汉族TOMM40基因多态性对遗忘型轻度认知障碍易感性和临床转归的神经网络机制研究

Exploring the susceptibility and clinical outcome in amnestic mild cognitive impairment (aMCI) based on genetic image strategy has become a hotspot in the field of late-onset Alzheimer's disease (LOAD). The translocase of outer mitochondrial membrane 40 (TOMM40) gene could regulate mitochondrial function and influence LOAD onset age and risk, besides, the disruption of neural network is the key point linking LOAD pathologies and clinical manifestation. However, the important issues about the exact relationship between TOMM40 gene and aMCI onset as well as progression in the Chinese Han population, and the specific neural network mechanism have not been studied systematically at present. Therefore, in this program, we want to utilize our current cognitive impairment dataset and enlarge it with TOMM40 rs10524523 genotype reference, integrate apolipoprotein E gene and age, longitudinally perform multi-dimension neuropsychological assessments and employ multimodal MRI scans on the Chinese Han population with aMCI and normal cognition, in order to systematically clarify the role of TOMM40 gene polymorphisms in the regulation of aMCI onset, progression and LOAD transformation in Chinese Han population, analyze preliminary neural network mechanism, and explore imaging genetics’ marker of LOAD. This program will provide a perspective for early diagnosis and treatment of LOAD.

基于遗传影像策略探寻遗忘型轻度认知障碍（aMCI）易感性和临床转归是晚发型阿尔茨海默病（LOAD）研究领域的热点。线粒体外膜转运蛋白40（TOMM40）基因可调控线粒体功能，影响LOAD发病年龄和风险，而神经网络损害是联系LOAD病理现象与临床表型的关键点。然而，目前汉族TOMM40基因与aMCI的确切关系不明，国内外尚缺乏TOMM40基因多态性调控aMCI发生及进展的神经网络机制研究。本项目组将基于遗传影像学研究的前期积累，参考TOMM40 rs10524523基因分型且融合载脂蛋白E基因和年龄，扩充认知障碍数据库，进一步对汉族aMCI患者和认知正常者行纵向的多维度认知评估及多模态MRI扫描，旨在系统阐述汉族TOMM40基因多态性对aMCI发生、进展及LOAD转化的调控作用，初步解析具体的认知神经网络机制，并探讨LOAD遗传影像学预测标记。本项目有望为LOAD早期诊治提供契机。

阿尔茨海默病（Alzheimer’s disease, AD）是一组以智能减退伴不同程度人格改变为特征的进行性神经退行性疾病。然而，其发病机制复杂不清，尚无延缓或逆转其病理进程的治疗方案，亟需阐明发病机制、早期诊断并拓展治疗策略。目前，线粒体功能障碍已被证实为AD早期病理现象。线粒体外膜转运蛋白40（TOMM40）基因可调控线粒体功能，影响AD发病年龄和风险。基于遗传影像学策略融合了分子遗传与神经影像技术，已成为在体研究遗传因素认知行为效应的理想手段，而神经网络损害是联系AD病理现象与临床表型的关键点。本项目组基于遗传影像学研究的前期积累，参考TOMM40 ‘523基因分型且融合载脂蛋白E基因和年龄，扩充认知障碍数据库，已纳入遗忘型轻度认知障碍患者140例，AD患者90例和正常对照者58例，对受试者进行多维度认知评估和多模态MRI扫描。研究发现TOMM40基因多态性可部分调控AD的疾病发生和转化，有待进一步深入分析其神经网络机制。项目组同时发现中国早发性AD家族中早老素1基因的S290C（c.869-2>G）可呈现与欧洲人不同的临床表型；磷脂酰肌醇结合网格蛋白组装蛋白基因rs541458变异可能调节遗忘型轻度认知障碍患者的自发脑活动；基于静息态功能连接技术挖掘的默认网络和额顶叶网络的功能重组，可能是重复经颅磁刺激改善意识水平的神经网络基础。即，本项目研究结果为AD的精准诊断，早期诊治和有效治疗提供契机。