{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T17:16:49Z","timestamp":1792689409958,"version":"4.5.0"},"reference-count":284,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T00:00:00Z","timestamp":1744588800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the progressive degeneration of upper and lower motor neurons, leading to muscle atrophy, paralysis, and respiratory failure. This comprehensive review synthesizes the current knowledge on ALS pathophysiology, clinical heterogeneity, diagnostic frameworks, and evolving therapeutic strategies. Mechanistically, ALS arises from complex interactions between genetic mutations (e.g., in C9orf72, SOD1, TARDBP (TDP-43), and FUS) and dysregulated cellular pathways, including impaired RNA metabolism, protein misfolding, nucleocytoplasmic transport defects, and prion-like propagation of toxic aggregates. Phenotypic heterogeneity, manifesting as bulbar-, spinal-, or respiratory-onset variants, complicates its early diagnosis, which thus necessitates the rigorous application of the revised El Escorial criteria and emerging biomarkers such as neurofilament light chain. Clinically, ALS intersects with frontotemporal dementia (FTD) in up to 50% of the cases, driven by shared TDP-43 pathology and C9orf72 hexanucleotide expansions. Epidemiological studies have revealed a lifetime risk of 1:350, with male predominance (1.5:1) and peak onset between 50 and 70 years. Disease progression varies widely, with a median survival of 2\u20134 years post-diagnosis, underscoring the urgency for early intervention. Approved therapies, including riluzole (glutamate modulation), edaravone (antioxidant), and tofersen (antisense oligonucleotide), offer modest survival benefits, while dextromethorphan\/quinidine alleviates the pseudobulbar affect. Non-pharmacological treatment advances, such as non-invasive ventilation (NIV), prolong survival by 13 months and improve quality of life, particularly in bulb-involved patients. Multidisciplinary care\u2014integrating physical therapy, respiratory support, nutritional management, and cognitive assessments\u2014is critical to addressing motor and non-motor symptoms (e.g., dysphagia, spasticity, sleep disturbances). Emerging therapies show promise in preclinical models. However, challenges persist in translating genetic insights into universally effective treatments. Ethical considerations, including euthanasia and end-of-life decision-making, further highlight the need for patient-centered communication and palliative strategies.<\/jats:p>","DOI":"10.3390\/life15040647","type":"journal-article","created":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T08:11:39Z","timestamp":1744704699000},"page":"647","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Pathophysiology, Clinical Heterogeneity, and Therapeutic Advances in Amyotrophic Lateral Sclerosis: A Comprehensive Review of Molecular Mechanisms, Diagnostic Challenges, and Multidisciplinary Management Strategies"],"prefix":"10.3390","volume":"15","author":[{"given":"Mar\u00eda","family":"Gonz\u00e1lez-S\u00e1nchez","sequence":"first","affiliation":[{"name":"Experimental and Clinical Physiopathology Research Group CTS-1039, Department of Health Sciences, School of Health Sciences, University of Ja\u00e9n, E23071 Ja\u00e9n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9379-203X","authenticated-orcid":false,"given":"Mar\u00eda Jes\u00fas","family":"Ram\u00edrez-Exp\u00f3sito","sequence":"additional","affiliation":[{"name":"Experimental and Clinical Physiopathology Research Group CTS-1039, Department of Health Sciences, School of Health Sciences, University of Ja\u00e9n, E23071 Ja\u00e9n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2950-5614","authenticated-orcid":false,"given":"Jos\u00e9 Manuel","family":"Mart\u00ednez-Martos","sequence":"additional","affiliation":[{"name":"Experimental and Clinical Physiopathology Research Group CTS-1039, Department of Health Sciences, School of Health Sciences, University of Ja\u00e9n, E23071 Ja\u00e9n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Fenoy, A. (2024). Scientific plurality and amyotrophic lateral sclerosis (ALS): A philosophical and historical perspective on Charcot\u2019s texts. J. Hist. Neurosci., 1\u201310.","DOI":"10.1080\/0964704X.2024.2380635"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1097\/WCO.0000000000001294","article-title":"The genetics of amyotrophic lateral sclerosis","volume":"37","author":"Nijs","year":"2024","journal-title":"Curr. Opin. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e16264","DOI":"10.1111\/ene.16264","article-title":"European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD)","volume":"31","author":"Andersen","year":"2024","journal-title":"Eur. J. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1002\/mus.28290","article-title":"Amyotrophic lateral sclerosis represents corticomotoneuronal system failure","volume":"71","author":"Eisen","year":"2025","journal-title":"Muscle Nerve"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e25567","DOI":"10.1002\/cne.25567","article-title":"Betz cells of the primary motor cortex","volume":"532","author":"Nolan","year":"2024","journal-title":"J. Comp. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.clinph.2024.02.001","article-title":"The Corticospinal System and Amyotrophic Lateral Sclerosis: IFCN handbook chapter","volume":"160","author":"Lemon","year":"2024","journal-title":"Clin. Neurophysiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5357","DOI":"10.1007\/s00415-024-12408-y","article-title":"Clinical spreading of muscle weakness in amyotrophic lateral sclerosis (ALS): A study in 910 patients","volume":"271","author":"Ludolph","year":"2024","journal-title":"J. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1016\/S1474-4422(21)00465-8","article-title":"Recent advances in the diagnosis and prognosis of amyotrophic lateral sclerosis","volume":"21","author":"Goutman","year":"2022","journal-title":"Lancet Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/S1474-4422(21)00414-2","article-title":"Emerging insights into the complex genetics and pathophysiology of amyotrophic lateral sclerosis","volume":"21","author":"Goutman","year":"2022","journal-title":"Lancet Neurol."},{"key":"ref_10","unstructured":"Brotman, R.G., Moreno-Escobar, M.C., Joseph, J., Munakomi, S., and Pawar, G. (2025). Amyotrophic Lateral Sclerosis. StatPearls, StatPearls."},{"key":"ref_11","unstructured":"Kaneko, K., Hoskin, J., and Hodis, B. (2025). Primary Lateral Sclerosis. StatPearls, StatPearls."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"C1029","DOI":"10.1152\/ajpcell.00725.2024","article-title":"Dysregulation of synaptic transcripts underlies network abnormalities in ALS patient-derived motor neurons","volume":"328","author":"Kollstrom","year":"2025","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_13","unstructured":"Ramroop, H., and Cruz, R. (2025). Electrodiagnostic Evaluation of Motor Neuron Disease. StatPearls, StatPearls."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.1212\/01.wnl.0000261045.57095.56","article-title":"Implications of ALS focality: Rostral-caudal distribution of lower motor neuron loss postmortem","volume":"68","author":"Ravits","year":"2007","journal-title":"Neurology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1212\/01.wnl.0000260965.20021.47","article-title":"Focality of upper and lower motor neuron degeneration at the clinical onset of ALS","volume":"68","author":"Ravits","year":"2007","journal-title":"Neurology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"102594","DOI":"10.1016\/j.arr.2024.102594","article-title":"Unknown roles of tau pathology in neurological disorders. Challenges and new perspectives","volume":"103","author":"Olesen","year":"2025","journal-title":"Ageing Res. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Pradat, P.F., and El Mendili, M.M. (2014). Neuroimaging to investigate multisystem involvement and provide biomarkers in amyotrophic lateral sclerosis. Biomed. Res. Int., 2014.","DOI":"10.1155\/2014\/467560"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1002\/mus.26801","article-title":"Addressing heterogeneity in amyotrophic lateral sclerosis CLINICAL TRIALS","volume":"62","author":"Goyal","year":"2020","journal-title":"Muscle Nerve"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1016\/S1474-4422(14)70167-X","article-title":"Neuroimaging in amyotrophic lateral sclerosis: Insights into structural and functional changes","volume":"13","author":"Chio","year":"2014","journal-title":"Lancet Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1080\/14737175.2025.2470324","article-title":"A comprehensive update on neuroimaging endpoints in amyotrophic lateral sclerosis","volume":"25","author":"Filippi","year":"2025","journal-title":"Expert Rev. Neurother."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"103749","DOI":"10.1016\/j.nicl.2025.103749","article-title":"Neuroimaging correlates of domain-specific cognitive deficits in amyotrophic lateral sclerosis","volume":"45","author":"Tan","year":"2025","journal-title":"Neuroimage Clin."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s13311-016-0484-9","article-title":"Neuroimaging Endpoints in Amyotrophic Lateral Sclerosis","volume":"14","author":"Menke","year":"2017","journal-title":"Neurotherapeutics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1136\/jnnp-2020-322992","article-title":"Progression of cognitive and behavioural impairment in early amyotrophic lateral sclerosis","volume":"91","author":"Beeldman","year":"2020","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1097\/WCO.0000000000000862","article-title":"Cognitive and behavioural impairment in amyotrophic lateral sclerosis","volume":"33","author":"Pender","year":"2020","journal-title":"Curr. Opin. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1080\/21678421.2020.1771732","article-title":"Decline of cognitive and behavioral functions in amyotrophic lateral sclerosis: A longitudinal study","volume":"21","author":"Bersano","year":"2020","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e1370","DOI":"10.1212\/WNL.0000000000006317","article-title":"ALS-specific cognitive and behavior changes associated with advancing disease stage in ALS","volume":"91","author":"Crockford","year":"2018","journal-title":"Neurology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1002\/ana.24306","article-title":"Amyotrophic lateral sclerosis onset is influenced by the burden of rare variants in known amyotrophic lateral sclerosis genes","volume":"77","author":"Cady","year":"2015","journal-title":"Ann. Neurol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6480","DOI":"10.1007\/s12035-017-0856-0","article-title":"Causative Genes in Amyotrophic Lateral Sclerosis and Protein Degradation Pathways: A Link to Neurodegeneration","volume":"55","author":"Maurel","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/S1474-4422(25)00026-2","article-title":"Amyotrophic lateral sclerosis caused by hexanucleotide repeat expansions in C9orf72: From genetics to therapeutics","volume":"24","author":"Mizielinska","year":"2025","journal-title":"Lancet. Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/S1474-4422(24)00517-9","article-title":"Amyotrophic lateral sclerosis caused by FUS mutations: Advances with broad implications","volume":"24","author":"Moens","year":"2025","journal-title":"Lancet Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/978-3-031-75980-2_3","article-title":"Epigenetics in Neurodegenerative Diseases","volume":"108","author":"Montecino","year":"2025","journal-title":"Subcell Biochem."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"AlAnazi, A., Alghadir, A.H., and Gabr, S.A. (2022). Handgrip Strength Exercises Modulate Shoulder Pain, Function, and Strength of Rotator Cuff Muscles of Patients with Primary Subacromial Impingement Syndrome. Biomed. Res. Int., 2022.","DOI":"10.1155\/2022\/9151831"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1093\/brain\/117.4.747","article-title":"Frontal lobe atrophy in motor neuron diseases","volume":"117","author":"Kiernan","year":"1994","journal-title":"Brain"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1016\/S0140-6736(10)61156-7","article-title":"Amyotrophic lateral sclerosis","volume":"377","author":"Kiernan","year":"2011","journal-title":"Lancet"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1212\/WNL.59.7.1077","article-title":"The overlap of amyotrophic lateral sclerosis and frontotemporal dementia","volume":"59","author":"Anderson","year":"2002","journal-title":"Neurology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1080\/17482960802654364","article-title":"Consensus criteria for the diagnosis of frontotemporal cognitive and behavioural syndromes in amyotrophic lateral sclerosis","volume":"10","author":"Strong","year":"2009","journal-title":"Amyotroph. Lateral Scler."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1212\/WNL.53.8.1665","article-title":"A prospective study of cognitive impairment in ALS","volume":"53","author":"Strong","year":"1999","journal-title":"Neurology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.bbrc.2006.10.093","article-title":"TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis","volume":"351","author":"Arai","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1126\/science.1134108","article-title":"Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis","volume":"314","author":"Neumann","year":"2006","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Dang, M., Wu, L., and Zhang, X. (2025). Structural insights and milestones in TDP-43 research: A comprehensive review of its pathological and therapeutic advances. Int. J. Biol. Macromol., 306.","DOI":"10.1016\/j.ijbiomac.2025.141677"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1007\/s00702-024-02850-7","article-title":"Mild cognitive impairment in amyotrophic lateral sclerosis: Current view","volume":"132","author":"Jellinger","year":"2025","journal-title":"J. Neural. Transm."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.neuron.2011.09.011","article-title":"Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS","volume":"72","author":"Mackenzie","year":"2011","journal-title":"Neuron"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.neuron.2011.09.010","article-title":"A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD","volume":"72","author":"Renton","year":"2011","journal-title":"Neuron"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1002\/mus.25712","article-title":"Improving symptom management for people with amyotrophic lateral sclerosis","volume":"57","author":"Nicholson","year":"2018","journal-title":"Muscle Nerve"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s00401-007-0237-2","article-title":"Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: Consensus of the Consortium for Frontotemporal Lobar Degeneration","volume":"114","author":"Cairns","year":"2007","journal-title":"Acta Neuropathol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"fcaf065","DOI":"10.1093\/braincomms\/fcaf065","article-title":"Frontotemporal dementia subtyping using machine learning, multivariate statistics and neuroimaging","volume":"7","author":"Metz","year":"2025","journal-title":"Brain Commun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1111\/j.1440-1789.2003.00544.x","article-title":"Amyotrophic lateral sclerosis with dementia: The clinicopathological spectrum","volume":"24","author":"Yoshida","year":"2004","journal-title":"Neuropathology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1007\/s12031-011-9561-z","article-title":"What are the different initial presentations of frontotemporal dementia?","volume":"45","author":"Chow","year":"2011","journal-title":"J. Mol. Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1001\/jamaneurol.2019.2044","article-title":"Lifetime Risk and Heritability of Amyotrophic Lateral Sclerosis","volume":"76","author":"Ryan","year":"2019","journal-title":"JAMA Neurol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1080\/21678421.2024.2405118","article-title":"Amyotrophic lateral sclerosis caused by the C9orf72 expansion in Norway\u2014Prevalence, ancestry, clinical characteristics and sociodemographic status","volume":"26","author":"Olsen","year":"2025","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1080\/21678421.2017.1418004","article-title":"Assessing amyotrophic lateral sclerosis prevalence in Norway from 2009 to 2015 from compulsory nationwide health registers","volume":"19","author":"Nakken","year":"2018","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"284","DOI":"10.3109\/17482968.2012.662689","article-title":"Incidence of amyotrophic lateral sclerosis in Sicily: A population based study","volume":"13","author":"Ragonese","year":"2012","journal-title":"Amyotroph. Lateral Scler."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1111\/j.1468-1331.2009.02586.x","article-title":"Incidence and lifetime risk of motor neuron disease in the United Kingdom: A population-based study","volume":"16","author":"Alonso","year":"2009","journal-title":"Eur. J. Neurol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1212\/01.wnl.0000343008.26874.d1","article-title":"Epidemiology of ALS in Italy: A 10-year prospective population-based study","volume":"72","author":"Chio","year":"2009","journal-title":"Neurology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1212\/CPJ.0b013e3182a1b8ab","article-title":"Prognosis and epidemiology of amyotrophic lateral sclerosis: Analysis of a clinic population, 1997\u20132011","volume":"3","author":"Traxinger","year":"2013","journal-title":"Neurol. Clin. Pract."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1111\/j.1468-1331.2011.03501.x","article-title":"EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS)--revised report of an EFNS task force","volume":"19","author":"Diagnosis","year":"2012","journal-title":"Eur. J. Neurol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1007\/s00415-016-8313-y","article-title":"Factors predicting survival in ALS: A multicenter Italian study","volume":"264","author":"Calvo","year":"2017","journal-title":"J. Neurol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1007\/s10654-018-0392-x","article-title":"Age-specific ALS incidence: A dose-response meta-analysis","volume":"33","author":"Marin","year":"2018","journal-title":"Eur. J. Epidemiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.15585\/mmwr.mm6746a1","article-title":"Prevalence of Amyotrophic Lateral Sclerosis\u2014United States, 2015","volume":"67","author":"Mehta","year":"2018","journal-title":"MMWR Morb. Mortal Wkly Rep."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1007\/s00415-019-09652-y","article-title":"Global variation in prevalence and incidence of amyotrophic lateral sclerosis: A systematic review and meta-analysis","volume":"267","author":"Xu","year":"2020","journal-title":"J. Neurol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1001\/jamaneurol.2020.4152","article-title":"Burden of Neurological Disorders Across the US From 1990-2017: A Global Burden of Disease Study","volume":"78","author":"Collaborators","year":"2021","journal-title":"JAMA Neurol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"12408","DOI":"10.1038\/ncomms12408","article-title":"Projected increase in amyotrophic lateral sclerosis from 2015 to 2040","volume":"7","author":"Arthur","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1159\/000351153","article-title":"Global epidemiology of amyotrophic lateral sclerosis: A systematic review of the published literature","volume":"41","author":"Chio","year":"2013","journal-title":"Neuroepidemiology"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1080\/21678421.2016.1195410","article-title":"Prognostic factors and survival of ALS patients from Belgrade, Serbia","volume":"17","author":"Stevic","year":"2016","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1080\/21678421.2020.1752252","article-title":"The epidemiology of amyotrophic lateral sclerosis in Moscow (Russia)","volume":"21","author":"Brylev","year":"2020","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1159\/000477126","article-title":"Epidemiology of Amyotrophic Lateral Sclerosis in the Republic of Cyprus: A 25-Year Retrospective Study","volume":"48","author":"Demetriou","year":"2017","journal-title":"Neuroepidemiology"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Demetriou, C.A., Hadjivasiliou, P.M., Kleopa, K.A., Christou, Y.P., Leonidou, E., Kyriakides, T., and Zamba-Papanicolaou, E. (2019). Retrospective longitudinal study of ALS in Cyprus: Clinical characteristics, management and survival. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0220246"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1159\/000493386","article-title":"Amyotrophic Lateral Sclerosis Descriptive Epidemiology: The Origin of Geographic Difference","volume":"52","author":"Logroscino","year":"2019","journal-title":"Neuroepidemiology"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1080\/21678421.2021.1909066","article-title":"Epidemiological and genetic features of amyotrophic lateral sclerosis in Latin America and the Caribbean: A systematic review","volume":"23","author":"Erazo","year":"2022","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_70","first-page":"1","article-title":"Prevalence of amyotrophic lateral sclerosis-United States, 2010\u20132011","volume":"63","author":"Mehta","year":"2014","journal-title":"MMWR Suppl."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1136\/jnnp.2009.183525","article-title":"Incidence of amyotrophic lateral sclerosis in Europe","volume":"81","author":"Logroscino","year":"2010","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1159\/000516752","article-title":"Estimated Prevalence and Incidence of Amyotrophic Lateral Sclerosis and SOD1 and C9orf72 Genetic Variants","volume":"55","author":"Brown","year":"2021","journal-title":"Neuroepidemiology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e613","DOI":"10.1212\/WNL.0000000000207474","article-title":"Global Prevalence and Incidence of Amyotrophic Lateral Sclerosis: A Systematic Review","volume":"101","author":"Wolfson","year":"2023","journal-title":"Neurology"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1111\/jnc.15255","article-title":"Cellular and physiological functions of C9ORF72 and implications for ALS\/FTD","volume":"157","author":"Pang","year":"2021","journal-title":"J. Neurochem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s12961-025-01287-y","article-title":"The EU project Real4Reg: Unlocking real-world data with AI","volume":"23","author":"Peltner","year":"2025","journal-title":"Health Res. Policy Syst."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Liu, Z., and Song, S.Y. (2025). Genomic and Transcriptomic Approaches Advance the Diagnosis and Prognosis of Neurodegenerative Diseases. Genes, 16.","DOI":"10.3390\/genes16020135"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"115242","DOI":"10.1016\/j.bbr.2024.115242","article-title":"Emerging targets in amyotrophic lateral sclerosis (ALS): The promise of ATP-binding cassette (ABC) transporter modulation","volume":"476","author":"Mohan","year":"2025","journal-title":"Behav. Brain Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/j.tig.2018.03.001","article-title":"ALS Genes in the Genomic Era and their Implications for FTD","volume":"34","author":"Nguyen","year":"2018","journal-title":"Trends Genet"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"4696","DOI":"10.1073\/pnas.1818415116","article-title":"Motor neuron disease-associated loss of nuclear TDP-43 is linked to DNA double-strand break repair defects","volume":"116","author":"Mitra","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1093\/brain\/awx082","article-title":"A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK","volume":"140","author":"Morgan","year":"2017","journal-title":"Brain"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.neuron.2017.07.029","article-title":"Lost in Transportation: Nucleocytoplasmic Transport Defects in ALS and Other Neurodegenerative Diseases","volume":"96","author":"Kim","year":"2017","journal-title":"Neuron"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"263","DOI":"10.24272\/j.issn.2095-8137.2024.286","article-title":"Ribosome-associated pathological TDP-43 alters the expression of multiple mRNAs in the monkey brain","volume":"46","author":"Deng","year":"2025","journal-title":"Zool Res."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Mengistu, D.Y., Terribili, M., Pellacani, C., Ciapponi, L., and Marzullo, M. (2025). Epigenetic regulation of TDP-43: Potential implications for amyotrophic lateral sclerosis. Front. Mol. Med., 5.","DOI":"10.3389\/fmmed.2025.1530719"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1038\/nature14974","article-title":"GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport","volume":"525","author":"Freibaum","year":"2015","journal-title":"Nature"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/nature14973","article-title":"The C9orf72 repeat expansion disrupts nucleocytoplasmic transport","volume":"525","author":"Zhang","year":"2015","journal-title":"Nature"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1038\/s41593-021-00859-9","article-title":"Interactions between ALS-linked FUS and nucleoporins are associated with defects in the nucleocytoplasmic transport pathway","volume":"24","author":"Lin","year":"2021","journal-title":"Nat. Neurosci."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.neuroscience.2017.03.024","article-title":"Aberrant distributions of nuclear pore complex proteins in ALS mice and ALS patients","volume":"350","author":"Shang","year":"2017","journal-title":"Neuroscience"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1038\/s41593-017-0047-3","article-title":"TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS\/FTD","volume":"21","author":"Chou","year":"2018","journal-title":"Nat. Neurosci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"eaav2606","DOI":"10.1126\/science.aav2606","article-title":"Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity","volume":"363","author":"Zhang","year":"2019","journal-title":"Science"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1248\/bpb.b24-00794","article-title":"Activated Fibroblast Growth Factor Receptor 1 Mitigated Poly-PR-Induced Oxidative Stress and Protein Translational Impairment","volume":"48","author":"Ito","year":"2025","journal-title":"Biol. Pharm. Bull"},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Kim, K.M., Girdhar, A., Cicardi, M.E., Kankate, V., Hayashi, M., Yang, R., Carey, J.L., Fare, C.M., Shorter, J., and Cingolani, G. (2025). NLS-binding deficient Kapbeta2 reduces neurotoxicity via selective interaction with C9orf72-ALS\/FTD dipeptide repeats. Commun. Biol., 8.","DOI":"10.1038\/s42003-024-07412-x"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/jmcb\/mjaa049","article-title":"Role and therapeutic potential of liquid-liquid phase separation in amyotrophic lateral sclerosis","volume":"13","author":"Pakravan","year":"2021","journal-title":"J. Mol. Cell Biol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1007\/978-3-031-68827-0_16","article-title":"Neurological Diseases can be Regulated by Phase Separation","volume":"187","author":"McCaig","year":"2025","journal-title":"Rev. Physiol. Biochem. Pharmacol."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Pokrishevsky, E., Grad, L.I., and Cashman, N.R. (2016). TDP-43 or FUS-induced misfolded human wild-type SOD1 can propagate intercellularly in a prion-like fashion. Sci. Rep., 6.","DOI":"10.1038\/srep22155"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/j.celrep.2016.09.032","article-title":"Cell-to-Cell Transmission of Dipeptide Repeat Proteins Linked to C9orf72-ALS\/FTD","volume":"17","author":"Westergard","year":"2016","journal-title":"Cell Rep."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"e102811","DOI":"10.15252\/embj.2019102811","article-title":"Cell-to-cell transmission of C9orf72 poly-(Gly-Ala) triggers key features of ALS\/FTD","volume":"39","author":"Khosravi","year":"2020","journal-title":"EMBO J."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Sackmann, C., Sackmann, V., and Hallbeck, M. (2020). TDP-43 Is Efficiently Transferred Between Neuron-Like Cells in a Manner Enhanced by Preservation of Its N-Terminus but Independent of Extracellular Vesicles. Front. Neurosci., 14.","DOI":"10.3389\/fnins.2020.00540"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"e2408582122","DOI":"10.1073\/pnas.2408582122","article-title":"Structural insights into the role of reduced cysteine residues in SOD1 amyloid filament formation","volume":"122","author":"Baek","year":"2025","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"e70256","DOI":"10.1002\/brb3.70256","article-title":"Prognostic Value of Cerebrospinal Fluid and Serum Neurofilament Light Chain in Amyotrophic Lateral Sclerosis: A Correlation Study","volume":"15","author":"Dong","year":"2025","journal-title":"Brain Behav."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Dragoni, F., Garofalo, M., Di Gerlando, R., Rizzo, B., Bordoni, M., Scarian, E., Viola, C., Bettoni, V., Fiamingo, G., and Tornabene, D. (2025). Whole transcriptome analysis of unmutated sporadic ALS patients\u2019 peripheral blood reveals phenotype-specific gene expression signature. Neurobiol. Dis., 206.","DOI":"10.1016\/j.nbd.2025.106823"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1002\/ana.26860","article-title":"Biomarker Qualification for Neurofilament Light Chain in Amyotrophic Lateral Sclerosis: Theory and Practice","volume":"95","author":"Benatar","year":"2024","journal-title":"Ann. Neurol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2711","DOI":"10.1093\/brain\/awac394","article-title":"Neurofilament light chain in drug development for amyotrophic lateral sclerosis: A critical appraisal","volume":"146","author":"Benatar","year":"2023","journal-title":"Brain"},{"key":"ref_103","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"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1002\/acn3.51078","article-title":"Longitudinal biomarkers in amyotrophic lateral sclerosis","volume":"7","author":"Huang","year":"2020","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_105","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."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"e1466","DOI":"10.1212\/WNL.0000000000012632","article-title":"Prediagnostic Neurofilament Light Chain Levels in Amyotrophic Lateral Sclerosis","volume":"97","author":"Bjornevik","year":"2021","journal-title":"Neurology"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1111\/nan.12511","article-title":"Serum neurofilament light chain levels as a marker of upper motor neuron degeneration in patients with Amyotrophic Lateral Sclerosis","volume":"45","author":"Gille","year":"2019","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"e213400","DOI":"10.1212\/WNL.0000000000213400","article-title":"Comparative Performances of 4 Serum NfL Assays, pTau181, and GFAP in Patients With Amyotrophic Lateral Sclerosis","volume":"104","author":"Mondesert","year":"2025","journal-title":"Neurology"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1771","DOI":"10.1038\/s41591-024-02937-4","article-title":"Plasma extracellular vesicle tau and TDP-43 as diagnostic biomarkers in FTD and ALS","volume":"30","author":"Chatterjee","year":"2024","journal-title":"Nat. Med."},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Sugimoto, K., Han, Y., Song, Y., and Gao, Y. (2020). Correlational Analysis of ALS Progression and Serum NfL Measured by Simoa Assay in Chinese Patients. Front. Neurol., 11.","DOI":"10.3389\/fneur.2020.579094"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1016\/j.acra.2017.04.008","article-title":"Quantitative FLAIR MRI in Amyotrophic Lateral Sclerosis","volume":"24","author":"Fabes","year":"2017","journal-title":"Acad. Radiol."},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Thomas, E.V., Han, C., Kim, W.J., Asress, S., Li, Y., Taylor, J.A., Gearing, M., Fournier, C.N., McEachin, Z.T., and Seyfried, N.T. (2025). ALS plasma biomarkers reveal neurofilament and pTau correlate with disease onset and progression. Ann. Clin. Transl. Neurol.","DOI":"10.1002\/acn3.70001"},{"key":"ref_113","first-page":"2325","article-title":"Transcriptomic profiling of cerebrospinal fluid identifies ALS pathway enrichment and RNA biomarkers in MND individuals","volume":"248","author":"Frohlich","year":"2023","journal-title":"Exp. Biol. Med."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"2799","DOI":"10.1038\/s41467-022-30387-4","article-title":"Poly(GR) and poly(GA) in cerebrospinal fluid as potential biomarkers for C9ORF72-ALS\/FTD","volume":"13","author":"Krishnan","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Ansari, A., Thibault, P.A., Salapa, H.E., Clarke, J.W.E., and Levin, M.C. (2025). Mutations in hnRNP A1 drive neurodegeneration and alternative RNA splicing of neuronal gene targets. Neurobiol. Dis., 206.","DOI":"10.1016\/j.nbd.2025.106814"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1093\/brain\/awy062","article-title":"TDP-43 regulates the alternative splicing of hnRNP A1 to yield an aggregation-prone variant in amyotrophic lateral sclerosis","volume":"141","author":"Deshaies","year":"2018","journal-title":"Brain"},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Noh, M.Y., Kwon, M.S., Oh, K.W., Nahm, M., Park, J., Jin, H.K., Bae, J.S., Son, B., and Kim, S.H. (2025). miRNA-214 to predict progression and survival in ALS. J. Neurol. Neurosurg. Psychiatry.","DOI":"10.1136\/jnnp-2024-335177"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.neurobiolaging.2017.03.027","article-title":"Serum miRNAs miR-206, 143\u20133p and 374b-5p as potential biomarkers for amyotrophic lateral sclerosis (ALS)","volume":"55","author":"Waller","year":"2017","journal-title":"Neurobiol. Aging"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"137493","DOI":"10.1016\/j.neulet.2023.137493","article-title":"Protective effects of EVs\/exosomes derived from permanently growing human MSC on primary murine ALS motor neurons","volume":"816","author":"Gschwendtberger","year":"2023","journal-title":"Neurosci. Lett."},{"key":"ref_120","doi-asserted-by":"crossref","unstructured":"Moreno-Garcia, L., Miana-Mena, F.J., Moreno-Martinez, L., de la Torre, M., Lunetta, C., Tarlarini, C., Zaragoza, P., Calvo, A.C., and Osta, R. (2021). Inflammasome in ALS Skeletal Muscle: NLRP3 as a Potential Biomarker. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052523"},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Si, Y., Kazamel, M., Benatar, M., Wuu, J., Kwon, Y., Kwan, T., Jiang, N., Kentrup, D., Faul, C., and Alesce, L. (2021). FGF23, a novel muscle biomarker detected in the early stages of ALS. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-91496-6"},{"key":"ref_122","doi-asserted-by":"crossref","unstructured":"Golini, E., Rigamonti, M., Iannello, F., De Rosa, C., Scavizzi, F., Raspa, M., and Mandillo, S. (2020). A Non-invasive Digital Biomarker for the Detection of Rest Disturbances in the SOD1G93A Mouse Model of ALS. Front. Neurosci., 14.","DOI":"10.3389\/fnins.2020.00896"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1186\/s12984-024-01514-7","article-title":"Free-living monitoring of ALS progression in upper limbs using wearable accelerometers","volume":"21","author":"Straczkiewicz","year":"2024","journal-title":"J. Neuroeng. Rehabil."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1080\/21678421.2023.2239312","article-title":"PROSA-a multicenter prospective observational study to develop low-burden digital speech biomarkers in ALS and FTD","volume":"24","author":"Troger","year":"2023","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_125","doi-asserted-by":"crossref","unstructured":"Troger, J., Dorr, F., Schwed, L., Linz, N., Konig, A., Thies, T., Barbe, M.T., Orozco-Arroyave, J.R., and Rusz, J. (2024). An automatic measure for speech intelligibility in dysarthrias-validation across multiple languages and neurological disorders. Front. Digit. Health, 6.","DOI":"10.3389\/fdgth.2024.1440986"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1007\/s00415-012-6665-5","article-title":"Endogenous female reproductive hormones and the risk of amyotrophic lateral sclerosis","volume":"260","author":"Huisman","year":"2013","journal-title":"J. Neurol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1054\/mehy.1999.1150","article-title":"The ratio of 2nd to 4th digit length: A new predictor of disease predisposition?","volume":"54","author":"Manning","year":"2000","journal-title":"Med. Hypotheses"},{"key":"ref_128","first-page":"635","article-title":"Low index-to-ring finger length ratio in sporadic ALS supports prenatally defined motor neuronal vulnerability","volume":"82","author":"Vivekananda","year":"2011","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1093\/aje\/kws015","article-title":"Smoking, alcohol consumption, and the risk of amyotrophic lateral sclerosis: A population-based study","volume":"176","author":"Huisman","year":"2012","journal-title":"Am. J. Epidemiol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1016\/j.arthro.2015.01.026","article-title":"Smoking Predisposes to Rotator Cuff Pathology and Shoulder Dysfunction: A Systematic Review","volume":"31","author":"Bishop","year":"2015","journal-title":"Arthroscopy"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1136\/jnnp-2024-334339","article-title":"Guidance for clinical management of pathogenic variant carriers at elevated genetic risk for ALS\/FTD","volume":"96","author":"Benatar","year":"2025","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1093\/epirev\/mxu001","article-title":"Military service, deployments, and exposures in relation to amyotrophic lateral sclerosis etiology and survival","volume":"37","author":"Beard","year":"2015","journal-title":"Epidemiol. Rev."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1080\/14660820600640596","article-title":"Analysis of factors that modify susceptibility and rate of progression in amyotrophic lateral sclerosis (ALS)","volume":"7","author":"Qureshi","year":"2006","journal-title":"Amyotroph. Lateral Scler."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1212\/01.WNL.0000069922.32557.CA","article-title":"Occurrence of amyotrophic lateral sclerosis among Gulf War veterans","volume":"61","author":"Horner","year":"2003","journal-title":"Neurology"},{"key":"ref_135","first-page":"e5","article-title":"Association of ALS and Military Service: Reflection of Survival Bias due to the \u201cHealthy Soldier Effect\u201d?","volume":"185","author":"Niazi","year":"2020","journal-title":"Mil. Med."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1007\/s10654-014-9923-2","article-title":"Epidemiological evidence that physical activity is not a risk factor for ALS","volume":"29","author":"Hamidou","year":"2014","journal-title":"Eur. J. Epidemiol."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1007\/s00113-024-01507-0","article-title":"Conservative treatment of injuries to the cervical spine: Mobilization or immobilization","volume":"128","author":"Arras","year":"2025","journal-title":"Unfallchirurgie"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1136\/jnnp-2012-304724","article-title":"Lifetime physical activity and the risk of amyotrophic lateral sclerosis","volume":"84","author":"Huisman","year":"2013","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1212\/WNL.0000000000001528","article-title":"A blow to the head trauma\u2014ALS hypothesis","volume":"84","author":"Armon","year":"2015","journal-title":"Neurology"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1007\/s00264-024-06363-6","article-title":"Outcomes of combined single-bundle anterior cruciate ligament reconstruction and anterolateral structure reconstruction through a modified single femoral tunnel","volume":"49","author":"Cao","year":"2025","journal-title":"Int. Orthop."},{"key":"ref_141","doi-asserted-by":"crossref","unstructured":"Falcao de Campos, C., Gromicho, M., Uysal, H., Grosskreutz, J., Kuzma-Kozakiewicz, M., Oliveira Santos, M., Pinto, S., Petri, S., Swash, M., and de Carvalho, M. (2021). Delayed Diagnosis and Diagnostic Pathway of ALS Patients in Portugal: Where Can We Improve?. Front. Neurol., 12.","DOI":"10.3389\/fneur.2021.761355"},{"key":"ref_142","doi-asserted-by":"crossref","unstructured":"Williams, J.R., Fitzhenry, D., Grant, L., Martyn, D., and Kerr, D.A. (2013). Diagnosis pathway for patients with amyotrophic lateral sclerosis: Retrospective analysis of the US Medicare longitudinal claims database. BMC Neurol., 13.","DOI":"10.1186\/1471-2377-13-160"},{"key":"ref_143","doi-asserted-by":"crossref","unstructured":"Dave, K.D., Oskarsson, B., Yersak, J., Krauss, R., Heiman-Patterson, T., Lomen-Hoerth, C., Selig, W.K.D., Halpern Paul, I., Schaeffer, M., and Garcia-Trujillo, B. (2024). Contributions of neurologists to diagnostic timelines of ALS and thinkALS as an early referral instrument for clinicians. Amyotroph. Lateral Scler. Front. Degener., 1\u201310.","DOI":"10.1080\/21678421.2024.2432034"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1002\/mus.25444","article-title":"Optimizing muscle selection for electromyography in amyotrophic lateral sclerosis","volume":"56","author":"Babu","year":"2017","journal-title":"Muscle Nerve"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1002\/mus.26158","article-title":"Distal Predominance of Electrodiagnostic Abnormalities in Early-Stage Amyotrophic Lateral Sclerosis","volume":"58","author":"Shayya","year":"2018","journal-title":"Muscle Nerve"},{"key":"ref_146","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."},{"key":"ref_147","first-page":"53","article-title":"Comprehensive rehabilitative care across the spectrum of amyotrophic lateral sclerosis","volume":"37","author":"Paganoni","year":"2015","journal-title":"NeuroRehabilitation"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1007\/s00415-010-5474-y","article-title":"Requests for euthanasia: Origin of suffering in ALS, heart failure, and cancer patients","volume":"257","author":"Maessen","year":"2010","journal-title":"J. Neurol."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1080\/21678421.2020.1732424","article-title":"An overview of screening instruments for cognition and behavior in patients with ALS: Selecting the appropriate tool for clinical practice","volume":"21","author":"Gosselt","year":"2020","journal-title":"Amyotroph. Lateral Scler. Front.l Degener."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1007\/s00415-024-12847-7","article-title":"Predicting ALS informant distress from cognitive and behavioural change in people with ALS","volume":"272","author":"Didcote","year":"2025","journal-title":"J. Neurol."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1093\/ptj\/78.12.1312","article-title":"Physical therapy for a patient through six stages of amyotrophic lateral sclerosis","volume":"78","author":"Kloos","year":"1998","journal-title":"Phys. Ther."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1016\/S0140-6736(22)01272-7","article-title":"Amyotrophic lateral sclerosis","volume":"400","author":"Feldman","year":"2022","journal-title":"Lancet"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"3056","DOI":"10.1111\/ene.15936","article-title":"Cognitive impairment is associated with gait variability and fall risk in amyotrophic lateral sclerosis","volume":"30","author":"Dubbioso","year":"2023","journal-title":"Eur. J. Neurol."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1159\/000530067","article-title":"Spatial-Temporal Analysis of Gait in Amyotrophic Lateral Sclerosis Using Foot-Worn Inertial Sensors: An Observational Study","volume":"8","author":"Lukac","year":"2024","journal-title":"Digit. Biomark."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1080\/14737175.2025.2471556","article-title":"Advances in the early diagnosis of amyotrophic lateral sclerosis","volume":"25","year":"2025","journal-title":"Expert Rev. Neurother."},{"key":"ref_156","first-page":"e71470","article-title":"Efficacy of Aerobic and Stretching Exercises in Managing Willis-Ekbom Disease (Restless Leg Syndrome) Among Hemodialysis Patients","volume":"16","author":"Daffalla","year":"2024","journal-title":"Cureus"},{"key":"ref_157","doi-asserted-by":"crossref","unstructured":"Young, C.A., Chaouch, A., McDermott, C.J., Al-Chalabi, A., Chhetri, S.K., Bidder, C., Edmonds, E., Ellis, C., Annadale, J., and Wilde, L. (2025). Determinants and progression of stigma in amyotrophic lateral sclerosis\/motor neuron disease. Amyotroph. Lateral Scler. Front. Degener., 1\u201311.","DOI":"10.1080\/21678421.2024.2435969"},{"key":"ref_158","first-page":"115","article-title":"Depression, pain and quality of life in patients with amyotrophic lateral sclerosis: A cross-sectional study","volume":"28","author":"Pizzimenti","year":"2013","journal-title":"Funct. Neurol."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"369","DOI":"10.3109\/21678421.2012.751614","article-title":"Prevalence and characteristics of pain in early and late stages of ALS","volume":"14","author":"Rivera","year":"2013","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1097\/CND.0b013e31821c5623","article-title":"Shoulder pain in amyotrophic lateral sclerosis","volume":"13","author":"Ho","year":"2011","journal-title":"J. Clin. Neuromuscul. Dis."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1007\/s10072-018-3633-6","article-title":"Analysis of clinical and electrophysiological characteristics of 150 patients with amyotrophic lateral sclerosis in China","volume":"40","author":"Liu","year":"2019","journal-title":"Neurol. Sci."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"e976","DOI":"10.1212\/NXI.0000000000000976","article-title":"Neuroprotective Properties of 4-Aminopyridine","volume":"8","author":"Dietrich","year":"2021","journal-title":"Neurol. Neuroimmunol. Neuroinflamm."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"243","DOI":"10.25122\/jml-2024-1004","article-title":"A positive effect of Cerebrolysin on motor functions and spasticity in ALS with limb or bulbar onset is questionable","volume":"17","author":"Firstenfeld","year":"2024","journal-title":"J. Med. Life"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1089\/acm.2013.0340","article-title":"Iyengar yoga therapy as an intervention for cramp management in individuals with amyotrophic lateral sclerosis: Three case reports","volume":"20","author":"Ribeiro","year":"2014","journal-title":"J. Altern. Complement. Med."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1212\/WNL.53.5.1059","article-title":"Nutritional status is a prognostic factor for survival in ALS patients","volume":"53","author":"Desport","year":"1999","journal-title":"Neurology"},{"key":"ref_166","first-page":"CD006981","article-title":"Treatment for sialorrhea (excessive saliva) in people with motor neuron disease\/amyotrophic lateral sclerosis","volume":"5","author":"James","year":"2022","journal-title":"Cochrane. Database. Syst. Rev."},{"key":"ref_167","doi-asserted-by":"crossref","unstructured":"Gibbons, C.J., Thornton, E.W., and Young, C.A. (2013). The patient experience of fatigue in motor neurone disease. Front. Psychol., 4.","DOI":"10.3389\/fpsyg.2013.00788"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"2658","DOI":"10.1002\/mds.23261","article-title":"Restless legs syndrome in patients with amyotrophic lateral sclerosis","volume":"25","author":"Piccoli","year":"2010","journal-title":"Mov. Disord."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1111\/j.1468-1331.2011.03637.x","article-title":"Fatigue, sleep, and nocturnal complaints in patients with amyotrophic lateral sclerosis","volume":"19","year":"2012","journal-title":"Eur. J. Neurol."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1038\/s41597-024-03597-2","article-title":"Voice signals database of ALS patients with different dysarthria severity and healthy controls","volume":"11","author":"Dubbioso","year":"2024","journal-title":"Sci. Data"},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1080\/21678421.2023.2222144","article-title":"A speech-based prognostic model for dysarthria progression in ALS","volume":"24","author":"Stegmann","year":"2023","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"4","DOI":"10.3109\/17482960802379004","article-title":"Dysarthria in amyotrophic lateral sclerosis: A review","volume":"11","author":"Tomik","year":"2010","journal-title":"Amyotroph. Lateral Scler."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/21678421.2024.2405130","article-title":"Subcortical grey matter involvement in ALS and PLS\u2014Vulnerable hubs of cortico-cortical and cortico-basal circuits: Extrapyramidal, cognitive, bulbar and respiratory correlates","volume":"26","author":"Kleinerova","year":"2025","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_174","doi-asserted-by":"crossref","unstructured":"Hermann, W., Langner, S., Freigang, M., Fischer, S., Storch, A., Gunther, R., and Hermann, A. (2022). Affection of Respiratory Muscles in ALS and SMA. J. Clin. Med., 11.","DOI":"10.3390\/jcm11051163"},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1136\/bmjspcare-2013-000470","article-title":"Issues for palliative medicine doctors surrounding the withdrawal of non-invasive ventilation at the request of a patient with motor neurone disease: A scoping study","volume":"4","author":"Faull","year":"2014","journal-title":"BMJ Support Palliat Care"},{"key":"ref_176","first-page":"e51048","article-title":"A Palliative Care Approach to Amyotrophic Lateral Sclerosis","volume":"15","author":"Gouveia","year":"2023","journal-title":"Cureus"},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1177\/10499091241248653","article-title":"Identifying the Unmet Needs of People Living With Amyotrophic Lateral Sclerosis: A National Survey to Inform Interdisciplinary Palliative Care","volume":"42","author":"Washington","year":"2025","journal-title":"Am. J. Hosp. Palliat Care"},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.chest.2020.08.2086","article-title":"Global Physiology and Pathophysiology of Cough: Part 1: Cough Phenomenology\u2014CHEST Guideline and Expert Panel Report","volume":"159","author":"Lee","year":"2021","journal-title":"Chest"},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1016\/j.chest.2021.04.039","article-title":"Global Physiology and Pathophysiology of Cough: Part 2. Demographic and Clinical Considerations: CHEST Expert Panel Report","volume":"160","author":"McGarvey","year":"2021","journal-title":"Chest"},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1007\/s00455-014-9554-5","article-title":"Associations between laryngeal and cough dysfunction in motor neuron disease with bulbar involvement","volume":"29","author":"Britton","year":"2014","journal-title":"Dysphagia"},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"108003","DOI":"10.1016\/j.rmed.2025.108003","article-title":"Longitudinal respiratory trajectories in motor neuron disease phenotypes: Multiparametric characterization and clinical management","volume":"239","author":"Ferraro","year":"2025","journal-title":"Respir. Med."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"S123","DOI":"10.1212\/WNL.47.4_Suppl_2.123S","article-title":"Management of ALS: Respiratory care","volume":"47","author":"Hopkins","year":"1996","journal-title":"Neurology"},{"key":"ref_183","doi-asserted-by":"crossref","unstructured":"Tankere, P., Cascarano, E., Saint Raymond, C., Mallaret, M., Toribio Ruiz, C., Herquelot, E., Denis, H., Cals Maurette, M., Tamisier, R., and Pepin, J.L. (2025). Care trajectories and adherence to respiratory management recommendations in persons living with amyotrophic lateral sclerosis: A ten-year cohort study in a French tertiary university centre. Amyotroph. Lateral Scler. Front. Degener., 1\u20139.","DOI":"10.1080\/21678421.2024.2447911"},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.rmed.2018.01.012","article-title":"Airway clearance techniques in neuromuscular disorders: A state of the art review","volume":"136","author":"Chatwin","year":"2018","journal-title":"Respir. Med."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.4187\/respcare.07005","article-title":"The Oral Secretion Scale and Prognostic Factors for Survival in Subjects With Amyotrophic Lateral Sclerosis","volume":"65","author":"Cazzolli","year":"2020","journal-title":"Respir. Care"},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.4187\/respcare.08298","article-title":"Saliva, Swallowing, and Breathing: The Ultimate Challenge of Amyotrophic Lateral Sclerosis","volume":"65","author":"Benditt","year":"2020","journal-title":"Respir. Care"},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1007\/s00455-015-9687-1","article-title":"Voluntary Cough Airflow Differentiates Safe Versus Unsafe Swallowing in Amyotrophic Lateral Sclerosis","volume":"31","author":"Plowman","year":"2016","journal-title":"Dysphagia"},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"14799731231175915","DOI":"10.1177\/14799731231175915","article-title":"Respiratory therapies for Amyotrophic Lateral Sclerosis: A state of the art review","volume":"20","author":"Olsen","year":"2023","journal-title":"Chron. Respir. Dis."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1080\/21678421.2021.1879865","article-title":"An old friend who has overstayed their welcome: The ALSFRS-R total score as primary endpoint for ALS clinical trials","volume":"22","author":"Nikolakopoulos","year":"2021","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1212\/WNL.0000000000012545","article-title":"Innovating Clinical Trials for Amyotrophic Lateral Sclerosis: Challenging the Established Order","volume":"97","author":"Nikolakopoulos","year":"2021","journal-title":"Neurology"},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"105456","DOI":"10.1016\/j.clineuro.2019.105456","article-title":"The prognostic value of spirometric tests in Amyotrophic Lateral Sclerosis patients","volume":"184","author":"Pirola","year":"2019","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1080\/21678421.2024.2428930","article-title":"Cerebrospinal fluid levels of NfM in relation to NfL and pNfH as prognostic markers in amyotrophic lateral sclerosis","volume":"26","author":"Olofsson","year":"2025","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/s41467-022-35494-w","article-title":"Molecular subtypes of ALS are associated with differences in patient prognosis","volume":"14","author":"Eshima","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_194","doi-asserted-by":"crossref","unstructured":"Foldvari, K.M., Stolee, P., Neiterman, E., Boscart, V., and Tong, C. (2024). \u201c...but I know something\u2019s not right here\u201d: Exploring the diagnosis and disclosure experiences of persons living with ALS. PLoS ONE, 19.","DOI":"10.1101\/2024.03.14.24304312"},{"key":"ref_195","doi-asserted-by":"crossref","unstructured":"Lajoie, I., Canadian, A.L.S.N.C., Kalra, S., and Dadar, M. (2025). Regional Cerebral Atrophy Contributes to Personalized Survival Prediction in Amyotrophic Lateral Sclerosis: A Multicentre, Machine Learning, Deformation-Based Morphometry Study. Ann. Neurol.","DOI":"10.1002\/ana.27196"},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.amjmed.2018.07.012","article-title":"Motor Neuron Disease: Pathophysiology, Diagnosis, and Management","volume":"132","author":"Foster","year":"2019","journal-title":"Am. J. Med."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1080\/14660820310016066","article-title":"Validation of quality of life instruments in ALS","volume":"5","author":"Bourke","year":"2004","journal-title":"Amyotroph. Lateral Scler. Other Motor Neuron Disord."},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1007\/s00415-017-8448-5","article-title":"Caregivers of patients with amyotrophic lateral sclerosis: Investigating quality of life, caregiver burden, service engagement, and patient survival","volume":"264","author":"Burke","year":"2017","journal-title":"J. Neurol."},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1056\/NEJM199403033300901","article-title":"A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS\/Riluzole Study Group","volume":"330","author":"Bensimon","year":"1994","journal-title":"N. Engl. J. Med."},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"S242","DOI":"10.1212\/WNL.47.6_Suppl_4.242S","article-title":"A confirmatory dose-ranging study of riluzole in ALS. ALS\/Riluzole Study Group-II","volume":"47","author":"Lacomblez","year":"1996","journal-title":"Neurology"},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1080\/21678421.2017.1361443","article-title":"Post-hoc analysis of randomised, placebo-controlled, double-blind study (MCI186-19) of edaravone (MCI-186) in amyotrophic lateral sclerosis","volume":"18","author":"Takei","year":"2017","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_202","doi-asserted-by":"crossref","unstructured":"Hamad, A.A., Alkhawaldeh, I.M., Nashwan, A.J., Meshref, M., and Imam, Y. (2025). Tofersen for SOD1 amyotrophic lateral sclerosis: A systematic review and meta-analysis. Neurol. Sci.","DOI":"10.1007\/s10072-025-07994-2"},{"key":"ref_203","doi-asserted-by":"crossref","first-page":"17562864251313915","DOI":"10.1177\/17562864251313915","article-title":"Tofersen and other antisense oligonucleotides in ALS","volume":"18","author":"Ludolph","year":"2025","journal-title":"Ther. Adv. Neurol. Disord."},{"key":"ref_204","doi-asserted-by":"crossref","first-page":"259","DOI":"10.29271\/jcpsp.2025.02.259","article-title":"Tofersen for Amyotrophic Lateral Sclerosis: A Step Forward or Another False Hope?","volume":"35","author":"Naveed","year":"2025","journal-title":"J. Coll. Physicians Surg. Pak."},{"key":"ref_205","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1002\/acn3.52264","article-title":"Tofersen treatment leads to sustained stabilization of disease in SOD1 ALS in a \u201creal-world\u201d setting","volume":"12","author":"Smith","year":"2025","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_206","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1111\/j.1468-1331.2008.02307.x","article-title":"Causes of death amongst French patients with amyotrophic lateral sclerosis: A prospective study","volume":"15","author":"Gil","year":"2008","journal-title":"Eur. J. Neurol."},{"key":"ref_207","doi-asserted-by":"crossref","first-page":"117080","DOI":"10.1016\/j.ejmech.2024.117080","article-title":"Promising breakthroughs in amyotrophic lateral sclerosis treatment through nanotechnology\u2019s unexplored frontier","volume":"282","author":"Sojdeh","year":"2025","journal-title":"Eur. J. Med. Chem."},{"key":"ref_208","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."},{"key":"ref_209","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1080\/21678421.2020.1771734","article-title":"Real-world evidence of riluzole effectiveness in treating amyotrophic lateral sclerosis","volume":"21","author":"Andrews","year":"2020","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_210","doi-asserted-by":"crossref","first-page":"2399962","DOI":"10.1080\/07853890.2024.2399962","article-title":"Clinical features and progress in diagnosis and treatment of amyotrophic lateral sclerosis","volume":"56","author":"Yuan","year":"2024","journal-title":"Ann. Med."},{"key":"ref_211","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1093\/brain\/awt085","article-title":"Riluzole exerts central and peripheral modulating effects in amyotrophic lateral sclerosis","volume":"136","author":"Vucic","year":"2013","journal-title":"Brain"},{"key":"ref_212","doi-asserted-by":"crossref","unstructured":"Edaravone Als 16 Study, G. (2017). A post-hoc subgroup analysis of outcomes in the first phase III clinical study of edaravone (MCI-186) in amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Front. Degener., 18, 11\u201319.","DOI":"10.1080\/21678421.2017.1363780"},{"key":"ref_213","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1002\/mus.26740","article-title":"Long-term edaravone efficacy in amyotrophic lateral sclerosis: Post-hoc analyses of Study 19 (MCI186-19)","volume":"61","author":"Shefner","year":"2020","journal-title":"Muscle Nerve"},{"key":"ref_214","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."},{"key":"ref_215","first-page":"216","article-title":"The effectiveness and value of AMX0035 and oral edaravone for amyotrophic lateral sclerosis: A summary from the Institute for Clinical and Economic Review\u2019s Midwest Comparative Effectiveness Public Advisory Council","volume":"29","author":"Nikitin","year":"2023","journal-title":"J. Manag. Care Spec. Pharm."},{"key":"ref_216","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1212\/01.WNL.0000142042.50528.2F","article-title":"Treatment of pseudobulbar affect in ALS with dextromethorphan\/quinidine: A randomized trial","volume":"63","author":"Brooks","year":"2004","journal-title":"Neurology"},{"key":"ref_217","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1080\/21678421.2022.2136994","article-title":"Incorporating patient preferences and burden-of-disease in evaluating ALS drug candidate AMX0035: A Bayesian decision analysis perspective","volume":"24","author":"Xu","year":"2023","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_218","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1136\/jnnp-2023-332106","article-title":"Effect of sodium phenylbutyrate and taurursodiol on plasma concentrations of neuroinflammatory biomarkers in amyotrophic lateral sclerosis: Results from the CENTAUR trial","volume":"95","author":"Bowser","year":"2024","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_219","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1136\/jnnp-2022-329024","article-title":"Effect of sodium phenylbutyrate\/taurursodiol on tracheostomy\/ventilation-free survival and hospitalisation in amyotrophic lateral sclerosis: Long-term results from the CENTAUR trial","volume":"93","author":"Paganoni","year":"2022","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_220","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1002\/mus.27091","article-title":"Long-term survival of participants in the CENTAUR trial of sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis","volume":"63","author":"Paganoni","year":"2021","journal-title":"Muscle Nerve"},{"key":"ref_221","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1002\/mus.27569","article-title":"Survival analyses from the CENTAUR trial in amyotrophic lateral sclerosis: Evaluating the impact of treatment crossover on outcomes","volume":"66","author":"Paganoni","year":"2022","journal-title":"Muscle Nerve"},{"key":"ref_222","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1007\/s40261-024-01371-1","article-title":"Sodium Phenylbutyrate and Tauroursodeoxycholic Acid: A Story of Hope Turned to Disappointment in Amyotrophic Lateral Sclerosis Treatment","volume":"44","author":"Ketabforoush","year":"2024","journal-title":"Clin. Drug. Investig."},{"key":"ref_223","first-page":"147","article-title":"Secretome\u2014The role of extracellular vesicles in the pathogenesis and therapy of neurodegenerative diseases","volume":"33","author":"Sulek","year":"2024","journal-title":"Postep. Psychiatr. Neurol."},{"key":"ref_224","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1038\/s41582-024-01049-4","article-title":"Targeting common disease pathomechanisms to treat amyotrophic lateral sclerosis","volume":"21","author":"Faller","year":"2025","journal-title":"Nat. Rev. Neurol."},{"key":"ref_225","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1007\/s00415-025-12975-8","article-title":"Advancements in genetic research and RNA therapy strategies for amyotrophic lateral sclerosis (ALS): Current progress and future prospects","volume":"272","author":"Ruffo","year":"2025","journal-title":"J. Neurol."},{"key":"ref_226","doi-asserted-by":"crossref","first-page":"125069","DOI":"10.1016\/j.ijpharm.2024.125069","article-title":"Present insights into the progress in gene therapy delivery systems for central nervous system diseases","volume":"669","author":"Yang","year":"2025","journal-title":"Int. J. Pharm."},{"key":"ref_227","doi-asserted-by":"crossref","unstructured":"Arnold, C. (2019). Tailored treatment for ALS poised to move ahead. Nat. Med.","DOI":"10.1038\/d41591-019-00013-w"},{"key":"ref_228","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/bs.irn.2024.04.007","article-title":"Recent advances in the genetics of familial and sporadic ALS","volume":"176","author":"Andrews","year":"2024","journal-title":"Int. Rev. Neurobiol."},{"key":"ref_229","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1056\/NEJMcibr1716741","article-title":"Finding a Treatment for ALS\u2014Will Gene Editing Cut It?","volume":"378","author":"Brown","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_230","first-page":"e48691","article-title":"Advances in Understanding and Treating Amyotrophic Lateral Sclerosis (ALS): A Comprehensive Review","volume":"15","author":"Gupta","year":"2023","journal-title":"Cureus"},{"key":"ref_231","doi-asserted-by":"crossref","unstructured":"Cappella, M., Ciotti, C., Cohen-Tannoudji, M., and Biferi, M.G. (2019). Gene Therapy for ALS-A Perspective. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20184388"},{"key":"ref_232","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/S1474-4422(13)70061-9","article-title":"An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: A phase 1, randomised, first-in-man study","volume":"12","author":"Miller","year":"2013","journal-title":"Lancet Neurol."},{"key":"ref_233","doi-asserted-by":"crossref","first-page":"eaai7866","DOI":"10.1126\/scitranslmed.aai7866","article-title":"Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis","volume":"9","author":"Gendron","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref_234","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1038\/s41591-021-01615-z","article-title":"Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis","volume":"28","author":"Korobeynikov","year":"2022","journal-title":"Nat. Med."},{"key":"ref_235","doi-asserted-by":"crossref","first-page":"6057","DOI":"10.1111\/ejn.16541","article-title":"Extracellular vesicle and CRISPR gene therapy: Current applications in Alzheimer\u2019s disease, Parkinson\u2019s disease, amyotrophic lateral sclerosis, and Huntington\u2019s disease","volume":"60","author":"Akyuz","year":"2024","journal-title":"Eur. J. Neurosci."},{"key":"ref_236","first-page":"643","article-title":"CRISPR-Cas9 guided rna based model for the treatment of Amyotrophic Lateral Sclerosis: A progressive neurodegenerative disorder","volume":"70","author":"Naveed","year":"2023","journal-title":"Acta. Biochim. Pol."},{"key":"ref_237","doi-asserted-by":"crossref","unstructured":"Shi, Y., Zhao, Y., Lu, L., Gao, Q., Yu, D., and Sun, M. (2023). CRISPR\/Cas9: Implication for modeling and therapy of amyotrophic lateral sclerosis. Front. Neurosci., 17.","DOI":"10.3389\/fnins.2023.1223777"},{"key":"ref_238","doi-asserted-by":"crossref","first-page":"eaar3952","DOI":"10.1126\/sciadv.aar3952","article-title":"In vivo genome editing improves motor function and extends survival in a mouse model of ALS","volume":"3","author":"Gaj","year":"2017","journal-title":"Sci. Adv."},{"key":"ref_239","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1056\/NEJMoa2005056","article-title":"SOD1 Suppression with Adeno-Associated Virus and MicroRNA in Familial ALS","volume":"383","author":"Mueller","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_240","doi-asserted-by":"crossref","first-page":"114385","DOI":"10.1016\/j.bbr.2023.114385","article-title":"Effects of brain-derived neurotrophic factor and adeno-associated viral vector on morphine-induced condition through target concentration changes in the ventral tegmental area and nucleus accumbens","volume":"445","author":"Deng","year":"2023","journal-title":"Behav. Brain Res."},{"key":"ref_241","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/mus.24143","article-title":"Rare combination of myasthenia and motor neuronopathy, responsive to Msc-Ntf stem cell therapy","volume":"49","author":"Petrou","year":"2014","journal-title":"Muscle Nerve"},{"key":"ref_242","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1016\/j.jcyt.2014.02.003","article-title":"Human mesenchymal stromal cell transplantation modulates neuroinflammatory milieu in a mouse model of amyotrophic lateral sclerosis","volume":"16","author":"Boido","year":"2014","journal-title":"Cytotherapy"},{"key":"ref_243","doi-asserted-by":"crossref","first-page":"3163","DOI":"10.1002\/stem.1812","article-title":"Intrathecal delivery of mesenchymal stromal cells protects the structure of altered perineuronal nets in SOD1 rats and amends the course of ALS","volume":"32","author":"Forostyak","year":"2014","journal-title":"Stem. Cells"},{"key":"ref_244","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.neuroscience.2013.05.034","article-title":"Systemic treatment with adipose-derived mesenchymal stem cells ameliorates clinical and pathological features in the amyotrophic lateral sclerosis murine model","volume":"248","author":"Marconi","year":"2013","journal-title":"Neuroscience"},{"key":"ref_245","doi-asserted-by":"crossref","first-page":"794","DOI":"10.2119\/molmed.2011.00498","article-title":"Intravenous mesenchymal stem cells improve survival and motor function in experimental amyotrophic lateral sclerosis","volume":"18","author":"Uccelli","year":"2012","journal-title":"Mol. Med."},{"key":"ref_246","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.nbd.2008.05.016","article-title":"Human mesenchymal stem cell transplantation extends survival, improves motor performance and decreases neuroinflammation in mouse model of amyotrophic lateral sclerosis","volume":"31","author":"Vercelli","year":"2008","journal-title":"Neurobiol. Dis."},{"key":"ref_247","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1080\/14653240701376413","article-title":"Human mesenchymal stromal cells ameliorate the phenotype of SOD1-G93A ALS mice","volume":"9","author":"Zhao","year":"2007","journal-title":"Cytotherapy"},{"key":"ref_248","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1002\/stem.1079","article-title":"Lumbar intraspinal injection of neural stem cells in patients with amyotrophic lateral sclerosis: Results of a phase I trial in 12 patients","volume":"30","author":"Glass","year":"2012","journal-title":"Stem. Cells"},{"key":"ref_249","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/scrt421","article-title":"Therapeutic applications of mesenchymal stem cells for amyotrophic lateral sclerosis","volume":"5","author":"Lewis","year":"2014","journal-title":"Stem. Cell Res. Ther."},{"key":"ref_250","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.expneurol.2009.08.007","article-title":"Mesenchymal stem cell transplantation in amyotrophic lateral sclerosis: A Phase I clinical trial","volume":"223","author":"Mazzini","year":"2010","journal-title":"Exp. Neurol."},{"key":"ref_251","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1002\/sctm.18-0154","article-title":"Results from Phase I Clinical Trial with Intraspinal Injection of Neural Stem Cells in Amyotrophic Lateral Sclerosis: A Long-Term Outcome","volume":"8","author":"Mazzini","year":"2019","journal-title":"Stem. Cells Transl. Med."},{"key":"ref_252","doi-asserted-by":"crossref","first-page":"313","DOI":"10.4103\/1673-5374.243723","article-title":"Safety of intrathecal injection of Wharton\u2019s jelly-derived mesenchymal stem cells in amyotrophic lateral sclerosis therapy","volume":"14","author":"Barczewska","year":"2019","journal-title":"Neural. Regen. Res."},{"key":"ref_253","first-page":"592","article-title":"Safety, Feasibility of Intravenous and Intrathecal Injection of Autologous Bone Marrow Derived Mesenchymal Stromal Cells in Patients with Amyotrophic Lateral Sclerosis: An Open Label Phase I Clinical Trial","volume":"20","author":"Nabavi","year":"2019","journal-title":"Cell J."},{"key":"ref_254","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1002\/ana.25302","article-title":"Repeated Intrathecal Mesenchymal Stem Cells for Amyotrophic Lateral Sclerosis","volume":"84","author":"Oh","year":"2018","journal-title":"Ann. Neurol."},{"key":"ref_255","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1001\/jamaneurol.2015.4321","article-title":"Safety and Clinical Effects of Mesenchymal Stem Cells Secreting Neurotrophic Factor Transplantation in Patients With Amyotrophic Lateral Sclerosis: Results of Phase 1\/2 and 2a Clinical Trials","volume":"73","author":"Petrou","year":"2016","journal-title":"JAMA Neurol."},{"key":"ref_256","doi-asserted-by":"crossref","first-page":"2230","DOI":"10.1212\/WNL.0000000000003359","article-title":"Safety of intrathecal autologous adipose-derived mesenchymal stromal cells in patients with ALS","volume":"87","author":"Staff","year":"2016","journal-title":"Neurology"},{"key":"ref_257","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1080\/17482960701856300","article-title":"Design, power, and interpretation of studies in the standard murine model of ALS","volume":"9","author":"Scott","year":"2008","journal-title":"Amyotroph. Lateral Scler."},{"key":"ref_258","doi-asserted-by":"crossref","unstructured":"Trudler, D., Ghatak, S., and Lipton, S.A. (2021). Emerging hiPSC Models for Drug Discovery in Neurodegenerative Diseases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22158196"},{"key":"ref_259","doi-asserted-by":"crossref","first-page":"145ra104","DOI":"10.1126\/scitranslmed.3004052","article-title":"Drug screening for ALS using patient-specific induced pluripotent stem cells","volume":"4","author":"Egawa","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_260","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1212\/WNL.0b013e3181bc01a4","article-title":"Practice parameter update: The care of the patient with amyotrophic lateral sclerosis: Multidisciplinary care, symptom management, and cognitive\/behavioral impairment (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology","volume":"73","author":"Miller","year":"2009","journal-title":"Neurology"},{"key":"ref_261","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/j.pmr.2008.04.004","article-title":"The amyotrophic lateral sclerosis center: A model of multidisciplinary management","volume":"19","author":"Mayadev","year":"2008","journal-title":"Phys. Med. Rehabil. Clin. N. Am."},{"key":"ref_262","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1002\/mus.28370","article-title":"Associations Between End-Stage ALS Care and Specialty Palliative Care: A Hypothesis-Generating Study","volume":"71","author":"Lero","year":"2025","journal-title":"Muscle Nerve"},{"key":"ref_263","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1080\/21678421.2024.2399154","article-title":"A nurse coaching intervention to improve support to individuals living with ALS","volume":"26","author":"Walsh","year":"2025","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_264","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1097\/NPT.0000000000000136","article-title":"Pulmonary Physical Therapy Techniques to Enhance Survival in Amyotrophic Lateral Sclerosis: A Systematic Review","volume":"40","author":"Macpherson","year":"2016","journal-title":"J. Neurol. Phys. Ther."},{"key":"ref_265","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1177\/1479972309345927","article-title":"Mechanisms of exercise limitation and pulmonary rehabilitation for patients with neuromuscular disease","volume":"6","author":"Aboussouan","year":"2009","journal-title":"Chron. Respir. Dis."},{"key":"ref_266","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/s10072-011-0921-9","article-title":"Exercise and amyotrophic lateral sclerosis","volume":"33","author":"Silvestre","year":"2012","journal-title":"Neurol. Sci."},{"key":"ref_267","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1080\/21678421.2021.1889000","article-title":"Progressive arm muscle weakness in ALS follows the same sequence regardless of onset site: Use of TOMS, a novel analytic method to track limb strength","volume":"22","author":"Thakore","year":"2021","journal-title":"Amyotroph. Lateral Scler. Frontotemporal. Degener."},{"key":"ref_268","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1002\/acn3.52019","article-title":"The central pattern of weakness of ALS: Morphological correlates in whole-body muscle MRI","volume":"11","author":"Wimmer","year":"2024","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_269","doi-asserted-by":"crossref","unstructured":"Jawdat, O., Rucker, J., Nakano, T., Takeno, K., Statland, J., Pasnoor, M., Dimachkie, M.M., Sabus, C., Badawi, Y., and Hunt, S.L. (2024). Resistance exercise in early-stage ALS patients, ALSFRS-R, Sickness Impact Profile ALS-19, and muscle transcriptome: A pilot study. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-72355-6"},{"key":"ref_270","doi-asserted-by":"crossref","first-page":"e25435","DOI":"10.2196\/25435","article-title":"Using an Extended Technology Acceptance Model to Understand the Factors Influencing Telehealth Utilization After Flattening the COVID-19 Curve in South Korea: Cross-sectional Survey Study","volume":"9","author":"An","year":"2021","journal-title":"JMIR Med. Inform."},{"key":"ref_271","doi-asserted-by":"crossref","first-page":"S148","DOI":"10.1097\/00002060-200211001-00015","article-title":"Response to aerobic exercise training in humans with neuromuscular disease","volume":"81","author":"Kilmer","year":"2002","journal-title":"Am. J. Phys. Med. Rehabil."},{"key":"ref_272","first-page":"CD005229","article-title":"Therapeutic exercise for people with amyotrophic lateral sclerosis or motor neuron disease","volume":"5","author":"Florence","year":"2008","journal-title":"Cochrane. Database. Syst. Rev."},{"key":"ref_273","first-page":"CD003907","article-title":"Strength training and aerobic exercise training for muscle disease","volume":"1","author":"Voet","year":"2010","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_274","first-page":"207","article-title":"Exercise in neuromuscular disorders: A promising intervention","volume":"38","author":"Voet","year":"2019","journal-title":"Acta. Myol."},{"key":"ref_275","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.physio.2021.04.005","article-title":"Aerobic, resistance and combined exercise training for patients with amyotrophic lateral sclerosis: A systematic review and meta-analysis","volume":"113","author":"Rahmati","year":"2021","journal-title":"Physiotherapy"},{"key":"ref_276","doi-asserted-by":"crossref","unstructured":"Zhu, Y., Xu, Y., Xuan, R., Huang, J., Istvan, B., Fekete, G., and Gu, Y. (2022). Mixed Comparison of Different Exercise Interventions for Function, Respiratory, Fatigue, and Quality of Life in Adults with Amyotrophic Lateral Sclerosis: Systematic Review and Network Meta-Analysis. Front. Aging Neurosci., 14.","DOI":"10.3389\/fnagi.2022.919059"},{"key":"ref_277","doi-asserted-by":"crossref","unstructured":"Su, W.M., Cheng, Y.F., Jiang, Z., Duan, Q.Q., Yang, T.M., Shang, H.F., and Chen, Y.P. (2021). Predictors of survival in patients with amyotrophic lateral sclerosis: A large meta-analysis. EBioMedicine, 74.","DOI":"10.1016\/j.ebiom.2021.103732"},{"key":"ref_278","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1007\/s11606-019-05344-5","article-title":"Continuing, Withdrawing, and Withholding Medical Treatment at the End of Life and Associated Characteristics: A Mortality Follow-back Study","volume":"35","author":"Penders","year":"2020","journal-title":"J. Gen. Intern. Med."},{"key":"ref_279","doi-asserted-by":"crossref","first-page":"829","DOI":"10.2147\/PPA.S37851","article-title":"What influences patient decision-making in amyotrophic lateral sclerosis multidisciplinary care? A study of patient perspectives","volume":"6","author":"Hogden","year":"2012","journal-title":"Patient Prefer Adherence"},{"key":"ref_280","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1111\/scs.12492","article-title":"Understanding the incomprehensible\u2014Patients\u2019 and spouses\u2019 experiences of comprehensibility before, at and after diagnosis of amyotrophic lateral sclerosis","volume":"32","author":"Ozanne","year":"2018","journal-title":"Scand. J. Caring Sci."},{"key":"ref_281","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1212\/WNL.0b013e318247cc56","article-title":"Discussions about treatment restrictions in chronic neurologic diseases: A structured review","volume":"78","author":"Seeber","year":"2012","journal-title":"Neurology"},{"key":"ref_282","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1212\/WNL.0b013e31820d57ee","article-title":"Amyotrophic lateral sclerosis: Ethical challenges","volume":"76","author":"Johnston","year":"2011","journal-title":"Neurology"},{"key":"ref_283","first-page":"670","article-title":"Freedom to choose treatments in incurable disease.Summary. The lack of knowledge and application of legal and ethical norms have often justified behaviors of many health workers not adequate to the care needs of people with ALS or other incurable diseases, highlighting their cultural unpreparedness. The narration of the experience and reflections of a palliativist doctor with an ALS patient can be reason for mainly ethical considerations","volume":"111","author":"Rigotti","year":"2020","journal-title":"Recenti. Prog. Med."},{"key":"ref_284","first-page":"25","article-title":"S3 Guideline: Treating Chronic Respiratory Failure with Non-invasive Ventilation","volume":"79","author":"Stanzel","year":"2025","journal-title":"Pneumologie"}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/15\/4\/647\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:14:25Z","timestamp":1760030065000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/15\/4\/647"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,14]]},"references-count":284,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["life15040647"],"URL":"https:\/\/doi.org\/10.3390\/life15040647","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,14]]}}}