老年认知功能障碍与颈动脉硬化及相关基因多态性研究
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摘要
认知功能障碍（cognitive impairment）是老年人常见的临床表现，认知功能与大脑的结构和功能活动、脑血流量及其分布有密切关系，一旦出现大脑半球局部血流供应障碍和结构异常，常伴有认知功能的损害。动脉粥样硬化可引起颈动脉IMT增加、斑块形成，导致颈动脉硬化性狭窄甚至闭塞。颈动脉硬化性狭窄不仅是缺血性脑血管病的重要危险因素，而且严重颈动脉硬化性狭窄可能与认知功能受损相关。但目前认知功能障碍与颈动脉硬化的相关性尚有争议。老年人为认知功能障碍和颈动脉硬化的高发人群，对认知功能障碍的高发人群的甄别及其预防性治疗成为亟待解决的问题。
老年认知功能障碍疾病临床上最多见的类型就是阿尔茨海默病(Alzheimer’sdisease,AD)和血管性痴呆（Vascular dementia,VaD）。既往普遍认为VaD与AD是两类不同性质的疾病，有着不同的病理基础和易感基因。但近年来血管因素在AD发病中的作用正逐渐受到重视。许多与血管因素或血流动力学相关的危险因素均能增大AD的患病风险。颈动脉硬化等疾病能引起大血管内膜增厚，血管狭窄、扭曲和缠结，导致慢性脑组织低灌注，甚至造成血脑屏障破坏，通透性增加。这些均可导致淀粉样前体蛋白破坏，微血管基底层变薄、裂解，血管内皮细胞及平滑肌细胞透明样变性，上述脑血管的损害及动脉硬化共同反过来进一步加重AD。AD具有极高的遗传性，但其发病机制仍不清楚，人们普遍认为是基因变异和环境因素共同作用的结果。寻找与AD遗传易感性相关的基因一直是亟待解决的问题。
Toll样受体4(Toll-like receptor4，TLR4)是天然免疫和适应性免疫应答的重要调控因子，TLR4识别病原体相关的分子模式，激活炎性细胞。TLR4在动脉硬化的功能研究已经在小鼠基因敲除实验和人类的TLR4基因多态性流行病学调查中进行，研究表明，TLR4功能影响动脉硬化的发生和发展。因此，TLR4的配体MyD88、TIRAP及影响TLR通路传导途径的负反馈蛋白TOLLIP（Toll-interacting protein）在动脉硬化中的作用也逐渐受到重视。近来，有越来越多的证据表明TLR4-TIRAP-MyD88信号通路在AD发病中起重要作用，而相关信号分子TIRAP、MyD88、TOLLIP基因多态性与AD发病的的相关性尚无研究报道。
本课题开展了老年认知功能障碍与颈动脉硬化及其相关基因多态性的临床和基础两个部分的研究：(1)观察老年人群中颈动脉硬化的发生特点及其与认知功能障碍的相关性。(2)采用病例对照的设计方法，检测颈动脉硬化相关基因多态性位点在老年认知功能障碍人群中的基因型和等位基因频率，探讨TIRAP、MyD88、TOLLIP基因多态性与老年认知功能障碍患病风险之间的关联。
目的：通过现状调查研究观察老年人群中颈动脉硬化的发生特点及其与认知功能障碍的相关性，明确65岁以上老年人颈动脉IMT、血管腔狭窄、斑块性质与认知功能障碍是否有独立相关性。
对象和方法:随机选择2009年2月－2012年10月期间，在我科就诊的65岁以上病人2015人进行了现状调查研究，全部患者行颈动脉B超检查颈动脉硬化，发现异常者行CTA或DSA，并进行一般临床资料收集和神经心理学测试。
结果：
1.基线特征分析
入组人数2015名，其中男性1048人(52.01％)，女性967人(47.99%),平均年龄69岁。有1733名（86.0％）发现颈动脉硬化，其中颈动脉硬化性狭窄有1028名（51.0％），平均IMT值为1.288±0.149mm。冠心病显示出对认知功能障碍患者的明显影响（P <0.05）。无认知功能障碍患者的IMT值显著低于有认知功能障碍的患者（P <0.001）。较无认知功能障碍患者，有认知功能障碍患者的严重颈动脉狭窄患病率更高（14％vs.8％，P<0.001），且平均IMT值更高（1.473vs.0.765，P <0.001）。
2.老年认知功能障碍的独立危险因素
为识别认知功能障碍的独立危险因素，多因素Logistic回归分析包括年龄、性别、受教育程度、高血压、糖尿病、高胆固醇血症、房颤、冠心病、吸烟、颈动脉狭窄程度、IMT值及颈动脉粥样硬化斑块。结果显示增厚的IMT值（odds ratio=1.96，95％CI=1.23-3.16），硬斑块（odds ratio=4.72，95％CI=2.56-11.2），较大的年龄（odds ratio=1.68;95％CI=1.25-2.34），较低的教育程度（odds ratio=4.68，95％CI=2.63-9.75）是老年认知功能障碍的独立危险因素。
3.不同程度的颈动脉硬化与老年认知功能障碍相关性
颈动脉正常组和轻-中度狭窄组之间的神经心理学评估的各个方面没有显着差异。与轻-中度狭窄组相比，严重狭窄组有较低的MMSE，FOM，RVR，DS，BD（P <0.001）水平和更高水平的ADL（P <0.001）。
4.不同部位的颈动脉硬化与老年认知功能障碍相关性
2015例老年患者中，颈动脉硬化性狭窄检测到1028例（51.0％），其中45.3％（466/1,028）为左侧狭窄，39.0％（401/1,028）为右侧狭窄，15.7％（161/1,028）为双侧狭窄。颈动脉硬化患者都包含在狭窄组中。33.9％（348/1,028）的颈动脉硬化性狭窄患者检测到有认知功能障碍。左侧颈动脉硬化性狭窄患者中,认知功能障碍组的患病率较认知完好组（50％vs43％，P<0.05）高。与此相反，右侧和双侧颈动脉硬化性狭窄患者中，认知功能障碍和认知完好的患病率没有显著的区别。左或右颈动脉硬化性狭窄患者的神经心理学评估的不同方面来看。右颈动脉硬化性狭窄患者的MMSE，RVR，DS，BD和ADL的值（P <0.05）显著更高。然而，左侧重度狭窄和右侧重度狭窄的患者各方面神经心理学评估值无明显差异。
结论：
1.与无老年认知功能障碍比较，有老年认知功能障碍患者的严重颈动脉硬化性狭窄患病率显著更高，且平均IMT值显著更高。
2.增厚的IMT值、硬斑块、年龄大、教育程度低是老年认知功能障碍的独立危险因素。
3.不同程度颈动脉硬化与老年认知功能障碍相关性来看，与轻-中度狭窄组相比，严重狭窄组认知功能显著较差。
4.不同部位颈动脉硬化与老年认知功能障碍相关性来看，左侧相关性更为明显。但严重狭窄组中左右侧狭窄对老年认知功能影响大体相当。
目的：采用病例对照的设计方法，检测TIRAP、MyD88、TOLLIP基因多态性位点在老年认知功能障碍人群中的基因型和等位基因频率，并从单位点分析、单倍型分析等方面，探讨TIRAP、MyD88、TOLLIP基因多态性与老年认知功能障碍患病风险之间的关联。
对象和方法:采用美国国立神经病、语言功能紊乱和卒中研究所及阿尔茨海默病和相关疾病协会（NINCDS-ADRDA）制定的临床诊断标准，选择2010年1月－2013年2月在我院门诊及住院的AD患者，经头颅MRI或CT检查排除其他类型的痴呆，最终确定为入组对象。收集患者临床资料，抽取所有AD患者及对照组的抗凝外周血，以PCR-LDR的方法，抽提全血基因组DNA，多重PCR扩增SNP位点的基因片断后，行PCR产物的连接酶检测反应（多重LDR），测序仪电泳读取检测结果，行哈代-温伯格平衡(HWE)检验，SNP位点与AD发病风险的关联分析。
结果：
1. AD组与对照组受教育程度分类比较中，未达到小学毕业文化程度的比例AD组明显较高，有显著性差异（P<0.05）。两组间患高胆固醇血症的比例AD组明显较高，有显著性差异（P<0.05）。两组间患高血压、糖尿病、吸烟的比例无明显差异（p>0.05）。
2.研究发现TIRAP、 MyD88、 TOLLIP基因的SNPs等位基因频率分布经Hardy-Weinberg平衡检验符合群体基因遗传平衡（P>0.05）。
3. AD组和对照组TIRAP基因的rs7932766位点CC、CT、TT基因型频率分别为12%、41.1%、46.8%；11%、39.5%、49.5%，两组各基因型频率分布经χ2无显著性差异（χ2=2.146，P=0.284）。AD组C及T等位基因频率分别为32.6%、67.4%，对照组则为30.8%、69.2%，两组各等位基因频率分布经χ2检验无显著性差异（χ2=1.126,P=0.433）。
4. AD组和对照组MyD88基因的rs7744位点AA、AG、GG基因型频率分别为16%、35.1%、48.9%；15.2%、36.8%、48.0%，两组各基因型频率分布经χ2检验无显著性差异（χ2=1.832，P=0.456）。AD组A及G等位基因频率分别为33.5%、66.5%，对照组则为33.7%、66.3%，两组各等位基因频率分布经χ2检验无显著性差异（χ2=2.128，P=0.634）。
5. AD组与对照组TOLLIP基因的rs5743942位点CC、CT、TT基因型频率分别为：59.0％、27.0％、13.9％；59.3％，39.4％，1.3％。AD组的TT基因型明显增高。AD组与对照组相比，基因型频率分布差异有统计学意义（χ2＝6.387，P＝0.034<0.05）,与CC＋CT基因型相比，经调整年龄、性别、血管危险因素等混杂因素后TT基因型的OR95％CI＝1.856（1.265－3.654）。
6. AD组与对照组TOLLIP基因的rs5743942位点C、T等位基因频率为72.5%,36.1%；78.9%,21.1%，AD组的T等位基因频率明显增高。AD组与对照组相比，等位基因频率分布差异有统计学意义（χ2＝8.492，P＝0.031<0.05），两组相比T等位基因的OR95％CI＝1.759（1.268－4.371）。
7. TOLLIP基因的rs3750920， rs5743867， rs3793964， rs3793963， rs5744002、rs5743944和rs5743947位点在AD组和对照组中分别的CC、CT、TT或AA、AG、GG三种基因型频率无明显统计学差异(P>0.05)。
结论：
1.在中国老年人群中，本研究首次发现TOLLIP基因的rs5743942位点与AD发病相关。T等位基因是AD发生的易感基因。
2. TOLLIP基因的rs3750920，rs5743867，rs3793964，rs3793963，rs5744002、rs5743944和rs5743947位点未发现与AD发病的相关性。
3.在中国老年人群中，本研究发现TIRAP、MyD88基因的rs7932766、rs7744位点与AD发病无相关性。
The clinical manifestations of cognitive impairment is common in the elderly people,cognitive function is closely related to brain structure,cerebral blood flow and itsdistribution. once the cerebral hemispheres local blood supply disorders and structuralabnormalities,the patients often appear cognitive impairment. Atherosclerosis can causeincreased carotid IMT and plaque formation, resulting in carotid atherosclerosis stenosis orocclusion. Carotid atherosclerotic stenosis is not only an important risk factor for ischemiccerebrovascular disease but also associated with impaired cognitive function. However, theassociation between cognitive impairment and carotid atherosclerosis remains controversial.The elderly is high-risk population of cognitive impairment and carotid atherosclerosis,screening and a preventive treatment high risk population of cognitive impairment on earlystage become an urgent problem.
The most common clinical type of elderly cognitive impairment are Alzheimer’sdisease(AD) and vascular dementia(VaD). It is generally accepted previously that the VaDand AD are two types of diseases, which have different pathological basis and susceptiblegene.But in recent years the role of vascular factors in the pathogenesis of AD is graduallytaken seriously. Many risk factors associated with vascular factors or hemodynamic canincrease the risk of AD. Carotid atherosclerosis and other diseases can cause vascularintimal thickening, vascular stenosis, twist and tangle, leading to chronic brain tissuehypoperfusion, and even cause the blood-brain barrier damage,increased permeability.These can lead to amyloid precursor protein damage, the microvascular basal layer thinning,cracking, vascular endothelial cells and smooth muscle cells hyaline degeneration, and thedamage of brain vascular and atherosclerosis common in turn further aggravate AD. AD hasa very high hereditary, but its pathogenesis remains unclear, it is generally considered to bethe result of the role of genetic variation and environmental factors. Looking for susceptiblegenes associated with AD has been an urgent problem.
Toll-like receptor4(TLR4) is an important regulator of innate and adaptive immuneresponses, TLR4recognition of pathogen-associated molecular patterns, activation ofinflammatory cells. The funcion studies of TLR4in atherosclerosis included the experimentof the mouse gene knock and epidemiological investigation of the human TLR4genepolymorphism, studies have shown that TLR4function affect the cccurrence anddevelopment of atherosclerosis. Therefore, the role of the adaptors of TLR4-MyD88,TIRAP and the negative feedback protein of the TLR pathway-TOLLP(Toll-interactingprotein) in atherosclerosis became improtant. Recently, more and more evidencedemonstrated that TLR4-TIRAP-MyD88signaling pathway plays an important role in thepathogenesis of AD, but no studies have reported the association between AD and TIRAP,MyD88,TOLLIP genetic polymorphism.
The research about carotid atherosclerosis and related gene polymorphism include twoparts in clinical and basic studies:(1) To observe the incidence of carotid atherosclerosisand the related cognitive impairment in the elderly population.(2) Using case-controldesign method, detecte genotype and allele frequencies of gene polymorphism related tocarotid atherosclerosis in elderly population, and through the unit point analysis, haplotypeanalysis,etc. explore the association between TIRAP,MyD88and TOLLIP geneticpolymorphism and AD risk.
Objects: In the present study, a large cohort of urban patients without stroke history inChongqing was analyzed to identify the association between carotid artery atherosclerosisand cognitive impairment in the Chinese population
Methods：From February2009-October2012, Randomly selected age of65years oldand over in our neurology department, all enrolled patients was conducted with a series ofneuropsychological test, meanwhile, carotid artery B-mode ultrasound was conducted toidentify carotid atherosclerosis, patients with abnormal findings were examined with CTAor DSA, and clinical data was collected.
Results：
1. Baseline characterictics in overall patients: In total,1,048men and967women wereregistered in this study (mean age of69years old; range65–85years old). Among the studypopulation,356(17.7%) of patients were diagnosed as having cognitive impairment whenthe MMSE value was less than24. Carotid atherosclerosis was defined in1,733(86.0%)patients, and carotid stenosis was detected in1,028patients (51.0%). The mean IMT was1.288±0.149mm.
2. The independent risk factors of elderly cognitive impairment: Multiple logisticregression analyses of age, gender, education level, hypertension, diabetes, hypercholesterolemia, atrial fibrillation, coronary artery disease, tobacco use, degree of carotidstenosis, IMT data, and carotid plaques were performed to identify independent risk factorsof cognitive impairment. increased IMT (odds ratio=1.96;95%CI=1.23–3.16),hyperdense carotid plaques (odds ratio=4.72;95%CI=2.56–11.2), older age (odds ratio=1.68;95%CI1.25–2.34), and lower education level (odds ratio=4.68;95%CI=2.63–9.75)were independent risk factors of cognitive impairment.
3. Cognitive status in patients with different levels of carotid artery stenosis:Therewere no significant differences in various aspects of neuropsychological assessment between patients with a normal carotid artery and those with mild to moderate stenosis.Compared with the mild to moderate carotid artery stenosis group, patients with severecarotid artery stenosis had lower levels of MMSE, FOM, RVR, DS, and BD (p <0.001,respectively) and a higher level of ADL (p <0.001).
4. Cognitive status in patients with left or right carotid artery stenosis: Among2,015elderly patients, carotid artery stenosis was detected in1,028patients (51.0%), of whom45.3%(466/1,028) had left carotid artery stenosis,39.0%(401/1,028) had right carotidartery stenosis, and15.7%(161/1,028) had bilateral stenosis. Atherosclerosis accounted forall of the stenosis. Cognitive impairment was detected in33.9%(348/1,028) of patients withcarotid artery stenosis. Among the patients with left carotid artery stenosis, the prevalencerate is high in cogitive impairmnt group compared with the cognition intact group.(50％vs43％，P<0.05).In contrast, Among the patients with the right side and bilateral carotidatherosclerotic stenosis, the prevalence of cognitive impairment and cognitive intact have nosignificant difference. As for different aspects of neuropsy chological assessment in patientswith left or right carotid atherosclerotic stenosis, the patients with right carotidatherosclerosis have higher values of MMSE,RVR,DS,BD and ADL(P <0.05). However, nosignificant difference between evaluation value of neurological psychology in patients withsevere left and right stenosis.
Conclusions：
1. Compared with patients of cognitive intact, patients of cognitive impairment withsevere carotid artery atherosclerotic stenosis prevalence rate is significately higher，and theaverage IMT values is significately higher.
2. Increased IMT value, high-density plaques, older age, lower educational level is anindependent risk factor of cognitive impairment.
3.As for different degree of atherosclerosis, compared with the mild to moderatecarotid artery stenosis group, patients with severe carotid artery stenosis had significantlyworse cognitive function.
4. Carotid artery atherosclerosis, especially left carotid artery, is positively associatedwith cognitive impairment in elderly patients, but the effects of the left and right stenosis oncognitive function is similar in severe stenosis group.
Objects：Toll like receptors(TLRs)signaling pathways，including the protein encodedby the TIRAP, MYD88, TOLLIP genes， play a central role in the development ofatherosclerosis and Alzheimer’s disease. The aim of this study was to investigate whethergenetic variants in TIRAP, MYD88, TOLLIP genes are associated with the development ofAD.
Methods：A case control collection from432healthy subjects,415AD patients wereincluded10tag single nucleotide polymorphisms(SNPs)of the TIRAP, MYD88, TOLLIPgenes and the SNPs that have previously showed association with susceptibility to otherdiseases were genotyped by PCR-LDR.
Results:
1Comparison of AD group and the control group by education level, the proportion ofAD group was significantly higher that of control group in the population which did notreach the higher primary school culture degree(P<0.05). The ratio of AD group wassignificantly higher than that of control groups of patients with hypercholesterolemia (P<0.05). No significant differences between the two groups ratio of hypertension, diabetes,smoking (P<0.05).
2. The present study found that the distribution of TIRAP,MyD88,TOLLIP genefrequency of SNPs allele were followed the Hardy-Weinberg equilibrium(p>0.05).
3. As for the SNP of TIRAP-rs7932766, The CC、CT、TT genotype frequency of ADgroup and control group are12%、41.1%、46.8%and11%、39.5%、49.5%, there was nosignificant difference between two groups（χ2＝2.146，P=0.284）.
4.As for the SNP of MyD88-rs7744, The AA、AG、GG genotype frequency of ADgroup and control group are16%、35.1%、48.9%and15.2%、36.8%、48.0%, there was nosignificant difference between two groups（χ2=1.832，P=0.456）.
5. As for the SNP of TOLLIP-rs5743942, The CC、CT、TT genotype frequency of AD group and control group are59.0％、27.0％、13.9％and59.3％，39.4％，1.3％. Therewas significant difference of genotype frequency distribution（χ2＝6.387，P＝0.034<0.05）between AD group and control group，and the OR95%CI of the TT genotype against theCC+CT genotype adjusted by age,blood glucose, blood pressure was1.856（1.265-3.654）.
6. There was significant difference of allele frequency between AD group and controlgroup（χ2＝8.492，P＝0.031<0.05），and the OR95%CI of the T allele was1.759（1.268-4.371）.
7. Between AD group and control group, the genotype frequencies of the rs3750920，rs5743867，rs3793964，rs3793963，rs5744002、rs5743944and rs5743947loci of TOLLIPgene have no significant difference(P>0.05).
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Conclusions：
1. Among the chinese population, the present study firstly found that TOLLIP-rs5743942gene polymorphism might be associated with AD, and T allele was probably asusceptible gene of AD.
2. The study found that there is no correlation between rs3750920，rs5743867，rs3793964，rs3793963，rs5744002、rs5743944and rs5743947loci of TOLLIP gene and AD.
3. The study found that there is no correlation between TIRAP-rs7932766、MyD88-rs7744and AD.
老年认知功能障碍疾病临床上最多见的类型就是阿尔茨海默病(Alzheimer’sdisease,AD)和血管性痴呆（Vascular dementia,VaD）。既往普遍认为VaD与AD是两类不同性质的疾病，有着不同的病理基础和易感基因。但近年来血管因素在AD发病中的作用正逐渐受到重视。许多与血管因素或血流动力学相关的危险因素均能增大AD的患病风险。颈动脉硬化等疾病能引起大血管内膜增厚，血管狭窄、扭曲和缠结，导致慢性脑组织低灌注，甚至造成血脑屏障破坏，通透性增加。这些均可导致淀粉样前体蛋白破坏，微血管基底层变薄、裂解，血管内皮细胞及平滑肌细胞透明样变性，上述脑血管的损害及动脉硬化共同反过来进一步加重AD。AD具有极高的遗传性，但其发病机制仍不清楚，人们普遍认为是基因变异和环境因素共同作用的结果。寻找与AD遗传易感性相关的基因一直是亟待解决的问题。
Toll样受体4(Toll-like receptor4，TLR4)是天然免疫和适应性免疫应答的重要调控因子，TLR4识别病原体相关的分子模式，激活炎性细胞。TLR4在动脉硬化的功能研究已经在小鼠基因敲除实验和人类的TLR4基因多态性流行病学调查中进行，研究表明，TLR4功能影响动脉硬化的发生和发展。因此，TLR4的配体MyD88、TIRAP及影响TLR通路传导途径的负反馈蛋白TOLLIP（Toll-interacting protein）在动脉硬化中的作用也逐渐受到重视。近来，有越来越多的证据表明TLR4-TIRAP-MyD88信号通路在AD发病中起重要作用，而相关信号分子TIRAP、MyD88、TOLLIP基因多态性与AD发病的的相关性尚无研究报道。
本课题开展了老年认知功能障碍与颈动脉硬化及其相关基因多态性的临床和基础两个部分的研究：(1)观察老年人群中颈动脉硬化的发生特点及其与认知功能障碍的相关性。(2)采用病例对照的设计方法，检测颈动脉硬化相关基因多态性位点在老年认知功能障碍人群中的基因型和等位基因频率，探讨TIRAP、MyD88、TOLLIP基因多态性与老年认知功能障碍患病风险之间的关联。
目的：通过现状调查研究观察老年人群中颈动脉硬化的发生特点及其与认知功能障碍的相关性，明确65岁以上老年人颈动脉IMT、血管腔狭窄、斑块性质与认知功能障碍是否有独立相关性。
对象和方法:随机选择2009年2月－2012年10月期间，在我科就诊的65岁以上病人2015人进行了现状调查研究，全部患者行颈动脉B超检查颈动脉硬化，发现异常者行CTA或DSA，并进行一般临床资料收集和神经心理学测试。
结果：
1.基线特征分析
入组人数2015名，其中男性1048人(52.01％)，女性967人(47.99%),平均年龄69岁。有1733名（86.0％）发现颈动脉硬化，其中颈动脉硬化性狭窄有1028名（51.0％），平均IMT值为1.288±0.149mm。冠心病显示出对认知功能障碍患者的明显影响（P <0.05）。无认知功能障碍患者的IMT值显著低于有认知功能障碍的患者（P <0.001）。较无认知功能障碍患者，有认知功能障碍患者的严重颈动脉狭窄患病率更高（14％vs.8％，P<0.001），且平均IMT值更高（1.473vs.0.765，P <0.001）。
2.老年认知功能障碍的独立危险因素
为识别认知功能障碍的独立危险因素，多因素Logistic回归分析包括年龄、性别、受教育程度、高血压、糖尿病、高胆固醇血症、房颤、冠心病、吸烟、颈动脉狭窄程度、IMT值及颈动脉粥样硬化斑块。结果显示增厚的IMT值（odds ratio=1.96，95％CI=1.23-3.16），硬斑块（odds ratio=4.72，95％CI=2.56-11.2），较大的年龄（odds ratio=1.68;95％CI=1.25-2.34），较低的教育程度（odds ratio=4.68，95％CI=2.63-9.75）是老年认知功能障碍的独立危险因素。
3.不同程度的颈动脉硬化与老年认知功能障碍相关性
颈动脉正常组和轻-中度狭窄组之间的神经心理学评估的各个方面没有显着差异。与轻-中度狭窄组相比，严重狭窄组有较低的MMSE，FOM，RVR，DS，BD（P <0.001）水平和更高水平的ADL（P <0.001）。
4.不同部位的颈动脉硬化与老年认知功能障碍相关性
2015例老年患者中，颈动脉硬化性狭窄检测到1028例（51.0％），其中45.3％（466/1,028）为左侧狭窄，39.0％（401/1,028）为右侧狭窄，15.7％（161/1,028）为双侧狭窄。颈动脉硬化患者都包含在狭窄组中。33.9％（348/1,028）的颈动脉硬化性狭窄患者检测到有认知功能障碍。左侧颈动脉硬化性狭窄患者中,认知功能障碍组的患病率较认知完好组（50％vs43％，P<0.05）高。与此相反，右侧和双侧颈动脉硬化性狭窄患者中，认知功能障碍和认知完好的患病率没有显著的区别。左或右颈动脉硬化性狭窄患者的神经心理学评估的不同方面来看。右颈动脉硬化性狭窄患者的MMSE，RVR，DS，BD和ADL的值（P <0.05）显著更高。然而，左侧重度狭窄和右侧重度狭窄的患者各方面神经心理学评估值无明显差异。
结论：
1.与无老年认知功能障碍比较，有老年认知功能障碍患者的严重颈动脉硬化性狭窄患病率显著更高，且平均IMT值显著更高。
2.增厚的IMT值、硬斑块、年龄大、教育程度低是老年认知功能障碍的独立危险因素。
3.不同程度颈动脉硬化与老年认知功能障碍相关性来看，与轻-中度狭窄组相比，严重狭窄组认知功能显著较差。
4.不同部位颈动脉硬化与老年认知功能障碍相关性来看，左侧相关性更为明显。但严重狭窄组中左右侧狭窄对老年认知功能影响大体相当。
目的：采用病例对照的设计方法，检测TIRAP、MyD88、TOLLIP基因多态性位点在老年认知功能障碍人群中的基因型和等位基因频率，并从单位点分析、单倍型分析等方面，探讨TIRAP、MyD88、TOLLIP基因多态性与老年认知功能障碍患病风险之间的关联。
对象和方法:采用美国国立神经病、语言功能紊乱和卒中研究所及阿尔茨海默病和相关疾病协会（NINCDS-ADRDA）制定的临床诊断标准，选择2010年1月－2013年2月在我院门诊及住院的AD患者，经头颅MRI或CT检查排除其他类型的痴呆，最终确定为入组对象。收集患者临床资料，抽取所有AD患者及对照组的抗凝外周血，以PCR-LDR的方法，抽提全血基因组DNA，多重PCR扩增SNP位点的基因片断后，行PCR产物的连接酶检测反应（多重LDR），测序仪电泳读取检测结果，行哈代-温伯格平衡(HWE)检验，SNP位点与AD发病风险的关联分析。
结果：
1. AD组与对照组受教育程度分类比较中，未达到小学毕业文化程度的比例AD组明显较高，有显著性差异（P<0.05）。两组间患高胆固醇血症的比例AD组明显较高，有显著性差异（P<0.05）。两组间患高血压、糖尿病、吸烟的比例无明显差异（p>0.05）。
2.研究发现TIRAP、 MyD88、 TOLLIP基因的SNPs等位基因频率分布经Hardy-Weinberg平衡检验符合群体基因遗传平衡（P>0.05）。
3. AD组和对照组TIRAP基因的rs7932766位点CC、CT、TT基因型频率分别为12%、41.1%、46.8%；11%、39.5%、49.5%，两组各基因型频率分布经χ2无显著性差异（χ2=2.146，P=0.284）。AD组C及T等位基因频率分别为32.6%、67.4%，对照组则为30.8%、69.2%，两组各等位基因频率分布经χ2检验无显著性差异（χ2=1.126,P=0.433）。
4. AD组和对照组MyD88基因的rs7744位点AA、AG、GG基因型频率分别为16%、35.1%、48.9%；15.2%、36.8%、48.0%，两组各基因型频率分布经χ2检验无显著性差异（χ2=1.832，P=0.456）。AD组A及G等位基因频率分别为33.5%、66.5%，对照组则为33.7%、66.3%，两组各等位基因频率分布经χ2检验无显著性差异（χ2=2.128，P=0.634）。
5. AD组与对照组TOLLIP基因的rs5743942位点CC、CT、TT基因型频率分别为：59.0％、27.0％、13.9％；59.3％，39.4％，1.3％。AD组的TT基因型明显增高。AD组与对照组相比，基因型频率分布差异有统计学意义（χ2＝6.387，P＝0.034<0.05）,与CC＋CT基因型相比，经调整年龄、性别、血管危险因素等混杂因素后TT基因型的OR95％CI＝1.856（1.265－3.654）。
6. AD组与对照组TOLLIP基因的rs5743942位点C、T等位基因频率为72.5%,36.1%；78.9%,21.1%，AD组的T等位基因频率明显增高。AD组与对照组相比，等位基因频率分布差异有统计学意义（χ2＝8.492，P＝0.031<0.05），两组相比T等位基因的OR95％CI＝1.759（1.268－4.371）。
7. TOLLIP基因的rs3750920， rs5743867， rs3793964， rs3793963， rs5744002、rs5743944和rs5743947位点在AD组和对照组中分别的CC、CT、TT或AA、AG、GG三种基因型频率无明显统计学差异(P>0.05)。
结论：
1.在中国老年人群中，本研究首次发现TOLLIP基因的rs5743942位点与AD发病相关。T等位基因是AD发生的易感基因。
2. TOLLIP基因的rs3750920，rs5743867，rs3793964，rs3793963，rs5744002、rs5743944和rs5743947位点未发现与AD发病的相关性。
3.在中国老年人群中，本研究发现TIRAP、MyD88基因的rs7932766、rs7744位点与AD发病无相关性。
The clinical manifestations of cognitive impairment is common in the elderly people,cognitive function is closely related to brain structure,cerebral blood flow and itsdistribution. once the cerebral hemispheres local blood supply disorders and structuralabnormalities,the patients often appear cognitive impairment. Atherosclerosis can causeincreased carotid IMT and plaque formation, resulting in carotid atherosclerosis stenosis orocclusion. Carotid atherosclerotic stenosis is not only an important risk factor for ischemiccerebrovascular disease but also associated with impaired cognitive function. However, theassociation between cognitive impairment and carotid atherosclerosis remains controversial.The elderly is high-risk population of cognitive impairment and carotid atherosclerosis,screening and a preventive treatment high risk population of cognitive impairment on earlystage become an urgent problem.
The most common clinical type of elderly cognitive impairment are Alzheimer’sdisease(AD) and vascular dementia(VaD). It is generally accepted previously that the VaDand AD are two types of diseases, which have different pathological basis and susceptiblegene.But in recent years the role of vascular factors in the pathogenesis of AD is graduallytaken seriously. Many risk factors associated with vascular factors or hemodynamic canincrease the risk of AD. Carotid atherosclerosis and other diseases can cause vascularintimal thickening, vascular stenosis, twist and tangle, leading to chronic brain tissuehypoperfusion, and even cause the blood-brain barrier damage,increased permeability.These can lead to amyloid precursor protein damage, the microvascular basal layer thinning,cracking, vascular endothelial cells and smooth muscle cells hyaline degeneration, and thedamage of brain vascular and atherosclerosis common in turn further aggravate AD. AD hasa very high hereditary, but its pathogenesis remains unclear, it is generally considered to bethe result of the role of genetic variation and environmental factors. Looking for susceptiblegenes associated with AD has been an urgent problem.
Toll-like receptor4(TLR4) is an important regulator of innate and adaptive immuneresponses, TLR4recognition of pathogen-associated molecular patterns, activation ofinflammatory cells. The funcion studies of TLR4in atherosclerosis included the experimentof the mouse gene knock and epidemiological investigation of the human TLR4genepolymorphism, studies have shown that TLR4function affect the cccurrence anddevelopment of atherosclerosis. Therefore, the role of the adaptors of TLR4-MyD88,TIRAP and the negative feedback protein of the TLR pathway-TOLLP(Toll-interactingprotein) in atherosclerosis became improtant. Recently, more and more evidencedemonstrated that TLR4-TIRAP-MyD88signaling pathway plays an important role in thepathogenesis of AD, but no studies have reported the association between AD and TIRAP,MyD88,TOLLIP genetic polymorphism.
The research about carotid atherosclerosis and related gene polymorphism include twoparts in clinical and basic studies:(1) To observe the incidence of carotid atherosclerosisand the related cognitive impairment in the elderly population.(2) Using case-controldesign method, detecte genotype and allele frequencies of gene polymorphism related tocarotid atherosclerosis in elderly population, and through the unit point analysis, haplotypeanalysis,etc. explore the association between TIRAP,MyD88and TOLLIP geneticpolymorphism and AD risk.
Objects: In the present study, a large cohort of urban patients without stroke history inChongqing was analyzed to identify the association between carotid artery atherosclerosisand cognitive impairment in the Chinese population
Methods：From February2009-October2012, Randomly selected age of65years oldand over in our neurology department, all enrolled patients was conducted with a series ofneuropsychological test, meanwhile, carotid artery B-mode ultrasound was conducted toidentify carotid atherosclerosis, patients with abnormal findings were examined with CTAor DSA, and clinical data was collected.
Results：
1. Baseline characterictics in overall patients: In total,1,048men and967women wereregistered in this study (mean age of69years old; range65–85years old). Among the studypopulation,356(17.7%) of patients were diagnosed as having cognitive impairment whenthe MMSE value was less than24. Carotid atherosclerosis was defined in1,733(86.0%)patients, and carotid stenosis was detected in1,028patients (51.0%). The mean IMT was1.288±0.149mm.
2. The independent risk factors of elderly cognitive impairment: Multiple logisticregression analyses of age, gender, education level, hypertension, diabetes, hypercholesterolemia, atrial fibrillation, coronary artery disease, tobacco use, degree of carotidstenosis, IMT data, and carotid plaques were performed to identify independent risk factorsof cognitive impairment. increased IMT (odds ratio=1.96;95%CI=1.23–3.16),hyperdense carotid plaques (odds ratio=4.72;95%CI=2.56–11.2), older age (odds ratio=1.68;95%CI1.25–2.34), and lower education level (odds ratio=4.68;95%CI=2.63–9.75)were independent risk factors of cognitive impairment.
3. Cognitive status in patients with different levels of carotid artery stenosis:Therewere no significant differences in various aspects of neuropsychological assessment between patients with a normal carotid artery and those with mild to moderate stenosis.Compared with the mild to moderate carotid artery stenosis group, patients with severecarotid artery stenosis had lower levels of MMSE, FOM, RVR, DS, and BD (p <0.001,respectively) and a higher level of ADL (p <0.001).
4. Cognitive status in patients with left or right carotid artery stenosis: Among2,015elderly patients, carotid artery stenosis was detected in1,028patients (51.0%), of whom45.3%(466/1,028) had left carotid artery stenosis,39.0%(401/1,028) had right carotidartery stenosis, and15.7%(161/1,028) had bilateral stenosis. Atherosclerosis accounted forall of the stenosis. Cognitive impairment was detected in33.9%(348/1,028) of patients withcarotid artery stenosis. Among the patients with left carotid artery stenosis, the prevalencerate is high in cogitive impairmnt group compared with the cognition intact group.(50％vs43％，P<0.05).In contrast, Among the patients with the right side and bilateral carotidatherosclerotic stenosis, the prevalence of cognitive impairment and cognitive intact have nosignificant difference. As for different aspects of neuropsy chological assessment in patientswith left or right carotid atherosclerotic stenosis, the patients with right carotidatherosclerosis have higher values of MMSE,RVR,DS,BD and ADL(P <0.05). However, nosignificant difference between evaluation value of neurological psychology in patients withsevere left and right stenosis.
Conclusions：
1. Compared with patients of cognitive intact, patients of cognitive impairment withsevere carotid artery atherosclerotic stenosis prevalence rate is significately higher，and theaverage IMT values is significately higher.
2. Increased IMT value, high-density plaques, older age, lower educational level is anindependent risk factor of cognitive impairment.
3.As for different degree of atherosclerosis, compared with the mild to moderatecarotid artery stenosis group, patients with severe carotid artery stenosis had significantlyworse cognitive function.
4. Carotid artery atherosclerosis, especially left carotid artery, is positively associatedwith cognitive impairment in elderly patients, but the effects of the left and right stenosis oncognitive function is similar in severe stenosis group.
Objects：Toll like receptors(TLRs)signaling pathways，including the protein encodedby the TIRAP, MYD88, TOLLIP genes， play a central role in the development ofatherosclerosis and Alzheimer’s disease. The aim of this study was to investigate whethergenetic variants in TIRAP, MYD88, TOLLIP genes are associated with the development ofAD.
Methods：A case control collection from432healthy subjects,415AD patients wereincluded10tag single nucleotide polymorphisms(SNPs)of the TIRAP, MYD88, TOLLIPgenes and the SNPs that have previously showed association with susceptibility to otherdiseases were genotyped by PCR-LDR.
Results:
1Comparison of AD group and the control group by education level, the proportion ofAD group was significantly higher that of control group in the population which did notreach the higher primary school culture degree(P<0.05). The ratio of AD group wassignificantly higher than that of control groups of patients with hypercholesterolemia (P<0.05). No significant differences between the two groups ratio of hypertension, diabetes,smoking (P<0.05).
2. The present study found that the distribution of TIRAP,MyD88,TOLLIP genefrequency of SNPs allele were followed the Hardy-Weinberg equilibrium(p>0.05).
3. As for the SNP of TIRAP-rs7932766, The CC、CT、TT genotype frequency of ADgroup and control group are12%、41.1%、46.8%and11%、39.5%、49.5%, there was nosignificant difference between two groups（χ2＝2.146，P=0.284）.
4.As for the SNP of MyD88-rs7744, The AA、AG、GG genotype frequency of ADgroup and control group are16%、35.1%、48.9%and15.2%、36.8%、48.0%, there was nosignificant difference between two groups（χ2=1.832，P=0.456）.
5. As for the SNP of TOLLIP-rs5743942, The CC、CT、TT genotype frequency of AD group and control group are59.0％、27.0％、13.9％and59.3％，39.4％，1.3％. Therewas significant difference of genotype frequency distribution（χ2＝6.387，P＝0.034<0.05）between AD group and control group，and the OR95%CI of the TT genotype against theCC+CT genotype adjusted by age,blood glucose, blood pressure was1.856（1.265-3.654）.
6. There was significant difference of allele frequency between AD group and controlgroup（χ2＝8.492，P＝0.031<0.05），and the OR95%CI of the T allele was1.759（1.268-4.371）.
7. Between AD group and control group, the genotype frequencies of the rs3750920，rs5743867，rs3793964，rs3793963，rs5744002、rs5743944and rs5743947loci of TOLLIPgene have no significant difference(P>0.05).
.
Conclusions：
1. Among the chinese population, the present study firstly found that TOLLIP-rs5743942gene polymorphism might be associated with AD, and T allele was probably asusceptible gene of AD.
2. The study found that there is no correlation between rs3750920，rs5743867，rs3793964，rs3793963，rs5744002、rs5743944and rs5743947loci of TOLLIP gene and AD.
3. The study found that there is no correlation between TIRAP-rs7932766、MyD88-rs7744and AD.
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