1型糖尿病大鼠前额叶和海马神经退行性病变的多模态磁共振研究

Cognitive dysfunction is associated with diabetes mellitus. Clinical studies utilizing functional, structural magnetic resonance imaging (MRI) and in vivo 1H magnetic resonance spectroscopy (MRS) techniques have found that diabetic patients had 1) reduced functional and structural connectivity between prefrontal and temporal lobe; 2) white matter lesions and atrophy in prefrontal lobe and hippocampus and 3) metabolic abnormalities in prefrontal lobe and hippocampus. Due to a variety of clinical limitations, there are several unresolved crucial issues needed to draw assistance from animal research. The evolution of the prefrontal and hippocampal neurodegeneration with the duration of diabetes is still not clear, no matter the blood glucose controlling. The neuropathology and biochemistry mechanism underlying the diffusion indexes and metabolic abnormalities in prefrontal lobe and hippocampus associated with diabetes still remains to be elucidated. We will explore the imaging biomarker to characterize the neurodegenerative changes in prefrontal lobe and hippocampus of the diabetic rats using multimodel MRI/MRS. The ultra-high field (7T) high-resolution structural imaging, DTI/diffusion tractography, and in vivo 1H-MRS techniques, combined with behavior and histology examination, are used to study structural alterations and metabolic disturbances in prefrontal lobe and hippocampus, white matter integrity injury and fiber connectivity changes between the two brain regions in streptozotocin-induced diabetic rats. This work will enrich our knowledge in the neuropathological mechanism underlying cognitive dysfunction associated with diabetes mellitus, provide basic data for clinical practice and benefit for early diagnosis, intervention and prognosis of cognitive deficits in diabetes.

糖尿病与认知功能障碍密切相关。功能、结构磁共振成像和活体磁共振波谱（in vivo 1H-MRS）技术发现糖尿病患者:1)前额叶和颞叶脑网络功能和结构连接改变；2）前额叶和海马萎缩、白质损伤；3）前额叶和海马代谢异常。由于临床研究受到诸多限制，一些重要问题需要借助动物模型来解决，即前额叶、海马神经退行性病变随糖尿病病程发展的演化规律，以及血糖控制对其影响，扩散和代谢异常的影像学指标所对应的神经病理和生化机制。本申请拟针对这些问题开展1型糖尿病大鼠前额叶和海马退行性改变的多模态磁共振研究。本申请利用超高场 (7T) 活体磁共振成像（高分辨结构成像、扩散张量成像/纤维束成像术）及氢质子波谱技术，结合行为和组织化学技术，阐明与认知功能密切相关的关键脑区（海马、前额叶）结构萎缩、海马和前额叶连接通路上白质完整性损伤、纤维连接改变及代谢物平衡失调的神经病理和生化机制，进一步理解糖尿病认知功能障碍。

糖尿病与脑功能障碍密切相关。已利用超高场 (7T) 活体磁共振成像（高分辨结构成像）及氢质子波谱技术，采集了STZ诱导的1型糖尿病大鼠认知功能密切相关的关键脑区（海马、前额叶）结构、小分子代谢物含量数据。结合水迷宫行为学实验，测量了学习记忆相关的认知功能行为学改变。利用扩散张量成像（DTI）技术评估1型糖尿病大鼠在造模后4周，8周和12周白质损伤情况，并且通过组织学方法对引起扩散性质改变的白质损伤机制进行探索，获得了在1型糖尿病发展过程中能反映大鼠中枢神经轴突和髓鞘完整性的活体影像数据。我们在STZ诱导后4周、8周和12周对糖尿病大鼠视神经进行DTI和组织学评估，以阐明引起DTI指标变化的微观结构改变。分别于STZ诱导后4周和12周进行视网膜和视神经的病理学观察。DTI结果显示，与对照组相比，糖尿病大鼠视神经在12周时的平均扩散率（MD）和轴向扩散率（Da）显著降低。组织学检查证实视神经轴突变性，无髓鞘丢失。此外，视神经扩散系数（MD和Da）降低与轴突总面积减少呈正相关。糖尿病大鼠视网膜4周后出现神经胶质细胞免疫反应增强，12周时内网丛层和神经纤维层厚度变薄。总之，DTI可在体内监测糖尿病视神经退行性变的进展，我们的研究结果有助于为糖尿病视网膜病变的临床前治疗提供轴突保护。