用功能磁共振研究血管危险因素相关性认知损害的脑生化代谢及血脑屏障改变

发布时间：2018-05-03 07:04

本文选题：血管危险因素 + 弗明汉卒中风险　；参考：《武汉大学》2014年博士论文

【摘要】：第一部分弗明汉卒中风险与认知损害目的：高血压、糖尿病等血管危险因素可以不依赖卒中事件及明显的脑结构性损害而增加认知损害的风险,但是多种共存的血管危险因素对认知功能的累积效应尚不明确。本研究探讨了弗明汉血管危险因素与认知损害之间的关系及其认知域损害特点。方法：这是一项基于社区人群的横断面研究。共有184名年龄在50—80岁的非卒中自愿者纳入研究,按照弗明汉10年卒中风险评估方法,将受试者分为低危组(10年卒中风险10%),中危组(10年卒中风险为10%--20%)及高危组(10年卒中风险20%)。使用一系列的认知量表测试受试者的认知功能,其中包括全脑认知功能、执行功能、注意力、延迟回忆及瞬时回忆能力。为了控制可能的混杂因素,所有受试者均完成了头颅磁共振扫描,计算了脑白质高信号体积及腔隙性脑梗死个数,并在回归模型中调整了这两个可能损害认知功能的混杂因素。采用线性回归方法分析了弗明汉卒中风险与各个认知域之间的相关性。为了探索弗明汉血管危险因素中各个变量对认知功能的归因权重,进一步行贝叶斯逐步判别分析法。结果：随着弗明汉10年卒中风险增加,受试者的总体认知功能、执行能力、记忆能力均有不同程度的损害。与低危组相比,高危组的Moca评分(P0.001)、数字符号转换测试(P0.001)、倒背(P=0.044)、延迟回忆评分(P0.001)及言语流畅性测试(P=0.041)均显著下降。与低危组相比,中危组的数字符号转换测试(P=0.034)和延迟回忆(P=0.014)显著下降。在调整脑白质高信号体积及腔梗后,弗明汉10年卒中风险仍与总体认知功能(r=-0.451,P=0.001)、延迟回忆(r=-0.352,P=0.010)和执行功能(r=-0.311,P=0.025)之间存在显著的线性相关性。贝叶斯逐步判别分析显示收缩压、年龄、糖尿病史及吸烟史是对认知功能状态影响重要的四个因素,其中风险越高,对于这些因素的要求也是相对越高。结论：基于结构磁共振观察,血管危险因素可以不依赖血管性脑损害途径而导致认知损害,其中延迟回忆和执行能力是两个主要受累的认知域。第二部分脑内生化代谢异常介导了血管危险因素相关的认知损害目的：在第一部分研究中,我们已经证实血管危险因素可以独立于卒中及明显的结构性脑损害而增加认知损害的风险,但是其病理生理基础尚未阐明。本部分研究目的是探讨脑内生化代谢改变是否介导了与血管危险因素相关的认知功能损害。方法：这是一项横断面病例对照研究,总共纳入了54例具有不同程度血管危险因素的受试者。使用弗明汉10年卒中风险评分来量化血管危险因素负担。所有受试者均完成了包括全脑认知功能、学习记忆功能和执行功能在内的完整的神经心理评估。所有受试者均接受了3.0T单体素磁共振波谱扫描(PRESS序列),感兴趣容积为左侧前额叶皮层、左侧海马。使用LC-Model分析波谱数据,计算出N乙酰天冬氨酸(NAA)、胆碱复合物(Cho)、肌醇(Ins)、谷氨酸复合物(Glx)和肌酸(Cr)浓度。按照弗明汉10年卒中风险大小,将受试者分为低危组(10%)、中危组(10—20%)和高危组(20%)。本研究注册号ChiCTR-RNC-12002205。结果：与低危组相比,高危组受试者的工作记忆能力(3.9±1.0vs4.8±1.1,P0.05)、延迟回忆能力(7.1±1.5vs9.1±1.5,P0.01)和执行功能(27.8±6.2vs37.1±6.5,P0.01)显著损害。高危组受试者左侧海马Glx/Cr值(1.21±0.25versus1.48±0.22,P0.01)和左侧额叶NAA/Cr值(1.33±0.14versus1.66±0.33,P0.01)明显低于低危组。就总体样本而言,在调整了腔隙性脑梗死计数及脑白质高信号体积后,FSRP评分与左侧海马Glx/Cr(r=-0.332,P=0.016)及左侧额叶NAA/Cr(r=-0.287,P=0.039)也呈显著的负性线性相关。左侧额叶皮层NAA/Cr值与数字符号测试(执行功能)之间呈显著的正性相关(r=0.327,P=0.016),左侧海马Glx/Cr值与延迟回忆测试呈显著的正向相关(r=0.419,P=0.002)。当逐步纳入左侧海马Glx/Cr值和左侧额叶NAA/Cr值后,FSRP与认知功能评估之间的相关性系数明显降低,提示上述神经生化代谢改变介导了弗明汉卒中风险与认知功能之间的关系。结论：延迟回忆及执行功能损害仍是血管危险因素相关性认知功能损害的两个主要的认知域损害。脑内生化物质代谢及谷氨酸递质水平的改变可能介导了血管危险因素相关的认知功能损害。第三部分血脑屏障通透性异常介导了血管危险因素相关的认知损害目的：血脑屏障功能损害在血管性痴呆及阿尔茨海默尔病中均起到了重要作用,但是在更为早期的血管危险因素相关性认知损害中的作用尚不明确。本部分研究目的是探讨左侧海马和左侧额叶皮层下白质血脑屏障通透性指数改变是否介导了血管危险因素相关的认知功能损害。方法：这是一项横断面小样本的初步研究,本部分研究的纳入对象来源于第一部分中的低危组和高危组,总共纳入了22例具有不同程度血管危险因素的受试者,我们使用弗明汉卒中风险评分来量化血管危险因素负担,按照弗明汉10年卒中风险大小,将受试者分为低危组(10%)和高危组(20%)。所有受试者均完成了包括全脑认知功能、学习记忆功能和执行功能在内的完整的神经心理评估。所有受试者均接受了3.0T动态对比增强磁共振(快速T1映像TAPIR序列),感兴趣区域为左侧额叶皮层下白质和左侧海马。使用CINE图像分析软件,基于改良的Tofts模型计算感兴趣区域血脑屏障通透性指数和血管容积指数。时间信号曲线对应的峰值(30秒时的感兴趣区域信号强度)定义为血管容积指数,反映了由对比剂填充的局部组织血管容积大小,定义180秒时的信号强度与峰值的比值为血脑屏障通透性指数。本研究注册号ChiCTR-RNC-12002205。结果：与低危组相比,高危组患者的年龄更大(74.3±3.7vs56.7±6.9,P0.01),收缩压更高(143.5±16.0vs129.0±13.0,P0.05),脑白质高信号更明显(1.5±2.2vs7.1±3.8,P0.01)。所有患者在注射对比剂后30秒时的信号强化达到高峰,此后随着时间的推移,信号强度逐渐减弱。在左侧海马水平,高危组的强化信号峰值(0.238±0.17)显著高于低危组(0.264±0.16),而两组受试者左侧额叶皮层下白质的血管容积指数无显著差异。在左侧海马水平,低危组受试者时间-信号曲线下降斜率显著高于高危组,提示对比剂在高危组滞留的量和时间要多于低危组,反映了高危组受试者左侧海马的血脑屏障通透性指数显著高于低危组,而在左侧额叶皮层下白质水平,两组受试者的通透性指数无显著差异。Pearson相关性分析结果显示,在调整脑白质病变体积和腔梗的情况下,FSRP与左侧海马血脑屏障通透性指数呈显著的线性正相关(r=-0.576,P=0.006)。左侧海马血脑屏障通透性指数与延迟回忆测试之间呈显著的负性相关(r=0.596,P=0.002)。结论：血脑屏障通透性改变可能是血管危险因素导致脑损伤的一种形式,并且可能介导了早期的危险因素相关性认知损害。
[Abstract]:The first part of fiminghan stroke risk and cognitive impairment
Objective: vascular risk factors such as hypertension and diabetes can increase the risk of cognitive impairment without dependence on stroke events and obvious brain structural damage, but the cumulative effect of various coexisting vascular risk factors on cognitive function is not clear. The characteristics of its cognitive domain damage.
Methods: This is a cross-sectional study based on community population. A total of 184 non stroke volunteers aged 50 to 80 years of age were enrolled in the study. The subjects were divided into low risk group (10 year stroke risk 10%), middle risk group (10 year apoplexy 10%--20%) and high-risk group (10 year stroke risk 20%). A series of cognitive scales were used to test the cognitive function of the subjects, including the whole brain cognitive function, executive function, attention, delayed recall, and instantaneous memory. In order to control possible confounding factors, all subjects completed the skull magnetic resonance scan, calculated the high signal volume of white matter and the number of lacunar cerebral infarction, and were regressive. This model adjusts the two confounding factors that may damage cognitive function. The linear regression method is used to analyze the correlation between the risk of fingham stroke and the different cognitive domains. In order to explore the attribution weight of each variable to cognitive function in the viminghan vascular risk factors, the Bayesian stepwise discriminant analysis is further carried out.
Results: with the increased risk of stroke in fingham 10 years, the subjects' overall cognitive function, executive ability and memory ability were impaired in varying degrees. Compared with the low risk group, the Moca score (P0.001), the digital symbol conversion test (P0.001), the reverse (P=0.044), the delayed recall score (P0.001) and the verbal fluency test (P=0.041) were all significant compared with the low risk group. Decline. Compared with the low risk group, the digital symbol conversion test (P=0.034) and the delayed memory (P=0.014) decreased significantly in the middle risk group. The 10 year stroke risk in fingham was still associated with the overall cognitive function (r=-0.451, P=0.001), delayed memory (r=-0.352, P=0.010) and executive function (r=-0.311, P=0.025) after adjusting the high signal volume and infarction of the brain white matter. A significant linear correlation. Bayes stepwise discriminant analysis showed that systolic pressure, age, diabetes history and smoking history were four important factors affecting cognitive function, and the higher the risk, the higher the requirements for these factors.
Conclusion: Based on structural MRI observation, vascular risk factors can lead to cognitive impairment without dependent on the vascular brain damage pathway, in which delayed recall and execution are two major cognitive domains.
The second part of brain metabolic abnormalities mediate cognitive impairment associated with vascular risk factors.
Objective: in the first part of the study, we have confirmed that vascular risk factors can increase the risk of cognitive impairment independently of stroke and obvious structural brain damage, but its pathophysiological basis has not been elucidated. The purpose of this study is to explore whether changes in biochemical metabolism in the brain mediate the knowledge related to vascular risk factors. Functional damage.
Methods: This is a cross-sectional case control study. A total of 54 subjects with a different degree of vascular risk were included. The 10 year stroke risk score was used to quantify the burden of vascular risk factors. All subjects completed a complete nerve including whole brain cognitive function, memorizing function, and performing function. Psychological assessment. All subjects received 3.0T monosin magnetic resonance spectroscopy (PRESS sequence). The interest volume was the left prefrontal cortex and the left hippocampus. Using LC-Model analysis, the N acetylaspartic acid (NAA), the choline complex (Cho), the muscle alcohol (Ins), the glutamic acid complex (Glx) and the creatine (Cr) concentration were calculated. 10 year risk of stroke, the subjects were divided into low risk group (10%), middle risk group (10 - 20%) and high-risk group (20%). Registration number ChiCTR-RNC-12002205.
Results: compared with the low risk group, the working memory ability of the subjects at high risk group (3.9 + 1.0vs4.8 + 1.1, P0.05), delayed recollection (7.1 + 1.5vs9.1 + 1.5, P0.01) and executive function (27.8 + 6.2vs37.1 6.5, P0.01) were significantly impaired. The left hippocampus Glx/Cr value (1.21 + 0.25versus1.48 + 0.22, P0.01) and the left frontal lobe NAA/Cr value (1.33 + 0) in the high risk group were (1.33 + 0). .14versus1.66 + 0.33, P0.01) was significantly lower than that in the low risk group. As to the overall sample, the FSRP score was also negatively correlated with the left hippocampus Glx/Cr (r=-0.332, P=0.016) and the left frontal lobe NAA/Cr (r=-0.287, P=0.039) after adjusting the lacunar cerebral infarction count and the high signal volume of the white matter. The NAA/Cr value and the digital character of the left frontal cortex There was a significant positive correlation between the number test (r=0.327, P=0.016). The left hippocampal Glx/Cr value was significantly positively correlated with the delayed memory test (r=0.419, P=0.002). The correlation coefficient between FSRP and cognitive energy assessment was significantly reduced when the left hippocampal Glx/Cr value and the left frontal lobe NAA/Cr value were gradually incorporated. Biochemical metabolic changes mediate the relationship between Framingham stroke risk and cognitive function.
Conclusion: delayed recall and executive functional impairment are still two major cognitive impairments of cognitive impairment associated with vascular risk factors. The changes in metabolism of biochemical substances and glutamate levels in the brain may mediate the impairment of cognitive function related to vascular risk factors.
The third part is the abnormal permeability of blood brain barrier, which mediates the cognitive impairment associated with vascular risk factors.
Objective: the impairment of blood brain barrier function plays an important role in both vascular dementia and Alzheimer's disease, but the role in the more early vascular risk factors related cognitive impairment is not clear. The purpose of this study is to explore the changes in the permeability index of the white matter blood brain barrier under the left hippocampus and left frontal cortex. Whether or not mediated the cognitive impairment of vascular risk factors.
Methods: This is a preliminary study of a small cross-sectional sample. This part of the study came from the low and high risk groups in the first part of the study. A total of 22 subjects with different degree of vascular risk were included. We used the famingham stroke risk score to quantify the burden of vascular risk factors, according to fingham's 10 years of death. The subjects were divided into low risk group (10%) and high risk group (20%). All subjects completed a complete neuropsychological assessment including whole brain cognitive function, learning memory function and executive function. All subjects received 3.0T dynamic contrast enhanced magnetic resonance (fast T1 image TAPIR sequence), and the region of interest was left to the left The subcortical white matter and the left hippocampus of the frontal cortex. Using the CINE image analysis software, the blood brain barrier permeability index and blood vessel volume index are calculated based on the improved Tofts model. The peak value of the time signal curve corresponding to the time signal (the intensity of the region of interest at 30 seconds) is defined as the volume index of the blood tube, reflecting the local area filled with the contrast agent. The ratio of signal intensity to peak value was defined as blood-brain barrier permeability index at 180 seconds. The registration number is ChiCTR-RNC-12002205.
Results: compared with the low risk group, the patients in the high risk group were older (74.3 + 3.7vs56.7 + 6.9, P0.01), the systolic pressure was higher (143.5 + 16.0vs129.0 + 13, P0.05), and the high signal of white matter was more obvious (1.5 + 2.2vs7.1 3.8, P0.01). The signal intensities reached the peak at 30 seconds after the injection of contrast agents. At the left hippocampal level, the peak value of the enhanced signal (0.238 + 0.17) in the high risk group was significantly higher than that in the low risk group (0.264 + 0.16), but there was no significant difference in the volume index of the blood vessel in the left frontal cortex of the two groups. The amount and time of retention in the high risk group were more than those in the low risk group. It showed that the blood brain barrier permeability index of the left hippocampus in the high risk group was significantly higher than that in the low risk group, while in the left frontal cortex, there was no significant difference in the permeability index between the two groups. The results of the.Pearson phase analysis showed that the brain white matter lesion was adjusted. There was a significant linear positive correlation between FSRP and the permeability index of the left hippocampal blood-brain barrier (r=-0.576, P=0.006). There was a significant negative correlation between the permeability index of the left hippocampal blood-brain barrier and the delayed memory test (r=0.596, P=0.002).
Conclusion: the change of blood brain barrier permeability may be a form of brain damage caused by vascular risk factors and may mediate early risk factors associated cognitive impairment.

【学位授予单位】：武汉大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R743.3;R445.2

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