A new look at mechanism-based Alzheimer's Disease biomarkers in blood

对血液中基于机制的阿尔茨海默病生物标志物的新认识

• 批准号: 9763401
• 负责人: DENNIS J SELKOE
• 金额: $ 22.38万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763401
• 关键词: Address; Adult; Age; Alzheimer' s Disease; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Antibodies; Antigen-Antibody Complex; Antigens; Autoantibodies; Autopsy; Binding; Binding Proteins; Biological Assay; Biological Markers; Blood; Blood Tests; Brain imaging; Caring; Cerebrospinal Fluid; Clinical; Clinical Chemistry; Cognitive; Complex; Conflict (Psychology); Cross-Sectional Studies; Data; Detection; Diagnosis; Diagnostic; Discrimination; Disease; Disease Progression; Down Syndrome; Early Diagnosis; Early intervention trials; Etiology; Genetic; Half-Life; Heterogeneity; Histopathology; Human; Immobilization; Immunoassay; Impaired cognition; Individual; Length; Link; Longitudinal Studies; Measurement; Measures; Medical Genetics; Microtubules; Molecular; Monitor; N-terminal; Nature; Pathogenesis; Pathologic; Pathologic Processes; Patients; Pattern; Phase; Pilot Projects; Plasma; Positron-Emission Tomography; Preparation; Presenile Alzheimer Dementia; Proteins; Reproducibility; Resistance; Risk; Sampling; Sampling Studies; Secondary Prevention; Specificity; Specimen; Statistical Data Interpretation; Study Subject; Symptoms; Testing; Therapeutic; Time; Universities; aged; analytical method; antigen binding; base; blood-based biomarker; cohort; demented; disorder control; exosome; experimental study; extracellular; human disease; human old age (65+); insight; mindfulness; neuropathology; novel; pre-clinical; prospective; protein B; prototype; tau Proteins; Address; Adult; Age; Alzheimer' s Disease; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Antibodies; Antigen-Antibody Complex; Antigens; Autoantibodies; Autopsy; Binding; Binding Proteins; Biological Assay; Biological Markers; Blood; Blood Tests; Brain imaging; Caring; Cerebrospinal Fluid; Clinical; Clinical Chemistry; Cognitive; Complex; Conflict (Psychology); Cross-Sectional Studies; Data; Detection; Diagnosis; Diagnostic; Discrimination; Disease; Disease Progression; Down Syndrome; Early Diagnosis; Early intervention trials; Etiology; Genetic; Half-Life; Heterogeneity; Histopathology; Human; Immobilization; Immunoassay; Impaired cognition; Individual; Length; Link; Longitudinal Studies; Measurement; Measures; Medical Genetics; Microtubules; Molecular; Monitor; N-terminal; Nature; Pathogenesis; Pathologic; Pathologic Processes; Patients; Pattern; Phase; Pilot Projects; Plasma; Positron-Emission Tomography; Preparation; Presenile Alzheimer Dementia; Proteins; Reproducibility; Resistance; Risk; Sampling; Sampling Studies; Secondary Prevention; Specificity; Specimen; Statistical Data Interpretation; Study Subject; Symptoms; Testing; Therapeutic; Time; Universities; aged; analytical method; antigen binding; base; blood-based biomarker; cohort; demented; disorder control; exosome; experimental study; extracellular; human disease; human old age (65+); insight; mindfulness; neuropathology; novel; pre-clinical; prospective; protein B; prototype; tau Proteins

A blood test to identify cognitively unimpaired individuals at risk for Alzheimer's disease (AD) and the emergence of AD in Down syndrome (DS) is desperately needed. Here, we propose experiments to address this unmet need. Specifically, we will measure (in plasma) levels of proteins (tau and Aβ) implicated in the etiology of AD, and naturally occurring autoantibodies (NAbs) against these proteins. In blood tau and Aβ are present in distinct pools, e.g. free floating, bound to other proteins, and inside exosomes. Numerous prior studies have measured Aβ in plasma, but few took account of the distinct pools and many were confounded by imperfect assays and/or patient specimens. Only a handful of studies have looked at tau in blood, none accounted for the molecular heterogeneity of tau or its occurrence in different pools. In contrast, we will be careful to use assays capable of detecting distinct forms of tau and to assess the contributions of different pools and how they may change with disease. Since tau is present in blood at very low levels and measurement of Aβ in plasma requires dilution to overcome matrix effects, we will use state-of-the-art in-house ultra-sensitive assays developed using the Simoa (tau) and Erenna (Aβ) platforms. NAbs-bound tau and Aβ will be liberated from antigen-antibody complexes and then measured, and free NAbs will be detected by quantifying binding to plate-immobilized antigen. Great care will be taken to include internal standards so as to monitor the sensitivity and reproducibility of our assays. Most prior studies evaluated analytes at only a single time point and there have been few longitudinal studies. Considering the long duration of both the pre-clinical and clinical phases of AD, and how distinct forms of tau, Aβ and NAbs may change during these protracted periods, it is not surprising that cross-sectional studies have, thus far, yielded conflicting and variable results. Mindful of these pitfalls, we propose for the first time to measure anti-tau and anti-Aβ NAbs and their cognate antigens in the same plasma samples using specimens from carefully characterized study subjects. To gain insight on how tau, Aβ and NAbs change throughout the course of the disease, we will apply our well- characterized assays to plasma samples from 3 distinct cohorts. These will include samples that have been collected prospectively before and just after clinical onset from individuals of whom a detailed set of clinical, genetic, and histopathology data exist, and plasma from 0-65 years old DS subjects. DS is the most common genetic cause of early-onset AD and most DS adults become demented before the age of 60. Thus, studying samples from different-aged DS subjects provides a window on different stages of AD, and should also identify the optimal therapeutic interval to treat AD in DS. Combining this systematic approach with careful statistical analysis we expect to identify one, or possibly a selection of analytes, that can: (i) accurately detect subjects at risk of developing AD, and (ii) determine an appropriate age range in which to treat AD in DS.

一项血液测试，以识别有认知的独立赛人患阿尔茨海默氏病风险（AD）和 迫切需要唐氏综合症（DS）中广告的出现。在这里，我们建议实验以解决 这个未满足的需求。具体而言，我们将测量（血浆中）在 AD的病因，以及针对这些蛋白质的自然发生自身抗体（NABS）。在血液和Aβ中 存在于不同的水池中，例如自由漂浮，与其他蛋白质绑定，外泌体内部。许多先前 研究已经测量了血浆中的Aβ，但很少有人考虑到不同的池，许多人被混淆了 不完美的测定和/或患者标本。只有少数研究看过鲜血的tau，没有 解释了tau的分子异质性或其在不同池中的发生。相反，我们将 谨慎使用能够检测到不同形式的tau的测定法，并评估不同的贡献 池以及它们如何随疾病而改变。由于tau在非常低的血液中存在，并且 血浆中Aβ的测量需要稀释以克服基质效应，我们将使用最新的内部 使用SIMOA（TAU）和Erenna（Aβ）平台开发的超敏感测定法。 NABS结合的tau和Aβ 将从抗原抗体复合物中解放，然后测量，并通过 量化与板弹性化抗原的结合。要格外小心，包括内部标准 监视我们评估的敏感性和可重复性。大多数先前的研究仅评估了一个分析物 时间点，纵向研究很少。考虑到两者的长期持续时间 AD的临床阶段，以及在这些持久期间，Tau，Aβ和NAB的不同形式如何变化 迄今为止，横断面研究产生了冲突和可变的结果，这并不奇怪。 请注意这些陷阱，我们首次提出测量抗TAU和抗AβNAB及其同源 使用仔细表征研究对象的标本中相同等离子体样品中的抗原。获得 洞悉tau，aβ和Nabs在整个疾病过程中如何变化，我们将运用我们的良好 从3个不同同类的血浆样品中表征了测定法。这些将包括已经 从他们的临床发作之前和之后收集了一套详细的临床， 存在遗传学和组织病理学数据，以及0-65岁DS受试者的血浆。 DS是最常见的 早发AD和大多数DS成年人的遗传原因在60岁之前痴呆。 来自不同年龄DS受试者的样本在AD的不同阶段提供了一个窗口，还应确定 最佳的热间隔，以DS处理AD。将这种系统的方法与仔细的统计结合 分析我们期望确定一个或可能选择的分析物，可以：（i）准确检测到受试者 开发AD的风险，以及（ii）确定在DS中处理AD的适当年龄范围。