{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T06:38:03Z","timestamp":1791959883117,"version":"4.3.4"},"reference-count":70,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T00:00:00Z","timestamp":1710288000000},"content-version":"vor","delay-in-days":12,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Methylation of plasma cell\u2010free DNA (cfDNA) has potential as a marker of brain damage in neurodegenerative diseases such as frontotemporal dementia (FTD). Here, we study methylation of cfDNA in presymptomatic and symptomatic carriers of genetic FTD pathogenic variants, next to healthy controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>cfDNA was isolated from cross\u2010sectional plasma of 10 presymptomatic carriers (4 <jats:italic>C9orf72<\/jats:italic>, 4 <jats:italic>GRN<\/jats:italic>, and 2 <jats:italic>MAPT<\/jats:italic>), 10 symptomatic carriers (4 <jats:italic>C9orf72<\/jats:italic>, 4 <jats:italic>GRN<\/jats:italic>, and 2 <jats:italic>MAPT<\/jats:italic>), and 9 healthy controls. Genome\u2010wide methylation of cfDNA was determined using a high\u2010resolution sequencing technique (MeD\u2010seq). Cumulative scores based on the identified differentially methylated regions (DMRs) were estimated for presymptomatic carriers (vs. controls and symptomatic carriers), and reevaluated in a validation cohort (8 presymptomatic: 3 <jats:italic>C9orf72<\/jats:italic>, 3 <jats:italic>GRN<\/jats:italic>, and 2 <jats:italic>MAPT<\/jats:italic>; 26 symptomatic: 7 <jats:italic>C9orf72<\/jats:italic>, 6 <jats:italic>GRN<\/jats:italic>, 12 <jats:italic>MAPT<\/jats:italic>, and 1 <jats:italic>TARDBP<\/jats:italic>; 13 noncarriers from genetic FTD families).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Presymptomatic carriers showed a distinctive methylation profile compared to healthy controls and symptomatic carriers. Cumulative DMR scores in presymptomatic carriers enabled to significantly differentiate presymptomatic carriers from healthy controls (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) and symptomatic carriers (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). In the validation cohort, these scores differentiated presymptomatic carriers from symptomatic carriers (<jats:italic>p<\/jats:italic>\u2009\u2264\u20090.007) only. Transcription\u2010start\u2010site methylation in presymptomatic carriers, generally associated with gene downregulation, was enriched for genes involved in ubiquitin\u2010dependent processes, while gene body methylation, generally associated with gene upregulation, was enriched for genes involved in neuronal cell processes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>A distinctive methylation profile of cfDNA characterizes the presymptomatic stage of genetic FTD, and could reflect neuronal death in this stage.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51997","type":"journal-article","created":{"date-parts":[[2024,3,14]],"date-time":"2024-03-14T05:43:30Z","timestamp":1710395010000},"page":"744-756","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Distinctive cell\u2010free <scp>DNA<\/scp> methylation characterizes presymptomatic genetic frontotemporal dementia"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3521-3693","authenticated-orcid":false,"given":"Lucia A. 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