{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T16:34:20Z","timestamp":1793982860901,"version":"4.8.0"},"reference-count":56,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"784","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2025,2,5]]},"abstract":"<jats:p>\n                    We used an untargeted mass spectrometric approach, tandem mass tag proteomics, for the identification of proteomic signatures in genetic frontotemporal dementia (FTD). A total of 238 cerebrospinal fluid (CSF) samples from the Genetic FTD Initiative were analyzed, including samples from 107 presymptomatic (44\n                    <jats:italic>C9orf72<\/jats:italic>\n                    , 38\n                    <jats:italic>GRN<\/jats:italic>\n                    , and 25\n                    <jats:italic>MAPT<\/jats:italic>\n                    ) and 55 symptomatic (27\n                    <jats:italic>C9orf72<\/jats:italic>\n                    , 17\n                    <jats:italic>GRN<\/jats:italic>\n                    , and 11\n                    <jats:italic>MAPT<\/jats:italic>\n                    ) mutation carriers as well as 76 mutation-negative controls (\u201cnoncarriers\u201d). We found shared and distinct proteomic alterations in each genetic form of FTD. Among the proteins significantly altered in symptomatic mutation carriers compared with noncarriers, we found that a set of proteins including neuronal pentraxin 2 and fatty acid binding protein 3 changed across all three genetic forms of FTD and patients with Alzheimer\u2019s disease from previously published datasets. We observed differential changes in lysosomal proteins among symptomatic mutation carriers with marked abundance decreases in\n                    <jats:italic>MAPT<\/jats:italic>\n                    carriers but not other carriers. Further, we identified mutation-associated proteomic changes already evident in presymptomatic mutation carriers. Weighted gene coexpression network analysis combined with gene ontology annotation revealed clusters of proteins enriched in neurodegeneration and glial responses as well as synapse- or lysosome-related proteins indicating that these are the central biological processes affected in genetic FTD. These clusters correlated with measures of disease severity and were associated with cognitive decline. This study revealed distinct proteomic changes in the CSF of patients with genetic FTD, providing insights into the pathological processes involved in the disease. In addition, we identified proteins that warrant further exploration as diagnostic and prognostic biomarker candidates.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adm9654","type":"journal-article","created":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T13:59:47Z","timestamp":1738763987000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":19,"title":["Proteomic analysis reveals distinct cerebrospinal fluid signatures across genetic frontotemporal dementia subtypes"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7869-8192","authenticated-orcid":true,"given":"Aitana","family":"Sogorb-Esteve","sequence":"first","affiliation":[{"name":"UK Dementia Research Institute at University College London, WC1N 3BG London, UK."},{"name":"Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London, WC1N 3BG London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2298-220X","authenticated-orcid":true,"given":"Sophia","family":"Weiner","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, 431 39 M\u00f6lndal, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5081-6604","authenticated-orcid":true,"given":"Joel","family":"Simr\u00e9n","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, 431 39 M\u00f6lndal, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imogen J.","family":"Swift","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute at University College London, WC1N 3BG London, UK."},{"name":"Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London, WC1N 3BG London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1814-5024","authenticated-orcid":true,"given":"Martina","family":"Bocchetta","sequence":"additional","affiliation":[{"name":"Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London, WC1N 3BG London, UK."},{"name":"Centre for Cognitive and Clinical Neuroscience, Division of Psychology, Department of Life Sciences, College of Health, Medicine, and Life Sciences, Brunel University, UB8 3PH London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1551-5691","authenticated-orcid":true,"given":"Emily G.","family":"Todd","sequence":"additional","affiliation":[{"name":"Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London, WC1N 3BG London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7833-616X","authenticated-orcid":true,"given":"David M.","family":"Cash","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute at University College London, WC1N 3BG London, UK."},{"name":"Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London, WC1N 3BG London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0267-8590","authenticated-orcid":true,"given":"Arabella","family":"Bouzigues","sequence":"additional","affiliation":[{"name":"Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London, WC1N 3BG London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5023-5893","authenticated-orcid":true,"given":"Lucy L.","family":"Russell","sequence":"additional","affiliation":[{"name":"Dementia 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