轻度认知功能障碍的生物学标志

轻度认知功能障碍是正常衰老和痴呆间的一种过渡状态，可分为遗忘型和血管型等亚型，其概念和诊断正趋向一致。轻度认知功能障碍老年人和痴呆患者在脑脊液Tau蛋白、Aβ、Aβ前体蛋白、胆碱乙酰转移酶活性和事件相关电位等方面有类似变化。文章总结了轻度认知功能障碍的诊断和部分神经生物学指标。     

轻度认知功能障碍与早期阿尔茨海默病诊断的外周标志

轻度认知功能障碍作为阿尔茨海默病的前期阶段，有着与阿尔茨海默病不同程度相似的外周标志。这些外周标志的研究进展主要表现在神经心理认知改变、生物学标志Aβ和Tau蛋白以及分子生物学标志ApoE等方面；重视轻度认知功能障碍，认识早期阿尔茨海默病外周标志对阿尔茨海默病的早期诊断和早期干预有重要的意义。     

正电子发射型计算机断层扫描在早期诊断阿尔茨海默病中的应用

Kirk等认为老年性痴呆（Alzheimer病，AD）患者从正常脑功能到痴呆形成过程分为5个阶段（症状前阶段、临床前阶段、轻度痴呆、中度痴呆和重度痴呆）。Crystal等认为AD的脑部病理变化早于临床症状15-20年。所以人们就有可能在痴呆症状出现前找出脑部的病理变化，作出AD的早期诊断。AD的典型病理表现为脑部出现老年斑、神经纤维缠结、神经元细胞丧失等。老年斑主要由神经纤维网（neuropil）、β-淀粉样蛋白（β-Amyloidp rotein，Aβ）异常突触和胶质细胞等构成。正电子发射型计算机断层（PET）扫描重要进展在于AD的早期或临床前阶段能找出脑内β淀粉样蛋白（Aβ）沉积和乙酰胆碱（Ach）神经元代谢障碍。     

老年病人血清Aβ42与磷酸化Tau蛋白检测的临床价值

目的 旨在探讨血清Aβ42与磷酸化Tau蛋白(p-Tau)检测的临床价值。方法 收集南京大学医学院附属鼓楼医院已开展的425例门诊或住院60岁以上老年病人的血清Aβ42与p-Tau检测结果(两项均为同时检测),分析其在痴呆或其他疾病病人中的阳性率情况。结果 血清Aβ42与p-Tau的总体阳性率分别为36.2%与24.7%,同时阳性率为21.4%。血清Aβ42在诊断为认知功能障碍、痴呆及AD的病人中的阳性率分别为23.8%、44.9%与50.0%,血清p-Tau分别为12.4%、22.4%与16.7%。然而,它们在具有肺部炎症或感染的病人中阳性率高达64.7%,并且两者几乎同时为阳性。结论 血清Aβ42与p-Tau水平对AD的辅助诊断价值可能有限,但对提示肺部感染可能具有临床价值。     

AMPK在阿尔茨海默病发病中的作用

阿尔茨海默病(AD)是发生在老年和老年前期、以进行性认知功能障碍和行为损害为特征的中枢神经系统退行性病变,是老年期痴呆的最常见类型,约占50%。据统计,65岁以上老年人约有5%患有AD。并且随着增龄,患病率增加。有关AD的确切病因,现有多种假说,主要是淀粉样蛋白-β(Aβ)和Tau     

β淀粉样蛋白清除的研究进展

阿尔茨海默病(AD)是常见的痴呆形式,占老年痴呆病人的60%~80%[1],主要表现为进行性记忆力和认知功能下降,死亡常常发生在诊断后几年内,AD的不可逆神经元功能障碍和致残将会造成巨大的社会经济负担,将成为全球最大的公共卫生挑战之一,迫切需要新的治疗方法。针对β淀粉样蛋白(Aβ)产生,聚集或其从脑中清除已成为预防或治疗AD的活跃研究领域。Aβ是由淀粉样前体蛋白(APP)代谢产生,APP可被α-分泌酶的神经外蛋白酶切割,产生可溶性细胞外片段(sAPPα),被β-分泌酶(BACE1)切割,产生可溶性细胞外片段(sAPP+)和细胞膜结合片段(C99),细胞膜结合片段在细胞内被γ-分泌酶裂解,释放淀粉样蛋白细胞内结构域和Aβ,Aβ聚集形成寡聚体,原纤维和斑块。在AD中,Aβ浓度的变化出现在脑脊液(CSF)中,依次是脑Aβ积聚,CSF增加,海马和灰质体积减少,葡萄糖代谢减少,记忆障碍和痴呆[2,3]。Aβ不仅在脑细胞中表达,也在神经元,星形胶质细胞和小胶质细胞中表达,还在外周器官和组织,例如肝肾胰脾等脏器及各种血液和内皮细胞中表达。本文对近年有关Aβ清除及针对该机制的治疗策略进展进行综述。     

轻度认知功能障碍脑电图同步化可能性研究进展

记忆的缺损超出了相应年龄和教育的平均水平,但尚未达到痴呆的程度就被称为轻度认知功能障碍。由于目前对痴呆缺乏有效的治疗手段,因此对痴呆的早期诊断显得尤为重要。介于正常状态与痴呆之间的轻度认知功能障碍就成为国内外的研究热点。脑电图同步化可能性是一种新型脑电分析法,本文就轻度认知功能障碍的脑电图同步化可能性研究进展综述如下。     

血清S100β蛋白测定在老年认知功能障碍疾病诊断中的意义

目的探讨老年认知功能障碍患者血清S100β蛋白含量变化的临床意义。方法采用双抗体夹心酶联免疫吸附法(ELISA)分别测定28例老年认知功能障碍患者(疾病组)、31例其他神经系统疾病患者(非认知功能障碍疾病组)和25例健康人血清中S100β蛋白含量。结果疾病组血清S100β蛋白含量明显高于非认知功能障碍疾病组和健康对照组(均P0.05);非认知功能障碍疾病组与健康对照组比较差异无统计学意义(P0.05);疾病组患者血清中S100β蛋白含量随增龄和病情加重有升高趋势,但并无统计学意义(P0.05)。结论血清S100β蛋白含量升高可能是老年认知功能障碍发生的生物化学机制之一,其可为该病的临床诊断提供客观的实验室依据。     

β淀粉样变与阿尔茨海默病

阿尔茨海默病(Alzheimer's disease,AD)是在1906年由Alzheimer教授首次报道了1例51岁的女性痴呆患者而命名的.它是一种进行性神经变性疾病,能严重损害患者的认知功能,造成生活自理能力障碍及精神行为异常.AD具有相对特异的病理改变,即老年斑、神经元纤维缠结及神经细胞的减少.自1985年首次从AD老年斑中分离出β淀粉样蛋白(Aβ1-42)以来,大量研究集中于Aβ与AD的关系上,旨在揭示AD的发病机制、帮助临床诊断,最终达到治疗AD的目的.     

轻度认知功能障碍早期诊断与治疗进展

轻度认知功能障碍是介于正常老化和痴呆之间的一种过渡状态,是老年性痴呆的高危人群,对其进行早期诊断和早期干预是防治痴呆的关键.近年来轻度认知功能障碍的神经影像学及神经生物学研究取得了新的进展,现综述如下.     

Proteomic analysis of plasma from rheumatoid arthritis patients with mild cognitive impairment

Rheumatoid arthritis (RA) patients may suffer from comorbid neuropsychiatric symptoms including mild cognitive impairment (MCI). Although comorbidity of MCI is common, there are currently no validated plasma biomarkers to aid MCI diagnosis. This study screened plasma from patients with RA with and without comorbid MCI to identify potential biomarkers useful in the differential diagnosis of comorbid MCI. Plasma samples were collected from patients with RA without comorbid MCI, with comorbid MCI, and from healthy controls. Plasma samples were examined by tandem mass tags (TMT) combined with two-dimensional liquid chromatography-tandem mass spectrometry (2D-LC-MSMS) to analyze protein expression. Differentially expressed proteins were identified by bioinformatics and validated by enzyme-linked immunosorbent assay (ELISA). A total of 746 reliable proteins and 158 differentially expressed proteins were identified. Fourteen patients with RA-MCI showed differential protein expression (six proteins upregulated and eight proteins downregulated) compared with those patients without MCI and with healthy controls. Bioinformatics analysis showed that the differentially expressed proteins were primarily involved in biological processes, such as cell adhesion, coagulation, apoptosis, and body fluid regulation. The results of the ELISA experiments, similar to those of the proteomic analysis, demonstrated that sonic hedgehog (SHH) was upregulated and serum paraoxonase (TTR) was downregulated in patients with RA-MCI. These results indicate that SHH and TTR may be candidate plasma biomarkers that could be used to distinguish patients with RA and comorbid MCI from those without comorbid MCI.     

血清中人再生胰岛衍生蛋白1α对阿尔茨海默病的早期诊断价值

目的通过比较阿尔茨海默病（Alzheimer's disease, AD）患者、轻度认知功能障碍（mild cognitive impairment,MCI）患者以及认知功能正常的健康对照者血清中人再生胰岛衍生蛋白1α（regenerating islet-derived1αprotein, Reg-1α）表达水平的差异,探讨血清Reg-1α作为AD早期诊断标志物的临床意义。 方法选取2015年6月至2017年6月浙江医院收治的60～90岁的93例AD患者（AD组）、82例MCI患者（MCI组）以及110例健康对照者（正常组）,收集所有研究对象的外周血样本,分别采用ELISA法和实时荧光定量RT-PCR法检测血清中Reg-1α蛋白和mRNA的表达水平。 结果3组研究对象Reg-1α蛋白及mRNA表达水平的差异均有统计学意义（F=4.522、2.629,均P<0.05）;AD组及MCI组Reg-1α蛋白及mRNA表达水平均显著高于正常组（q=-5.958、-6.914、-5.223、-7.679;均P<0.01）;AD组Reg-1α蛋白表达水平显著高于MCI组（q=7.681,P<0.01）,但Reg-1αmRNA表达水平与MCI组无明显差异（q=3.028,P>0.05）。 结论血清中Reg-1α的表达水平与AD进展相关,或可作为AD的早期诊断标志物。     

轻度认知损害患者的静息态功能磁共振成像

识别轻度认知损害(mild cognitive impairment,MCI)的意义在于能尽早进行干预并推迟甚至阻止其进展为痴呆.不过,由于受到诊断方法和标准的限制,MCI患者的诊断较为困难.近年来,静息态功能磁共振成像(resting-state functional magnetic resonance imaging,rs-fMRI)作为一种新兴的功能影像学技术得到迅速发展,被广泛应用于MCI的研究,有可能为MCI的诊断提供客观的生物学标记物.文章就rs-fMRI在MCI中的研究进展进行了综述.     

Neurofilament light chain in cerebrospinal fluid or blood as a biomarker for mild cognitive impairment: A systematic review and meta-analysis

Background:To allow early diagnosis and monitoring of disease progression, there is a need for biomarkers in mild cognitive impairment (MCI). Neurofilament light chain (NfL) is emerging protein biomarkers in neurodegenerative diseases and is of possible use in MCI. We aimed to assess the utility of NfL in blood and cerebrospinal fluid (CSF) as a biomarker in patients with MCI.Methods:A systematic search with comparison of NfL level between individuals with MCI and healthy controls were retrieved from PubMed, Embase, and Web of Science. The standard mean difference and 95% confidence interval were calculated using the random-effect model to analyze the differentiation of NfL between patients and controls.Results:A total of 7 studies were included. NfL was higher in 676 MCI than 504 healthy controls. Subgroup analysis according to sample type indicated that differentiation of NfL in CSF between patients with MCI and controls showed significant results but in blood. Moreover, the NfL increasing still existed when the NfL expression level was detected by enzyme-linked immunosorbent assay but single molecule array assay. However, no difference of NfL in MCI between Caucasian and Asian was found.Conclusions:NfL expression level in CSF was increased in MCI individuals, which indicated that NfL in CSF could be a potential biomarker of MCI.     

Complex activities of daily living in mild cognitive impairment: conceptual and diagnostic issues

BACKGROUND: The impact of cognitive impairment on activities of daily living (ADL) is being used as a major criterion for differentiating between mild cognitive impairment (MCI) and dementia. The concept of an ADL threshold that separates MCI from dementia, however, appears to be improbable for several reasons. OBJECTIVES: To determine whether complex ADL are impaired in patients with MCI; to examine the usefulness of the assessment of ADL impairment for the diagnosis of MCI; to explore whether both cognitive testing and assessment of impaired ADL are significant predictors of the diagnosis according to the diagnostic gold standard of MCI. DESIGN: Cross-sectional study. SETTING: University-based outpatient clinic. SUBJECTS: A total of 45 elderly MCI patients diagnosed according to research diagnostic criteria and 30 age-matched cognitively unimpaired controls. METHODS: Clinical assessment - Alzheimer's disease Assessment scale, cognitive subscale (ADAS-cog) for the assessment of cognitive functions, Alzheimer's disease Cooperative Study scale for ADL in MCI (ADCS-MCI-ADL) for the assessment of impairments of complex ADL. Statistical evaluation - Mann-Whitney U tests for significant differences on measures of cognition and everyday functioning. Non-parametric correlations for associations between ADL and cognitive ability. Receiver operator curve (ROC) analyses to identify optimal cut-off scores on the ADCS-MCI-ADL and ADAS-cog scales to differentiate between MCI patients and controls. Binary logistic regression analyses to predict the diagnosis of MCI on the basis of the above-mentioned instruments. RESULTS: Patients scored significantly higher than controls on the ADAS-cog scale and significantly lower on the ADCS-MCI-ADL scale. There was a significant negative correlation of the above-mentioned scales in MCI patients (r = -0.46, P < 0.01). Both instruments discriminated well between patients and controls (ADCS-MCI-ADL: optimal cut-off 52 points, sensitivity 0.89, specificity 0.97; ADAS-cog: optimal cut-off 10 points, sensitivity 0.78, specificity 1.0). With regard to the linear predictor in the logistic regression built, both instruments were strong predictors of the diagnosis according to the diagnostic gold standard (ADCS-MCI-ADL: P = 0.002; ADAS-cog: P = 0.041). CONCLUSION: Impairment of ADL is already present in MCI. Therefore, intact ADL cannot be used as a criterion to define the syndrome of MCI and to distinguish it from mild dementia. The assessment of complex ADL is probably useful for the diagnosis of MCI.     

Advance prediction of Mild Cognitive Impairment (MCI) using (99m)Tc-ECD SPECT brain blood flow imaging

AIM: Mild Cognitive Impairment (MCI) is considered as a precursor state of Alzheimer disease (AD). SPECT brain blood flow imaging was investigated in MCI and it's relevance to the prognosis of MCI was evaluated in an attempt define the characteristics of brain blood flow imaging of MCI (amnestic MCI; aMCI) converting to AD. METHODS: Ninety-two patients over 60 years old with amnesia were studied. (99m)Tc-ECD SPECT brain blood flow examinations of the subject under drug-free conditions were conducted and imaging was analyzed according to the first clinical diagnosis. Patients given a diagnosis of MCI on the first clinical diagnosis, were examined again after 2 years and the SPECT imaging before 2 years previously was classified and analyzed. RESULTS: Of them, there were 35 MCI patients, converting of 13 AD patients (37.1%; aMCI), 10 MCI patients (28.6%; non-converter), 4 depression patients (11.4%; Depression type MCI (dMCI)), 1 Geriatric psychosis patient, but 7 patients dropped out. In the aMCI group, relative hypoperfusion was recognized in the posterior cingulate and the precuneus. In the dMCI group, relative hypoperfusion was recognized in the dorsolateral prefrontal cortex (DLPFC) and the anterior cingulate. In the non-converter group, relative hypoperfusion was recognized in the basal forebrain. CONCLUSIONS: The hypoperfusion of the precuneus in aMCI, and the hypoperfusion of the right frontal lobe (DLPFC, dorsal-anterior cingulate) in dMCI were characteristic brain blood-flow abnormalities. We believe (99m)Tc-ECD SPECT brain blood flow imaging to be useful in the diagnosis of aMCI and in the early detection of depression.     

From mild cognitive impairment to prodromal Alzheimer disease: A nosological evolution

Despite of the positive medical and scientific advances generated through the mild cognitive impairment (MCI) diagnosis, as we will see along this paper, the concept of MCI presents several major limitations. MCI defines a syndrome and therefore it may be the consequence of different diseases with distinct aetiologies. Furthermore, the philosophy behind the MCI scenario has been to detect a group of symptoms that eventually will evolve into a distinct disease. In contrast, our nowadays aim is to detect a disease in its earlier stages that eventually will evolve from one clinical syndrome to another. As an example, our aim now is to detect early AD that initially will manifest as a memory syndrome and eventually will evolve into a dementia syndrome. Consequently, in order to overcome the syndromical diagnosis behind MCI, the concept of prodromal AD (Prd-AD) has recently emerged. Prd-AD is defined as the symptomatic predementia phase of AD, generally included in the MCI category; this stage is characterised by symptoms not severe enough to meet currently accepted diagnostic criteria for AD. Being a nosological concept, it has several potential advantages related with early diagnosis and treatment, together with the possibility to contribute to the development of disease modifying drugs.     

蒙特利尔认知评估量表在帕金森病认知功能损害筛查中的应用

目的探讨蒙特利尔认知评估量表(MoCA)和简易智能状态检查量表(MMSE)在帕金森病(PD)患者认知功能损害筛查中的应用。方法选取1 29例年龄≥60岁的PD患者,根据认知功能将其分为正常组(60例)、轻度认知功能障碍(MCI,37例)组和PD痴呆(PDD,32例)组,采用MoCA和MMSE对患者进行评估和分析。结果 3组MoCA得分差异有统计学意义(P<0.01)。与正常组比较,MCI组和PDD组患者在画立方体、复述、1 mm动物数、抽象能力、延迟回忆得分较低(P<0.01);与PDD组比较,正常组和MCI组患者在命名、数字广度和定向力得分较高(P<0.05)。此外,受试者ROC曲线结果显示,MMSE诊断MCI的曲线下面积为0.803;MoCA诊断MCI的曲线下面积为0.947。MMSE诊断PDD的曲线下面积为0.952;MoCA诊断PDD的曲线下面积为0.990。结论 MoCA可作为有效的PD患者认知功能损害的筛查工具,且随着PD患者病情的进展,MoCA得分逐渐降低。MoCA筛查MCI的最佳界值为≤23分,且MoCA在筛查PD患者MCI方面的敏感性较MMSE高。     

Is it time to separate subjective cognitive complaints from the diagnosis of mild cognitive impairment?

Subjective cognitive complaints (SCC) are currently considered to be a core feature of mild cognitive impairment (MCI). Yet the implications of including or excluding subjective complaints has not been previously considered. The key questions are how many healthy people complain of SCC compared to those with MCI? How is the epidemiology of MCI affected by the requirement for SCC? How is the prognosis of MCI influenced by SCC? and how should SCC be defined and measured? Findings to date suggest that subjective complaints are one of many variables that comprise risk in individuals with MCI. Individuals who do not have subjective complaints and might not qualify under current definitions of MCI may still have a disorder that is of clinical significance. Despite a close association, SCC may be neither necessary nor sufficient for a diagnosis of either MCI or dementia.     

蒙特利尔认知评估量表筛查轻度认知功能障碍分界值的研究

目的研究蒙特利尔认知评估量表(Montreal cognitive assessment,MoCA)在筛查轻度认知功能障碍(MCI)中的应用价值,初步探讨MoCA筛查MCI的最佳界值。方法分别采用简易智能状态检查量表(MMSE)及MoCA评估入组的男性患者153例,根据诊断标准分为对照组69例、MCI组60例、AD组24例。进行2种量表得分的相关性分析,并且计算MoCA筛查MCI患者的敏感性、特异性、Kappa值、约登指数等,并选取最佳分界值。结果与对照组比较,MCI组和AD组MMSE评分和MoCA评分明显降低(P<0.05)。MMSE评分与MoCA评分呈正相关(r=0.847,P<0.01);以26分为分界值,MoCA诊断MCI的敏感性为98.3%,特异性为85.5%,Kappa值=0.830;绘制ROC曲线得到MoCA筛查MCI的最佳分界值为25分,敏感性为93.3%,特异性为97.1%,Kappa值=0.906。结论本研究人群MMSE评分与MoCA评分有很好的相关性,并且与临床诊断一致性好,推荐25分为该类人群MCI的分界值。