ACE及APOE基因多态性对血管性认知障碍患者记忆环路调控的多模态MRI研究

Genetic factors play an important role in the development of vascular cognitive impairment (VCI). Previous studies have found that angiotensin-converting enzyme (ACE) gene and apolipoprotein E (APOE) gene are related not only to cerebrovascular diseases, but also to such cognitive impairments as memory and executive functions. Moreover, ε4 genotype of APOE combined with DD genotype of ACE has been found to increase memory impairment. The mechanism underlying memory neural circuit regulated by APOE gene polymorphism has been well investigated. However, the way how ACE gene polymorphism influences memory neural circuit has remained little explored. Using multimodal magnetic resonance imaging (MRI) techniques, the current project aims to address the relationship between the mechanisms underlying structure and function of memory neural circuit regulated by gene polymorphism of ACE and APOE and memory impairment. Patients with subcortical ischemic vascular disease (SIVD) but non-cognitive impairment, patients with SIVD and cognitive impairment, patients with SIVD and dementia, and age-matched healthy controls are included in the experiments. Specifically, the current project investigates the main effects and interaction effects ACE and APOE gene polymorphism upon memory neural circuit regulation of different sample populations in order to reveal the neural mechanisms underlying memory impairment of VCI patients that contributes to the variation of APOE and ACE genotypes, in particular the regulating mechanisms of the subregions in the memory neural circuit. The current project may help to elucidate the neural mechanisms by which genetic risk factors cause cognitive impairment or even vascular dementia, providing genetic imaging markers for the early identification of VCI risk category on the one hand and a theoretical basis for early diagnosis and effective intervention of VCI on the other.

遗传因素在血管性认知障碍（VCI）发生中具有重要作用。ACE和APOE基因变异不仅与脑血管病的发生有关，还与记忆损害密切相关，且APOE基因ε4型合并ACE基因DD型会加重记忆损害。APOE基因多态性对记忆环路调控机制研究较多，但ACE基因多态性对记忆环路的影响尚不清楚。本课题利用多模态MRI技术系统研究ACE及APOE基因多态性对老年人、皮层下缺血性脑血管病（SIVD）无认知障碍者，SIVD认知障碍者及SIVD痴呆者记忆环路结构和功能的调控机制及与记忆损害的关系。重点阐述ACE及APOE基因多态性对不同人群记忆环路调控的主效应及交互效应，尤其是记忆相关脑区的亚区调控机制，进而揭示上述基因变异所致VCI患者记忆减退的神经机制。本研究将有助于明确遗传风险因素造成认知损害乃至进展为血管性痴呆的神经机制，为早期识别VCI风险人群提供影像遗传学指标，并对VCI早期诊断、有效干预提供理论基础。

遗传因素在血管性认知障碍（VCI）发生中具有重要作用。血管紧张素转化酶（ACE）和载脂蛋白Ｅ（APOE）基因变异不仅与脑血管病的发生有关，还导致患者认知功能受损。本课题采用多模态MRI技术对皮层下缺血性脑血管病（SIVD）患者记忆功能减退的神经影像机制以及ACE及APOE基因多态性对记忆环路的调控机制进行了初步研究。本课题组首先建立了健康老年人、SIVD无认知障碍者、SIVD轻度认知障碍者及SIVD痴呆者的脑影像遗传数据库。包括一般临床资料、血液生化检测、多模态MRI数据和APOE和ACE基因的表型。其次，采用先进的图像后处理技术对SIVD患者脑结构、功能及功能网络进行分析。研究表明，SIVD患者表现出广泛的低灌注，破坏脑神经血管单元正常的协同性，进而导致记忆功能损害。一些重要脑网络功能连接失衡及其时间动态性的异常，也是导致SIVD患者记忆功能减退的原因之一。SIVD认知功能减退患者主要是破坏前额叶-皮层下环路和长联合纤维，从而引起内侧颞叶、海马及楔前叶等脑区的萎缩，其中内侧颞叶和海马部分亚区的萎缩与情景记忆功能减退密切相关。通过研究SIVD患者APOE基因表达发现载脂蛋白Ｅ基因启动子-491位点基因型AA可能诱导血管性痴呆的发生。进一步对APOE和ACE基因多态性表达与脑影像特征间关系的研究发现，APOE基因位点变异患者主要表现为内侧颞叶和海马体积的萎缩，同时影响认知控制和默认网络的稳定性。ACE基因位点的变异患者主要表现为背侧注意网络相关脑区的结构萎缩和功能连接减退。综上所述，本研究为探讨APOE及ACE基因多态性对VCI患者记忆功能障碍的神经影像机制奠定了坚实的基础。同时为我们早期甄别VCI风险人群提供影像遗传学指标。