Peptide Biomarkers for Alzheimer Disease

总结 在使用神经影像学和脑脊液（CSF）蛋白方面取得了重大进展 作为阿尔茨海默病（AD）生物标志物的测量。然而，仍然迫切需要 鉴定更可靠和可重复的生物标志物，进一步提高诊断准确性， 特别是将AD与其他痴呆区分开来，跟踪或监测疾病进展， 客观评价药物疗效。人们对发展小说的兴趣也越来越大。 可以反映AD病理学的不同方面并准确检测致病性的生物标志物 在出现显著认知下降之前，AD的组成部分，从而协助AD 在早期症状甚至临床前阶段进行诊断。该提案旨在满足 当前生物标志物研究的几个主要挑战，具体而言：1）开发困难 基于抗体的定量蛋白质测定，用于通过蛋白质组学鉴定的大多数新候选物 与大多数现有免疫测定相关的谱分析和显著变化，2）低灵敏度 和特异性的血液为基础的标志物，和3）检测AD在早期甚至临床前阶段。 为了解决基于抗体的检测的问题，我们的策略是开发靶向质量 基于光谱的技术，如选择性反应监测（SRM），以确定独特的 源自蛋白质的肽标记物，或者在先前的蛋白质组学分析中显示出前景，或者 已知在人脑脊液（CSF）中对AD发病机理至关重要。为了便于发现 和基于血液的生物标志物的验证，源自中枢神经系统的特定群体 血浆外泌体，最近认识到的携带货物的微泡运输生物分子 在不同细胞或器官系统中，将在SRM分析之前分离。独特的肽 标记物将在几个大的、良好建立的群组中进行测试，例如，阿尔茨海默病 俄勒冈州华盛顿大学附属研究中心（ADRC） 科学大学、加州大学圣地亚哥分校和宾夕法尼亚大学，以及 ADNI（阿尔茨海默病神经影像学倡议），横截面和纵向样本 收集，沿着广泛的临床表征。最后，为了提高早期诊断，我们将 利用由AD高风险受试者组成的极早期MCI队列，目标是 发现能够鉴定患有早期或临床前AD的受试者的生物标志物。研究 如果成功，有可能产生一组生物标志物， 是稳健的，具有比目前可以实现的更少的变化，并且在体液中， 可在常规临床环境中使用。AD的早期诊断和进展的标志物至关重要 了解如何阻止或减缓AD的进展

Summary Significant progress has been made in using neuroimaging and cerebrospinal fluid (CSF) protein measurements as Alzheimer disease (AD) biomarkers. However, there is still a critical need to identify more reliable and reproducible biomarkers with further improved diagnostic accuracy, especially to differentiate AD from other dementias, to track or monitor the disease progression and to objectively evaluate drug effects. There is also a growing interest in developing novel biomarkers that could reflect different aspects of AD pathology and accurately detect pathogenic components of AD before appearance of significant cognitive decline, thereby assisting with AD diagnosis at early symptomatic and even preclinical stages. This proposal is designed to meet several major challenges of current biomarker research, specifically: 1) difficulties in development of antibody-based, quantitative protein assays for most novel candidates identified by proteomic profiling and significant variations associated with most existing immunoassays, 2) low sensitivity and specificity of blood-based markers, and 3) detection of AD at early or even preclinical stages. To address the problems of antibody-based assays, our strategy is development of targeted mass spectrometry-based techniques, such as selected reaction monitoring (SRM), to identify unique peptide markers derived from proteins either showing promise in previous proteomics profiling, or known to be critical to AD pathogenesis in human cerebrospinal fluid (CSF). To facilitate discovery and validation of blood based biomarkers, a specific population of central nervous system derived plasma exosomes, the cargo-carrying microvesicles recognized recently to transport biomolecules among different cells or organ systems, will be isolated before SRM analysis. The unique peptide markers will be tested in several large, well-established cohorts, e.g., Alzheimer's Disease Research Centers (ADRCs) affiliated with the University of Washington, Oregon Health and Science University, University of California at San Diego, and University of Pennsylvania, and ADNI (Alzheimer's Disease Neuroimaging Initiative), with cross-sectional and longitudinal samples collected, along with extensive clinical characterization. Finally, to improve early diagnosis, we will make use of a very early MCI cohort consisting of subjects at elevated risk for AD, with the goal of discovering biomarkers capable of identifying subjects with early or preclinical AD. The studies designed for this project, if successful, have the potential to result in a panel(s) of biomarkers that are robust, with less variation than can currently be achieved, and in a body fluid that is readily accessible in a regular clinical setting. Markers for early diagnosis and progression of AD are critical in understanding how to arrest or slow AD progression.