血管内皮功能障碍及叶酸缺乏与皮质下缺血性脑血管病认知功能损害关系的研究

Subcortical ischemic vascular disease (SIVD) is a leading cause of vascular cognitive impairment, which is caused by cerebral small vessel disease and cerebral hypoperfusion. Endothelial dysfunction is closely related to the pathological features of SIVD, which may lead to the damage of blood-brain barrier and the decline of cognitive function. Folic acid can regulate the level of homocysteine, which is closely related to endothelial dysfunction, and cognitive impairment. Endothelial dysfunction and folic acid deficiency have their own effects on cognitive function. They also can interact with each other and affect cognitive function. The different pathological features of SIVD, endothelial dysfunction and cognitive impairment can interact with each other, and whether these interaction effects are enhanced or diminished with folate deficiency has not been reported..The aim of this study was to screen plasma markers of endothelial dysfunction associated with cognitive impairment, and analyze the effect of folic acid deficiency on cognitive impairment in SIVD. The interaction analysis of latent variable was used to explore the interaction between endothelial dysfunction and folic acid deficiency in the development of cognitive impairment in SIVD. The moderating effect of folic acid deficiency on the relationship between SIVD, endothelial dysfunction and cognitive impairment was analyzed using multi-group structural equation modeling. The results of this study can provide an important basis for the prevention and treatment of cognitive impairment in SIVD.

皮质下缺血性脑血管病(subcortical ischemic vascular disease，SIVD)是血管性认知功能损害的主要病因。血管内皮功能障碍与SIVD的病理损害特征密切相关，可导致血脑屏障破坏引发认知功能下降。叶酸缺乏与内皮功能障碍、认知损害皆密切关联。内皮功能障碍与叶酸缺乏对认知功能有各自的影响，可相互作用，共同影响认知功能。SIVD的病理损害特征、内皮功能障碍与认知损害之间相互联系，其作用强度是否随叶酸缺乏改变尚未有报道。. 本研究筛选与SIVD认知功能损害相关的内皮功能障碍血浆标志物，并分析叶酸缺乏对SIVD认知功能损害的影响；采用潜变量交互效应分析探索内皮功能障碍、叶酸缺乏在SIVD认知功能损害中的交互作用；利用多群组结构方程模型探讨叶酸缺乏在SIVD、内皮功能障碍与认知功能损害相互关系中的调节作用。项目研究结果可为SIVD认知功能损害的防治工作提供重要依据。

皮质下缺血性脑血管病是老年认知功能损害的常见病因，目前对其致病因素尚不明确。叶酸缺乏可引发高同型半胱氨酸血症，高同型半胱氨酸血症对老年健康危害极大，是认知损害的重要危险因素。同时内皮功能障碍与心脑血管发病关系密切。本课题收集皮质下缺血性脑血管病患者的临床资料，同时根据核磁共振检查结果对其病理损害特征进行评估，由于内皮功能障碍指标在临床较难按样本量要求收集，因此课题在研究中期选择了与血管内皮功能指标关系密切的血管炎症指标进行分析。本研究共纳入433例皮质下缺血性脑血管病患者，分析发现不同认知功能水平的皮质下缺血性脑血管病患者的同型半胱氨酸、C反应蛋白及白介素-6有统计学差异。不同脑白质损伤程度的皮质下缺血性脑血管病患者的同型半胱氨酸及叶酸水平有统计学差异。不同腔隙性脑梗死严重程度的皮质下缺血性脑血管病患者的同型半胱氨酸、叶酸及C反应蛋白水平有统计学差异。不同脑区的脑白质损伤、腔隙性梗死与皮质下缺血性脑血管病患者认知功能均相关。Logistic回归分析显示同型半胱氨酸是认知功能的危险因素，OR值为1.364（1.187, 1.568），脑白质损伤、腔隙性梗死与同型半胱氨酸、C反应蛋白对认知功能的影响存在交互作用。结构方程模型分析发现同型半胱氨酸经皮质下缺血性脑血管病患者病理损害特征对认知功能影响的中介作用。对小鼠脑微血管内皮细胞添加不同浓度的同型半胱氨酸，发现越高浓度的同型半胱氨酸对小鼠脑微血管内皮细胞影响越大。上述研究结果为防治皮质下缺血性脑血管病认知功能损害提供了科学依据。