{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T11:51:00Z","timestamp":1791460260999,"version":"4.3.4"},"reference-count":21,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"vor","delay-in-days":7,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["RF-2016-02362405"],"award-info":[{"award-number":["RF-2016-02362405"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003407","name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["2017SNW5MB"],"award-info":[{"award-number":["2017SNW5MB"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003407","name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["20228N7573"],"award-info":[{"award-number":["20228N7573"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Commission's Health Seventh Framework Programme","award":["259867"],"award-info":[{"award-number":["259867"]}]},{"DOI":"10.13039\/100010661","name":"Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["101017598"],"award-info":[{"award-number":["101017598"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010661","name":"Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["101137074"],"award-info":[{"award-number":["101137074"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013278","name":"EU Joint Programme \u2013 Neurodegenerative Disease Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013278","id-type":"DOI","asserted-by":"publisher"}]},{"name":"ARISLA","award":["project DIG-ALS"],"award-info":[{"award-number":["project DIG-ALS"]}]},{"name":"Emilia Romagna Regional Health Authority"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Neurol"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The pre-diagnostic ALSFRS-R slope is frequently used in a clinical trial design and clinical practice under the implicit assumption that it reflects subsequent functional decline. We assessed the association between the pre-diagnostic ALSFRS-R slope and subsequent functional decline.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The Piemonte and Valle d\u2019Aosta ALS Registry (PARALS) was used as the primary cohort. The associations between pre- and post-diagnostic slopes at 6, 12, and 18\u00a0months were examined using correlation coefficients and multivariable linear regression. Linear and quadratic mixed-effects models used all ALSFRS-R assessments obtained during the first 18\u00a0months to evaluate longitudinal trajectories and quantify the incremental contribution of the pre-diagnostic slope. All analyses were replicated in the Emilia Romagna Registry for ALS (ERRALS).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 2,222 patients from PARALS and 1,543 from ERRALS were included. In PARALS, the pre-diagnostic ALSFRS-R slope showed only a modest monotonic association with post-diagnostic functional decline (Spearman\u2019s\n                      <jats:italic>\u03c1<\/jats:italic>\n                      = 0.19\u20130.30) and explained 6.1% of its variance at 6\u00a0months, with this proportion decreasing thereafter. Quadratic mixed-effects models estimated that, at 12\u00a0months, the difference in ALSFRS-R change between patients in the highest and lowest pre-diagnostic slope quartiles was 2.04 points in PARALS (95% CI 1.25\u20132.83) and 2.47 points in ERRALS (95% CI 1.07\u20133.86). However, the linear and quadratic interactions together increased the marginal\n                      <jats:italic>R<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      by only 0.43 percentage points in PARALS and 1.68 percentage points in ERRALS.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The pre-diagnostic ALSFRS-R slope identifies meaningful average differences in subsequent decline between patient groups but provides limited information for predicting individual trajectories.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00415-026-14177-2","type":"journal-article","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T10:59:44Z","timestamp":1791457184000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pre-diagnostic ALSFRS-R slope provides limited incremental information about the variability in subsequent functional decline in amyotrophic lateral sclerosis: a population-based study"],"prefix":"10.1007","volume":"273","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0393-4736","authenticated-orcid":false,"given":"Rosario","family":"Vasta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Calvo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Moglia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Canosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umberto","family":"Manera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Gianferrari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Zucchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Martinelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Mora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Cabras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Palumbo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico","family":"Matteoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Maccabeo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio","family":"Pellegrino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilio","family":"Minerva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Pascariu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Callegaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizio","family":"D\u2019Ovidio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Letizia","family":"Mazzini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabiola","family":"De Marchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Mandrioli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriano","family":"Chi\u00f2","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,8]]},"reference":[{"key":"14177_CR1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000213467","volume":"104","author":"R Vasta","year":"2025","unstructured":"Vasta R, De Mattei F, Tafaro S et al (2025) Changes to average survival of patients with amyotrophic lateral sclerosis (1995-2018): results from the Piemonte and Valle d\u2019Aosta Registry. Neurology 104:e213467. https:\/\/doi.org\/10.1212\/WNL.0000000000213467","journal-title":"Neurology"},{"key":"14177_CR2","doi-asserted-by":"publisher","first-page":"1182","DOI":"10.1016\/S1474-4422(16)30199-5","volume":"15","author":"A Al-Chalabi","year":"2016","unstructured":"Al-Chalabi A, Hardiman O, Kiernan MC et al (2016) Amyotrophic lateral sclerosis: moving towards a new classification system. Lancet Neurol 15:1182\u20131194. https:\/\/doi.org\/10.1016\/S1474-4422(16)30199-5","journal-title":"Lancet Neurol"},{"key":"14177_CR3","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1038\/s43588-022-00299-w","volume":"2","author":"D Ramamoorthy","year":"2022","unstructured":"Ramamoorthy D, Severson K, Ghosh S et al (2022) Identifying patterns in amyotrophic lateral sclerosis progression from sparse longitudinal data. Nat Comput Sci 2:605\u2013616. https:\/\/doi.org\/10.1038\/s43588-022-00299-w","journal-title":"Nat Comput Sci"},{"key":"14177_CR4","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1038\/nrneurol.2014.250","volume":"11","author":"A Chi\u00f2","year":"2015","unstructured":"Chi\u00f2 A, Traynor BJ (2015) Motor neuron disease in 2014. Biomarkers for ALS-in search of the promised land. Nat Rev Neurol 11:72\u201374. https:\/\/doi.org\/10.1038\/nrneurol.2014.250","journal-title":"Nat Rev Neurol"},{"key":"14177_CR5","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/S0022-510X(99)00210-5","volume":"169","author":"JM Cedarbaum","year":"1999","unstructured":"Cedarbaum JM, Stambler N, Malta E et al (1999) The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS study group (Phase III). J Neurol Sci 169:13\u201321","journal-title":"J Neurol Sci"},{"key":"14177_CR6","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1212\/01.wnl.0000194316.91908.8a","volume":"66","author":"F Kimura","year":"2006","unstructured":"Kimura F, Fujimura C, Ishida S et al (2006) Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS. Neurology 66:265\u2013267. https:\/\/doi.org\/10.1212\/01.wnl.0000194316.91908.8a","journal-title":"Neurology"},{"key":"14177_CR7","doi-asserted-by":"publisher","first-page":"310","DOI":"10.3109\/17482960802566824","volume":"10","author":"A Chi\u00f2","year":"2009","unstructured":"Chi\u00f2 A, Logroscino G, Hardiman O et al (2009) Prognostic factors in ALS: a critical review. Amyotroph Lateral Scler 10:310\u2013323. https:\/\/doi.org\/10.3109\/17482960802566824","journal-title":"Amyotroph Lateral Scler"},{"key":"14177_CR8","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1016\/S1474-4422(18)30089-9","volume":"17","author":"H-J Westeneng","year":"2018","unstructured":"Westeneng H-J, Debray TPA, Visser AE et al (2018) Prognosis for patients with amyotrophic lateral sclerosis: development and validation of a personalised prediction model. Lancet Neurol 17:423\u2013433. https:\/\/doi.org\/10.1016\/S1474-4422(18)30089-9","journal-title":"Lancet Neurol"},{"key":"14177_CR9","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1080\/21678421.2024.2443985","volume":"26","author":"RPA van Eijk","year":"2025","unstructured":"van Eijk RPA, Weemering DN, Opie-Martin S et al (2025) Natural history of the revised ALS functional rating scale and its association with survival: the PRECISION-ALS extant study. Amyotroph Lateral Scler Frontotemporal Degener 26:30\u201340. https:\/\/doi.org\/10.1080\/21678421.2024.2443985","journal-title":"Amyotroph Lateral Scler Frontotemporal Degener"},{"key":"14177_CR10","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000214937","volume":"106","author":"DN Weemering","year":"2026","unstructured":"Weemering DN, van Unnik JWJ, Genge A et al (2026) Heterogeneity in the analysis of the ALSFRS-R in ALS clinical trials and its effect on the validity and precision of trial conclusions. Neurology 106:e214937. https:\/\/doi.org\/10.1212\/WNL.0000000000214937","journal-title":"Neurology"},{"key":"14177_CR11","doi-asserted-by":"publisher","first-page":"1097","DOI":"10.1001\/jamaneurol.2017.1387","volume":"74","author":"A Chi\u00f2","year":"2017","unstructured":"Chi\u00f2 A, Mora G, Moglia C et al (2017) Secular trends of amyotrophic lateral sclerosis: The Piemonte and Valle d\u2019aosta Register. JAMA Neurol 74:1097\u20131104. https:\/\/doi.org\/10.1001\/jamaneurol.2017.1387","journal-title":"JAMA Neurol"},{"key":"14177_CR12","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1080\/146608200300079536","volume":"1","author":"BR Brooks","year":"2000","unstructured":"Brooks BR, Miller RG, Swash M et al (2000) El escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 1:293\u2013299","journal-title":"Amyotroph Lateral Scler Other Motor Neuron Disord"},{"key":"14177_CR13","doi-asserted-by":"publisher","DOI":"10.1111\/ene.16264","volume":"31","author":"P Van Damme","year":"2024","unstructured":"Van Damme P, Al-Chalabi A, Andersen PM et al (2024) 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). Eur J Neurol 31:e16264. https:\/\/doi.org\/10.1111\/ene.16264","journal-title":"Eur J Neurol"},{"key":"14177_CR14","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines10040819","volume":"10","author":"G Gianferrari","year":"2022","unstructured":"Gianferrari G, Martinelli I, Zucchi E et al (2022) Epidemiological, clinical and genetic features of ALS in the last decade: a prospective population-based study in the Emilia Romagna region of Italy. Biomedicines 10:819. https:\/\/doi.org\/10.3390\/biomedicines10040819","journal-title":"Biomedicines"},{"key":"14177_CR15","unstructured":"R: The R Project for Statistical Computing. https:\/\/www.r-project.org\/. Accessed 6 Jun 2017"},{"key":"14177_CR16","doi-asserted-by":"publisher","first-page":"2243","DOI":"10.1007\/s10072-015-2343-6","volume":"36","author":"J Mandrioli","year":"2015","unstructured":"Mandrioli J, Biguzzi S, Guidi C et al (2015) Heterogeneity in ALSFRS-R decline and survival: a population-based study in Italy. Neurol Sci 36:2243\u20132252. https:\/\/doi.org\/10.1007\/s10072-015-2343-6","journal-title":"Neurol Sci"},{"key":"14177_CR17","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2019-321153","author":"U Manera","year":"2019","unstructured":"Manera U, Calvo A, Daviddi M et al (2019) Regional spreading of symptoms at diagnosis as a prognostic marker in amyotrophic lateral sclerosis: a population-based study. J Neurol Neurosurg Psychiatry. https:\/\/doi.org\/10.1136\/jnnp-2019-321153","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"14177_CR18","doi-asserted-by":"publisher","first-page":"1397","DOI":"10.1111\/ene.14287","volume":"27","author":"R Vasta","year":"2020","unstructured":"Vasta R, D\u2019Ovidio F, Canosa A et al (2020) Plateaus in amyotrophic lateral sclerosis progression: results from a population-based cohort. Eur J Neurol 27:1397\u20131404. https:\/\/doi.org\/10.1111\/ene.14287","journal-title":"Eur J Neurol"},{"key":"14177_CR19","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1080\/21678421.2024.2309989","volume":"25","author":"T Hamatani","year":"2024","unstructured":"Hamatani T, Atsuta N, Sano F et al (2024) ALSFRS-R decline rate prior to baseline is not useful for stratifying subsequent progression of functional decline. Amyotroph Lateral Scler Frontotemporal Degener 25:388\u2013399. https:\/\/doi.org\/10.1080\/21678421.2024.2309989","journal-title":"Amyotroph Lateral Scler Frontotemporal Degener"},{"key":"14177_CR20","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1080\/21678421.2021.1879865","volume":"22","author":"RPA van Eijk","year":"2021","unstructured":"van Eijk RPA, de Jongh AD, Nikolakopoulos S et al (2021) An old friend who has overstayed their welcome: the ALSFRS-R total score as primary endpoint for ALS clinical trials. Amyotroph Lateral Scler Frontotemporal Degener 22:300\u2013307. https:\/\/doi.org\/10.1080\/21678421.2021.1879865","journal-title":"Amyotroph Lateral Scler Frontotemporal Degener"},{"key":"14177_CR21","doi-asserted-by":"publisher","first-page":"1432","DOI":"10.1212\/WNL.0b013e318232ab9b","volume":"77","author":"A Chi\u00f2","year":"2011","unstructured":"Chi\u00f2 A, Canosa A, Gallo S et al (2011) ALS clinical trials: do enrolled patients accurately represent the ALS population? Neurology 77:1432\u20131437. https:\/\/doi.org\/10.1212\/WNL.0b013e318232ab9b","journal-title":"Neurology"}],"container-title":["Journal of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00415-026-14177-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00415-026-14177-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00415-026-14177-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T10:59:46Z","timestamp":1791457186000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00415-026-14177-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10]]},"references-count":21,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["14177"],"URL":"https:\/\/doi.org\/10.1007\/s00415-026-14177-2","relation":{},"ISSN":["0340-5354","1432-1459"],"issn-type":[{"value":"0340-5354","type":"print"},{"value":"1432-1459","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10]]},"assertion":[{"value":"20 July 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 September 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 September 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 October 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Andrea Calvo serves on scientific advisory boards for Biogen and Zambon Biotech and has received research grants from Cytokinetics. Adriano Chi\u00f2 serves on scientific advisory boards for Mitsubishi Tanabe, Biogen, Roche, Denali Pharma, Cytokinetics, Lilly, Ferrer, Zambon Biotech, and Amylyx Pharmaceuticals, and has received a research grant from Biogen. Jessica Mandrioli serves on scientific advisory boards for Biogen, Amylyx, Zambon, Italfarmaco, Maat Pharma, Clarivate; research support from Pfizer, Biogen, Ionis, Roche, Apellis, Ferrer, ABScience, Amylix, PTC Therapeutics, Novartis. All other authors do not report any conflict of interest.","order":1,"name":"Ethics","label":"Conflicts of interest","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"651"}}