【作者】 张涛；

【导师】 周华东；

【作者基本信息】 第三军医大学 ， 神经病学， 2008， 博士

【摘要】 动脉硬化是老年人最常见的疾病之一,随着人口老龄化的加速,脑血管疾病发生率也逐渐升高,颅内外动脉硬化是脑血管疾病的重要危险因素。颅内外动脉硬化与认知功能障碍之间的关系正日益引起人们的重视。本课题开展了颅内外动脉硬化临床和基础两个部分的研究:(1)观察老年人群中颅内外动脉硬化的发生特点及其与认知功能障碍的关系。(2)研究大鼠颈动脉硬化发生发展的病理变化过程及机制,大鼠海马组织病理学特点,探讨老龄大鼠认知功能的变化。第一部分老年颅内外动脉硬化的发生及其与认知功能障碍关系的临床研究目的:通过现状调查观察老年人群中颅内外动脉硬化的发生特点及其与认知功能障碍的关系。对象和方法:随机选择2005年10月-2008年2月期间,在我科就诊的65岁以上病人2115人进行了现状调查,经DSA、CTA或颈动脉B超检查颅内外动脉硬化,并进行一般临床资料收集、血清学炎性因子检测和神经心理学测试。有颅内外动脉硬化的311人;血清学炎性因子检测包括IL-6,TNF-а以及Hs-CRP;神经心理检测。对临床资料和检测结果进行单因素和多因素分析。结果:(1)颅内外动脉硬化基线特征:与无颅内外动脉硬化组相比,颅内外动脉硬化组年龄大(P<0.05),受教育程度低(P<0.01),体重指数、收缩压、舒张压、血糖、甘油三酯、血尿酸均较高(P<0.01),低密度脂蛋白明显较低(P<0.01)。颅内外动脉硬化组高血压病,糖尿病和高尿酸血症明显高于无颅内外动脉硬化组,统计学差异显著( P < 0.01),颅内外动脉硬化组代谢综合症高于无颅内外动脉硬化组( P < 0.05)。(2)颅内外动脉硬化的特点:颅内外动脉硬化好发于颈内动脉颅外段(39.87%),其次为椎动脉(15.11%)、锁骨下动脉(10.29%)、颈内动脉颅内段(8.04%)、基底动脉(6.43%)、大脑中动脉(6.11%)、颈总动脉(5.14%)。大脑中动脉、椎动脉和锁骨下动脉的硬化,左侧明显高于右侧,统计学差异显著(P<0.01)。颅内外动脉硬化的311人中,女性(52.09%)所占比例高于男性(47.91%)。(3)颅内外动脉硬化组血清学IL-6(92.70±46.80vs72.88±25.12),TNF-а(36.27±24.11vs33.96±14.78)及Hs-CRP (1.73±1.43vs1.06±0.65)高于无颅内外动脉硬化组,有统计学意义(P<0.05)(4)颅内外动脉硬化危险因素的多因素分析:颅内外动脉硬化的危险因素有年龄、血糖、血尿酸、收缩压、低密度脂蛋白;(5)颅内外动脉硬化与认知功能障碍的关系:与无颅内外动脉硬化组相比,颅内外动脉硬化组MMSE、RVR、DS、BD均明显降低(P<0.01),ADL升高(P < 0.05)。与颅内外动脉硬化无高尿酸血症组相比,颅内外动脉硬化合并高尿酸血症组MMSE评分降低(P<0.05)。与颅内外动脉硬化无糖尿病组相比,颅内外动脉硬化合并糖尿病组MMSE评分降低,有显著性差异(P<0.01)。结论:(1)老年颅内外动脉硬化好发于颈内动脉颅外段,椎动脉、锁骨下动脉、颈内动脉颅内段、基底动脉;老年颅内外动脉硬化发病率左侧高于右侧;(2)颅内外动脉硬化的危险因素有年龄、血糖、血尿酸、收缩压、低密度脂蛋白;高血糖、高尿酸是特别值得重视的危险因素;(3)颅内外动脉硬化的老年病人中,认知功能障碍的比例增加。第二部分老龄鼠颈动脉硬化的发生及其与认知功能障碍关系的实验研究目的:通过观察不同月龄组大鼠颈动脉组织学特点和大鼠海马组织学特点,研究大鼠颈动脉硬化发生发展的病理变化过程及机制,探讨老龄大鼠认知功能的变化。对象和方法: 30只大鼠按不同月龄分组,分别为低龄组,成年组和老龄组,每组各10只。对各组大鼠颈动脉进行显微结构和超微结构的观察,并检测血清学炎性因子变化,行为学(穿梭箱和Morris水迷宫检测)检测大鼠认知功能的变化。结果:(1)老年大鼠颈动脉组织学结构特点:与低龄组大鼠相比,老龄大鼠内膜结构破坏严重,各层结构欠清晰,内皮细胞出现形态改变、脱落衰老凋亡现象。有红细胞等附着。在颈动脉内,TNF-α与IL-6 mRNA表达量随年龄递增,老龄组表达量最多。(2)与低龄组相比,成年组血清ICAM-I、TNF-α升高(P<0.05);老龄组血清ICAM-I、TNF-α、IL-6、IL-1显著升高(P<0.01),Hs-CRP浓度升高(P<0.05)。(3)老龄组大鼠海马神经细胞数量减少,齿状回区和CA3区神经细胞排列稀疏,破坏较严重。老龄组大鼠海马神经细胞、胶质细胞、神经毡和神经髓鞘均出现广泛的老化、凋亡改变。老龄组大鼠神经细胞内细胞器出现肿胀等损伤改变。(4)老龄组大鼠认知功能特点:与成年组相比,老龄组主动回避反应率(AAR)、被动回避反应率(PAR)及空间分辨力的下降(P<0.05),大鼠的学习记忆能力受损;水迷宫定位航行实验中,平均逃避潜伏期和游泳距离长。水迷宫空间搜索实验中,老龄组初次找到平台的时间长,跨越平台的次数少。平均游泳速度结果表明组间差异并非运动功能下降。穿梭箱实验和水迷宫实验表明老龄大鼠条件性学习记忆能力和空间学习记忆能力的损害。结论:(1)低龄组大鼠动脉内皮特点:内皮排列规则流畅,内膜表面光滑,内皮细胞长梭型,胞浆和细胞器丰富,核区饱满,核膜完整,细胞间紧密连接,膜表面有大量微绒毛结构;成年组大鼠动脉内皮细胞特点:内皮细胞完整性较好,欠光滑,内皮排列与血管长径一致较规则,内皮细胞胞浆稀少,细胞器减少,含丰富吞饮小泡,细胞核所在部位隆起,突出于管腔,细胞表面有红细胞,膜表面微绒毛减少,内皮细胞与内皮下层分界欠清晰;老龄组大鼠动脉内皮细胞特点:内皮排列规则欠流畅,表面欠光滑,内皮细胞胞浆稀薄,形态明显异常,体积缩小,细胞核嵌于内弹性膜间缝隙内,膜表面呈大小不等的火山口状缺损,可见血小板、血细胞核细胞碎屑纤维素等附着,膜表面微绒毛消失,细胞连接疏松;内皮细胞改变有三种即形态改变,萎缩和脱落。内弹性膜不规则,粗细不均,并且有断裂、分层现象,甚至消失。(2)老龄大鼠血清学炎性因子ICAM-I, TNF-α,IL-6,IL-1,Hs-CRP升高;(3)老龄大鼠海马神经元呈退行性改变,(4)老龄大鼠认知功能下降。更多还原

【Abstract】 Arterial sclerosis is the most common disease among old people . In the elderly , more and more people would have cerebrovascular disease. Extracranial -intracranial arterial sclerosis is a main risk factor of cerebrovascular disease. The relationship between carotid arteriosclerosis and cognitive dysfunction is increasingly aroused people’s attention .The study on extracranial-intracranial arterial sclerosis function included an clinical study and an experimental study: (1) To investigate the characteristic of extracranial-intracranial arterial sclerosis and the relationship with cognitive dysfunction; (2) To explore the pathologic characters and mechanism of carotid arteriosclerosis, and the cognitive dysfunction in old rats.Part One A clinical study of extracranial-intracranial arterial sclerosis and it’s effect on the cognitive functionObjectives The report focused on investigating the characteristic of extracranial-intracranial arterial sclerosis and the relationship with cognitive dysfunction in elderly people through a random sample investigate.Methods From 2005 Oct to 2008 Feb, 2115 participants , aged 65 years old and over, were random selected from the inpatients and outpatients in our hospital. All participants were screened with digital subtraction angiography (DSA), CT angiography(CTA) or ultrasonography(US) and a baseline screening . Participants classified as with extracranial-intracranial arterial (311 patients) and without extracranial- intracranial arterial sclerosis(1804 patients) based on the result of imaging examination. At baseline screening, the following data were collected: demographic data , blood serum inflammatory factors tests (IL-6,TNF-аand Hs-CRP)and neuropsychological test (including MMSE, ADL, FOM, RVR, POD, DS subtest and BS subtest).Results(1) The baseline characteristics The baseline characteristics of the subjects were compared according to the existence of extracranial-intracranial arterial sclerosis. Compared with subjects without extracranial-intracranial arterial sclerosis, those with extracranial-intracranial arterial sclerosis had older age (p<0.05), lower education(p<0.01) ,higher BMI(p<0.01), higher systolic blood pressure and diastolic blood pressure (p< 0.01), higher fasting plasma glucose, Triglyceride and uric acid (p< 0.01).The distribution of diabetes and hyperuricemia in the patients with extracranial-intracranial arterial sclerosis were more higher than subjects without(P < 0.01). Extracranial- intracranial arterial sclerosis were more frequent in women(52.09% vs 47.91%).(2)The characters of extracranial-intracranial arterial sclerosis Extracranial- intracranial arterial sclerosis are more frequently happened to the extracranial of internal carotid artery(39.87%)、vertebral artery(15.11%), then to ubclavical artery(10.29%)、intracranial of internal carotid artery(8.04%)、basilar artery(6.43%)、middle cerebral artery(6.11%)、and the common carotid artery (5.14%).Among them , The distribution of left middle cerebral artery, left vertebral artery and left ubclavical artery were more than those in right(P<0.01).311patientents with extracranial-intracranial arterial sclerosis were more frequent in women(52.09% vs 47.91%).(3)Compared with without extracranial-intracranial arterial sclerosis group, the expression of IL-6、TNF-Аand Hs-CRP increased significantly in the blood serum in extracranial-intracranial arterial sclerosis group(P<0.05).(4) Multivariate analysis for the association between risk factors and the occurrence of extracranial-intracranial arterial sclerosis After correcting confusing factors including demographic data and some diseases , the following risk factors including age、fasting plasma glucose、uric acid、systolic blood pressure and LDL were associated with the occurrence of extracranial-intracranial arterial sclerosis.(5)The relationship between extracranial-intracranial arterial sclerosis and cognitive dysfunction Compared with the group without extracranial-intracranial arterial sclerosis ,extracranial-intracranial arterial sclerosis have lower scores in MMSE、RVR、DS and BD(P<0.01),higher score in ADL(P<0.05).Patients with extracranial-intracranial arterial sclerosis and hyperuricemia had higher scores in MMSE(P<0.05)、FOM and RVR (P<0.01)than those people who with extracranial-intracranial arterial sclerosis but hyperuricemia. when extracranial-intracranial arterial sclerosis have diabetes ,their scores in subentry of MMSE were lower than those without diabetes(P<0.01).Conclusions(1) Extracranial- intracranial arterial sclerosis are more frequently happened to the extracranial of internal carotid artery、vertebral artery、ubclavical artery、intracranial of internal carotid artery、basilar artery . The distribution of left middle cerebral artery, left vertebral artery and left ubclavical artery were more than those in right.(2) Age、fasting plasma glucose、uric acid、systolic blood pressure and LDL were associated with the occurrence of extracranial-intracranial arterial sclerosis .(3)The elderly people with extracranial-intracranial arterial sclerosis have more cognitive dysfunction than those without.Part two A experimental study of carotid atherosclerosis and the relationship with the cognitive dysfunction in old ratsObjectives: To investigate the histological characters of carotid in different age of rats , explore the pathologic change of carotid atherosclerosis and the relationship with the cognitive dysfunction in old rats.Methods 30 rats were divided into three groups :youth, manhood and agedness. Each group has 10 rats. Observed the microstructure and ultramicrostructure of the carotid endotheliocytal and hippocampus . Testing the expression of inflammatory factors in blood serum. Each rat Was evaluated in ethology to observed for the change of cognitive function.Results(1) The histological characters of old rat’s carotid endotheliocyte Compared with the youth group, the aged rat’s carotid endotheliocytal were badly destroyed, appeared hyperplasia and desquamation. Each structure of the carotid were unclear. The expression of TNF-αprotein and mRNA, IL-6 protein and mRNA in aortic wall were increased along with the age increased.(2) Compared with the group of youth, the expression of ICAM-I and TNF-αin blood serum were increased in the group of manhood(P<0.05);the expression of Hs-CRP were significantly increased (P<0.01),ICAM-I、TNF-α、IL-6、IL-1 were increased (P<0.05)in the group of agedness.(3) The number of leukocytes in the hippocampus decreased significantly in the group of agedness than the groups of young and manhood, especially in the DG and CA3, but there were no significant difference between groups. The leukocytes、astrocytes、synapse and myelinate in the hippocampus were aging in group of agedness.(4) The old rats showed decreased ability of AAR,PAR and spatial resolution(P<0.05).Conclution(1) The histological characters of carotid endotheliocyte in group of youth: The endotheliocyte formed regularly and liquidly with abundant cytoplasm and organelle, the surfaces of subendothelial were smooth. The endotheliocyte’s Karyotheca were integrated. There were abundant microvillus On the surface of endotheliocyte. The histological characters of endotheliocyte in group of manhood: The endotheliocyte were integrated but not smooth. The endotheliocyte formed regularly and contained exiguities’cytoplasm and organelles. On the surface of endotheliocyte, there were some red cell, the microvillus were reduced or disappeared. The endotheliocyte’s structure were obscure.The histological characters of endotheliocyte in group of agedness: The endotheliocyte lack of regularly and liquidly with rare cytoplasm and organelle, the surfaces of subendothelial were not smooth. The endotheliocyte’s Karyotheca were not integrated. There were plenty of microvillus On the surface of endotheliocyte . there are three kinds of character in endotheliocyte: change、apoptosis and dispeared.(2) In group of agedness, the expression of ICAM-I、TNF-α、IL-6、IL-1 and Hs-CRP in blood serum were increased.(3) Degeneration of leukocytes cells could be seen in the group of agedness.(4) Cognitive function declined in old rats.更多还原