ROS积聚引发轴突脱髓鞘导致2型糖尿病相关认知功能障碍的多模态MRI研究

The reactive oxygen species (ROS) played an important role in the myelin damage of the T2DM related cognitive impairment. The oligodendrocytes, which comprised the myelin, were very sensitive to the ROS damage. The myelin damage caused by the ROS is an early event in the process of cognition decline, and then can lead to the dysfunction of the axons, white matter and the whole network circuits of the brain. Gene or surrounding factors such as ferritin, glutathione and glutamate could accelerate this process. This theory makes it possible to find an effective biomarker for predicting T2DM related cognitive impairment and being used as a new therapeutic target at an earlier stage. We plan to use the compromised myelin rats model, created by knocking out the IRP2 gene of oligodendrocytes, as well as the T2DM patients as the subjects. The Multi-modal MRI technology (DTI/DKI, QSM, fMRI), combined with the histology examinations, are going to be applied in this study in order to clarify the dynamic changes and relationship between ROS, ferritin, glutathione, glutamate and myelin/axonal damage in the pathogenesis of cognition decline in T2DM. Hopefully it can supply a MR diagnostic marker as well as suggestive value for T2DM related MCI, and predict its evolution. This project can assist in understanding the mechanism, predicting the occurrence and providing new therapeutic target for T2DM related cognition impairment.

活性氧自由基（ROS）在糖尿病相关认知功能障碍的髓鞘损伤中发挥重要作用。构成髓鞘的少突胶质细胞对ROS损伤敏感，ROS导致髓鞘破坏是认知功能障碍发病过程中的早期事件，进而导致轴突、白质乃至整个脑网络功能异常。基因或环境因素（铁蛋白、还原型谷胱甘肽等）可致进程加速。本项目以敲除少突胶质细胞IRP2基因构建的小鼠髓鞘损伤模型和2型糖尿病患者为研究对象，采用7T/3T多模态MRI技术（DTI/DKI、QSM、fMRI）与病理学检查（ROS活性染料染色、抗髓鞘碱性蛋白染色、轴突染色、铁染色）对比研究，以阐明ROS、铁蛋白、还原型谷胱甘肽、谷氨酸与髓鞘破坏、轴突损害在认知障碍发病过程中的动态变化及相互关系，可望为糖尿病相关认知障碍的早期预测提供有效的MR诊断标志物及参考值，并早期预测其演变。本项目的完成对于进一步明确糖尿病相关认知障碍的发病机制、早期诊断预测及提供干预治疗新靶点等具有重要意义。

本项目应用多模态磁共振技术研究了2型糖尿病患者脑部微结构的改变，与认知功能减低的关系；并构建了2型糖尿病大鼠模型和相关病理研究，探讨了糖尿病相关认知功能减低的机制。整合高端弥散成像技术（DTI、DKI、NODDI）并结合TBSS、ABA等先进的图像后处理方法，更加敏感的检测2型糖尿病（T2DM）患者脑部白质（尤其是交叉纤维，如桥脑交叉束、后放射冠等）和一些灰质核团（双侧丘脑内侧核、尾状核）的微结构改变（完整性和复杂性减低、神经突起密度减低）。临床发现并不是所有T2DM病人都会进展为认知障碍，而且认知功能减低的变化过程长短和程度也差异很大。我们研究结果不仅揭示了伴有轻度认知障碍（MCI）的T2DM患者较不伴MCI患者脑灰白质结构完整性的破坏更加显著、并和病情进展程度密切相关；而且对各本征值的细化研究提示，髓鞘破坏很可能是部分T2DM患者由认知正常向认知障碍转变过程的始动机制之一，随后才出现轴突病变。动物实验结果也提示相似结论。