Circulating Blood-Based Diagnostic for Mild Cognitive Impaired Victims

针对轻度认知障碍患者的循环血液诊断

• 批准号: 8595368
• 负责人: EUGENIA WANG
• 金额: $ 19.97万
• 依托单位: ADVANCED GENOMIC TECHNOLOGY, LLC
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8595368
• 关键词: Alzheimer' s Disease; Archives; Biological Assay; Biological Markers; Bipolar Disorder; Blood; Blood Tests; Blood specimen; Boxing; Brain; Cancer Diagnostics; Cardiovascular Diseases; Cells; Central Nervous System Diseases; Cerebrospinal Fluid; Clinical; Cognitive; Companions; Comparative Study; Data; Data Quality; Data Set; Dementia; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Elderly; Family; Frontotemporal Dementia; Funding; Genomics; Goals; Grant; Healthcare; Healthcare Systems; Huntington Disease; Image; Impaired cognition; Individual; Injury; Lead; Lewy Bodies; Lewy Body Dementia; Magnetic Resonance Imaging; Measurable; Measurement; Messenger RNA; Metric; MicroRNAs; Mind; Mission; Monitor; Nature; Nerve Degeneration; Onset of illness; Parkinson Disease; Parkinson' s Dementia; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Phase; Plasma; Population; Pregnancy Trimesters; Proteins; Protocols documentation; Reporting; Reproducibility; Risk; Risk Assessment; Sampling; Small Business Innovation Research Grant; Specificity; Specimen; Staging; Technology; Testing; Training; Validation; Work; aging population; base; cohort; commercialization; cost effective; drug efficacy; indexing; member; mental state; mild cognitive impairment; neuropsychological; novel; outcome forecast; prototype; public health relevance; success; tool

DESCRIPTION (provided by applicant): This project aims to generate blood tests for: 1. mild cognitive impairment (MCI), and 2. conversion risk from MCI to full-blown Alzheimer's disease (AD). We have reported that systemic footprints, increases in key micro- RNA (miR) levels, are identifiable in AD blood samples; here we suggest that this is also true for MCI, the pre- AD phase. Our recent results suggest two stages of cognitive decline continuum: Stage 1, for key microRNAs increased from circulating blood of normal elderly controls (NEC) to that of MCI patients, but not further to AD; and Stage 2, for specific circulating blood microRNA increases from MCI to AD. This led us to suggest our mo- del: Stage 1 circulating microRNAs as MCI-specific biomarkers and Stage 2 circulating microRNAs as biomark- ers for conversion of MCI to AD. Prototypes of these biomarkers are: Stage 1, miR-181b increases from NEC to MCI levels, but not further in AD plasma samples; Stage 2, increased miR-34a & miR-34c levels, observed only from MCI to AD, but not from NEC to MCI plasma. These results suggest that the MCI cognitive decline may start with increased Stage 1 microRNAs' expression, then Stage 2 increases add insult to injury; the for- mer being MCI-specific biomarkers, and the latter specific for AD and/or converter patients. Our goal is then to establish two sets of stage-specific biomarkers, based on: a. highly reproducible data for identified blood micro- RNAs; b. training datasets for next-stage development for FDA approval; and c. validated specificity for de- mentia due to AD, in contrast to other types of dementia. Toward this end, Phase I will study 30 archived sam- ples each of MCI, NEC, and AD blood, to attain: Aim 1, establishing the reproducibility of our protocol for opti- mal blood microRNA assays, and identifying lead microRNAs' origins by determining concordance and/or dis- cordance among the above three microRNAs' increases in three circulating blood compartments: peripheral blood mononuclear cells (PBMC), plasma/serum, and its derivative, exosomes; and Aim 2, identifying other members of four lead array-profiled and PCR-validated microRNA families: miR-34, -181, 200, & Let-7, to expand our pool of candidate Stage 1 and Stage 2 biomarkers. In Phase II, Aim 1 expands to a larger cohort of 200 MCI patients' samples, to establish a Stage 1 biomarker training dataset tracing 21 microRNAs of these 4 families; Aim 2 establishes a repertoire of Stage 2 biomarkers, in archived specimens from 22 MCI subjects in our study, 12 of whom have converted to AD within the past decade, by comparing freshly collected with archived blood samples from converters versus non-converters by qPCR assays of the 21 listed miRNAs, and array profiling to identify additional novel ones; and Aim 3 establishes the identified biomarkers as specific for AD in contrast with non-AD dementias, i.e. Frontotemporal (FTD), Lewy body (LBD), and Parkinson's disease (PD) with dementia (PDD). Success of this project will provide blood miRNA-based diagnostics for MCI, and predict conversion from MCI to AD, unprecedented tests to monitor disease onset, progression, and drug efficacy for novel therapies to retard the decline of MCI to bona fide AD.

描述（由申请人提供）：该项目旨在针对以下情况进行血液检测：1. 轻度认知障碍 (MCI)，以及 2. 从 MCI 转变为全面阿尔茨海默病 (AD) 的风险。我们报告说，在 AD 血液样本中可以识别出全身足迹，即关键 microRNA (miR) 水平的增加；在此，我们建议 MCI（AD 前阶段）也是如此。我们最近的结果表明认知能力下降连续体有两个阶段：第 1 阶段，关键 microRNA 从正常老年人对照 (NEC) 的循环血液中增加到 MCI 患者的循环血液中，但不会进一步发展为 AD；第 2 阶段，特定循环血液 microRNA 从 MCI 到 AD 增加。这促使我们提出了我们的模型：第一阶段循环 microRNA 作为 MCI 特异性生物标志物，第二阶段循环 microRNA 作为 MCI 向 AD 转化的生物标志物。这些生物标志物的原型是： 第 1 阶段，miR-181b 从 NEC 水平增加到 MCI 水平，但在 AD 血浆样本中不再进一步增加；第 2 阶段，仅在 MCI 至 AD 血浆中观察到 miR-34a 和 miR-34c 水平升高，但从 NEC 至 MCI 血浆中未观察到。这些结果表明，MCI 认知能力下降可能始于第 1 阶段 microRNA 表达的增加，然后第 2 阶段的增加雪上加霜；前者是 MCI 特异性生物标志物，后者是特定的 适用于 AD 和/或转换患者。我们的目标是建立两组阶段特异性生物标志物，基于：已识别的血液 micro-RNA 的高度可重复的数据； b.下一阶段开发的训练数据集以供 FDA 批准；和c。与其他类型的痴呆相比，已验证 AD 引起的痴呆的特异性。为此，第一阶段将研究 MCI、NEC 和 AD 血液各 30 个存档样本，以实现： 目标 1，建立我们最佳血液 microRNA 检测方案的可重复性，并通过以下方式识别先导 microRNA 的起源：确定三个循环血液区室中上述三种 microRNA 增加的一致性和/或不一致：外周血单核细胞（PBMC）、血浆/血清及其衍生物，外泌体；目标 2，确定四个先导阵列分析和 PCR 验证的 microRNA 家族的其他成员：miR-34、-181、200 和 Let-7，以扩大我们的候选第 1 阶段和第 2 阶段生物标志物库。在第二阶段，目标 1 扩展到更大的 200 名 MCI 患者样本队列，建立第一阶段生物标志物训练数据集，追踪这 4 个家族的 21 个 microRNA；目标 2 通过 qPCR 检测比较新采集的转化者与非转化者的存档血液样本，在我们研究中 22 名 MCI 受试者的存档样本中建立了 2 阶段生物标志物库，其中 12 名受试者在过去十年内转化为 AD列出的 21 种 miRNA，以及阵列分析以识别其他新的 miRNA；目标 3 建立了 AD 特异性生物标志物，与非 AD 痴呆症相比，即额颞叶 (FTD)、路易体 (LBD) 和帕金森病 (PD) 伴痴呆 (PDD)。该项目的成功将为 MCI 提供基于血液 miRNA 的诊断，并预测从 MCI 到 AD 的转化，前所未有的测试来监测疾病的发作、进展和新疗法的药物疗效，以延缓 MCI 向真正 AD 的衰退。