Distinctive cell-free DNA methylation characterizes presymptomatic genetic frontotemporal dementia.

Autor: Giannini LAA; Department of Neurology, Alzheimer Center Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands., Boers RG; Department of Developmental Biology, Erasmus Medical Center, Rotterdam, The Netherlands., van der Ende EL; Department of Neurology, Alzheimer Center Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands.; Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherlands., Poos JM; Department of Neurology, Alzheimer Center Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands., Jiskoot LC; Department of Neurology, Alzheimer Center Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands., Boers JB; Department of Developmental Biology, Erasmus Medical Center, Rotterdam, The Netherlands., van IJcken WFJ; Erasmus Center for Biomics, Erasmus University Medical Center, Rotterdam, The Netherlands., Dopper EG; Department of Neurology, Alzheimer Center Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands., Pijnenburg YAL; Alzheimer Center Amsterdam, Neurology, Vrije Universiteit, Amsterdam UMC location Vumc, Amsterdam, The Netherlands.; Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands., Seelaar H; Department of Neurology, Alzheimer Center Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands., Meeter LH; Department of Neurology, Alzheimer Center Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands., van Rooij JGJ; Department of Neurology, Alzheimer Center Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands., Scheper W; Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands.; Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Faculty of Science, Vrije Universiteit, Amsterdam, The Netherlands.; Department of Human Genetics, Vrije Universiteit, Amsterdam UMC location Vumc, Amsterdam, The Netherlands., Gribnau J; Department of Developmental Biology, Erasmus Medical Center, Rotterdam, The Netherlands., van Swieten JC; Department of Neurology, Alzheimer Center Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands.
Jazyk: angličtina
Zdroj: Annals of clinical and translational neurology [Ann Clin Transl Neurol] 2024 Mar; Vol. 11 (3), pp. 744-756. Date of Electronic Publication: 2024 Mar 13.
DOI: 10.1002/acn3.51997
Abstrakt: Objective: Methylation of plasma cell-free 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.
Methods: cfDNA was isolated from cross-sectional plasma of 10 presymptomatic carriers (4 C9orf72, 4 GRN, and 2 MAPT), 10 symptomatic carriers (4 C9orf72, 4 GRN, and 2 MAPT), and 9 healthy controls. Genome-wide methylation of cfDNA was determined using a high-resolution sequencing technique (MeD-seq). 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 C9orf72, 3 GRN, and 2 MAPT; 26 symptomatic: 7 C9orf72, 6 GRN, 12 MAPT, and 1 TARDBP; 13 noncarriers from genetic FTD families).
Results: 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 (p < 0.001) and symptomatic carriers (p < 0.001). In the validation cohort, these scores differentiated presymptomatic carriers from symptomatic carriers (p ≤ 0.007) only. Transcription-start-site methylation in presymptomatic carriers, generally associated with gene downregulation, was enriched for genes involved in ubiquitin-dependent processes, while gene body methylation, generally associated with gene upregulation, was enriched for genes involved in neuronal cell processes.
Interpretation: A distinctive methylation profile of cfDNA characterizes the presymptomatic stage of genetic FTD, and could reflect neuronal death in this stage.
(© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
Databáze: MEDLINE
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