{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T17:40:46Z","timestamp":1788975646852,"version":"build-2803163510"},"reference-count":113,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T00:00:00Z","timestamp":1754352000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100003607","name":"Association for Frontotemporal Degeneration","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100003607","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000971","name":"ALS Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000971","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,11,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The idea that it might be possible to prevent some forms of amyotrophic lateral sclerosis and frontotemporal dementia has finally come of age. The hexanucleotide repeat expansion in the C9orf72 gene accounts for \u223c10% of all amyotrophic lateral sclerosis and 10%\u201315% of all frontotemporal dementia diagnoses, with the two clinical syndromes co-manifesting in a significant number of patients. As a result, clinically unaffected carriers of pathogenic C9orf72 repeat expansions are currently the largest identifiable population at significantly elevated risk for both amyotrophic lateral sclerosis and frontotemporal dementia, and in whom it might be possible to prevent the emergence of clinically manifest disease. Strategies for the design of disease prevention trials among clinically unaffected C9orf72 carriers have begun to emerge separately in the amyotrophic lateral sclerosis and frontotemporal dementia fields. However, recognition of the need to define neurodegenerative diseases based on biology underscores the need to consider all potential clinical manifestations of a C9orf72 repeat expansion together, rather than the traditional siloed approach of focusing on only amyotrophic lateral sclerosis or only frontotemporal dementia. Indeed, emerging clinical and biological markers that might be used to quantify pre-symptomatic disease progression and to predict the short-term risk of phenoconversion to clinically manifest disease are shared across the phenotypic spectrum.<\/jats:p>\n                  <jats:p>Given the anticipated progress in the development of therapeutic strategies to target the C9orf72 repeat expansion, and the enthusiasm for prevention trials among the unaffected C9orf72 repeat expansion carrier population, now is the time to begin work on the design of disease prevention trials. To this end, The Association for Frontotemporal Degeneration and The ALS Association supported a multi-stakeholder workshop (in Washington D.C., June 2024) to unify efforts to design a prevention trial for the population at elevated genetic risk for the phenotypic spectrum of C9orf72 disease. Here we describe recommendations emanating from this workshop for the selection of outcome measures, delineation of eligibility criteria, optimal use of biomarkers and digital health technologies, potential analytic frameworks and relevant regulatory considerations related to C9orf72 disease prevention trials. We also emphasize the importance of the amyotrophic lateral sclerosis and frontotemporal dementia communities working together in partnership with the C9orf72 repeat expansion carrier community, the regulatory authorities and the broader drug development community.<\/jats:p>","DOI":"10.1093\/brain\/awaf290","type":"journal-article","created":{"date-parts":[[2025,8,3]],"date-time":"2025-08-03T11:25:33Z","timestamp":1754220333000},"page":"3844-3855","source":"Crossref","is-referenced-by-count":5,"title":["Design considerations for\n                    <i>C9orf72<\/i>\n                    disease prevention trials"],"prefix":"10.1093","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4241-5135","authenticated-orcid":false,"given":"Michael","family":"Benatar","sequence":"first","affiliation":[{"name":"Department of Neurology and the ALS Center, Miller School of Medicine, University of Miami , Miami, FL 33129 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3903-9805","authenticated-orcid":false,"given":"Adam M","family":"Staffaroni","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of California San Francisco , San Francisco, CA 94158 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9643-9855","authenticated-orcid":false,"given":"Joanne","family":"Wuu","sequence":"additional","affiliation":[{"name":"Department of Neurology and the ALS Center, Miller School of Medicine, University of Miami , Miami, FL 33129 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7443-9145","authenticated-orcid":false,"given":"Michael P","family":"McDermott","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry , Rochester, NY 14642 ,","place":["USA"]},{"name":"Department of Neurology, University of Rochester School of Medicine and Dentistry , Rochester, NY 14642 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1763-2704","authenticated-orcid":false,"given":"Melanie","family":"Quintana","sequence":"additional","affiliation":[{"name":"Berry Consultants , Austin, TX 78746 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3605-6183","authenticated-orcid":false,"given":"Jean","family":"Swidler","sequence":"additional","affiliation":[{"name":"Genetic ALS & FTD: End the Legacy , Philadelphia, PA 19107 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gail","family":"Andersen","sequence":"additional","affiliation":[{"name":"The Association for Frontotemporal Dementia , King of Prussia, PA 19406 ,","place":["USA"]}],"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 02906 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0267-3180","authenticated-orcid":false,"given":"Martin R","family":"Turner","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford , Oxford OX3 9DU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1618-3502","authenticated-orcid":false,"given":"Eric A","family":"Macklin","sequence":"additional","affiliation":[{"name":"Departments of Neurology and Medicine, Massachusetts General Hospital, Harvard Medical School , Boston, MA 02145 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0898-6081","authenticated-orcid":false,"given":"James D","family":"Berry","sequence":"additional","affiliation":[{"name":"Sean M. Healey and AMG Center for ALS, Massachusetts General Hospital , Boston, MA 02114 ,","place":["USA"]}],"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, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7335-2627","authenticated-orcid":false,"given":"Tania","family":"Gendron","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic , Jacksonville, FL 32224 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2255-4437","authenticated-orcid":false,"given":"Chiadi","family":"Onyike","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine , Baltimore, MD 21205 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9281-7402","authenticated-orcid":false,"given":"Howard","family":"Rosen","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of California San Francisco , San Francisco, CA 94158 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3776-1685","authenticated-orcid":false,"given":"Hilary W","family":"Heuer","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of California San Francisco , San Francisco, CA 94158 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7167-5983","authenticated-orcid":false,"given":"Anne-Laure","family":"Grignon","sequence":"additional","affiliation":[{"name":"Department of Neurology and the ALS Center, Miller School of Medicine, University of Miami , Miami, FL 33129 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuldip D","family":"Dave","sequence":"additional","affiliation":[{"name":"The ALS Association , Arlington, VA 22209 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Calaneet","family":"Balas","sequence":"additional","affiliation":[{"name":"The ALS Association , Arlington, VA 22209 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Gleixner","sequence":"additional","affiliation":[{"name":"The Association for Frontotemporal Dementia , King of Prussia, PA 19406 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6523-3946","authenticated-orcid":false,"given":"Andrew","family":"Satlin","sequence":"additional","affiliation":[{"name":"Transposon Therapeutics Inc. , New York, NY 92122 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Billy","family":"Dunn","sequence":"additional","affiliation":[{"name":"The Michael J. 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