【作者】 李海员；

【导师】 王延平；

【作者基本信息】 广州医学院 ， 神经病学， 2009， 硕士

【摘要】 研究背景轻度认知功能障碍(Mild cognitive impairment ,MCI)是介于痴呆和正常老化之间的一种认知缺损状态,临床表现为轻度记忆力或认知障碍但未达到痴呆的诊断。由于MCI被认为是临床可识别的痴呆前状态,特别是阿尔茨海默病(Alzheimer disease ,AD)前状态而成为认知领域研究的热点。近年国外的研究表明MCI患者除记忆受损外其他认知功能也可受损,MCI能否作为一独立诊断国内外尚有争议,目前国内研究主要为单一评价MCI患者的记忆功能,全面评估MCI患者认知功能的研究很少。至今国内外尚无公认有效的筛查MCI的量表,简易智能精神状态量表(Mini-mental state examination,MMSE)在认知缺损筛查中最常用,研究表明以26分为分界值其筛查MCI的敏感性为17%～24.2%,特异性为100%,可见用MMSE作为MCI的筛查工具显然不足。蒙特利尔认知评估量表(Montréal cognitive assessment,,MoCA)是专为筛查MCI而设计的,国外研究表明其筛查MCI的敏感性高达90%,明显优于MMSE,但国内应用非常少且无中文版常模。有关MoCA用来筛查MCI的研究国内亦极少报道。近年来,许多流行病学研究结果表明高同型半胱氨酸(hyperhomocysteine,HHcy)血症是AD的独立危险因素,体外实验也提示高浓度的同型半胱氨酸(homocysteine,Hcy)具有神经毒性作用,但国内有关血浆Hcy代谢异常与MCI之间关系的研究未见报道。本研究旨在探讨MCI患者的神经心理学特征及其与轻度AD患者的比较,为早期诊断AD提供依据;探讨MoCA筛查MCI患者的优越性以为其推广应用提供理论支持;探讨MCI患者血浆Hcy、叶酸、VitB12水平及其与认知功能的关系,为MCI患者的早期干预治疗提供依据。材料与方法1、研究对象研究对象来源于2008年3月至2009年2月广州市老人院在院老人和广州医学院第二附属医院健康体检者及神经内科住院和门诊病人。MCI组42例,纳入标准采用Petersen等2001年修订的MCI临床诊断标准。AD组17例,纳入标准为符合美国神经病学、语言障碍和卒中-老年性痴呆和相关疾病学会(NINCDS-ADRDA)诊断标准中“很可能AD”标准。对照组55例,无痴呆及神经系统变性病,性别、年龄、文化程度与病例组相匹配。排除嗜酒,长期服用精神病药物,严重的头部外伤史,抑郁症,精神分裂症,甲状腺疾病,贫血,维生素B12及叶酸缺乏,糖尿病伴并发症,心、肝、肾功能障碍者及近一个月内服用影响血浆Hcy水平的药物者(如:避孕药、抗癫痫药物、多巴胺类药物和叶酸和/或VitB12等)。2、神经心理量表评估所有研究对象接受MMSE评估的同一天接受MoCA评估,并在一周内完成RVR、逻辑记忆、联想学习、视觉再认、图片回忆、相似性、积木测验(BD)、数字广度(DS)、日常生活能力量表(ADL)、临床痴呆评定量表(CDR)、Hachinski缺血量表(HIS)、听觉词语学习测验(AVLT)。3、收集血标本抽取研究对象清晨空腹静脉血4ml,置于普通干燥管中,保存于4℃冰箱,1小时内离心(3000rpm,10min),分离出血细胞和血浆,取上层血浆0.5ml转装1ml离心管中-20℃冰箱保存成批测定血浆Hcy、叶酸、VitB12浓度。4、血浆Hcy、叶酸、VitB12浓度测定取-20度保存血浆,用荧光偏振免疫分析法(Fluorescence polarization immunoassay,FPIA)检测血浆Hcy浓度。微粒子酶免疫分析法(Microparticle enzyme immunoassay ,MEIA)测定血浆叶酸、VitB12浓度。5、统计学分析用SSPS11.5统计软件进行分析。结果1.MCI组、轻度AD组及对照组神经心理量表评分结果与对照组比较,MCI组在DS倒背、DS顺背、相似性等测试中评分降低且差异有统计学意义(P<0.05),MCI组在MMSE总分、MoCA总分、BD、RVR、视觉再认、图片回忆、联想学习、逻辑记忆等测试中评分降低且差异有统计学意义(P<0.01),但两组的ADL评分差异无统计学意义(P>0.05);与轻度AD组比较,MCI组BD得分高且差异有统计学意义(P<0.05),在ADL、MMSE总分、MoCA总分、DS倒背、相似性、RVR、视觉再认、图片回忆、联想学习、逻辑记忆等测试中两组间评分比较差异有统计学意义(P<0.01),但DS顺背评分两组间比较差异无统计学意义(P>0.05)。2.MCI组、轻度AD组及对照组MoCA评分比较MoCA各亚项评分:与正常对照组比较,MCI组在命名、持续注意、复述、流畅性、抽象、延迟回忆、时间定向等评分两组间差异有统计学意义(P<0.05),在连线、复制图、画钟、注意、计算等评分两组间差异有统计学意义(P<0.01),但地点定向力的评分两组间差异无统计学意义(P>0.05);与轻度AD组比较,MCI组在复述、抽象、地点定向力方面评分差异有统计学意义(P<0.05),在命名、计算、延迟回忆、时间定向力等方面评分高且差异有统计学意义(P<0.01),但在连线、复制图、画钟、注意、持续注意、流畅性等方面两组间比较差异无统计学意义(P>0.05)。3.MCI组、轻度AD组及对照组MMSE评分比较MMSE各亚项评分:与对照组比较,MCI组仅计算与注意力、延迟回忆两项比较差异有统计学意义(P<0.01),其余各项差异均无统计学意义(P>0.05);与轻度AD组比较,MCI组在地点定向力、即刻记忆、延迟回忆、三步指令、结构等方面评分高且差异有统计学意义(P<0.05),在时间定向力、计算与注意力中评分高且差异有统计学意义(P<0.01)但在命名、复述、书面书写中两组间比较差异无统计学意义(P>0.05)。4.MoCA和MMSE筛查MCI的敏感度和特异度以26分为分界值,MMSE、MoCA筛查MCI:敏感度分别为45.23%、95.23%,特异度分别为96.36%、72.72%,假阴性率分别为54.76%、5.00%,假阳性率分别为3.63%、30.00%、,准确度分别为74.22%、82.47%,阳性预测值分别为90.47%、72.72%,阴性预测值分别为69.73%、95.23%。MoCA总分和MMSE总分相关系数为0.741(P<0.01),说明MoCA具有较好的效度。5.MCI组、轻度AD组及对照组血浆Hcy、叶酸、VitB12水平s对照组、MCI组、轻度AD组三组间血浆Hcy水平依次升高,其VitB12水平依次降低,但差异无统计学意义(P>0.05);三组间叶酸水平未显示规律性。6.血浆Hcy与认知功能认知受损组(MCI组+轻度AD组)和对照组中高Hcy血症的比率分别为17/32(53.13%),10/37(27.02%)。认知受损组高Hcy血症者明显增多(OR值=3.060,95%CI 1.137～8.233,χ2值=4.907,P<0.01)。结论1.MCI患者的记忆、语言、执行功能、视空间能力、注意与计算力均可受损。2.延迟记忆、计算与注意力受损可能为早期诊断MCI的敏感指标。3.MoCA为高敏感性的MCI筛查工具,能全面评估MCI患者的认知功能,且可用于筛查MMSE得分正常的MCI患者。4.MCI患者血浆Hcy水平高于正常。更多还原

【Abstract】 BackgroundMild Cognitive Impairment (MCI) is a clinical diagnosis in which deficits in cognitive function are evident but not of sufficient severity to warrant a diagnosis of dementia .For the majority of patients, MCI represents a transitional state between normal aging and mild dementia, usually Alzheimer’s disease (AD).Now it becomes a hot area of cognitive research. In recent years, studies shown that in addition to presentations featuring memory impairment, symptoms in other cognitive domains (eg, executive function, language, visuospatial skills and calculation/attention) have been identified. MCI, as an independent diagnosis is still controversial. Studies which comprehensively assess the cognitive functions of patients with MCI are few at home. So far there is no recognized MCI screening scale at home and abroad. Mini-mental state examination(MMSE) is the most commonly used in screening cognitive impairment, but several studies have shown that using a cutoff score 26 the MMSE had a sensitivity of 17% to 24.2% to detect MCI and the specificity was 100%.It can be obviously seen that MMSE as a main screening tool for MCI is not enough . Montreal Cognitive Assessment Scale (MoCA) is designed for screening MCI in patients scoring between 24 and 30 points on the MMSE, but it isn’t wildly used at home and without the Chinese version of the norm. There are a few reports about MoCA to detect MCI at home. Recent epidemiological studies have indicated that hyperhomocysteine (HHcy) is an independent risk factor for AD, and numerous studies showed that homocysteine (Hcy) plays a neurotoxic role in vitro. There is no systematic study report about the relationship between the plasma Hcy metabolic abnormalities and MCI at home. We aimed to investigate the neuropsychological characteristics of patients with MCI and comparison with the mild AD; to explore the advantages of MoCA in screening for MCI and provide the basis for its application; to determine the relationship of plasma Hcy, folate and vitaminB12 levels of MCI patients with cognitive function, and provide the basis for early intervention therapy of MCI patients.Materials and methods1. SubjectsThe three groups were recruited from the homes for the aged of Guangzhou and the Second Affiliated Hospital of Guangzhou Medical College during March 2008 to February 2009 hospitalization and outpatient department of neurology. The MCI group consisted of 42 elderly participants. MCI was defined according to the criteria of Petersen .the AD group consisted of 20 patients with a diagnosis of probable AD meeting the NINCDS-ADRDA criteria and clinical dementia rating scale (CDR) was 1. The NC group consisted of 55 healthy elderly without dementia and neurological degenerative disease. These three groups were gender, age, complications matched. Individuals who were drug or alcohol abuse ,long-term use of neuroleptic drugs ,with history of serious head injury, depression, schizophrenia, thyroid disease, anemia, vitamin B12 and folate deficiency, diabetes with serious complications, heart, liver, renal dysfunction were excluded. All the subjects were older than 65y and had no history of taking any drugs affected the level of plasma Hcy with last 30 days.2. Neuropsychological testingThe MMSE and the MoCA were administered to all groups in the same day. all groups completed neuropsychological tests in a week which including RVR, logical memory(LM), associate learning, visual recognition, picture recall, similarity , blocks design test (BD), digit span (DS), activities of daily living scale (ADL), clinical dementia rating (CDR), Hachinski Ischemic Scale (HIS), Auditory Verbal Learning Test(AVLT).3. Collection of blood sample4ml fasting venous blood sample, under general drying tube stored in 4℃refrigerator, was collected from each subjects. In 1 hour centrifugation (3000rpm, 10min), Blood plasma and blood cells were separated and admitted to the upper plasma 0.5ml centrifuge tube installed in 1ml stored at -20℃until analyzed plasma Hcy, folate and vitamin B12 concentration.4. Measurement of plasma Hcy, folate and vitaminB12Plasma Hcy concentrations were assayed by fluorescence polarization immunoassay technology. Plasma concentrations of folate and vitaminB12 were assayed by microparticle enzyme immunoassay.5. Statistical analysisAll data were analyzed by SPSS 11.5 software package.Results1. Neuropsychological scales scores of MCI group, mild AD group and NC groupCompared with NC group, the scores of MCI group in DS, similarity were significant lower (P <0.05 ),and the scores of MMSE total score, MoCA total score, BD , RVR, visual recognition ,picture recall, association learning, LM were significant lower (P <0.01 ), but there was no significant difference in the score of ADL between two groups (P> 0.05). Compared with mild AD group, BD scores were significantly higher in MCI group (P <0.05); MCI group had significantly higher scores in the MMSE total score, MoCA scores, DS(back) similarity ,RVR ,visual recognition, picture recall, association learning, LM and lower ADL scores, the differences were significant between two groups (P <0.01), but there was no significant difference in DS(forward ) in the two groups (P> 0.05).2. Comparison of the MoCA score between MCI group, mild AD group and NC groupFor the MoCA sub-items ,the elderly patients with MCI had significantly lower scores than healthy elderly in naming , sustain attention , sentence repetition task, phonemic fluency, abstract, delay recall and time orientation(P<0.05);there were significant differences in trail making, cube drawing, clock drawing, attention and calculation task between the two groups (P<0.01); there was no significant difference in fixed orientation(P> 0.05). Whereas the difference of sentence repetition task, abstract, fixed orientation in MCI group and mild AD group was significant (P<0.05); the difference of naming, calculation task, delay recall, time orientation in MCI group and mild AD group was significant (P<0.01), but there were no significant difference in trail making, cube drawing, clock drawing, attention, sustain attention, phonemic fluency between the two groups (P> 0.05).3. Comparison of the MMSE score between MCI group, mild AD group and NC groupIn MMSE sub-items, there were only significant differences in calculation /attention and delayed recall between MCI group and NC group(P<0.01), although the rest sub-items of the scale MCI group had lower scores but the difference was no significant between the two groups (P> 0.05 ). Compared with mild AD group, MCI cases achieved better and the difference of fixed orientation, immediate memory, delayed recall, three-step instructions, visuospatial structure was significant between the two groups (P <0.05) and there were significant differences in time orientation and calculation task (P <0.01), but there were no significant difference in naming, sentence repetition task, write a sentence between the two groups (P> 0.05).4. Comparison of the sensitivity and specificity of MoCA and MMSE in detecting MCI in the MCI group and NC groupUsing a cutoff score of 26 , sensitivity for MMSE and MoCA to detect MCI was 45.23% and 95.23% respectively, specificity was 96.36%and 72.72% respectively, false negative rate was 54.76% and 5% respectively, false positive rate was 3.63% and 30% respectively, accuracy was 74.22% and 82.47% respectively, positive predictive value was 90.47% and 72.72% respectively, negative predictive value was 69.73% and 95.23% respectively. MoCA and MMSE total score correlation coefficient is 0.741 (P <0.01), showing significant correlation of the two scales.5. Plasma Hcy, folate and VitaminB12 levels in MCI group, mild AD group and NC groupNC group, MCI group and mild AD group among the three groups followed by increased levels of plasma HCY, and reduced the level of VitaminB12 but the differences weren’t significant among the three groups(P> 0.05); folate levels among the three groups had no regularity.6. HHcy and cognitive functionThe prevalence of HHcy in patients with cognitive impairment (MCI and mild AD group)and controls was 53.13% and 27.02%(OR=3.060,95%CI 1.137～8.233,χ~2=4.907,P<0.01)。Conclusions1. MCI patients’memory and other cognitive domains were impaired, such as language, executive function, visual spatial ability, attention /calculation.2. Delay recall and calculation / attention may be the sensitive indicators of early diagnosis of MCI. 3. The MoCA is a brief cognitive screening tool with high sensitivity for detecting MCI .It could comprehensively assessment MCI patients’cognitive functions and can be used for screening MCI patients performing in the normal rang on the MMSE.4. The levels of plasma Hcy in patients with MCI were higher than normal.更多还原