II型糖尿病神经元凋亡低氧影响机制的MRI结构及功能成像研究

Compared to the healthy people, the patients with Type II diabetes are more prone to cerebral atrophy and the corresponding function change. Neuronal apoptosis is the immediate cause of global or local cerebral atrophy. Cerebral small vascular diseases are common in patients with Type II diabetes, which may causes decreased cerebral blood flow, followed by chronic hypoxia. However, whether long-term hypoxia directly affects the apoptosis of neurons and the degree of influence is not clear. Moreover, the evidence of corresponding research in vivo is still lack. Our group first measured cerebral vein φ value to calculate cerebral oxygen extraction fraction (OEF) by susceptibility weighted imaging (SWI) and then got more accurate OEF value from the improved quantitative susceptibility mapping (QSM). On the basis of our previous research, this project intends to explore the effective MRI metrics which can evaluate the brain structural and functional changes in patients with Type II diabetes. In order to obtain the relationship between hypoxia and apoptosis of neurons, dynamic MRI scanning is performed on rabbit models and patients of type II diabetes with 3D ASL, QSM, DKI and resting-state functional sequences. Furthermore, Comprehensive quantitative analysis is also performed from cerebral blood flow, oxygen metabolism, structural and functional changes. Besides, we also explore the new and effective markers to assess the cerebral structural and functional changes with analyzing the correlation between MRI and clinical, pathological-immunohistochemical index.

II型糖尿病患者相比正常人群更容易发生脑萎缩及相应的功能改变，而神经元凋亡是造成全脑或局部脑萎缩的直接原因；患者普遍存在脑微血管病变，引起脑血流降低，继而出现慢性低氧状态。然而，长期低氧状态是否直接影响神经元凋亡以及影响程度尚不清楚，而且缺乏在体研究依据。本课题组在国内首先利用磁敏感加权成像（SWI）测量脑内静脉φ值来推算脑氧摄取分数（OEF），并在改进的定量磁敏感成像（QSM）上得到了更准确的OEF值。基于课题组前期丰富的工作基础，本课题拟用3D ASL、QSM、DKI及静息态功能成像技术对II型糖尿病家兔模型及患者进行多时间点动态扫描，从脑血流、氧代谢、灰白质结构和功能改变等多个方面进行综合定量分析，并与临床资料、病理免疫组化指标进行关联性分析，以期获得低氧与神经元凋亡的关系，并探求有力的评估糖尿病脑结构、功能改变的MRI指标。

项目组利用多模态MR技术（3D T1WI、SWI、ASL、APT、DTI/DKI），揭示了T2DM脑血流-脑氧-脑铁-灰白质结构与功能变化规律，发现T2DM患者存在明确的脑低灌注、铁异常沉积、灰白质微结构损伤及脑网络连接异常。. 项目组成功建立T2DM大耳白兔模型，通过对兔脑行序贯MR检查（2周、6周、10周）证实利用SWI及DKI技术可以检测T2DM兔海马区铁沉积与微结构变化，发现T2DM兔海马区有明确铁沉积，并与Aβ1-42增多具有显著负相关，进而发现局部微结构异常。. T2DM患者基线MR研究发现（1）脑深部核团铁沉积增加，并与高糖化血红蛋白、高空腹血糖、脂代谢紊乱密切相关；（2）灰质血流灌注减低，受长病程、高糖化血红蛋白、高空腹血糖水平影响，灌注减低引起认知、执行功能下降；（3）脑皮层萎缩，以视觉、听觉处理脑区为主，并与执行力、记忆力（延迟回忆）、语言复述能力及视空间认知评分相关；（4）白质完整性破坏，主要累及胼胝体、双侧放射冠、双侧上额枕束、下额枕束、双侧上纵束、下纵束、双侧丘脑辐射及双侧皮质脊髓束，且以髓鞘损伤为主；（5）白质APTw值增高，与认知水平下降相关；（6）脑网络局部效率减低，部分脑区节点效率显著受影响。. T2DM伴AD患者MR随访研究发现（1）脑深部灰质核团铁沉积增加，但未伴随脑氧水平的显著减低；（2）脑灰质体积萎缩，以额叶、颞叶为主，与运动语言、学习记忆脑区相关，并伴随认知功能下降；（3）白质完整性的逐渐破坏，主要累及小脑中脚、左侧皮质脊髓束、左侧丘脑辐射、双内侧丘系、右侧放射冠后部、右扣带回及右侧绒毡层。. AD患者基线MR研究进一步发现（1）AD患者脑灰质核团脑氧水平降低而铁沉积增多，二者具有明确相关性；脑氧水平降低、铁沉积增加进一步降低认知功能；（2）DKI可以定量评估AD患者灰质核团微结构的病理性变化，苍白球Dr值是鉴别AD与HC的最佳指标；（3）AD患者普遍存在脑小血管疾病，脑血流灌注减低，影响患者认知状态；EPVS评分和室周脑白质病变程度可以作为病情监测的影像学指标。