卒中后认知障碍早期诊断分子靶标的临床研究

发布时间：2018-10-19 10:36

【摘要】：背景和目的：血管性认知障碍(vascular cognitive impairment, VCI)是由脑血管危险因素、明显或不明显的脑血管病引起的从轻度认知障碍到痴呆的一类临床常见综合征。卒中后认知障碍(post stroke cognitive impairment, PSCI)作为其最常见的一类,其发生机制仍不明确,导致其早期诊断及治疗的困难性。近些年来,越来越多的研究结果表明VaD和AD在发病机制及病理学改变上存在诸多重叠现象。在脑卒中动物模型和VaD患者脑组织均发现BACE1表达增加和Aβ42沉积现象。NEP作为主要的Aβ降解酶,在AD患者体内表达降低,可能在VaD患者体内也有着同样改变。sRAGE作为RAGE的可溶性片段,也可能是VaD和AD的生物学标志。APOE ε4等位基因是迟发型AD的重要危险因素,在很多临床研究中也被认为是VaD的危险因素。本研究的目的就是验证我们的假设：BACE1、sRAGE和NEP的血清含量变化早于卒中后认知障碍的临床表现,且与APOE基因型有显著的相关性。方法：152名新发缺血性脑卒中患者,症状持续6-72小时,并为头颅CT或MRI证实。NIHSS及mRs评估神经功能缺损程度；入院后立即快速抽取静脉血进行分子标志物的检测；于卒中发生后2周左右进行神经心理学评估；Pearson's相关系数及logistic回归分析评估分子标志物与认知障碍的相关性。结果：152名初发缺血性脑卒中患者,分成以下四组：脑卒中组64例,血管性认知障碍非痴呆组37例,血管性痴呆组36例及混合性痴呆组15例。40例正常健康人作为对照组。结果发现存在认知障碍各组相对于正常对照组及脑卒中组,血清sRAGE含量明显下降,BACE1及NEP则呈现相反的趋势。研究还提示认知障碍各组APOE ε3/ε4基因型和ε4等位基因比例均明显高于脑卒中组和正常对照组。相关性分析结果提示血清sRAGE、BACE1和NEP水平与神经心理学评估呈现显著相关性。然而,Logistic回归分析发现只有sRAGE和BACE1可以作为预测血管性认知障碍是否发生的标志。结论：BACE1和sRAGE可能是卒中后认知障碍的早期诊断分子靶标。
[Abstract]:Background and objective: vascular cognitive impairment (vascular cognitive impairment, VCI) is a common clinical syndrome from mild cognitive impairment to dementia caused by cerebrovascular risk factors, obvious or insignificant cerebrovascular diseases. (post stroke cognitive impairment, PSCI) is the most common type of post-stroke cognitive impairment, and its mechanism is still unclear, which leads to the difficulty of early diagnosis and treatment. In recent years, more and more studies have shown that VaD and AD have many overlapping phenomena in pathogenesis and pathological changes. The increased expression of BACE1 and the deposition of A 尾 42 were found in both the animal model of stroke and the brain tissue of VaD patients. As the main A 尾 -degrading enzyme, the expression of NEP decreased in the patients with AD, and it may have the same change in the patients with VaD. SRAGE is the soluble fragment of RAGE. APOE 蔚 4 allele is an important risk factor for delayed AD and is also considered to be a risk factor for VaD in many clinical studies. The aim of this study was to verify our hypothesis that the changes in serum levels of BACE1,sRAGE and NEP were earlier than the clinical manifestations of post-stroke cognitive impairment and were significantly correlated with APOE genotypes. Methods: the symptoms of 152 newly diagnosed ischemic stroke patients lasted 6 to 72 hours and were confirmed by cranial CT or MRI. NIHSS and mRs were used to evaluate the degree of neurological impairment, and the venous blood samples were taken immediately after admission for the detection of molecular markers. Neuropsychological evaluation was performed about 2 weeks after stroke, and the correlation between molecular markers and cognitive impairment was evaluated by Pearson's correlation coefficient and logistic regression analysis. Results: 152 patients with primary ischemic stroke were divided into four groups: stroke group (n = 64), vascular cognitive impairment group (n = 37), vascular dementia group (n = 36) and mixed dementia group (n = 15). The results showed that the levels of serum sRAGE in the groups with cognitive impairment were significantly lower than those in the normal control group and stroke group, while BACE1 and NEP showed a reverse trend. The results also indicated that APOE 蔚 3 / 蔚 4 genotype and 蔚 4 allele ratio in cognitive impairment group were significantly higher than those in stroke group and normal control group. The results of correlation analysis suggested that serum sRAGE,BACE1 and NEP levels were significantly correlated with neuropsychological evaluation. However, Logistic regression analysis showed that only sRAGE and BACE1 could be used as markers to predict the occurrence of vascular cognitive impairment. Conclusion: BACE1 and sRAGE may be molecular targets for early diagnosis of post-stroke cognitive impairment.
【学位授予单位】：南京大学
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R749.1

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