| 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 populationMethods：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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