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

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，可识别认知能力未受损且有阿尔茨海默病 (AD) 风险的个体 唐氏综合症 (DS) 中 AD 的出现是迫切需要的。在这里，我们提出实验来解决 这种未满足的需求。具体来说，我们将测量（血浆中）与 AD 的病因学以及针对这些蛋白质的天然自身抗体 (NAb)。血液中的 tau 和 Aβ 是 存在于不同的池中，例如自由漂浮，与其他蛋白质结合，并位于外泌体内部。无数先前的 研究测量了血浆中的 Aβ，但很少考虑到不同的池，而且许多研究都被混淆了 不完善的测定和/或患者标本。只有少数研究关注了血液中的 tau 蛋白，没有一个 解释了 tau 的分子异质性或其在不同池中的出现。相比之下，我们将 小心使用能够检测不同形式 tau 的检测方法，并评估不同形式的贡献 池以及它们如何随疾病而变化。由于 tau 蛋白在血液中的含量非常低， 血浆中 Aβ 的测量需要稀释以克服基质效应，我们将使用最先进的内部 使用 Simoa (tau) 和 Erenna (Aβ) 平台开发的超灵敏测定法。 NAbs 结合的 tau 蛋白和 Aβ 将从抗原-抗体复合物中释放出来，然后进行测量，并且游离的 NAb 将通过以下方法检测： 定量与板固定抗原的结合。将非常谨慎地纳入内部标准，以便 监测我们检测的灵敏度和重现性。大多数先前的研究仅评估单一的分析物 时间点，并且很少有纵向研究。考虑到临床前的持续时间较长 AD 的临床阶段，以及 tau、Aβ 和 NAb 的不同形式在这些漫长的过程中如何变化 迄今为止，横断面研究得出了相互矛盾且变化多端的结果，这并不奇怪。 考虑到这些陷阱，我们首次建议测量抗 tau 和抗 Aβ NAb 及其同源抗体 使用来自仔细表征的研究对象的样本，在相同的血浆样本中检测抗原。为了获得 深入了解 tau、Aβ 和 NAb 在整个疾病过程中如何变化，我们将应用我们的良好技术 对来自 3 个不同群体的血浆样本进行了特征化验。这些将包括已被 前瞻性地在临床发作之前和之后从个体中收集数据，这些个体具有一组详细的临床、 存在遗传和组织病理学数据，以及来自 0-65 岁 DS 受试者的血浆。 DS是最常见的 早发性 AD 的遗传原因，大多数 DS 成年人在 60 岁之前就会变得痴呆。因此，研究 来自不同年龄 DS 受试者的样本提供了了解 AD 不同阶段的窗口，并且还应该识别 DS 中治疗 AD 的最佳治疗间隔。将这种系统方法与仔细的统计相结合 我们期望通过分析来识别一种或可能选择的分析物，这些分析物可以：（i）准确地检测受试者 患 AD 的风险，以及 (ii) 确定在 DS 中治疗 AD 的适当年龄范围。