發(fā)布時間：2018-04-21 06:15

  本文選題：卒中后認知功能障礙 + 基質(zhì)金屬蛋白酶9��； 參考：《鄭州大學》2017年博士論文

【摘要】：背景:卒中后認知功能障礙(Post-stroke cognitive impairment,PSCI)是腦卒中(缺血性或出血性)后繼發(fā)的認知功能減退,臨床治療效果差,嚴重影響腦卒中患者的預后和生活質(zhì)量,對該病的早期發(fā)現(xiàn)和干預是治療關(guān)鍵,但由于PSCI起病隱匿,早期不易被察覺和診斷,因此急需一種有效的生物學指標來輔助早期診斷�；|(zhì)金屬蛋白酶9(Matrix metallprotenaine 9,MMP9)生理狀態(tài)下參與調(diào)控海馬突觸可塑性和學習記憶過程,病理狀態(tài)下參與細胞外基質(zhì)破壞、炎癥浸潤和血腦屏障破壞,在動脈粥樣硬化、缺血性腦損傷及血管性癡呆中表達增高,因此,PSCI中MMP9表達水平及與認知功能減退可能存在一定關(guān)系;另外,MMP9/C1562T(rs3918242)基因多態(tài)性與動脈粥樣硬化、缺血性腦梗死的發(fā)生有關(guān),有必要進一步探討MMP9/C1562T(rs3918242)基因多態(tài)性與PSCI發(fā)生的關(guān)系,為早期干預提供依據(jù)。目的:1.篩查PSCI在腦梗死急性期和恢復期發(fā)生情況及可能的危險因素,2.明確MMP9/C1562T(rs3918242)基因多態(tài)性與腦梗死及PSCI的發(fā)病關(guān)系,3.確定血清MMP9水平對缺血性腦卒中患者認知功能的影響以及不同部位梗死認知域受損的差異。方法:1.連續(xù)登記2013年5月至2016年9月在新鄉(xiāng)醫(yī)學院第一附屬醫(yī)院神經(jīng)內(nèi)科就診的缺血性腦卒中患者,收集臨床資料及各種腦血管疾病危險因素,所有患者均完成相關(guān)檢查,所有納入患者均同意登記臨床資料、認知功能評估、抽血及定期隨訪。2.按照卒中后認知功能障礙篩查流程分別在發(fā)病2周和3月兩個時間節(jié)點進行認知功能篩查,對缺血性腦卒中繼發(fā)認知功能障礙的患者進行詳細認知功能評估,并抽血備檢。3.采用PCR-限制性內(nèi)切酶技術(shù)及瓊脂糖凝膠電泳技術(shù)對最終入組患者進行MMP9/C1562T(rs3918242)基因多態(tài)性分型,統(tǒng)計各基因型頻率;采用酶聯(lián)免疫吸附試驗檢測樣本中MMP9濃度。結(jié)果:1.PSCI在卒中后2周發(fā)病率為7.9%(61/769),卒中后3月發(fā)病率25.59%(151/590),總發(fā)病率27.57%(212/769)2.PSCI組與認知正常腦梗死組在神經(jīng)功能缺損程度比較顯示,兩組之間NIHSS評分無顯著性差異(P0.05);按照TOAST分型各類型構(gòu)成比兩組之間比較無顯著性差異(P0.05)。3.腦血管疾病危險因素多因素分析顯示,高同型半胱氨酸血癥分別增加了腦梗死(P0.01)和PSCI(P0.01)的發(fā)病風險;OSAS增加了腦梗死的發(fā)病風險(P0.01),但是對于PSCI的發(fā)病風險無統(tǒng)計學意義(P0.05);糖尿病雖增加了腦梗死以及PSCI的風險,但均不具有統(tǒng)計學意義(P0.05)。4.MMP9/C1562T(rs3918242)基因位點突變對腦梗死的發(fā)生具有統(tǒng)計學意義(χ2=10.35,P0.01)。其中CC基因型對腦梗死發(fā)病的風險具有統(tǒng)計學意義(OR=4.06,95%CI:1.49-11.11,P0.01),提示CC基因型是腦梗死發(fā)生的危險因素。而且C等位基因頻率分布差異與腦梗死的發(fā)生具有統(tǒng)計學意義(OR=0.59,95%CI:0.42-0.82,P0.01)。但MMP9/C1562T(rs3918242)基因位點突變對PSCI的發(fā)生不具有統(tǒng)計學意義(χ2=4.43,P0.05)5.三組受試者血清MMP9濃度比較顯示,差別具有統(tǒng)計學意義(P0.05)。組間比較顯示PSCI組明顯高于腦梗死組(P0.05)和正常對照組(P0.01),差別具有統(tǒng)計學意義;認知正常腦梗死患者血清MMP9濃度也明顯高于正常對照組,差別具有統(tǒng)計學意義(P0.01)。6.認知功能缺損程度危險因素分析:三組受試Mo CA分值與糖尿病、高同型半胱氨酸血癥及MMP9進行偏相關(guān)性分析顯示,Mo CA分值與空腹血糖值(P0.05)、血同型半胱氨酸水平(P0.01)顯著負相關(guān),具有統(tǒng)計學意義(P0.01)。而且血清MMP9水平與空腹血糖值(P0.05)、血同型半胱氨酸水平(P0.01)、NIHSS評分(P0.01)呈正相關(guān),具有統(tǒng)計學意義。血清MMP9水平、NIHSS評分與Mo CA分值均不相關(guān)(P0.05)。7.PSCI患者在視空間能力(P0.01)、執(zhí)行功能(P0.01)及計算力(P0.05)3個認知領(lǐng)域受損嚴重,而在學習記憶、注意力、語言功能和定向力幾個認知域受損不明顯(P0.05)。8.PSCI組患者額葉(P0.01)及基底節(jié)區(qū)(P0.01)部位梗死所占比例明顯升高,差異具有統(tǒng)計學意義。而在枕葉(P0.05)及腦干(P0.05)部位梗死所占比例明顯減少,差異具有統(tǒng)計學意義。額葉梗死患者在視空間能力(P0.05)、語言功能(P0.05)、執(zhí)行功能(P0.05)下降明顯,而基底節(jié)區(qū)梗死在學習記憶(P0.05)和計算力(P0.05)方面下降明顯。結(jié)論:1.MMP9/C1562T(rs3918242)基因多態(tài)性與腦梗死的發(fā)病密切相關(guān),C等位基因是腦梗死發(fā)病的危險因素;MMP9/C1562T(rs3918242)基因多態(tài)性與腦梗死后是否出現(xiàn)認知功能障礙關(guān)系不明顯。2.血清MMP9水平在PSCI中明顯升高,血清同型半胱氨酸水平可作為評估PSCI認知功能損害程度的間接指標。3.額葉和基底節(jié)區(qū)腦梗死更容易出現(xiàn)認知功能障礙,額葉梗死患者在視空間能力、語言功能、執(zhí)行功能下降明顯,而基底節(jié)區(qū)梗死的患者在學習記憶和計算力方面下降明顯。背景:海馬神經(jīng)元突觸后膜NMDA受體被激活后可調(diào)控突觸后膜鈣離子通道,介導鈣離子內(nèi)流,參與了學習記憶的形成和突觸功能可塑性。有研究證實,MMP9可通過激活海馬CA1區(qū)NMDA受體,提高CA3-CA1神經(jīng)傳導通路長時程增強(Long-term potentiation,LTP),改善神經(jīng)突觸可塑性,促進學習記憶。但是在血管性癡呆或血管性認知功能障礙小鼠模型中,發(fā)現(xiàn)海馬CA1區(qū)MMP9表達增高,因此,MMP9/NMDA受體通路在低灌注腦損傷后認知功能障礙中的作用需要深入探討。目的:探討MMP9/NMDA受體通路在血管性認知功能障礙中對LTP的作用及機制。方法:1.采用雙側(cè)頸動脈結(jié)扎方法制作慢性大腦低灌注模型,采用水迷宮自動記錄儀評估模型鼠學習記憶能力。2.應用場電位記錄系統(tǒng)分析記錄海馬離體腦片CA3/CA1通路LTP變化。3.通過調(diào)控MMP9濃度及NMDA受體活性研究MMP9/NMDA受體通路對LTP的作用和機制。結(jié)果:1.慢性大腦低灌注小鼠海馬LTP受損(P0.01),學習記憶能力下降(P0.01)。2.外源性MMP9提高了正常小鼠海馬CA1區(qū)LTP(P0.01),在慢性大腦低灌注腦損傷中,MMP9可加重VCI后LTP的損害(P0.01),應用MMP9抑制劑或NMDA受體拮抗劑分別作用于VCI小鼠海馬腦片,可使受損的LTP提高(P0.01)。3.同時應用MMP9抑制劑和NMDA受體拮抗劑作用于VCI小鼠海馬腦片使LTP提高程度大于二者分別應用之和(P0.05)。結(jié)論:生理狀態(tài)下MMP9激活NMDA受體,有助于增強LTP,改善突觸可塑性,提高學習記憶;慢性大腦低灌注后引起的VCI小鼠中MMP9過度激活了NMDA受體,使海馬CA3-CA1區(qū)LTP減弱,損害突觸可塑性,導致學習記憶受損。
[Abstract]:Background: Post-stroke cognitive impairment (PSCI) is a secondary cognitive impairment after stroke (ischemic or hemorrhagic). The effect of clinical treatment is poor, which seriously affects the prognosis and quality of life of stroke patients. Early detection and intervention of this disease is the key to treatment, but because of PSCI onset, the early stage is not. It is easy to be detected and diagnosed, so an effective biological indicator is urgently needed to assist early diagnosis. The physiological state of matrix metalloproteinase 9 (Matrix metallprotenaine 9, MMP9) is involved in the regulation of hippocampal synaptic plasticity and learning and memory process, in pathological condition, involvement of extracellular matrix damage, inflammatory infiltration and blood brain barrier damage, in porridge There is a certain relationship between the expression level of MMP9 in PSCI and the impairment of cognitive function. In addition, the polymorphism of MMP9/C1562T (rs3918242) gene is related to atherosclerosis and ischemic cerebral infarction. It is necessary to further explore the polymorphism of MMP9/C1562T (rs3918242) gene. The relationship between sex and PSCI in order to provide evidence for early intervention. Objective: 1. screening of PSCI in acute and Convalescent Cerebral Infarction and possible risk factors. 2. the relationship between MMP9/C1562T (rs3918242) gene polymorphism and cerebral infarction and PSCI, and 3. to determine the effect of serum MMP9 level on cognitive function of ischemic stroke patients Methods: 1. patients with ischemic stroke in the Department of Neurology, First Affiliated Hospital of Xinxiang Medical College, were registered from May 2013 to September 2016. Clinical data and risk factors of various cerebrovascular diseases were collected and all patients were completed. All the patients agreed to register. Bed data, cognitive function assessment, blood extraction, and regular follow-up.2. were screened for cognitive function at two time nodes of 2 weeks and March respectively according to the post-stroke cognitive dysfunction screening process, and a detailed cognitive function assessment was performed for patients with secondary cognitive dysfunction secondary to ischemic stroke, and PCR- restrictive endonuclease was used for.3.. Techniques and agarose gel electrophoresis were used for the MMP9/C1562T (rs3918242) polymorphism of the final group, and the frequency of each genotype was counted. The MMP9 concentration in the sample was detected by ELISA. Results: the incidence of 1.PSCI was 7.9% (61/769) at 2 weeks after stroke and 25.59% (151/590) after stroke in March, and the total incidence rate was 27.57%. 212/769) in the group 2.PSCI and the cognitive normal cerebral infarction group, there was no significant difference in the degree of neural function defect between the two groups (P0.05), and there was no significant difference between the types of TOAST types and the two groups (P0.05), the multiple factor analysis of the risk factors of.3. cerebrovascular disease showed that hyperhomocysteinemia increased respectively. The risk of cerebral infarction (P0.01) and PSCI (P0.01) was added; OSAS increased the risk of cerebral infarction (P0.01), but there was no statistical significance for the risk of PSCI (P0.05); diabetes increased the risk of cerebral infarction and PSCI, but did not have statistical meaning (P0.05).4.MMP9/C1562T (rs3918242) mutation to cerebral infarction. There were statistical significance (x 2=10.35, P0.01). Among them, the CC genotype was statistically significant (OR=4.06,95%CI:1.49-11.11, P0.01), suggesting that the CC genotype was a risk factor for cerebral infarction, and the difference in the frequency distribution of C alleles was statistically significant (OR=0.59,95%CI:0.42-0.82, P). 0.01). But the mutation of MMP9/C1562T (rs3918242) gene loci did not have statistical significance to the occurrence of PSCI (x 2=4.43, P0.05) 5. three groups, the serum MMP9 concentration comparison showed that the difference was statistically significant (P0.05). The comparison between groups showed that PSCI group was significantly higher than the cerebral infarction group (P0.05) and normal control group (P0.01), the difference was statistically significant. The serum MMP9 concentration in the patients with normal cerebral infarction was also significantly higher than that in the normal control group, and the difference was statistically significant (P0.01).6. cognitive impairment risk factors analysis: three groups of subjects Mo CA score and diabetes, hyperhomocysteinemia and MMP9 partial correlation analysis showed that the Mo CA score and fasting blood glucose (P0.05), blood same type The significant negative correlation of cysteine level (P0.01) was statistically significant (P0.01). The serum MMP9 level was positively correlated with the fasting blood glucose (P0.05), blood homocysteine level (P0.01) and NIHSS score (P0.01). The serum MMP9 level was not related to the Mo CA score (P0.05) in the visual space ability ( P0.01), 3 cognitive domains of executive function (P0.01) and computing power (P0.05) were severely damaged, while in the cognitive domains of learning, memory, attention, language function and orientation (P0.05), the proportion of the frontal lobe (P0.01) and the basal ganglia (P0.01) site of the.8.PSCI group was significantly increased, and the difference was statistically significant. In the occipital lobe (P0.05), the difference was statistically significant. The proportion of infarcts in the brain stem (P0.05) site was significantly reduced, and the difference was statistically significant. The patients with frontal lobe infarction were significantly decreased in visual space ability (P0.05), language function (P0.05) and executive function (P0.05), while basal ganglia infarction decreased in learning memory (P0.05) and calculation force (P0.05). Conclusion: 1.MMP9/C1562T (rs3918242) gene is more than that of P0.05 (rs3918242) gene. State sex is closely related to the onset of cerebral infarction. C allele is a risk factor for cerebral infarction. The relationship between MMP9/C1562T (rs3918242) gene polymorphism and cognitive impairment after cerebral infarction is not obvious. The level of.2. serum MMP9 is significantly increased in PSCI. Serum homocysteine level can be used to evaluate the degree of impairment of PSCI cognitive function. Cognitive impairment is more likely to occur in the frontal lobe and the basal ganglia infarction. The patients with frontal lobe infarction have a significant decline in visual spatial ability, language function, and executive function, while the patients with basal ganglia infarction decrease in learning and memory and computational power. Background: the NMDA receptor in the hippocampal neurons of the hippocampal neurons can be regulated after the activation of the postsynaptic membrane. The postsynaptic membrane calcium channel, which mediates calcium ion influx, participates in the formation of learning and memory and the plasticity of synaptic function. Some studies have shown that MMP9 can enhance the long term enhancement (Long-term potentiation, LTP) of the CA3-CA1 nerve conduction pathway by activating the NMDA receptor in the hippocampus CA1 region, improving the plasticity of synapse and promoting learning and memory. In the mice model of vascular dementia or vascular cognitive impairment, the expression of MMP9 in the CA1 region of the hippocampus is increased. Therefore, the role of MMP9/NMDA receptor pathway in cognitive dysfunction after low perfusion brain injury needs to be explored. Objective: To explore the role and mechanism of MMP9/NMDA receptor pathway to LTP in vascular cognitive impairment. Methods: 1. The model of chronic cerebral hypoperfusion was made with bilateral carotid artery ligation. The learning and memory ability of model rats was evaluated by water maze automatic recorder (.2.). The field potential recording system was used to record the LTP change of CA3/CA1 pathway in the brain slices of the hippocampus. The effect of MMP9/NMDA receptor pathway on LTP by regulating the concentration of MMP9 and the activity of NMDA receptor was studied and the effect of MMP9/NMDA receptor pathway on LTP was studied. Results: 1. the hippocampal LTP damage in chronic cerebral hypoperfusion mice (P0.01), learning and memory ability decreased (P0.01).2. exogenous MMP9 increased the CA1 region LTP (P0.01) in normal mice hippocampus. In chronic cerebral hypoperfusion brain injury, MMP9 could aggravate VCI LTP damage after VCI (P0.01). Hippocampal slices can make the damaged LTP increase (P0.01).3. and use MMP9 inhibitors and NMDA receptor antagonists to act on VCI mouse hippocampal slices to make LTP increase more than two, respectively, and (P0.05). Conclusion: MMP9 activation NMDA receptor in physiological state helps to enhance LTP, improve synaptic plasticity, improve learning and memory; chronic brain low After reperfusion, MMP9 overactivates NMDA receptor in VCI mice, resulting in the weakening of LTP in CA3-CA1 area and damage of synaptic plasticity, resulting in impaired learning and memory.

【學位授予單位】：鄭州大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R749.13

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