阿尔茨海默病生物标志物及其在新药研发中的应用

理想的生物标志物是实现阿尔茨海默病（AD）早期精确诊断和预测疾病发展的重要前提。新版AD 诊断标准从临床无症状期到 痴呆阶段的区分也有赖于生物标志物的应用。介绍目前临床应用的AD 生物标志物及其在药物研发中的应用,重点对AD 血液生物标志 物研究的现状和瓶颈进行综述。     

阿尔茨海默症生物标志物在脑脊液和血液中的研究

阿尔茨海默症(Alzheimer's disease, AD)是一种常见的神经退行性疾病。因为疾病本身很难被治愈,因此早期预测诊断对AD的防治尤为重要。目前,痴呆前期AD的主要诊断方法是脑脊液生物标志物的检测和正电子发射式计算机断层扫描(PET),但是这两种诊断方法侵入性强,价格昂贵,不容易普及。而对血液中的AD相关标志物进行检测,可以使AD的诊断更为普及且更为方便。该文总结了目前AD主要的几种生物标志物,概述了它们在AD患者和正常个体脑脊液和血液中的变化,最后也讨论和分析了未来AD生物标志物在血液检测中可能遇到的挑战。     

综述与专论：阿尔茨海默病体外诊断纳米技术

阿尔茨海默病(Alzheimer’s disease,AD)是一种最常见的神经退行性疾病。AD的精准诊断技术,特别是早期诊断技术是临床亟需的。近年来,以生物标志物为基础的非侵入性体外诊断技术发展迅速,特别是利用纳米材料和纳米技术的高表面活性、独特的光电特性、生物相容性好、易于表面修饰、小型化、集成化等特点,发展了新型的AD体外检测和诊断的纳米技术,大大提升了AD检测的灵敏度和准确性,并且具有简便快速等特点,在AD疾病的早期诊断、预后判断以及疗效评估等方面发挥着重要的作用。本文综述了AD蛋白质类生物标志物检测纳米技术的研究进展,介绍了纳米材料在生物标志物富集方面发挥的重要作用,阐述了以纳米材料为基础的光电信号转导技术以及增强检测信号和提高检测灵敏度的方法。除此之外,还简要介绍了AD纳米检测技术在临床诊断、预后和疗效评估方面的应用前景,总结了AD体外诊断技术的优势及面临的挑战,为AD精准诊疗研究提供参考信息。     

成像技术在阿尔茨海默病诊断中的应用

阿尔茨海默病(Alzheimer’s disease, AD)是最常见的神经退行性疾病,目前临床尚缺乏有效的治疗方法。由于AD的病理变化发生在临床症状之前几十年,早期诊断和干预有助于缓解疾病进展。目前,研究正在从基于症状的临床诊断转向基于病理标志物的生物学诊断。本文综述了AD最常用的早期诊断成像技术,介绍其成像原理、局限性和最新研究进展,并展望了AD早期诊断未来可能的发展方向。预测多模态成像和诊疗一体化可能是未来AD研究和临床实践的最佳方案。     

外泌体microRNAs在阿尔茨海默病中的潜在诊断价值北大核心CSCD

阿尔茨海默病(Alzheimer's disease,AD)作为一类复杂的神经退行性疾病,其临床潜伏期长发病治愈率低等特点使得该病的早期诊断具有重要意义。脑脊液和外周血理化分析等手段可以对具有指示神经功能受损情况作用的生物标记物进行评估以用于AD的早期临床诊断。神经细胞分泌的外泌体中含有与其细胞功能改变密切相关的蛋白质和核酸,在疾病的早期临床诊断中具有潜在价值。本文总结了AD患者脑内外泌体microRNAs的研究进展,探讨外泌体microRNAs是否可作为AD早期生物诊断标志物。     

外泌体microRNAs在阿尔茨海默病中的潜在诊断价值

阿尔茨海默病(Alzheimer's disease,AD)作为一类复杂的神经退行性疾病,其临床潜伏期长发病治愈率低等特点使得该病的早期诊断具有重要意义。脑脊液和外周血理化分析等手段可以对具有指示神经功能受损情况作用的生物标记物进行评估以用于AD的早期临床诊断。神经细胞分泌的外泌体中含有与其细胞功能改变密切相关的蛋白质和核酸,在疾病的早期临床诊断中具有潜在价值。本文总结了AD患者脑内外泌体microRNAs的研究进展,探讨外泌体microRNAs是否可作为AD早期生物诊断标志物。     

阿尔茨海默病血浆和肠道菌群中生物标志物的研究进展

阿尔茨海默病(Alzheimer’s disease, AD)是一种常见的神经退行性疾病,在老年人中患病率高.但目前其发生机制尚不明确,而且缺乏便捷的早期诊断手段,因而难以在疾病早期进行干预和治疗.近几年,随着质谱、免疫学方法等新技术的发展,外周血Aβ、P-tau、外泌体、miRNA、肠道细菌等成为AD早期诊断及病情监测的潜在生物学标志物.本文就目前AD外周血生物标志物及AD相关肠道菌群生物标志物现况进行了综述,旨在为AD的早期诊断和预测疾病进展提供参考.     

阿尔茨海默病早期诊断的体液生物标志物

阿尔茨海默病(Alzheimer’s disease,AD)是目前发病率较高的神经退行性疾病,主要临床表现为不可逆的记忆力丧失与认知功能的衰退。AD起病隐秘,不易察觉,病程长达数十年,尚无有效治疗手段,因此AD早期的诊断与干预尤为重要;但是,当前AD早期诊断缺乏灵敏、简便的检测方案。体液(特别是血液)中的生物标志物受到了越来越多的关注,可能成为AD早期诊断的有效手段。现主要综述了与AD病理进程相关的脑脊液、血液、尿液中的生物标志物,并对其应用与前景做一展望。     

阿尔茨海默病体外诊断纳米技术

阿尔茨海默病(Alzheimer's disease,AD)是一种最常见的神经退行性疾病.AD的精准诊断技术,特别是早期诊断技术是临床亟需的.近年来,以生物标志物为基础的非侵入性体外诊断技术发展迅速,特别是利用纳米材料和纳米技术的高表面活性、独特的光电特性、生物相容性好、易于表面修饰、小型化、集成化等特点,发展了新型的...     

基于体素的形态测量学在阿尔茨海默病及轻度认知功能障碍研究中的应用

阿尔茨海默病(Alzheimer's disease,AD)是发生于老年和老年前期、以进行性认知功能障碍和行为异常为特征的中枢神经系统退行性疾病,是老年痴呆中最常见类型。轻度认知功能障碍(mild cognitive impairment,MCI)是介于正常衰老和痴呆之间的一种中间状态,指有轻度的记忆或认知损伤,但尚未达到痴呆程度的一种状态,日常生活和社会功能不受影响,其中很大一部分患者最终进展为AD。临床诊断AD患者多已达中晚期,为了能早期诊断AD及预测MCI的转归,有关AD的生物学标注物的研究成为近年来的科研热点。AD患者颅脑的大体病理特征为脑萎缩,其萎缩有别于正常老龄化所致的退行性改变,有其自身特点,这种特定形式的萎缩有可能成为AD早期诊断的生物学标志物。基于体素的形态测量学(voxel-based morphometry,VBM)是一种基于像素水平对脑核磁图像进行自动、全面、客观分析的技术,可以定量分析全脑结构、刻画出局部脑区结构特征,是一种较好的脑形态分析工具,广泛用于阿尔茨海默病及轻度认知功能障碍的研究中,本文综述了近年来其研究进展,期望为临床及科研提供参考。     

Biomarkers of Alzheimer’s disease in body fluids

Various innovative diagnostic methods for Alzheimer’s disease (AD) have been developed in view of the increasing preva-lence and consequences of later-life dementia. Biomarkers in cerebrospinal fluid (CSF) and blood for AD are primarily based on the detection of components derived from amyloid plaques and neurofibrillary tangles (NFTs). Published reports on CSF and blood biomarkers in AD indicate that although biomarkers in body fluids may be utilized in the clinical diagnosis of AD, there are no specific markers that permit accurate and reliable diagnosis of early-stage AD or the monitoring of disease pro-gression.     

PET amyloid-beta imaging in preclinical Alzheimer's disease

Alzheimer's disease (AD) is the leading cause of dementia, accounting for 60-70% of all cases [Hebert et al., 2003, 1]. The need for effective therapies for AD is great. Current approaches, including cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists, are symptomatic treatments for AD but do not prevent disease progression. Many diagnostic and therapeutic approaches to AD are currently changing due to the knowledge that underlying pathology starts 10 to 20 years before clinical signs of dementia appear [Holtzman et al., 2011, 2]. New therapies which focus on prevention or delay of the onset or cognitive symptoms are needed. Recent advances in the identification of AD biomarkers now make it possible to detect AD pathology in the preclinical stage of the disease, in cognitively normal (CN) individuals; this biomarker data should be used in the selection of high-risk populations for clinical trials. In vivo visualization of AD neuropathology and biological, biochemical or physiological confirmation of the effects of treatment likely will substantially improve development of novel pharmaceuticals. Positron emission tomography (PET) is the leading neuroimaging tool to detect and provide quantitative measures of AD amyloid pathology in vivo at the early stages and follow its course longitudinally. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.     

Neural regeneration therapies for Alzheimer's and Parkinson's disease-related disorders

Neurodegenerative diseases are devastating mental illnesses without a cure. Alzheimer's disease (AD) characterized by memory loss, multiple cognitive impairments, and changes in personality and behavior. Although tremendous progress has made in understanding the basic biology in disease processes in AD and PD, we still do not have early detectable biomarkers for these diseases. Just in the United States alone, federal and nonfederal funding agencies have spent billions of dollars on clinical trials aimed at finding drugs, but we still do not have a drug or an agent that can slow the AD or PD disease process. One primary reason for this disappointing result may be that the clinical trials enroll patients with AD or PD at advances stages. Although many drugs and agents are tested preclinical and are promising, in human clinical trials, they are mostly ineffective in slowing disease progression. One therapy that has been promising is ‘stem cell therapy’ based on cell culture and pre-clinical studies. In the few clinical studies that have investigated therapies in clinical trials with AD and PD patients at stage I. The therapies, such as stem cell transplantation – appear to delay the symptoms in AD and PD. The purpose of this article is to describe clinical trials using 1) stem cell transplantation methods in AD and PD mouse models and 2) regenerative medicine in AD and PD mouse models, and 3) the current status of investigating preclinical stem cell transplantation in patients with AD and PD.     

PET amyloid-beta imaging in preclinical Alzheimer's disease

Alzheimer's disease (AD) is the leading cause of dementia, accounting for 60-70% of all cases [Hebert et al., 2003, 1]. The need for effective therapies for AD is great. Current approaches, including cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists, are symptomatic treatments for AD but do not prevent disease progression. Many diagnostic and therapeutic approaches to AD are currently changing due to the knowledge that underlying pathology starts 10 to 20 years before clinical signs of dementia appear [Holtzman et al., 2011, 2]. New therapies which focus on prevention or delay of the onset or cognitive symptoms are needed. Recent advances in the identification of AD biomarkers now make it possible to detect AD pathology in the preclinical stage of the disease, in cognitively normal (CN) individuals; this biomarker data should be used in the selection of high-risk populations for clinical trials. In vivo visualization of AD neuropathology and biological, biochemical or physiological confirmation of the effects of treatment likely will substantially improve development of novel pharmaceuticals. Positron emission tomography (PET) is the leading neuroimaging tool to detect and provide quantitative measures of AD amyloid pathology in vivo at the early stages and follow its course longitudinally. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.     

治疗阿尔茨海默病的早老素/γ-分泌酶抑制剂和调节剂

阿尔茨海默病（Alzheimer’s disease,AD）又称老年痴呆症,是一种中枢神经系统（central nervous system,CNS）退行性疾病。β-淀粉样蛋白（β-amyloid,Aβ42）被认为在阿尔茨海默病（AD）的发生、发展过程中起核心作用。Aβ42由APP经β-和γ-分泌酶相继切割产生。γ-分泌酶是一个蛋白酶复合体,早老素（presenilin,PS）是γ-分泌酶的催化组分。因此,抑制PS/γ分泌酶的活性是治疗AD的关键,因而PS/γ分泌酶也是治疗AD的主要靶点。根据这些理论,人们提出了一些治疗AD的新方法,其中PS/γ-分泌酶抑制剂和调节剂成为近年来人们关注的焦点。     

阿尔茨海默病运动治疗研究进展

阿尔茨海默病(Alzheimer's disease,AD)是一种神经退行性疾病,目前对其发病机制尚未完全阐明,治疗效果也不佳。最近不少研究者根据运动对人体,特别是对脑的益处,提出运动治疗AD的可能。本文综述了运动治疗AD的研究进展及其可能机制,展望其可能的治疗前景。     

Disease modifying therapy for AD?1

Alzheimer's disease (AD) is the most common form of dementia in industrialized nations. If more effective therapies are not developed that either prevent AD or block progression of the disease in its very early stages, the economic and societal cost of caring for AD patients will be devastating. Only two types of drugs are currently approved for the treatment of AD: inhibitors of acetyl cholinesterase, which symptomatically enhance cognitive state to some degree but are not disease modifying; and the adamantane derivative, memantine. Memantine preferentially blocks excessive NMDA receptor activity without disrupting normal receptor activity and is thought to be a neuroprotective agent that blocks excitotoxicty. Memantine therefore may have a potentially disease modifying effect in multiple neurodegenerative conditions. An improved understanding of the pathogeneses of AD has now led to the identification of numerous therapeutic targets designed to alter amyloid beta protein (Abeta) or tau accumulation. Therapies that alter Abeta and tau through these various targets are likely to have significant disease modifying effects. Many of these targets have been validated in proof of concept studies in preclinical animal models, and some potentially disease modifying therapies targeting Abeta or tau are being tested in the clinic. This review will highlight both the promise of and the obstacles to developing such disease modifying AD therapies.     

Environmental enrichment compensates for the effects of stress on disease progression in Tg2576 mice, an Alzheimer's disease model

Various environmental factors are known to influence the onset and progression of Alzheimer's disease (AD). Environmental enrichment was reported to improve cognitive performance in various Alzheimer's transgenic mice via an amyloid-related or unrelated mechanism. However, stress has been found to accelerate amyloid deposition and cognitive deficits in many AD models. The aim of this study was to determine whether environmental enrichment compensates for the effects of stress on disease progression in the Tg2576 mice, an established AD model. We housed Tg2576 mice under environmental enrichment, enrichment plus stress, stress, or control conditions at 3 months of age. In this study, we first report that environmental enrichment counteracts the effects of stress in terms of cognitive deficits, tau phosphorylation, neurogenesis, and neuronal proliferation during AD-like disease progression. These results strongly implicate the importance of environmental factors as a major modulator for the disease progression of AD.     

The Utility of Cerebral Blood Flow as a Biomarker of Preclinical Alzheimer’s Disease

There is accumulating evidence suggesting that changes in brain perfusion are present long before the clinical symptoms of Alzheimer’s disease (AD), perhaps even before amyloid-β accumulation or brain atrophy. This evidence, consistent with the vascular hypothesis of AD, implicates cerebral blood flow (CBF) in the pathogenesis of AD and suggests its utility as a biomarker of preclinical AD. The extended preclinical phase of AD holds particular significance for disease modification, as treatment would likely be most effective in this early asymptomatic stage of disease. This highlights the importance of identifying reliable and accurate biomarkers of AD that can differentiate normal aging from preclinical AD prior to clinical symptom manifestation. Cerebral perfusion, as measured by arterial spin labeling magnetic resonance imaging (ASL-MRI), has been shown to distinguish between normal controls and adults with AD. In addition to demonstrating diagnostic utility, CBF has shown usefulness as a tool for identifying those who are at risk for AD and for predicting subtle cognitive decline and conversion to mild cognitive impairment and AD. Taken together, this evidence not only implicates CBF as a useful biomarker for tracking disease severity and progression, but also suggests that ASL-measured CBF may be useful for identifying candidates for future AD treatment trials, especially in the preclinical, asymptomatic phases of the disease.     

Anti-aβ therapeutics in Alzheimer's disease: the need for a paradigm shift

Most current Alzheimer's disease (AD) therapies in advanced phases of development target amyloid β-peptide (Aβ) production, aggregation, or accumulation. Translational models suggest that anti-Aβ therapies may be highly effective if tested as agents to prevent or delay development of the disease or as therapies for asymptomatic patients with very early signs of AD pathology. However, anti-Aβ therapeutics are currently being tested in symptomatic patients where they are likely to be much less effective or ineffective. The lack of alignment between human clinical studies and preclinical studies, together with predictions about optimal trial design based on our understanding of the initiating role of Aβ aggregates in AD, has created a treatment versus prevention dilemma. In this perspective, we discuss why it is imperative to resolve this dilemma and suggest ways for moving forward in the hopes of enhancing the development of truly effective AD therapeutics.