{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T16:59:15Z","timestamp":1783702755122,"version":"3.55.0"},"reference-count":38,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2023,7,24]],"date-time":"2023-07-24T00:00:00Z","timestamp":1690156800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Reta Lila Weston Institute of Neurological Studies, UCL Queen Square Institute of Neurology","award":["ARUK-RF2019B-005"],"award-info":[{"award-number":["ARUK-RF2019B-005"]}]},{"name":"Multiple System Atrophy Trust","award":["ARUK-RF2019B-005"],"award-info":[{"award-number":["ARUK-RF2019B-005"]}]},{"DOI":"10.13039\/501100002283","name":"Alzheimer\u2019s Research UK","doi-asserted-by":"publisher","award":["ARUK-RF2019B-005"],"award-info":[{"award-number":["ARUK-RF2019B-005"]}],"id":[{"id":"10.13039\/501100002283","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Frontotemporal lobar degeneration (FTLD) includes a heterogeneous group of disorders pathologically characterized by the degeneration of the frontal and temporal lobes. In addition to major genetic contributors of FTLD such as mutations in MAPT, GRN, and C9orf72, recent work has identified several epigenetic modifications including significant differential DNA methylation in DLX1, and OTUD4 loci. As aging remains one of the major risk factors for FTLD, we investigated the presence of accelerated epigenetic aging in FTLD compared to controls. We calculated epigenetic age in both peripheral blood and brain tissues of multiple FTLD subtypes using several DNA methylation clocks, i.e., DNAmClockMulti, DNAmClockHannum, DNAmClockCortical, GrimAge, and PhenoAge, and determined age acceleration and its association with different cellular proportions and clinical traits. Significant epigenetic age acceleration was observed in the peripheral blood of both frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP) patients compared to controls with DNAmClockHannum, even after accounting for confounding factors. A similar trend was observed with both DNAmClockMulti and DNAmClockCortical in post-mortem frontal cortex tissue of PSP patients and in FTLD cases harboring GRN mutations. Our findings support that increased epigenetic age acceleration in the peripheral blood could be an indicator for PSP and to a smaller extent, FTD.<\/jats:p>","DOI":"10.3390\/cells12141922","type":"journal-article","created":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T01:27:32Z","timestamp":1690248452000},"page":"1922","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Epigenetic Age Acceleration in Frontotemporal Lobar Degeneration: A Comprehensive Analysis in the Blood and Brain"],"prefix":"10.3390","volume":"12","author":[{"given":"Megha","family":"Murthy","sequence":"first","affiliation":[{"name":"Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London WC1N 1PJ, UK"},{"name":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London WC1N 1PJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"Rizzu","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE), 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Heutink","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE), 72076 T\u00fcbingen, Germany"},{"name":"Alector, Inc., South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Mill","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter EX4 5DW, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7389-0348","authenticated-orcid":false,"given":"Tammaryn","family":"Lashley","sequence":"additional","affiliation":[{"name":"Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London WC1N 1PJ, UK"},{"name":"Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London WC1N 1PJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9090-7690","authenticated-orcid":false,"given":"Concei\u00e7\u00e3o","family":"Bettencourt","sequence":"additional","affiliation":[{"name":"Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London WC1N 1PJ, UK"},{"name":"Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London WC1N 1PJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1111\/nan.12250","article-title":"Review: An update on clinical, genetic and pathological aspects of frontotemporal lobar degenerations","volume":"41","author":"Lashley","year":"2015","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"375","DOI":"10.2165\/11533100-000000000-00000","article-title":"Frontotemporal lobar degeneration: Epidemiology, pathophysiology, diagnosis and management","volume":"24","author":"Rabinovici","year":"2010","journal-title":"CNS Drugs"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s00401-007-0237-2","article-title":"Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: Consensus of the Consortium for Frontotemporal Lobar Degeneration","volume":"114","author":"Cairns","year":"2007","journal-title":"Acta Neuropathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.neurobiolaging.2019.02.006","article-title":"Genetics and molecular mechanisms of frontotemporal lobar degeneration: An update and future avenues","volume":"78","author":"Ferrari","year":"2019","journal-title":"Neurobiol. Aging"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"S55","DOI":"10.4103\/0972-2327.74246","article-title":"Genetics of frontotemporal lobar degeneration","volume":"13","author":"Aswathy","year":"2010","journal-title":"Ann. Indian Acad. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Li, Y., Chen, J.A., Sears, R.L., Gao, F., Klein, E.D., Karydas, A., Geschwind, M.D., Rosen, H.J., Boxer, A.L., and Guo, W. (2014). An epigenetic signature in peripheral blood associated with the haplotype on 17q21.31, a risk factor for neurodegenerative tauopathy. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1004211"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2929","DOI":"10.1038\/s41467-018-05325-y","article-title":"Epigenome-wide DNA methylation profiling in Progressive Supranuclear Palsy reveals major changes at DLX1","volume":"9","author":"Weber","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/s00401-023-02583-z","article-title":"Brain DNA methylomic analysis of frontotemporal lobar degeneration reveals OTUD4 in shared dysregulated signatures across pathological subtypes","volume":"146","author":"Fodder","year":"2023","journal-title":"Acta Neuropathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1212\/WNL.58.11.1615","article-title":"The prevalence of frontotemporal dementia","volume":"58","author":"Ratnavalli","year":"2002","journal-title":"Neurology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"15353","DOI":"10.1038\/ncomms15353","article-title":"Genetic architecture of epigenetic and neuronal ageing rates in human brain regions","volume":"8","author":"Lu","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.molcel.2012.10.016","article-title":"Genome-wide methylation profiles reveal quantitative views of human aging rates","volume":"49","author":"Hannum","year":"2013","journal-title":"Mol. Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"R115","DOI":"10.1186\/gb-2013-14-10-r115","article-title":"DNA methylation age of human tissues and cell types","volume":"14","author":"Horvath","year":"2013","journal-title":"Genome Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3763","DOI":"10.1093\/brain\/awaa334","article-title":"Recalibrating the epigenetic clock: Implications for assessing biological age in the human cortex","volume":"143","author":"Shireby","year":"2020","journal-title":"Brain"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"573","DOI":"10.18632\/aging.101414","article-title":"An epigenetic biomarker of aging for lifespan and healthspan","volume":"10","author":"Levine","year":"2018","journal-title":"Aging"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"303","DOI":"10.18632\/aging.101684","article-title":"DNA methylation GrimAge strongly predicts lifespan and healthspan","volume":"11","author":"Lu","year":"2019","journal-title":"Aging"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1038\/s41576-018-0004-3","article-title":"DNA methylation-based biomarkers and the epigenetic clock theory of ageing","volume":"19","author":"Horvath","year":"2018","journal-title":"Nat. Rev. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.2217\/epi-2022-0209","article-title":"Epigenetic aging as a biomarker of dementia and related outcomes: A systematic review","volume":"14","author":"Zhou","year":"2022","journal-title":"Epigenomics"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1007\/s00401-017-1713-y","article-title":"DNA methylation age-acceleration is associated with disease duration and age at onset in C9orf72 patients","volume":"134","author":"Zhang","year":"2017","journal-title":"Acta Neuropathol."},{"key":"ref_19","first-page":"S52","article-title":"Genetic investigation in frontotemporal dementia and Alzheimer\u2019s disease: The GIFT study","volume":"62","author":"Coppola","year":"2007","journal-title":"Ann. Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Menden, K., Francescatto, M., Nyima, T., Blauwendraat, C., Dhingra, A., Lizardo, M.C., Fernandes, N., Kaurani, L., Kronenberg-Versteeg, D., and Atarsu, B. (2021). Integrated multi-omics analysis reveals common and distinct dysregulated pathways for genetic subtypes of Frontotemporal Dementia. bioRxiv.","DOI":"10.21203\/rs.3.rs-153135\/v1"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Pidsley, R., CC, Y.W., Volta, M., Lunnon, K., Mill, J., and Schalkwyk, L.C. (2013). A data-driven approach to preprocessing Illumina 450K methylation array data. BMC Genom., 14.","DOI":"10.1186\/1471-2164-14-293"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1093\/bioinformatics\/btu049","article-title":"Minfi: A flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays","volume":"30","author":"Aryee","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3982","DOI":"10.1093\/bioinformatics\/btx513","article-title":"ChAMP: Updated methylation analysis pipeline for Illumina BeadChips","volume":"33","author":"Tian","year":"2017","journal-title":"Bioinformatics"},{"key":"ref_24","unstructured":"R Core Team (2022). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing. Available online: https:\/\/www.R-project.org\/."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Houseman, E.A., Accomando, W.P., Koestler, D.C., Christensen, B.C., Marsit, C.J., Nelson, H.H., Wiencke, J.K., and Kelsey, K.T. (2012). DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinform., 13.","DOI":"10.1186\/1471-2105-13-86"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e12872","DOI":"10.1111\/nan.12872","article-title":"Epigenetic age acceleration is associated with oligodendrocyte proportions in MSA and control brain tissue","volume":"49","author":"Murthy","year":"2023","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2137659","DOI":"10.1080\/15592294.2022.2137659","article-title":"Uncertainty quantification of reference-based cellular deconvolution algorithms","volume":"18","author":"Vellame","year":"2023","journal-title":"Epigenetics"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1844","DOI":"10.18632\/aging.101020","article-title":"DNA methylation-based measures of biological age: Meta-analysis predicting time to death","volume":"8","author":"Chen","year":"2016","journal-title":"Aging"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Smith, J.A., Raisky, J., Ratliff, S.M., Liu, J., Kardia, S.L.R., Turner, S.T., Mosley, T.H., and Zhao, W. (2019). Intrinsic and extrinsic epigenetic age acceleration are associated with hypertensive target organ damage in older African Americans. BMC Med. Genom., 12.","DOI":"10.1186\/s12920-019-0585-5"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"419","DOI":"10.18632\/aging.101168","article-title":"Epigenetic clock analysis of diet, exercise, education, and lifestyle factors","volume":"9","author":"Quach","year":"2017","journal-title":"Aging"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1002\/ijc.31189","article-title":"DNA methylation-based biological aging and cancer risk and survival: Pooled analysis of seven prospective studies","volume":"142","author":"Dugue","year":"2018","journal-title":"Int. J. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1007\/s11357-017-0001-z","article-title":"A longitudinal study of DNA methylation as a potential mediator of age-related diabetes risk","volume":"39","author":"Grant","year":"2017","journal-title":"Geroscience"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5641","DOI":"10.18632\/aging.204196","article-title":"Aging the brain: Multi-region methylation principal component based clock in the context of Alzheimer\u2019s disease","volume":"14","author":"Thrush","year":"2022","journal-title":"Aging"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5620","DOI":"10.1038\/s41467-022-33394-7","article-title":"DNA methylation signatures of Alzheimer\u2019s disease neuropathology in the cortex are primarily driven by variation in non-neuronal cell-types","volume":"13","author":"Shireby","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1038\/s41582-019-0231-z","article-title":"Neuroinflammation in frontotemporal dementia","volume":"15","author":"Bright","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e28645","DOI":"10.1097\/MD.0000000000028645","article-title":"Differences in peripheral immune system gene expression in frontotemporal degeneration","volume":"101","author":"Sawyer","year":"2022","journal-title":"Medicine"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.18632\/aging.100859","article-title":"Increased epigenetic age and granulocyte counts in the blood of Parkinson\u2019s disease patients","volume":"7","author":"Horvath","year":"2015","journal-title":"Aging"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.neurobiolaging.2017.02.009","article-title":"Maintained memory in aging is associated with young epigenetic age","volume":"55","author":"Degerman","year":"2017","journal-title":"Neurobiol. 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