{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T18:15:45Z","timestamp":1781374545397,"version":"3.54.1"},"reference-count":39,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004257","name":"Helse Vest","doi-asserted-by":"publisher","award":["F\u201012830"],"award-info":[{"award-number":["F\u201012830"]}],"id":[{"id":"10.13039\/501100004257","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>The prodromal phase of amyotrophic lateral sclerosis (ALS) is poorly defined. We aimed to characterize prescription drug use patterns in the pre\u2010diagnostic period by analyzing nationwide prescription data to identify the earliest divergence between individuals who developed ALS and matched healthy controls. We used this divergence as an indirect marker to estimate the onset and duration of the prodrome.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a nested case\u2010control study using nationwide Norwegian registries (2005\u20132019). ALS cases were individually matched to 100 controls by sex, age, and education level using incidence density sampling. Drug prescription data were gathered from the Norwegian Prescription Database (NorPD). We calculated prescription rates up to 10\u2009years before diagnosis, performed lag\u2010time analyses, and used machine learning to predict ALS based on drug prescription patterns.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified 2,084 incident patients with ALS and 208,400 matched healthy controls. Overall, changes in prescription patterns occurred 2 to 3\u2009years before ALS diagnosis. Among specific drug groups, 25 of 42 therapeutic drug classes were prescribed more frequently to patients with ALS than matched controls. Muscle relaxants and bone disease treatments were prescribed significantly more frequently 6 and 5\u2009years before diagnosis, respectively.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>Prescription pattern changes occurred as early as 6\u2009years before ALS diagnosis. These findings are consistent with a prodromal phase preceding the clinical stage of ALS, which may last several years. In contrast, the broad increase in medication use during the final year before diagnosis likely reflects increased health care utilization as patients seek treatment for the various emerging symptoms of the clinically manifest disease. 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H. Chan School of Public Health  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ola","family":"Nakken","sequence":"additional","affiliation":[{"name":"Department of Neurology Akershus University Hospital  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ole\u2010Bj\u00f8rn","family":"Tysnes","sequence":"additional","affiliation":[{"name":"Department of Neurology Haukeland University Hospital  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jannicke","family":"Igland","sequence":"additional","affiliation":[{"name":"Department of Global Public Health and Primary Care University of Bergen  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2892-6986","authenticated-orcid":false,"given":"Kjetil","family":"Bjornevik","sequence":"additional","affiliation":[{"name":"Department of Nutrition Harvard T. H. Chan School of Public Health  Boston MA USA"},{"name":"Department of Epidemiology Harvard T. H. Chan School of Public Health  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,10]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mayocpiqo.2024.07.008"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2019.2044"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1080\/21678421.2018.1497065"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.3109\/17482968.2010.495158"},{"key":"e_1_2_9_6_1","unstructured":"The Norwegian Registry for ALS and other motor neuron diseases \u2010 Annual report for 2024.Available at:https:\/\/www.stolav.no\/49d829\/siteassets\/medisinske\u2010kvalitetsregistre\/norskalsregister\/documents\/rapporter\/arsrapport\u2010for\u20102024\u2010als\u2010registeret.pdf(accessed October 13 2025)."},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-024-00961-z"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1080\/21678421.2019.1587634"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.51.2.165"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinph.2010.03.002"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awac185"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1080\/21678421.2019.1646769"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000012632"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000007401"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcad211"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1080\/21678421.2017.1418004"},{"key":"e_1_2_9_17_1","unstructured":"WHOCC.Structure and principles n.d. 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