2型糖尿病记忆损害机制的影像遗传学研究

Type 2 diabetes mellitus (T2DM) is associated with memory decline and increases the risk of dementia. Based on cross-sectional analysis, our preliminary studies have revealed modest gray matter atrophy in the brain regions responsible for declarative memory. Previous studies also found decreased structural and functional connectivity involved in these key brain regions in T2DM. However, the characteristics and biological mechanisms for longitudinal memory decline and brain imaging changes in T2DM remains unclear. We hypothesize that the dynamic changes in memory function and brain structure/function may be related to the Apolipoprotein E (APOE) and Haptoglobin (Hp) genes. In the current design, 400 elder T2DM patients and 200 matched normal controls will be recruited and followed up after 2 years. The single nucleotide polymorphism (SNP) for candidate genes will be tested. Two-year changes in components of declarative memory performance and brain multi-modal magnetic resonance imaging parameters, including the gray matter morphology, white matter fiber connectivity, resting-state brain functional connectivity and topological properties of brain structural/functional networks, will be assessed. After cross-sectional comparisons between groups, we can reveal the alternations of memory and imaging measures in T2DM patients. In addition, correlation analyses between the brain imaging measures at baseline and memory decline rate in T2DM patients will be performed. Finally, the relationships between individual genotypes and brain imaging parameters related to memory impairment as well as the change rate of imaging measures during two years will be explored based on imaging genetics approach. Taking together, our findings is likely to yield more precise information about underlying biological mechanisms on memory impairment in T2DM, and may provide the imaging markers for predicting and treating memory decline in patients with T2DM .

2型糖尿病（T2DM）可引起记忆下降并增加痴呆风险。利用横断面研究，我们发现T2DM患者存在陈述性记忆相关脑区萎缩，既往也发现这些脑区的结构和功能连接降低。但纵向上T2DM患者记忆和脑影像学改变的特征和机制仍不清楚。根据以往研究，本课题假设载脂蛋白E和结合珠蛋白基因在T2DM记忆下降和脑影像学改变过程中起重要作用。研究拟招募400名T2DM病人和200名正常对照组并检测候选基因多态性，评价陈述性记忆能力和多模态磁共振影像学指标，包括灰质形态、纤维连接、静息态功能连接及脑网络拓扑属性，随访两年后再次检测。横断面组间对照检测T2DM组记忆和影像学测量的差异；相关分析检测认知下降率和基线状态影像指标的关系；利用影像遗传学方法分析基因多态性与记忆下降相关影像学指标及影像学纵向改变程度之间是否存在关联。本研究可揭示T2DM记忆损害的神经生物学机制，为临床预测和治疗T2DM患者记忆下降提供影像学标记。

2型糖尿病（type 2 diabetes mellitus，T2DM）是糖尿病中最常见的类型，占所有糖尿病病例的90%。T2DM可以加速病人认知功能下降，同时病人罹患痴呆的风险增加6~7%。存在认知损害特别是进展为痴呆的T2DM病人不仅自身生活质量下降，也给家庭和社会带来巨大压力。在充分理解T2DM认知损害机制的基础之上，或许可以采取有效的早期干预措施。.本课题首先对T2DM病人脑皮质厚度、体积以及灰质下核团体积展开研究；然后利用静息态fMRI数据，探讨T2DM病人局部自发性活动特点，识别是否存在长程和短程功能连接比例平衡被打破，分析异常脑功能活动同步性是否存在由近到远的空间分布特点，并对异常的中心节点及这些中心节点之间的相互作用进行了研究；最后，本研究对T2DM病人脑铁沉积水平进行了定量研究。.研究结果提示，T2DM病人存在与认知功能损害相关的脑结构改变，包括：扣带回、海马旁回、颞中回等脑区皮层厚度减低，内嗅皮层体积减低，海马CA1区体积减低。T2DM病人的脑自发性活动紊乱累及了额上回、枕中回、舌回和颞下回等脑区，且在亚频段上具有不同的空间分布特点；能耗低的短程功能连接显著升高，能耗高的长程功能连接显著减低，提示T2DM病人大脑可能在能量消耗与网络效率之间互相妥协；脑功能活动同步性异常在空间上的分布存在由近到远的特点，其中远距离连接的正负倒置与在阿尔茨海默病病人中所见类似。T2DM病人在视觉信息的获取及目标导向行为中担当重要角色的脑中心节点受到了疾病的影响，且它们之间的连接发生改变。T2DM病人双侧尾状核、左侧壳核、右侧黑质及双侧海马的铁含量水平显著升高，部分区域在T2DM病人存在轻度认知损害时升高更为显著。.T2DM病人存在脑结构、功能及铁代谢的异常，这些异常为进一步理解T2DM认知损害的机制提供了影像学证据，且有望成为疾病诊断和监测T2DM病人认知损害的影像学标记。