TY - JOUR
T1 - Distinctive cell-free DNA methylation characterizes presymptomatic genetic frontotemporal dementia
AU - Giannini, Lucia A. A.
AU - Boers, Ruben G.
AU - van der Ende, Emma L.
AU - Poos, Jackie M.
AU - Jiskoot, Lize C.
AU - Boers, Joachim B.
AU - van IJcken, Wilfred F. J.
AU - Dopper, Elise G.
AU - Pijnenburg, Yolande A. L.
AU - Seelaar, Harro
AU - Meeter, Lieke H.
AU - van Rooij, Jeroen G. J.
AU - Scheper, Wiep
AU - Gribnau, Joost
AU - van Swieten, John C.
N1 - Publisher Copyright: © 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
PY - 2024/3/1
Y1 - 2024/3/1
N2 - 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.
AB - 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.
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U2 - 10.1002/acn3.51997
DO - 10.1002/acn3.51997
M3 - Article
C2 - 38481040
SN - 2328-9503
VL - 11
SP - 744
EP - 756
JO - Annals of clinical and translational neurology
JF - Annals of clinical and translational neurology
IS - 3
ER -