Possible new biomarker for early neuronal death in mesial temporal lobe epilepsy

Brain-derived cell-free DNA (cfDNA) in serum of patients with mesial temporal lobe epilepsy (MTLE) may constitute a promising new biomarker for early detection of neuronal death. Notwithstanding the equal release into the bloodstream of neuron-derived cfDNA in MTLE patients and controls, differential methylation patterns could be observed.

cfDNA consist of highly degraded DNA fragments that are released into the peripheral blood stream in both people with and without health conditions [1]. Apoptosis is generally considered to be the main source of cfDNA due to the matching size of cfDNA and apoptotic DNA cleavage fragments. DNA fragmentation during apoptosis is mediated by caspase-associated DNase.

cfDNA in circulation presents specific DNA methylation patterns that may allow for detecting and localising cell death. Recent studies have used cell-type specificity of DNA methylation to determine the tissue of origin, thus detecting ongoing cell death taking place in specific body compartments. This approach is yet to be developed in epilepsy.

MTLE with hippocampal sclerosis (MTLE-HS) is characterised by severe neuronal death in the mesial regions [2]. Mr Ricardo Martins-Ferreira (University of Porto, Spain) and colleagues hypothesised that the predominant hippocampal sclerosis and hippocampal cell death occurring in MTLE is associated with an increased release of brain-derived cfDNA. To this end, cfDNA methylation profiling was performed in serum of 12 MTLE-HS patients and 11 controls without epilepsy [3].

The use of a deconvolution tool could not detect significant differences in the proportion of cortical neuron-derived cfDNA between the 2 groups. This may be partly due to low precision of the current deconvolution tools and the possibility that release of brain-derived cfDNA is an acute event triggered by a seizure or by apoptosis. Also, no enrichment of neuron-specific differentially methylated regions (DMRs) in cfDNA was detected.

However, direct differential comparison of methylation between patients and controls did identify 235 differentially methylated CpG positions between patients and controls. Enrichment of pathways associated with cerebral function could be demonstrated by gene ontology analysis of the hypomethylated cluster (151 CpG). Examples of these pathways are chemical synaptic transmission, positive regulation of oligodendrocyte progenitor proliferation, and glutamate receptor activity. The researchers speculated that even though there was no difference in cfDNA in the circulation of MTLE patients and controls, the observed enrichment of epileptic patterns in hippocampal tissue of these patients was preserved, and may therefore be a valuable serum biomarker of epilepsy.

1. Martins-Ferreira R, et al. Front Cell Neurosci. 2022;16:852151.
2. Blümcke I, et al. Epilepsia. 2013;54(7):1315–29.
3. Martins-Ferreira R, et al. DNA methylation profiling of cfDNA in epilepsy patients demonstrates potential cerebral origin. OPR-066, EAN 2022, 25–28 April, Vienna, Austria.

Copyright ©2022 Medicom Medical Publishers



Posted on 22 August 202217 May 2024