160117","article-title":"Far beyond the motor neuron: The role of glial cells in amyotrophic lateral sclerosis","volume":"74","author":"Souza","year":"2016","journal-title":"Arq Neuro-Psiquiatr"},{"issue":"5","key":"2021103110133989800_awab167-B5","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1038\/nn.3357","article-title":"Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis","volume":"16","author":"Kang","year":"2013","journal-title":"Nat Neurosci"},{"issue":"16","key":"2021103110133989800_awab167-B6","doi-asserted-by":"crossref","first-page":"1602","DOI":"10.1056\/NEJMc1710379","article-title":"Amyotrophic lateral sclerosis","volume":"377","author":"Brown","year":"2017","journal-title":"N Engl J Med"},{"issue":"6059","key":"2021103110133989800_awab167-B7","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1126\/science.1209038","article-title":"The unfolded protein response: From stress pathway to homeostatic regulation","volume":"334","author":"Walter","year":"2011","journal-title":"Science"},{"issue":"1","key":"2021103110133989800_awab167-B8","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.neuron.2017.05.026","article-title":"Physico-pathologic mechanisms involved in neurodegeneration: misfolded protein-plasma membrane interactions","volume":"95","author":"Shrivastava","year":"2017","journal-title":"Neuron"},{"issue":"7465","key":"2021103110133989800_awab167-B9","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/nature12481","article-title":"Self-propagation of pathogenic protein aggregates in neurodegenerative diseases","volume":"501","author":"Jucker","year":"2013","journal-title":"Nature"},{"issue":"11","key":"2021103110133989800_awab167-B10","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.4161\/cc.10.11.15560","article-title":"Self-propagation and transmission of misfolded mutant SOD1: Prion or prion-like phenomenon?","volume":"10","author":"Munch","year":"2011","journal-title":"Cell Cycle"},{"issue":"9","key":"2021103110133989800_awab167-B11","doi-asserted-by":"crossref","first-page":"3548","DOI":"10.1073\/pnas.1017275108","article-title":"Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells","volume":"108","author":"Munch","year":"2011","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"3","key":"2021103110133989800_awab167-B12","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/j.cell.2011.10.011","article-title":"The seeds of neurodegeneration: Prion-like spreading in ALS","volume":"147","author":"Polymenidou","year":"2011","journal-title":"Cell"},{"issue":"1","key":"2021103110133989800_awab167-B13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.5607\/en.2015.24.1.1","article-title":"Prion-like mechanism in amyotrophic lateral sclerosis: Are protein aggregates the key?","volume":"24","author":"Lee","year":"2015","journal-title":"Exp Neurobiol"},{"issue":"2","key":"2021103110133989800_awab167-B14","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1007\/s12035-009-8054-3","article-title":"ER stress and unfolded protein response in amyotrophic lateral sclerosis","volume":"39","author":"Kanekura","year":"2009","journal-title":"Mol Neurobiol"},{"issue":"8","key":"2021103110133989800_awab167-B15","doi-asserted-by":"crossref","first-page":"798","DOI":"10.15252\/embj.201694117","article-title":"ER strikes again: Proteostasis dysfunction in ALS","volume":"35","author":"Maharjan","year":"2016","journal-title":"EMBO J"},{"issue":"Pt B","key":"2021103110133989800_awab167-B16","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/j.brainres.2016.04.010","article-title":"Protein folding alterations in amyotrophic lateral sclerosis","volume":"1648","author":"Parakh","year":"2016","journal-title":"Brain Res"},{"issue":"5","key":"2021103110133989800_awab167-B17","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1093\/hmg\/ddq546","article-title":"The unfolded protein response in familial amyotrophic lateral sclerosis","volume":"20","author":"Wang","year":"2011","journal-title":"Hum Mol Genet"},{"issue":"9","key":"2021103110133989800_awab167-B18","first-page":"754","article-title":"Stress signaling from the endoplasmic reticulum: A central player in the pathogenesis of amyotrophic lateral sclerosis","volume":"63","author":"Walker","year":"2011","journal-title":"IUBMB Life"},{"key":"2021103110133989800_awab167-B19","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.jns.2018.01.035","article-title":"Expression analysis of protein homeostasis pathways in the peripheral blood mononuclear cells of sporadic amyotrophic lateral sclerosis patients","volume":"387","author":"Vats","year":"2018","journal-title":"J Neurol Sci"},{"issue":"3","key":"2021103110133989800_awab167-B20","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.nbd.2008.02.009","article-title":"Endoplasmic reticulum stress and induction of the unfolded protein response in human sporadic amyotrophic lateral sclerosis","volume":"30","author":"Atkin","year":"2008","journal-title":"Neurobiol Dis"},{"issue":"Pt B","key":"2021103110133989800_awab167-B21","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/j.brainres.2016.03.032","article-title":"Proteostasis impairment in ALS","volume":"1648","author":"Ruegsegger","year":"2016","journal-title":"Brain Res"},{"issue":"4","key":"2021103110133989800_awab167-B22","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1111\/jnc.13575","article-title":"Walking the tightrope: Proteostasis and neurodegenerative disease","volume":"137","author":"Yerbury","year":"2016","journal-title":"J Neurochem"},{"key":"2021103110133989800_awab167-B23","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1146\/annurev.pathmechdis.3.121806.151434","article-title":"Endoplasmic reticulum stress in disease pathogenesis","volume":"3","author":"Lin","year":"2008","journal-title":"Annu Rev Pathol"},{"issue":"12","key":"2021103110133989800_awab167-B24","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a013177","article-title":"Protein-folding homeostasis in the endoplasmic reticulum and nutritional regulation","volume":"4","author":"Ron","year":"2012","journal-title":"Cold Spring Harb Perspect Biol"},{"issue":"Pt 12","key":"2021103110133989800_awab167-B25","doi-asserted-by":"crossref","first-page":"3111","DOI":"10.1093\/brain\/awm190","article-title":"Oxidative and endoplasmic reticulum stress interplay in sporadic amyotrophic lateral sclerosis","volume":"130","author":"Ilieva","year":"2007","journal-title":"Brain"},{"issue":"4","key":"2021103110133989800_awab167-B26","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1097\/NEN.0b013e3181d44992","article-title":"Endoplasmic reticulum stress in motor neurons of the spinal cord in sporadic amyotrophic lateral sclerosis","volume":"69","author":"Sasaki","year":"2010","journal-title":"J Neuropathol Exp Neurol"},{"issue":"6489","key":"2021103110133989800_awab167-B27","doi-asserted-by":"crossref","first-page":"eaat5314","DOI":"10.1126\/science.aat5314","article-title":"The integrated stress response: From mechanism to disease","volume":"368","author":"Costa-Mattioli","year":"2020","journal-title":"Science"},{"issue":"6025","key":"2021103110133989800_awab167-B28","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1126\/science.1201396","article-title":"Selective inhibition of a regulatory subunit of protein phosphatase 1 restores proteostasis","volume":"332","author":"Tsaytler","year":"2011","journal-title":"Science"},{"key":"2021103110133989800_awab167-B29","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.nbd.2013.03.015","article-title":"Pharmacological reduction of ER stress protects against TDP-43 neuronal toxicity in vivo","volume":"55","author":"Vaccaro","year":"2013","journal-title":"Neurobiol Dis"},{"issue":"1","key":"2021103110133989800_awab167-B30","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1002\/emmm.201000109","article-title":"Antiprion drugs 6-aminophenanthridine and guanabenz reduce PABPN1 toxicity and aggregation in oculopharyngeal muscular dystrophy","volume":"3","author":"Barbezier","year":"2011","journal-title":"EMBO Mol Med"},{"key":"2021103110133989800_awab167-B31","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.nbd.2014.08.010","article-title":"Guanabenz, which enhances the unfolded protein response, ameliorates mutant SOD1-induced amyotrophic lateral sclerosis","volume":"71","author":"Wang","year":"2014","journal-title":"Neurobiol Dis."},{"key":"2021103110133989800_awab167-B32","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.neuroscience.2014.03.047","article-title":"Guanabenz delays the onset of disease symptoms, extends lifespan, improves motor performance and attenuates motor neuron loss in the SOD1 G93A mouse model of amyotrophic lateral sclerosis","volume":"277","author":"Jiang","year":"2014","journal-title":"Neuroscience"},{"issue":"6231","key":"2021103110133989800_awab167-B33","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1126\/science.aaa4484","article-title":"Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit","volume":"348","author":"Das","year":"2015","journal-title":"Science"},{"issue":"8","key":"2021103110133989800_awab167-B34","doi-asserted-by":"crossref","first-page":"e015434","DOI":"10.1136\/bmjopen-2016-015434","article-title":"Protein misfolding, amyotrophic lateral sclerosis and guanabenz: Protocol for a phase II RCT with futility design (ProMISe trial)","volume":"7","author":"Dalla Bella","year":"2017","journal-title":"BMJ Open"},{"issue":"5","key":"2021103110133989800_awab167-B35","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1080\/146608200300079536","article-title":"El Escorial revisited: Revised criteria for the diagnosis of amyotrophic lateral sclerosis","volume":"1","author":"Brooks","year":"2000","journal-title":"Amyotroph Lateral Scler Other Motor Neuron Disord"},{"issue":"4","key":"2021103110133989800_awab167-B36","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1093\/occmed\/kqv043","article-title":"The Hamilton Rating Scale for Depression","volume":"65","author":"Sharp","year":"2015","journal-title":"Occup Med (Lond)"},{"issue":"1","key":"2021103110133989800_awab167-B37","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1136\/jnnp-2013-306589","article-title":"Development and evaluation of a clinical staging system for amyotrophic lateral sclerosis","volume":"86","author":"Chio","year":"2015","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"11","key":"2021103110133989800_awab167-B38","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1136\/jnnp-2014-310176","article-title":"The MITOS system predicts long-term survival in amyotrophic lateral sclerosis","volume":"86","author":"Tramacere","year":"2015","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"8","key":"2021103110133989800_awab167-B39","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1136\/jnnp-2014-308996","article-title":"Erythropoietin in amyotrophic lateral sclerosis: A multicentre, randomised, double blind, placebo controlled, phase III study","volume":"86","author":"Lauria","year":"2015","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"5","key":"2021103110133989800_awab167-B40","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/S1474-4422(18)30054-1","article-title":"Stage at which riluzole treatment prolongs survival in patients with amyotrophic lateral sclerosis: A retrospective analysis of data from a dose-ranging study","volume":"17","author":"Fang","year":"2018","journal-title":"Lancet Neurol"},{"issue":"11","key":"2021103110133989800_awab167-B41","doi-asserted-by":"crossref","first-page":"3258","DOI":"10.1007\/s00415-020-09993-z","article-title":"The Italian multicenter experience with edaravone in amyotrophic lateral sclerosis","volume":"267","author":"Lunetta","year":"2020","journal-title":"J Neurol"},{"issue":"2","key":"2021103110133989800_awab167-B42","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1212\/01.wnl.0000194316.91908.8a","article-title":"Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS","volume":"66","author":"Kimura","year":"2006","journal-title":"Neurology"},{"issue":"19","key":"2021103110133989800_awab167-B43","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1212\/WNL.0000000000000951","article-title":"The PRO-ACT database: Design, initial analyses, and predictive features","volume":"83","author":"Atassi","year":"2014","journal-title":"Neurology"},{"issue":"3","key":"2021103110133989800_awab167-B44","doi-asserted-by":"crossref","first-page":"259","DOI":"10.3109\/17482960903358865","article-title":"Toward more efficient clinical trials for amyotrophic lateral sclerosis","volume":"11","author":"Cudkowicz","year":"2010","journal-title":"Amyotroph Lateral Scler"},{"issue":"3-4","key":"2021103110133989800_awab167-B45","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1080\/21678421.2018.1556698","article-title":"Lunasin does not slow ALS progression: Results of an open-label, single-center, hybrid-virtual 12-month trial","volume":"20","author":"Bedlack","year":"2019","journal-title":"Amyotroph Lateral Scler Frontotemporal Degener"},{"issue":"4","key":"2021103110133989800_awab167-B46","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1212\/WNL.0000000000002889","article-title":"Transplantation of spinal cord-derived neural stem cells for ALS: Analysis of phase 1 and 2 trials","volume":"87","author":"Glass","year":"2016","journal-title":"Neurology"},{"issue":"6","key":"2021103110133989800_awab167-B47","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1002\/acn3.567","article-title":"Long-term Phase 1\/2 intraspinal stem cell transplantation outcomes in ALS","volume":"5","author":"Goutman","year":"2018","journal-title":"Ann Clin Transl Neurol"},{"issue":"1-2","key":"2021103110133989800_awab167-B48","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1080\/21678421.2016.1221971","article-title":"Phase I clinical trial of safety of L-serine for ALS patients","volume":"18","author":"Levine","year":"2017","journal-title":"Amyotroph Lateral Scler Frontotemporal Degener"},{"issue":"10","key":"2021103110133989800_awab167-B49","doi-asserted-by":"crossref","first-page":"e0139684","DOI":"10.1371\/journal.pone.0139684","article-title":"Interleukin-1 antagonist anakinra in amyotrophic lateral sclerosis\u2013A pilot study","volume":"10","author":"Maier","year":"2015","journal-title":"PLoS One"},{"issue":"10","key":"2021103110133989800_awab167-B50","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1212\/WNL.0b013e31822dc7a5","article-title":"Phase II screening trial of lithium carbonate in amyotrophic lateral sclerosis: Examining a more efficient trial design","volume":"77","author":"Miller","year":"2011","journal-title":"Neurology"},{"issue":"2","key":"2021103110133989800_awab167-B51","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1002\/mus.26335","article-title":"Rasagiline for amyotrophic lateral sclerosis: A randomized, controlled trial","volume":"59","author":"Statland","year":"2019","journal-title":"Muscle Nerve"},{"issue":"10","key":"2021103110133989800_awab167-B52","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1056\/NEJMoa1916945","article-title":"Trial of sodium phenylbutyrate-taurursodiol for amyotrophic lateral sclerosis","volume":"383","author":"Paganoni","year":"2020","journal-title":"N Engl J Med"},{"issue":"3-4","key":"2021103110133989800_awab167-B53","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1080\/21678421.2016.1265565","article-title":"Comparison of the King's and MiToS staging systems for ALS","volume":"18","author":"Fang","year":"2017","journal-title":"Amyotroph Lateral Scler Frontotemporal Degener"},{"issue":"7","key":"2021103110133989800_awab167-B54","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1007\/s00415-017-8538-4","article-title":"Assessment of the factorial validity and reliability of the ALSFRS-R: A revision of its measurement model","volume":"264","author":"Bakker","year":"2017","journal-title":"J Neurol"},{"issue":"12","key":"2021103110133989800_awab167-B55","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.1136\/jnnp-2012-304701","article-title":"Evidence of multidimensionality in the ALSFRS-R Scale: A critical appraisal on its measurement properties using Rasch analysis","volume":"84","author":"Franchignoni","year":"2013","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"4","key":"2021103110133989800_awab167-B56","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1001\/jamaneurol.2019.4490","article-title":"Development and validation of the Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS)","volume":"77","author":"Fournier","year":"2020","journal-title":"JAMA Neurol"},{"issue":"5-6","key":"2021103110133989800_awab167-B57","doi-asserted-by":"crossref","first-page":"397","DOI":"10.3109\/21678421.2013.764568","article-title":"Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for ALS","volume":"14","author":"Beghi","year":"2013","journal-title":"Amyotroph Lateral Scler Frontotemporal Degener"},{"key":"2021103110133989800_awab167-B58","doi-asserted-by":"crossref","DOI":"10.1016\/S1474-4422(13)70221-7","article-title":"Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): A randomised, double-blind, phase 3 trial","author":"Cudkowicz","year":"2013","journal-title":"Lancet Neurol"},{"issue":"5","key":"2021103110133989800_awab167-B59","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1136\/jnnp-2011-302021","article-title":"Lithium lacks effect on survival in amyotrophic lateral sclerosis: A phase IIb randomised sequential trial","volume":"83","author":"Verstraete","year":"2012","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"14","key":"2021103110133989800_awab167-B60","doi-asserted-by":"crossref","first-page":"e1610","DOI":"10.1212\/WNL.0000000000007242","article-title":"Revised Airlie House consensus guidelines for design and implementation of ALS clinical trials","volume":"92","author":"van den Berg","year":"2019","journal-title":"Neurology"},{"issue":"2","key":"2021103110133989800_awab167-B61","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1136\/jnnp-2018-318704","article-title":"Neurofilament light chain in serum for the diagnosis of amyotrophic lateral sclerosis","volume":"90","author":"Verde","year":"2019","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"1","key":"2021103110133989800_awab167-B62","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1002\/ana.25276","article-title":"Neurofilament light: A candidate biomarker of presymptomatic amyotrophic lateral sclerosis and phenoconversion","volume":"84","author":"Benatar","year":"2018","journal-title":"Ann Neurol"},{"issue":"1","key":"2021103110133989800_awab167-B63","doi-asserted-by":"crossref","first-page":"e59","DOI":"10.1212\/WNL.0000000000009559","article-title":"Validation of serum neurofilaments as prognostic and potential pharmacodynamic biomarkers for ALS","volume":"95","author":"Benatar","year":"2020","journal-title":"Neurology"},{"issue":"9","key":"2021103110133989800_awab167-B64","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1038\/nsmb.3443","article-title":"Decoding the selectivity of eIF2\u03b1 holophosphatases and PPP1R15A inhibitors","volume":"24","author":"Carrara","year":"2017","journal-title":"Nat Struct Mol Biol"},{"issue":"3","key":"2021103110133989800_awab167-B65","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1083\/jcb.201302044","article-title":"Stress granules as crucibles of ALS pathogenesis","volume":"201","author":"Li","year":"2013","journal-title":"J Cell Biol"},{"issue":"5","key":"2021103110133989800_awab167-B66","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/nn.2297","article-title":"A role for motoneuron subtype-selective ER stress in disease manifestations of FALS mice","volume":"12","author":"Saxena","year":"2009","journal-title":"Nat Neurosci"},{"key":"2021103110133989800_awab167-B67","doi-asserted-by":"crossref","first-page":"e147","DOI":"10.1038\/emm.2014.117","article-title":"Degradation of misfolded proteins in neurodegenerative diseases: Therapeutic targets and strategies","volume":"47","author":"Ciechanover","year":"2015","journal-title":"Exp Mol Med"},{"issue":"6","key":"2021103110133989800_awab167-B68","doi-asserted-by":"crossref","first-page":"354","DOI":"10.2976\/1.2995726","article-title":"SOD1-associated ALS: A promising system for elucidating the origin of protein-misfolding disease","volume":"2","author":"Nordlund","year":"2008","journal-title":"HFSP J."},{"issue":"6","key":"2021103110133989800_awab167-B69","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1083\/jcb.200908164","article-title":"Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond","volume":"187","author":"Ilieva","year":"2009","journal-title":"J Cell Biol"},{"issue":"3","key":"2021103110133989800_awab167-B70","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1093\/jnen\/nlz130","article-title":"Neuropathology of speech network distinguishes bulbar from nonbulbar amyotrophic lateral sclerosis","volume":"79","author":"Shellikeri","year":"2020","journal-title":"J Neuropathol Exp Neurol"}],"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awab167\/40439784\/awab167.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/brain\/article-pdf\/144\/9\/2635\/40880300\/awab167.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/brain\/article-pdf\/144\/9\/2635\/40880300\/awab167.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,31]],"date-time":"2021-10-31T10:15:31Z","timestamp":1635675331000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/article\/144\/9\/2635\/6255742"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,27]]},"references-count":70,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,4,27]]},"published-print":{"date-parts":[[2021,10,22]]}},"URL":"https:\/\/doi.org\/10.1093\/brain\/awab167","relation":{},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,9,1]]},"published":{"date-parts":[[2021,4,27]]}}}