Zhi Dongmei, Wu Wenyue, Xiao Bo, Qi Shile, Jiang Rongtao, Yang Xingdong, Yang Jian, Xiao Wenbiao, Liu Chaorong, Long Hongyu, Calhoun Vince D, Long Lili, Sui Jing
Brainnetome Center and National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China.
University of Chinese Academy of Sciences, Beijing, China.
Front Neurosci. 2020 Jul 14;14:727. doi: 10.3389/fnins.2020.00727. eCollection 2020.
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.
DNA高甲基化在颞叶癫痫（TLE）中已被广泛观察到，据报道在小鼠模型中敲低NR4A1能够减轻癫痫发作的严重程度，而在TLE患者中，由NR4A1异常甲基化水平调节的潜在甲基化成像途径仍有待阐明。在此，通过使用多部位典型相关分析并以血液中NR4A1的甲基化水平为先验信息，来指导对56例TLE患者和65名健康对照者的三种MRI特征进行融合：功能连接（FC）、分数各向异性（FA）和灰质体积（GMV）。进一步评估所确定的与NR4A1相关的脑区成分与疾病发作之间的事后相关性。结果表明，TLE患者中较高的NR4A1甲基化水平与颞叶 - 小脑和枕叶 - 小脑的FC强度受损、扣带（海马）的FA降低以及壳核、颞极和小脑的GMV减少有关。此外，在仅患有右侧TLE或左侧TLE的两个患者亚组中，研究结果也得到了很好的重复。特别是，右侧TLE患者的认知能力比左侧TLE患者更差，脑损伤更严重，尤其是丘脑的GMV减少更多。总之，这项工作通过数据挖掘揭示了TLE中由较高的NR4A1甲基化调节的潜在成像 - 甲基化途径，这可能会影响上述多模态脑回路，并且还与疾病更早发作和更多认知缺陷相关。
