{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T19:48:10Z","timestamp":1793994490264,"version":"4.8.0"},"reference-count":94,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Motor neuron disease (MND), also known as amyotrophic lateral sclerosis (ALS), is a progressive neurodegenerative disorder characterized by motor neuron degeneration, leading to muscle weakness, paralysis, and eventual respiratory failure. Despite advances in understanding its pathology, effective therapies remain limited, underscoring the need for reliable biomarkers to aid early diagnosis, monitor disease progression, and optimize clinical trials. This systematic review explores the role of biomarkers in ALS, focusing on their application in clinical trials to accelerate therapeutic development and enhance patient care.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A comprehensive search of PubMed, EMBASE, MedLine, and Google Scholar identified 93 studies investigating various biomarkers, including neurofilament light chain (NFL), inflammatory markers, genetic markers like\n                      <jats:italic>SOD1<\/jats:italic>\n                      and\n                      <jats:italic>C9orf72<\/jats:italic>\n                      , and imaging modalities.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      NFL emerged as a robust biomarker, strongly correlating with disease progression and therapeutic response, and was frequently used in trials like RESCUE-ALS and CENTAUR. Genetic biomarkers, such as\n                      <jats:italic>C9orf72<\/jats:italic>\n                      and\n                      <jats:italic>SOD1<\/jats:italic>\n                      mutations, provided insights into ALS mechanisms and informed targeted therapeutic approaches. Emerging biomarkers, such as retroviral elements, show potential but require further validation. Included studies span key trials such as Lighthouse-II, MIROCALS, and MND-SMART.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>This systematic review evaluates which biomarkers are currently validated for monitoring disease progression and therapeutic response in ALS clinical trials, including protein, genetic, inflammatory, metabolic, and imaging markers. It also highlights the critical role of biomarkers in advancing MND clinical trials by enabling adaptive trial designs, patient stratification, and the use of surrogate endpoints, thereby reducing trial duration and improving efficiency. The review also highlights the translational gap between biomarker discovery and clinical application, emphasizing their potential to optimize trial design and patient stratification. While biomarkers like NFL have transformed trial methodologies, challenges such as disease specificity and inter-patient heterogeneity persist. Future efforts should focus on multimodal biomarker approaches to achieve comprehensive disease assessment and advance personalized therapeutic strategies, ultimately improving outcomes for patients with MND.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnins.2025.1636303","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T06:28:56Z","timestamp":1764311336000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Biomarkers in ALS trials: from discovery to clinical utility"],"prefix":"10.3389","volume":"19","author":[{"given":"Triparna","family":"Roy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ammar","family":"Al-Chalabi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfredo","family":"Iacoangeli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad","family":"Al Khleifat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"270","DOI":"10.3389\/fnhum.2014.00270","article-title":"Use of diffusion spectrum imaging in preliminary longitudinal evaluation of amyotrophic lateral sclerosis: Development of an imaging biomarker.","volume":"8","author":"Abhinav","year":"2014","journal-title":"Front. 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