刘海涛 张淑玲△ 白宏英
1)郑州人民医院神经内科一病区,河南 郑州 450000 2)郑州大学第二附属医院,河南 郑州 450014
血管认知功能障碍是由血管疾病引起的异常认知状态,好发于老年人群,患者认知缺陷严重不足,但未达到痴呆标准,基本功能不会丧失。早期识别和治疗血管性认知障碍尤为重要[1-3]。研究显示,寻找准确的生物标志物以及危险因素,用于早期诊断以及预防血管性认知障碍,对临床探索血管性认知障碍发病机制、疾病特点以及临床治疗具有重要意义[4-5]。血清胱抑素C(Cys-C)是一种由Cys C(CST3)基因编码,由人体组织分泌的半胱氨酸蛋白酶抑制剂,近年来,其在血管认知功能障碍以及阿尔茨海默病中的研究越来越多[6-8]。作为肾功能的生物标志物,其也是血管认知功能障碍的有效预测因子[9-10]。多种证据表明,Cys C具有抗炎功能,并对年龄相关疾病发挥保护作用[11-13]。目前,临床对于血管性认知功能障碍的影响因素结论并不统一。本研究探讨血清Cys-C水平与血管性认知功能障碍的相关性,并分析其在发生血管性认知功能障碍中的意义。
1.1研究对象选择2014-02-30—2017-07-30于郑州人民医院神经内科住院的110例血管性认知功能障碍患者(认知障碍组),选取同期90例健康体检者为对照组。男127例,女73例,年龄35~77(53.8±6.4)岁。记录2组基础资料(年龄、吸烟史、饮酒史、性别、高血压史等)。本研究经过我院伦理委员会审核,患者或其家属对研究内容知情且签订书面同意书。
1.2纳入排除标准纳入标准:(1)认知障碍组患者均接受蒙特利尔认知评估量表(MoCA,共7个项目,满分30分,≥26分为正常)评估认知功能[14],且MoCA评分<26分;(2)认知障碍组患者头颅MRI或CT提示存在脑缺血病灶;(3)对照组MoCA评分≥26分。排除标准:(1)先天性疾病或精神病引起的身体残疾;(2)合并阿尔茨海默病;(3)疼痛综合征、晚期糖尿病、恶性肿瘤、肾衰竭、肝功能衰竭、严重贫血者;(4)甲状腺功能异常者;(5)正在接受认知障碍治疗者;(6)严重交流障碍者。
1.3检测方法入院后清晨抽取空腹5 mL静脉血,样品收集1 h内以3 000 r/min离心10 min,分离血浆。实验室检测前,将分离的血浆储存在-30 ℃冰箱内。使用Behring BN ProSpec分析仪(Dade Behring)检测Cys C(免疫比浊法)、血糖、甘油三酯(TC)、血肌酐、低密度脂蛋白(LDL-C)、高密度脂蛋白(HDL-C)等水平。所有检测结果重复3次。
1.4观察指标比较2组一般资料以及Cys C水平,分析血管性认知功能障碍的独立危险因素。
2.1 2组临床资料比较2组年龄、性别、吸烟史、高血压史、糖尿病史、TC、血肌酐、血糖、Cys-C水平差异有统计学意义(P<0.05)。血管性认知功能障碍患者年龄、TC、血肌酐、血糖、Cys-C水平,以及男性比例、吸烟史、高血压史、糖尿病史比例高于对照组。见表1。
2.2多因素分析Logistic回归分析示,Cys-C、TC、高血压史、糖尿病史、年龄是血管性认知功能障碍的独立影响因素(P<0.05)。高水平Cys-C、TC、高龄以及合并高血压史、糖尿病史是血管性认知功能障碍的独立危险因素。见表2。
认知功能障碍是老年群体高发疾病。近年来,随着人口老龄化进程加快,发病率呈现上升趋势,是引起老年痴呆的第2大疾病,严重影响其健康和生活质量[15-16]。大多数认知功能障碍患者存在多发性脑梗死或脑白质缺血,如未得到及时有效治疗,多数患者最终发展为痴呆[17-23]。血管性认知功能障碍包括各种脑血管疾病引起的认知障碍,如脑出血、脑栓塞、脑血流灌流异常等。Cys-C是由Cys C(CST3)基因编码的Cys超家族成员,属于内源性组织蛋白酶抑制物,可抑制蛋白酶B,具有平衡血管壁内组织蛋白酶、抗蛋白酶活性的作用[18]。早期研究重点为Cys-C作为肾功能的生物标志物,在肾脏疾病中起作用。近年来,其在血管性认知功能障碍以及阿尔茨海默病中的研究越来越多[19]。已有研究证实,Cys-C与脑血管病变具有显著相关性,Cys C不仅可调节痴呆,还与血管功能相关,并介导血管舒张、炎症和氧化应激等反应[24-30]。
表1 2组临床资料比较
表2 血管性认知功能障碍的Logistic回归分析结果
ZHANG等[31]分析了阿尔茨海默病脑组织中淀粉样沉积物成分时发现Cys-C,提示Cys-C可能参与了神经组织损伤。已有研究证实,Cys-C基因多态性与阿尔茨海默病、认知功能障碍具有相关性[5,20]。本研究显示,血管性认知功能障碍患者Cys-C水平高于正常体检者;此外,2组年龄、性别、吸烟史、高血压史、糖尿病史、TC、血肌酐、血糖差异有统计学意义(P<0.05)。血管性认知功能障碍患者年龄、TC、血肌酐、血糖、Cys-C水平,以及男性比例、吸烟史、高血压史、糖尿病史比例高于正常体检者。Logistic回归分析示,Cys-C、TC、高血压史、糖尿病史、年龄是血管性认知功能障碍的独立影响因素(P<0.05)。高水平Cys-C、TC、高龄以及合并高血压史、糖尿病史是血管性认知功能障碍的独立危险因素。ZUO等[32-35]研究不同类型痴呆症(血管性认知功能障碍和阿尔茨海默病)患者的Cys C和HDL水平,调查Cys C和HDL是否与不同类型痴呆的严重程度和患病率相关,结果显示,与健康对照组相比,血管性认知功能障碍患者血浆Cys C水平较高,HDL水平较低,血浆Cys C/HDL对痴呆具有诊断价值。本研究中血管性认知功能障碍Cys C水平较健康体检者高,与相关研究[36-38]一致。HDL是存在于全身循环和脑中脂蛋白颗粒的异质组的一部分,主要分别促进脂质和脂质相关分子从体内和整个身体的清除和递送。有证据表明,血浆HDL及其主要蛋白质组分ApoA-Ⅰ也具有有效的血管保护特性,如促进血管功能改善,抑制炎症,抑制内皮修复,防止脂质氧化和刺激内皮修复[10,39]。本研究中,2组HDL差异无统计学意义,可能与纳入患者种族差异、检测方法以及纳入标准差异有关。研究认为,Cys C可能在痴呆发病机制中起重要作用,血浆Cys C水平可能是区分血管性认知功能障碍与健康受试者的有效筛选工具[17]。
在排除混杂影响因素后,本研究显示,高水平Cys-C、TC、高龄以及合并高血压史、糖尿病史是血管性认知功能障碍的独立危险因素。刘利红等[24]分析了411例血管性认知功能障碍的危险因素,结果显示,Cys-C是血管性认知功能障碍的独立危险因素,与本研究一致。此外,RAFAILIDIS等[40]研究认为,血管危险因素,如年龄、TC、高血压史、糖尿病史等增加血管性认知功能障碍的发病率,并促进其向痴呆发展。血清Cys-C水平异常可促进动脉粥样硬化发生,动脉硬化狭窄影响脑组织血供;此外,动脉损伤促进炎性细胞因子释放,造成脑组织损伤;Cys-C可通过血脑屏障参与脑部炎症反应,促进认知功能障碍发展[41-43],本研究进一步证实了Cys-C在血管性认知功能障碍中作用。
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