NR4A1 Methylation Associated Multimodal Neuroimaging Patterns Impaired in Temporal Lobe Epilepsy

• Authors: Dongmei Zhi, Chinese Academy of Sciences; Wenyue Wu, Central South University; Bo Xiao, Central South University; Shile Qi, Chinese Academy of Sciences; Rongtao Jiang, Chinese Academy of Sciences; Xingdong Yang, Beijing Haidian Hospital; Jian Yang, Beijing Institute of Technology; Wenbiao Xiao, Central South University; Chaorong Liu, Central South University; Hongyu Long, Central South University; Vince D. Calhoun, Emory University; Lili Long, Central South University; Jing Sui, Chinese Academy of Sciences
• Journal Title: Frontiers in Neuroscience
• Volume: Volume 14
• Publisher: Frontiers Media | 2020-07-14
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.3389/fnins.2020.00727
• Subjects: Biology, Neuroscience; Health Sciences, Medicine and Surgery
• Keywords: temporal lobe epilepsy; multimodal fusion; methylation levels of NR4A1; functional connectivity; fractional anisotropy; gray matter volume

Abstract

DNA hypermethylation has been widely observed in temporal lobe epilepsy (TLE), in which NR4A1 knockdown has been reported to be able to alleviate seizure severity in mouse model, while the underlying methylation-imaging pathway modulated by aberrant methylation levels of NR4A1 remains to be clarified in patients with TLE. Here, using multi-site canonical correlation analysis with reference, methylation levels of NR4A1 in blood were used as priori to guide fusion of three MRI features: functional connectivity (FC), fractional anisotropy (FA), and gray matter volume (GMV) for 56 TLE patients and 65 healthy controls. Post-hoc correlations were further evaluated between the identified NR4A1-associated brain components and disease onset. Results suggested that higher NR4A1 methylation levels in TLE were related with impaired temporal-cerebellar and occipital-cerebellar FC strength, lower FA in cingulum (hippocampus), and reduced GMV in putamen, temporal pole, and cerebellum. Moreover, findings were also replicated well in both patient subsets with either right TLE or left TLE only. Particularly, right TLE patients showed poorer cognitive abilities and more severe brain impairment than left TLE patients, especially more reduced GMV in thalamus. In summary, this work revealed a potential imaging-methylation pathway modulated by higher NR4A1 methylation in TLE via data mining, which may impact the above-mentioned multimodal brain circuits and was also associated with earlier disease onset and more cognitive deficits.