{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T09:52:20Z","timestamp":1776678740687,"version":"3.51.2"},"reference-count":32,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T00:00:00Z","timestamp":1776470400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Perner Yaacov memorial fund","award":["-"],"award-info":[{"award-number":["-"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Objectives: The aim of this study was to assess the differences in diagnostic delay and disease progression in people with ALS (PALS) based on site of onset. Methods: A retrospective analysis of prospectively collected data was performed, including all PALS seen in the ALS clinic in the Hadassah Medical Center between January 2009 and March 2022. PALS were divided to three groups based on site of onset (upper limb onset\u2014ULO, lower limb onset\u2014LLO, or bulbar onset\u2014BO). A linear mixed-effects model was constructed with the following variables: diagnostic delay, site of onset, age of onset and time since the initial visit. The model was applied to the ALSFRS-R total score and the bulbar and motor subscales. Results: Data from 1255 visits of 281 PALS were included in the study. PALS with LLO had longer diagnostic delays than PALS in the BO group. Slower decline of total ALSFRS-R score was observed in younger PALS, and in PALS with LLO when compared with PALS with BO or ULO. The slower decline of ALSFRS-R in PALS with LLO was due to a slower decline in the motor subscale. Longer diagnostic delays were associated with lower total ALSFRS-R scores at the initial visit and with slower rates of decline. Conclusions: Comparison among PALS with ULO, LLO and BO revealed differences in the diagnostic delay and in the rate of functional decline, suggesting that differentiating between ULO and LLO ALS may be useful in the stratification of PALS in clinical trials.<\/jats:p>","DOI":"10.3390\/jcm15083096","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T08:24:23Z","timestamp":1776673463000},"page":"3096","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Slower Progression Rates in Lower Limb-Onset ALS"],"prefix":"10.3390","volume":"15","author":[{"given":"Yehuda","family":"Shovman","sequence":"first","affiliation":[{"name":"Department of Neurology, Hadassah Medical Organization and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel"},{"name":"The Concern Foundation Laboratories at the Lautenberg Center for Immunology and Cancer Research, Israel-Canada Medical Research Institute, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yossef","family":"Lerner","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hadassah Medical Organization and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2541-6232","authenticated-orcid":false,"given":"Marc","family":"Gotkine","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hadassah Medical Organization and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17071","DOI":"10.1038\/nrdp.2017.71","article-title":"Amyotrophic Lateral Sclerosis","volume":"3","author":"Hardiman","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","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_3","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_4","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1007\/s00415-015-7731-6","article-title":"Predicting Prognosis in Amyotrophic Lateral Sclerosis: A Simple Algorithm","volume":"262","author":"Elamin","year":"2015","journal-title":"J. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/S1474-4422(18)30176-5","article-title":"Safety and Efficacy of Rasagiline as an Add-On Therapy to Riluzole in Patients with Amyotrophic Lateral Sclerosis: A Randomised, Double-Blind, Parallel-Group, Placebo-Controlled, Phase 2 Trial","volume":"17","author":"Ludolph","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1837","DOI":"10.1016\/S0140-6736(25)00262-4","article-title":"Efficacy and Safety of Low-Dose IL-2 as an Add-On Therapy to Riluzole (MIROCALS): A Phase 2b, Double-Blind, Randomised, Placebo-Controlled Trial","volume":"405","author":"Bensimon","year":"2025","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S0022-510X(99)00210-5","article-title":"The ALSFRS-R: A Revised ALS Functional Rating Scale That Incorporates Assessments of Respiratory Function","volume":"169","author":"Cedarbaum","year":"1999","journal-title":"J. Neurol. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1136\/jnnp-2016-314661","article-title":"What Does the ALSFRS-R Really Measure? A Longitudinal and Survival Analysis of Functional Dimension Subscores in Amyotrophic Lateral Sclerosis","volume":"88","author":"Rooney","year":"2017","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2243","DOI":"10.1007\/s10072-015-2343-6","article-title":"Heterogeneity in ALSFRS-R Decline and Survival: A Population-Based Study in Italy","volume":"36","author":"Mandrioli","year":"2015","journal-title":"Neurol. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1080\/21678421.2017.1418001","article-title":"A Retrospective Investigation of the Relationship between Baseline Covariates and Rate of ALSFRS-R Decline in ALS Clinical Trials","volume":"19","author":"Daghlas","year":"2018","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_11","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"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Kj\u00e6ldgaard, A.L., Pilely, K., Olsen, K.S., Jessen, A.H., Lauritsen, A.\u00d8., Pedersen, S.W., Svenstrup, K., Karlsborg, M., Thagesen, H., and Blaabjerg, M. (2021). Prediction of Survival in Amyotrophic Lateral Sclerosis: A Nationwide, Danish Cohort Study. BMC Neurol., 21.","DOI":"10.1186\/s12883-021-02187-8"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1002\/mus.26042","article-title":"Trajectories of Impairment in Amyotrophic Lateral Sclerosis: Insights from the Pooled Resource Open-Access ALS Clinical Trials Cohort","volume":"57","author":"Thakore","year":"2018","journal-title":"Muscle Nerve"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1002\/acn3.51098","article-title":"Spreading in ALS: The Relative Impact of Upper and Lower Motor Neuron Involvement","volume":"7","author":"Gromicho","year":"2020","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1080\/21678421.2019.1704012","article-title":"Epidemiological and Clinical Features of Amyotrophic Lateral Sclerosis in a Tunisian Cohort","volume":"21","author":"Kacem","year":"2020","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1473981","DOI":"10.1155\/2020\/1473981","article-title":"Minimizing the Diagnostic Delay in Amyotrophic Lateral Sclerosis: The Role of Nonneurologist Practitioners","volume":"2020","author":"Matharan","year":"2020","journal-title":"Neurol. Res. Int."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"117054","DOI":"10.1016\/j.jns.2020.117054","article-title":"Time to Diagnosis and Factors Affecting Diagnostic Delay in Amyotrophic Lateral Sclerosis","volume":"417","author":"Richards","year":"2020","journal-title":"J. Neurol. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1007\/s00415-010-5609-1","article-title":"Progression in ALS Is Not Linear but Is Curvilinear","volume":"257","author":"Gordon","year":"2010","journal-title":"J. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4105","DOI":"10.1093\/brain\/awad129","article-title":"Regional Spreading Pattern Is Associated with Clinical Phenotype in Amyotrophic Lateral Sclerosis","volume":"146","author":"Maranzano","year":"2023","journal-title":"Brain"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s40035-021-00250-5","article-title":"A Perspective on Therapies for Amyotrophic Lateral Sclerosis: Can Disease Progression Be Curbed?","volume":"10","author":"Xu","year":"2021","journal-title":"Transl. Neurodegener."},{"key":"ref_21","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_22","doi-asserted-by":"crossref","unstructured":"Antonioni, A., Govoni, V., Brancaleoni, L., Don\u00e0, A., Granieri, E., Bergamini, M., Gerdol, R., and Pugliatti, M. (2023). Amyotrophic Lateral Sclerosis and Air Pollutants in the Province of Ferrara, Northern Italy: An Ecological Study. Int. J. Environ. Res. Public Health, 20.","DOI":"10.3390\/ijerph20085591"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1080\/21678421.2022.2127324","article-title":"Occupational History Associates with ALS Survival and Onset Segment","volume":"24","author":"Goutman","year":"2023","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1136\/jnnp-2020-322909","article-title":"Prognostic Value of Weight Loss in Patients with Amyotrophic Lateral Sclerosis: A Population-Based Study","volume":"91","author":"Tan","year":"2020","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Nogueira-Machado, J.A., Rocha-Silva, F., and Gomes, N.A. (2025). The Role of mTOR in Amyotrophic Lateral Sclerosis. Biomedicines, 13.","DOI":"10.3390\/biomedicines13040952"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"116811","DOI":"10.1016\/j.celrep.2025.116811","article-title":"PDX1 Phosphorylation at S61 by mTORC1 Links Nutrient Signaling to \u03b2 Cell Function and Metabolic Disease","volume":"45","author":"Fan","year":"2026","journal-title":"Cell Rep."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Zhao, T., Fan, J., Abu-Zaid, A., Burley, S.K., and Zheng, X.F.S. (2024). Nuclear mTOR Signaling Orchestrates Transcriptional Programs Underlying Cellular Growth and Metabolism. Cells, 13.","DOI":"10.3390\/cells13090781"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"151240","DOI":"10.1016\/j.ejcb.2022.151240","article-title":"Amino Acids Control Blood Glucose Levels through mTOR Signaling","volume":"101","author":"Fan","year":"2022","journal-title":"Eur. J. Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Fan, J., Khanzada, Z., and Xu, Y. (2025). Mechanisms Underlying Muscle-Related Diseases and Aging: Insights into Pathophysiology and Therapeutic Strategies. Muscles, 4.","DOI":"10.20944\/preprints202507.2086.v1"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Fan, J., and Xu, Y. (2026). Molecular Mechanisms Underlying the Lifespan and Healthspan Benefits of Dietary Restriction across Species. Front. Genet., 17.","DOI":"10.3389\/fgene.2026.1771707"},{"key":"ref_31","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_32","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1056\/NEJMoa1916945","article-title":"Trial of Sodium Phenylbutyrate\u2013Taurursodiol for Amyotrophic Lateral Sclerosis","volume":"383","author":"Paganoni","year":"2020","journal-title":"N. Engl. J. Med."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/8\/3096\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T08:58:14Z","timestamp":1776675494000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/8\/3096"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,18]]},"references-count":32,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["jcm15083096"],"URL":"https:\/\/doi.org\/10.3390\/jcm15083096","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,18]]}}}