轻度认知障碍的研究进展

老年性痴呆(阿尔茨海默病,Alzheimer disease,AD)是目前严重影响老年人生存质量的疾病,且疗效不佳。据推测到2050年阿尔茨海默病的患病率将是现今的三倍。轻度认知障碍(mild cognitive impairment,MCI)是介于阿尔茨海默病和正常衰老之间的一种认知功能损害状态,是发生阿尔茨海默病的高危因素。文献报道轻度认知障碍每年以8%-25%的比例进展为阿尔茨海默病,较正常人群阿尔茨海默病发病率高10倍。与阿尔茨海默病病理损害不可逆相比,轻度认知障碍患者通过早期干预治疗,可延缓或阻止病情发展为阿尔茨海默病。因此,对阿尔茨海默病早期出现的轻度认知功能障碍诊断及干预尤为重要。本文就认知功能早期阶段,轻度认知功能障碍的历年(2000年到2014年3月)研究进展从概念及分型、临床表现、诊断标准、病理生理及其影像学研究、危险因素及其预防、干预措施(药物和非药物)等方面的最新进展进行论述。     

血清色氨酸、酪氨酸与阿尔茨海默病之间的关系

目的 越来越多的研究表明,代谢物的失衡与阿尔茨海默病（Alzheimer’s disease,AD）之间存在密切的联系。近年来,代谢组学的发展使研究AD周围代谢的特征性变化成为可能。有研究表明,血清色氨酸（tryptophan,Trp）、酪氨酸 （tyrosine,Tyr）水平与轻度认知功能障碍（mild cognitive impairment,MCI）、AD相关。本文拟进一步阐明MCI和AD中色氨酸、酪氨酸水平的特征。方法 将来自阿尔茨海默病神经影像学倡议1（Alzheimer’s Disease Neuroimaging Initiative-1,ADNI-1）队列的765位参与者,分为认知正常（cognitive normal,CN,n=207）、稳定性轻度认知功能障碍（stable mild cognitive impairments,sMCI,n=201）、进行性认知功能障碍（progressive mild cognitive impairments,pMCI,n=171）和AD所致痴呆（n=186）。分析血清色氨酸、酪氨酸对MCI、AD是否具有诊断价值。分析在不同诊断组中,血清色氨酸、酪氨酸分别与脑脊液生物标志物、脑结构、脑代谢及认知功能之间的关系。结果 与CN组相比,sMCI、pMCI、AD组血清色氨酸水平偏低。pMCI组、AD组血清酪氨酸水平显著低于CN组。血清色氨酸对pMCI、AD有诊断价值。血清酪氨酸仅对AD有诊断价值。结论 血清色氨酸、酪氨酸有助于AD的早期诊断。色氨酸、酪氨酸的检测可以为AD的病理学机制研究提供新思路。血清色氨酸、酪氨酸与AD核心标志物、认知功能、脑结构、脑代谢之间均无明显相关性,故血清色氨酸、酪氨酸可能不是AD较好的外周生物标志物。     

综述:2型糖尿病与轻度认知障碍

阿尔茨海默病(Alzheimer's disease,AD)是一个连续的病理生理过程,包括轻度认知障碍前期(pre-MCI)、轻度认知障碍期(mild cognitive impairment,MCI)和痴呆期．AD临床期病程不可逆转,因此,pre-MCI和MCI的早期发现和干预就成为延缓和逆转AD发生的重要环节．大量研究表明,2型糖尿病(T2DM)胰岛素抵抗是导致MCI和AD的独立危险因素,T2DM与AD及AD前期认知功能障碍有密切关系．本文重点综述2型糖尿病与MCI及AD之间的相关性,探讨2型糖尿病治疗对AD的发生进行有效干预的可能性,为AD早期发现和临床治疗提供新线索．     

血清S100β,内皮素-1和血管内皮生长因子测定在老年认知功能障碍疾病诊断中的意义

目的:老年认知功能障碍尤其老年轻度认知功能障碍的早期诊断仍有一定的困难,本研究通过观察血清Sl00β,内皮素-1(ET-1)和血管内皮生长因子(VEGF)测定在老年认知功能障碍疾病诊断的意义.方法:选取2008年10月～2012年4月对我院的认知功能障碍的患者117例,其中阿尔茨海默病患者(AD组)55例和轻度认知功能障碍患者(MCI组)有62例.选取同期在我院体检的健康老年志愿者(对照组)20例.分别检测血清S100β,ET-1,VEGF和蒙特利尔认知评分(MoCA).结果:血清S100β和ET-1水平,从AD组,MIC组和对照组依次降低,而VEGF水平和MoCA评分依次升高,差异有统计学意义(P＜0.01).AD组患者血浆S100β,ET-1与MoCA评分存在负相关(r=-0.387,r=-0A08,P＜0.05),AD组患者血浆VEGF与MoCA评分呈正相关(r=0.363,P＜0.05);而MIC组患者血浆Sl00β,ET-1,VEGF水平与MoCA之间无明显相关性(P＞0.05).结论:S100β,ET-1和VEGF参与老年认知功能障碍的形成过程,血浆S100β,ET-1水平与AD的病情正相关,血浆VEGF与AD的病情成负相关,对于早期发现MCI,和检测AD疾病的病情具有重要意义.     

综述:轻度认知障碍的神经心理损伤特征及其早期识别与干预——预防和延缓阿尔茨海默病的发生

轻度认知障碍(mild cognitive impairment,MCI)是介于正常老化和痴呆之间的过渡阶段,MCI患者是阿尔茨海默病(Alzheimer's disease,AD)的风险人群．本文介绍了国际上MCI诊断标准及其变化和修订,提出了理想的诊断模型．根据国内外研究,从认知和精神行为两个方面综述了MCI的神经心理损伤特征及其相应的诊断工具,简要回顾了现有针对MCI开展干预的各种方法．指出早期识别和干预研究需要从实验室小样本扩展到社区大样本老年人群,从横断研究扩展到纵向追踪,综合采用多种识别指标,并结合多种干预方法以达到最优效果．     

阿尔茨海默病和轻度认知损伤计算机辅助诊断模型（英文）

阿尔茨海默病的早期诊断对于患者具有重要意义,然而轻度认知损伤患者与早期阿尔茨海默病患者十分相似的临床症状却让阿尔茨海默病的早期诊断变得异常困难。通过对391例包括正常人、阿尔茨海默病患者以及轻度认知损伤患者的33项临床指标的研究,用逐步Fisher判别分析构建不同优先级的分类器,筛选出11项指标建立综合诊断模型,对于正常人、轻度认知损伤患者以及阿尔茨海默病患者诊断的平均正确率达到77.16%,最高正确率达到81.68%,提高了阿尔茨海默病患者以及轻度认知损伤的诊断正确率,为科研和临床诊断提供了一种新途径.     

瘦素在脑老化认知发展不同阶段中的作用

脑老化过程中伴随脑结构、功能退化和认知能力减退,其认知发展呈异质性,即发展的不均一性,有成功脑老化、正常脑老化、轻度认知功能障碍和阿尔茨海默病等状态。瘦素在不同认知状态下含量不同。研究发现,无神经病理改变的老年人群瘦素水平高,认知功能减退不明显;多数轻度认知功能障碍者瘦素水平降低;瘦素可改善阿尔茨海默病患者的认知障碍,被认为是一种潜在的认知增强剂。瘦素水平降低在脑老化认知障碍的发展中起重要作用。     

轻度认知障碍的早期检测与转化预测研究进展

轻度认知障碍(mild cognitive impairment,MCI)具有发展为阿尔茨海默症(Alzheimer's disease,AD)的高度危险性,其发病机理、早期检测与进展状况跟踪预测是轻度认知障碍研究中3个重要问题。Aβ沉积与tau蛋白异常较好地解释了MCI/AD的致病机理与过程,是对MCI最为敏感的生化特征;认知能力评分适用于评估与确诊出现临床症状的患者;神经影像学,包括脑结构、脑功能与脑网络的研究,有效地推动了MCI/AD的研究,为临床诊断提供更直接的客观依据。将生化特征、神经心理学与神经影像学特征相结合,应用模式分类与预测模型,实现MCI/AD的分类,以及MCI的动态跟踪和进展状况预测,具有重要的研究意义与临床应用价值。     

阿尔茨海默病生物标志物研究进展

阿尔茨海默病(Alzheimer's disease, AD)是一种常见的神经退行性疾病,以胞外淀粉样蛋白(amyloid-β, Aβ)沉积和胞内神经纤维缠结为主要病理特征。AD发病机理尚未完全探明,并且缺乏有效的早期临床诊断方法,AD患者往往在轻度认知障碍(mild cognitive impairment, MCI)和痴呆(dementia)阶段才会就医,错过治疗的最佳有效期。生物标志物可以帮助诊断特定疾病的有无及其病理进程,因此,研发AD生物标志物对筛查早期AD患者和及时干预治疗MCI患者具有重要的临床意义。与现有AD可能的致病假说相似,AD生物标志物的研究主要集中在Aβ、微管相关蛋白(tau protein, Tau)和炎症相关因子等方面。该文对近年来AD生物标志物的类别、应用依据及优缺点等方面展开综述。     

线粒体结构和功能改变对阿尔茨海默病发生的影响

阿尔茨海默病(Alzheimer's disease,AD)是一种以进行性认知障碍和行为损害为主要特征的神经退行性疾病,主要临床表现为认知功能障碍,同时伴发精神障碍和情绪障碍.AD患者脑中早期即表现出细胞内线粒体功能紊乱和结构变化,纠正线粒体稳态失衡及由其引起的细胞病理改变可能是早期治疗AD的潜在靶点.该文主要对线粒体...     

Mild cognitive impairment: searching for the prodrome of Alzheimer's disease

The concept of mild cognitive impairment (MCI) identifies persons who are neither cognitively normal nor demented. There is increasing evidence that MCI defines a group of persons who are at near-term risk of developing dementia and particularly Alzheimer''s disease (AD). MCI thus constitutes an attractive target population for preventive treatments of AD. MCI is associated with aging and is more prevalent than dementia. There are several clinical and biological markers that are predictive of MCI prognosis, including depressive symptoms, cognitive deficits, brain imaging and neurochemical findings. The clinician needs to be especially alert to depressive and other mood symptoms which are common in MCI and potentially treatable. Trials of current medications for prevention of MCI progression to dementia have been largely negative. There are observational data suggesting that lifestyle modifications including exercise, leisure activities, cognitive stimulation, and social activities may be effective for prevention of MCI progression. There are many novel therapies currently in trials for early AD, and if effective they may prove to be helpful in prevention of MCI progression as well.     

Déficit cognitif léger : mythe ou réalité ?

The concept of mild cognitive impairment, MCI, has been proposed by Petersen and described like a state between the cognitive changes of normal aging and very early dementia. However, MCI appears to be a heterogeneous clinical syndrome in term of etiological factors, clinical patterns or clinical course. New criteria of MCI are proposed for use in clinical research. Identification of patients at risk for Alzheimer disease, AD, is an important goal. Ongoing clinical and neuroimaging (magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT),¹⁸F flouorodeoxyglucose-photo emission tomography (FDG-PET)) studies are focusing on the identification of those individuals with mild cognitive impairment (MCI) who are most likely to convert to AD.     

Analysis of lipophilic fluorescent products in blood of Alzheimer's disease patients

Alzheimer's disease (AD) is a severe neurodegenerative disorder characterized by cognitive decline. Prodromal stage of AD, also called mild cognitive impairment (MCI), especially its amnestic type (aMCI), precedes dementia stage of AD. There are currently no reliable diagnostic biomarkers of AD in the blood. Alzheimer's disease is accompanied by increased oxidative stress in brain, which leads to oxidative damage and accumulation of free radical reaction end‐products. In our study, specific products of lipid peroxidation in the blood of AD patients were studied. Lipophilic extracts of erythrocytes (AD dementia = 19, aMCI = 27, controls = 16) and plasma (AD dementia = 11, aMCI = 17, controls = 16) were analysed by fluorescence spectroscopy. The level of these products is significantly increased in erythrocytes and plasma of AD dementia and aMCI patients versus controls. We concluded that oxidative stress end‐products are promising new biomarkers of AD, but further detailed characterisation of these products is needed.     

Copper subtype of Alzheimer's disease (AD): Meta-analyses,genetic studies and predictive value of non-ceruloplasmim copper in mild cognitive impairment conversion to full AD

Alzheimer's disease (AD) is the most common form of dementia. A myriad of complex factors contribute to AD, promoting the deposition in plaques of amyloid-beta (Aβ), which is the main constituent of this pathognomonic sign of AD at autopsy brain inspection. Aβ toxicity is related to oxidative stress, which results in synaptic loss in specific brain areas, eventually leading to cognitive decline. Metal, and especially copper, dyshomeostasis is a key factor in these processes. Recent studies have demonstrated that the serum fraction of copper that is not bound to ceruloplasmin (Non-Cp copper, also known as ‘free’ or labile copper) increases in a percentage of AD patients and mild cognitive impairment (MCI) subjects; this is considered a precursor of AD. Non-Cp copper is the exchangeable fraction of low molecular weight copper in serum. It is distinguished from the copper structurally bound to the ceruloplasmin protein, a master protein of iron metabolism. Non-Cp copper levels are higher than normal reference values (range 0–1.6 μmol/L) in about 50% of amnestic MCI subjects and 60% of AD patients, typifying them in a subset of AD. Meta-analyses, genetic studies and a prognostic study evaluating the predictive value of Non-Cp copper in MCI conversion to full AD demonstrate the existence of this copper phenotype of AD.     

磁共振技术在轻度认知障碍与阿尔茨海默病中的研究进展

阿尔茨海默病(Alzheimer’s disease,AD)是当今老年人最常见的一种原发性神经退行性疾病。其主要病理学特征表现为神经元的脱失、神经纤维缠结及老年斑形成。轻度认知障碍(mild cognitive impairment,MCI)被认为是AD及其他老年痴呆症的前驱阶段,可进一步转化成AD,且MCI与AD有着相似的病理变化。随着MCI和AD患病数的逐年增加,其给患者家属及社会增添了巨大负担,因此,对MCI和AD作出早期诊断变得尤为重要。然而,MCI和AD早期的临床表现并不突出,且实验室检查也缺乏足够的特异性,当临床医生做出明确诊断时,多数患者已处于AD的中晚期。近年来,随着磁共振技术的不断发展,多种磁共振技术已广泛地应用于MCI和AD的研究中,并为MCI及AD的早期诊断提供了重要的影像学依据。本文分别从结构性磁共振(s MRI)、静息态f MRI、磁共振弥散张量成像(DTI)、磁共振波谱成像(MRS)、磁敏感加权成像(SWI)及MRI分子影像几个方面,阐述多种磁共振技术在MCI和AD研究中的进展。     

Analysis of grey matter in thalamus and basal ganglia based on EEG α3/α2 frequency ratio reveals specific changes in subjects with mild cognitive impairment

GM (grey matter) changes of thalamus and basal ganglia have been demonstrated to be involved in AD (Alzheimer''s disease). Moreover, the increase of a specific EEG (electroencephalogram) marker, α3/α2, have been associated with AD-converters subjects with MCI (mild cognitive impairment). To study the association of prognostic EEG markers with specific GM changes of thalamus and basal ganglia in subjects with MCI to detect biomarkers (morpho-physiological) early predictive of AD and non-AD dementia. Seventy-four adult subjects with MCI underwent EEG recording and high-resolution 3D MRI (three-dimensional magnetic resonance imaging). The α3/α2 ratio was computed for each subject. Three groups were obtained according to increasing tertile values of α3/α2 ratio. GM density differences between groups were investigated using a VBM (voxel-based morphometry) technique. Subjects with higher α3/α2 ratios when compared with subjects with lower and middle α3/α2 ratios showed minor atrophy in the ventral stream of basal ganglia (head of caudate nuclei and accumbens nuclei bilaterally) and of the pulvinar nuclei in the thalamus; The integrated analysis of EEG and morpho-structural markers could be useful in the comprehension of anatomo-physiological underpinning of the MCI entity.     

Memory Concerns,Memory Performance and Risk of Dementia in Patients with Mild Cognitive Impairment

Background

Concerns about worsening memory (“memory concerns”; MC) and impairment in memory performance are both predictors of Alzheimer''s dementia (AD). The relationship of both in dementia prediction at the pre-dementia disease stage, however, is not well explored. Refined understanding of the contribution of both MC and memory performance in dementia prediction is crucial for defining at-risk populations. We examined the risk of incident AD by MC and memory performance in patients with mild cognitive impairment (MCI).

Methods

We analyzed data of 417 MCI patients from a longitudinal multicenter observational study. Patients were classified based on presence (n = 305) vs. absence (n = 112) of MC. Risk of incident AD was estimated with Cox Proportional-Hazards regression models.

Results

Risk of incident AD was increased by MC (HR = 2.55, 95%CI: 1.33–4.89), lower memory performance (HR = 0.63, 95%CI: 0.56–0.71) and ApoE4-genotype (HR = 1.89, 95%CI: 1.18–3.02). An interaction effect between MC and memory performance was observed. The predictive power of MC was greatest for patients with very mild memory impairment and decreased with increasing memory impairment.

Conclusions

Our data suggest that the power of MC as a predictor of future dementia at the MCI stage varies with the patients'' level of cognitive impairment. While MC are predictive at early stage MCI, their predictive value at more advanced stages of MCI is reduced. This suggests that loss of insight related to AD may occur at the late stage of MCI.     

An MRI-derived definition of MCI-to-AD conversion for long-term, automatic prognosis of MCI patients

Alzheimer''s disease (AD) and mild cognitive impairment (MCI) are of great current research interest. While there is no consensus on whether MCIs actually “convert” to AD, this concept is widely applied. Thus, the more important question is not whether MCIs convert, but what is the best such definition. We focus on automatic prognostication, nominally using only a baseline brain image, of whether an MCI will convert within a multi-year period following the initial clinical visit. This is not a traditional supervised learning problem since, in ADNI, there are no definitive labeled conversion examples. It is not unsupervised, either, since there are (labeled) ADs and Controls, as well as cognitive scores for MCIs. Prior works have defined MCI subclasses based on whether or not clinical scores significantly change from baseline. There are concerns with these definitions, however, since, e.g., most MCIs (and ADs) do not change from a baseline CDR = 0.5 at any subsequent visit in ADNI, even while physiological changes may be occurring. These works ignore rich phenotypical information in an MCI patient''s brain scan and labeled AD and Control examples, in defining conversion. We propose an innovative definition, wherein an MCI is a converter if any of the patient''s brain scans are classified “AD” by a Control-AD classifier. This definition bootstraps design of a second classifier, specifically trained to predict whether or not MCIs will convert. We thus predict whether an AD-Control classifier will predict that a patient has AD. Our results demonstrate that this definition leads not only to much higher prognostic accuracy than by-CDR conversion, but also to subpopulations more consistent with known AD biomarkers (including CSF markers). We also identify key prognostic brain region biomarkers.