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

Publisher: Wiley Periodicals, Inc on behalf of American Neurological Association Country of Publication: United States NLM ID: 101623278 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2328-9503 (Electronic) Linking ISSN: 23289503 NLM ISO Abbreviation: Ann Clin Transl Neurol Subsets: MEDLINE

Original Publication: [Hoboken, NJ] : Wiley Periodicals, Inc on behalf of American Neurological Association, [2014]-

Frontotemporal Dementia*/pathology ; Pick Disease of the Brain*/genetics ; Cell-Free Nucleic Acids*/genetics; Humans ; C9orf72 Protein/genetics ; Cross-Sectional Studies ; DNA Methylation ; Mutation

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.)

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733050103 Deltaplan Dementie (ZonMw and Alzheimer Nederland); 733050513 Deltaplan Dementie (ZonMw and Alzheimer Nederland); 733050813 Deltaplan Dementie (ZonMw and Alzheimer Nederland); European Joint Programme - Neurodegenerative Disease Research; Bluefield Project to Cure Frontotemporal Dementia

0 (C9orf72 Protein)
0 (Cell-Free Nucleic Acids)

Date Created: 20240314 Date Completed: 20240327 Latest Revision: 20240328

20240329

PMC10963298

10.1002/acn3.51997

38481040