利用影像遗传策略探讨血脑屏障破坏影响AD谱系人群脑网络机制研究

阿尔茨海默病（AD）已经成为全球公共健康的主要问题。最新研究表明血脑屏障（BBB）破坏在AD病理进程中扮演重要作用，甚至更早于AD病理标记物的出现！然而，AD谱系人群（ADS）BBB破坏启动时机、与AD病理进程的内在关系及其影响ADS向痴呆转化机制远未清楚！本研究将基于前期积累，利用影像遗传学策略，在中国汉族老年人群中同期选择主观记忆损害、AD所致轻度认知功能损害、轻度AD以及匹配的健康对照组，结合脑脊液、外周血及动态对比增强MRI技术在体评估ADS记忆核心脑区BBB完整性；分析ADS记忆相关脑网络的共性与差异性、信息整合功能等；基于APOE基因型分层探讨BBB破坏影响AD病理表型、脑网络动态变化特征、认知功能下降及其内在关联机制，揭示APOE基因型影响BBB完整性在调控AD病理进程中的演变规律，筛选出可用于AD不同病理阶段的生物-影像学标记物，为临床预防和干预AD的个体化治疗提供依据。

Alzheimer's disease (AD) has become a global public health issue. To date, its etiology and pathogenesis are far from clear. Recent studies have suggested that the destruction of the blood brain barrier (BBB) integrity was closely associated with the pathogenesis of AD, and even the destructed BBB integrity appeared to early manifest of AD pathological markers including Amyloid-β, total Tau and phosphorylated Tau. However, little is known about that when the BBB destruction initiates, how the BBB destruction affects AD pathological markers, and subsequently leads to cognitive decline in the AD spectrum (ADS). Therefore, building on our progress corroborated by previous findings, firstly, we will recruit the ADS populations including subjective memory impairment, mild cognitive impairment due to AD, mild AD, and well-matched cognitive normal healthy elders. Secondly, we will assess the BBB integrity in the memory-related regions reflecting by specific biomarkers in the serum and cerebral spinal fluid and using dynamic contrast-enhanced MRI in the ADS population. Thirdly, we will investigate the common and differential characteristics of large-scale brain networks involved in the memory process, its capacity of information integration of these brain networks, as well as its relationship with AD pathological biomarkers in the ADS population. Fourthly, we will explore the potential importance of how BBB destruction contributes to the appearance of AD pathological biomarkers, the dynamic changes of large-scale brain networks, and cognitive decline based on different APOE genotypes. Finally, we will integrate above findings and screen out the potential biological-imaging markers for early identification of ADS population depending on the distinctive pathological stages of AD, and provide empirical evidence for individualized prevention and intervention of AD at the clinical practice.