Glial and neuronal cell-free DNA in plasma of sporadic bvFTD and late onset primary psychiatric disease patients

Behavioral variant frontotemporal dementia (bvFTD) and primary psychiatric disorders (PPD) have symptomatic overlap that leads to diagnostic challenges. Cell-free DNA (cfDNA) tests have revolutionized prenatal non-invasive testing and cancer diagnostics. This study investigated the diagnostic potential of brain-derived cfDNA in plasma to differentiate sporadic bvFTD from PPD subjects. Targeted bisulfite sequencing was conducted to quantify glial and neuronal cfDNA levels in plasma samples from 179 bvFTD and 102 PPD subjects of the multi-center DIPPA-FTD study. No significant differences were observed in the absolute levels of glial or neuronal cfDNA between the groups. However, the neuronal-to-glial cfDNA ratio (NGR) was significantly higher in PPD cases (p = 0.0002), suggesting a relative increase in neuronal cfDNA in PPD compared to bvFTD. Diagnostic performance analysis revealed that neuronal cfDNA and NGR achieved an area under the curve (AUC) of 0.74, with a sensitivity of 90% but a specificity of 44% in distinguishing bvFTD from PPD. While increased serum levels of neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) have been shown to effectively differentiate bvFTD from PPD, the addition of brain-derived cfDNA did not provide any incremental diagnostic benefit over these established biomarkers.

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Journal
Scientific Reports
Published
2025-11-06
DOI
https://doi.org/10.1038/s41598-025-22667-y
Citations
1
Primary Topic
Cancer Genomics and Diagnostics
Type
article
Field-Weighted Citation Impact
0.94
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Glial and neuronal cell-free DNA in plasma of sporadic bvFTD and late onset primary psychiatric disease patients

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Scientific Reports
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Glial and neuronal cell-free DNA in plasma of sporadic bvFTD and late onset primary psychiatric disease patients

Ishana Rue, Ramón Landín-Romero, Andrea Arighi, Dean Southwood, Zac Chatterton, Glenda Margaret Halliday, Olivier Piguet, Lina Riedl, Chiara Fenoglio, Janine Diehl‐Schmid, Daniela Galimberti, Sterre C.M. de Boer, Yolande A.L. Pijnenburg, Simon Ducharme, Sophie Matis
article en
1 citations

Abstract

Behavioral variant frontotemporal dementia (bvFTD) and primary psychiatric disorders (PPD) have symptomatic overlap that leads to diagnostic challenges. Cell-free DNA (cfDNA) tests have revolutionized prenatal non-invasive testing and cancer diagnostics. This study investigated the diagnostic potential of brain-derived cfDNA in plasma to differentiate sporadic bvFTD from PPD subjects. Targeted bisulfite sequencing was conducted to quantify glial and neuronal cfDNA levels in plasma samples from 179 bvFTD and 102 PPD subjects of the multi-center DIPPA-FTD study. No significant differences were observed in the absolute levels of glial or neuronal cfDNA between the groups. However, the neuronal-to-glial cfDNA ratio (NGR) was significantly higher in PPD cases (p = 0.0002), suggesting a relative increase in neuronal cfDNA in PPD compared to bvFTD. Diagnostic performance analysis revealed that neuronal cfDNA and NGR achieved an area under the curve (AUC) of 0.74, with a sensitivity of 90% but a specificity of 44% in distinguishing bvFTD from PPD. While increased serum levels of neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) have been shown to effectively differentiate bvFTD from PPD, the addition of brain-derived cfDNA did not provide any incremental diagnostic benefit over these established biomarkers.

Scientific ReportsVol. 15(1)
Montreal Neurological Institute and Hospital (CA), The University of Sydney (AU), University of Milan (IT), Douglas Mental Health University Institute (CA), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Cooperative Trials Group for Neuro-Oncology (AU), Amsterdam Neuroscience (NL), Inn-Salzach-Klinikum (DE), Amsterdam University Medical Centers (NL), McGill University (CA), Technical University of Munich (DE), Vrije Universiteit Amsterdam (NL)
Openalex Percentile: Top 19%
Cancer Genomics and Diagnostics
0.94
DOIOpen Access PDFOpenAlex
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