{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:03:42Z","timestamp":1792785822015,"version":"4.5.0"},"reference-count":286,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T00:00:00Z","timestamp":1788566400000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"ALS Society"},{"DOI":"10.13039\/501100017562","name":"Temerty Family Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100017562","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Biogen Canada"},{"DOI":"10.13039\/100009017","name":"ALS Society of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009017","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Alector","id":[{"id":"https:\/\/ror.org\/03vagve85","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/100004312","name":"Eli Lilly and Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004312","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000406","name":"Motor Neurone Disease Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000406","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012351","name":"Mistubishi Tanabe Pharma","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012351","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Determining the optimal timing of disease-modifying therapies for neurodegenerative disorders will necessitate identification of when the underlying pathobiological process becomes active, well in advance of the point at which clinical manifestations appear. Phenoconversion, the emergence of clinically manifest syndromes, may be preceded by years to decades of silent pathobiological activity that can only be mapped by an array of biomarkers.<\/jats:p>\n                  <jats:p>Amyotrophic lateral sclerosis (ALS) and frontotemporal dementias (FTD), traditionally identified as distinct clinical syndromes, are increasingly recognized to exist along a spectrum of clinical syndromes with shared genetic risk and underlying pathology. This clinicopathological spectrum is underpinned by cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43) as the common neuropathological hallmark. In contrast, the majority of neuropathologically-defined frontotemporal lobar degeneration (FTLD) is associated with alterations in either TDP-43 metabolism (FTLD-TDP) or of the microtubule associated protein tau (FTLD-tau), with a smaller percentage associated with either autosomal dominant genetic mutations or impairments in the ubiquitin proteasome system. As the field of neurodegenerative disorders increasingly shifts towards the frameworks of a pathobiological definition of disease, there is a growing imperative to develop biomarkers that reflect the varied pathobiologies that underly these disorders, and to determine the sensitivity of such biomarkers to detect the presence of these pathobiologies before phenoconversion.<\/jats:p>\n                  <jats:p>To that end, an international workshop was convened in London, Canada in 2025 to review the evidence for existing or evolving biomarkers suitable for (i) the detection of either ALS or FTD pathobiology prior to phenoconversion and\/or (ii) predict phenoconversion in at-risk individuals. Such biomarkers might be conceptualized as \u2018biotypic biomarkers\u2019, capturing their ability to describe an underlying pathophysiology whilst being agnostic to the emergent clinical manifestations. While currently no single biotypic marker can predict the emergence of ALS, FTD or their intersection, a multimodal approach to developing a biotypic biomarker profile holds promise for the detection of relevant pathobiological processes. The strength of such an approach would be augmented by also addressing issues of resiliency\/susceptibility both in terms of genetic risk susceptibility profiles and developing sensitive biomarkers of genomic and cellular ageing. By including such non-traditional markers of disease, a more robust picture of not only the degenerative process but also of those factors that might potentially mitigate or drive a heightened probability of disease can be derived.<\/jats:p>","DOI":"10.1093\/brain\/awag297","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T11:25:44Z","timestamp":1788521144000},"source":"Crossref","is-referenced-by-count":0,"title":["Progress towards a biotypic biomarker profile for amyotrophic lateral sclerosis\u2013frontotemporal spectrum disorders"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1988-6262","authenticated-orcid":false,"given":"Michael J","family":"Strong","sequence":"first","affiliation":[{"name":"Molecular Medicine Group, Robarts Research Institute, Schulich School of Medicine & Dentistry, Western University , London N6A 3K7 ,","place":["Canada"]},{"name":"Department of Clinical Neurological Sciences, Schulich School of Medicine & Dentistry, Western University , London N6A 5A5 ,","place":["Canada"]},{"name":"Department of Pathology and Laboratory Medicine, Schulich School of Medicine & Dentistry, Western University , London N6A 5C1 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8630-7481","authenticated-orcid":false,"given":"Neil","family":"Donison","sequence":"additional","affiliation":[{"name":"Molecular Medicine Group, Robarts Research Institute, Schulich School of Medicine & Dentistry, Western University , London N6A 3K7 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4924-7712","authenticated-orcid":false,"given":"Ammar","family":"Al-Chalabi","sequence":"additional","affiliation":[{"name":"Department of Basic and Clinical Neuroscience, King\u2019s College London , London SE5 9RT \u00a0","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4153-8187","authenticated-orcid":false,"given":"Bradley","family":"Boeve","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic , Rochester, MN 55905 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4461-7427","authenticated-orcid":false,"given":"Elizabeth C","family":"Finger","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurological Sciences, Schulich School of Medicine & Dentistry, Western University , London N6A 5A5 ,","place":["Canada"]},{"name":"Department of Cognitive Neurology, St Joseph's Health Care London , London, ON N6C 0A7 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7688-3087","authenticated-orcid":false,"given":"Henne","family":"Holstege","sequence":"additional","affiliation":[{"name":"Alzheimer Centre Amsterdam, Amsterdam University Medical Centers , Amsterdam 1081 HZ ,","place":["The Netherlands"]},{"name":"Department of Clinical Genetics, Amsterdam University Medical Centers , Amsterdam 1105 AZ ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8295-5884","authenticated-orcid":false,"given":"Edward D","family":"Huey","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University , Providence, RI 02912 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4589-1180","authenticated-orcid":false,"given":"Edward 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Psychology, University of Stirling , Stirling FK9 4LA ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7581-6405","authenticated-orcid":false,"given":"Corey T","family":"McMillan","sequence":"additional","affiliation":[{"name":"Department of Neurology, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4273-4267","authenticated-orcid":false,"given":"Markus","family":"Otto","sequence":"additional","affiliation":[{"name":"Department of Neurology, Martin-Luther-University Halle-Wittenberg , Halle (Saale) 06120 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2959-129X","authenticated-orcid":false,"given":"Leonard","family":"Petrucelli","sequence":"additional","affiliation":[{"name":"Department of Neurology, 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