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: 8791173
• 负责人: EUGENIA WANG
• 金额: $ 68.88万
• 依托单位: ADVANCED GENOMIC TECHNOLOGY, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8791173
• 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; Health; 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; 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）：本项目旨在生成血液测试：1。轻度认知障碍（MCI），和2.从轻度认知障碍转变为全面阿尔茨海默病（AD）的风险。我们已经报道了在AD血液样本中可识别的系统足迹，即关键微RNA（miR）水平的增加;在这里，我们认为这对于MCI（AD前阶段）也是如此。我们最近的研究结果表明，认知能力下降的连续体分为两个阶段：第一阶段，从正常老年对照（NEC）的循环血液中增加的关键microRNA增加到MCI患者的循环血液中，但不会进一步增加到AD;第二阶段，从MCI到AD的特定循环血液microRNA增加。这使我们提出了我们的模型：第1阶段循环microRNA作为MCI特异性生物标志物，第2阶段循环microRNA作为MCI转化为AD的生物标志物。这些生物标志物的原型是：第1阶段，miR-181 b从NEC水平增加到MCI水平，但在AD血浆样品中没有进一步增加;第2阶段，miR-34 a和miR-34 c水平增加，仅从MCI到AD观察到，但从NEC到MCI血浆没有观察到。这些结果表明，MCI认知功能下降可能始于第1阶段microRNA表达增加，然后第2阶段增加，增加损伤;前一阶段是MCI特异性生物标志物，后一阶段是MCI特异性生物标志物。 对于AD和/或转换患者。然后，我们的目标是建立两组阶段特异性生物标志物，基于：鉴定的血液微RNA的高度可重复的数据; B.用于FDA批准的下一阶段开发的训练数据集;以及c.与其他类型的痴呆相比，验证了AD所致痴呆的特异性。为此，I期将研究MCI、NEC和AD血液各30个存档样本，以达到：目的1，建立我们用于最佳血液microRNA测定的方案的再现性，并通过确定上述三种microRNA在三个循环血液隔室中的增加之间的一致性和/或不一致性来鉴定前导microRNA的来源：外周血单核细胞（PBMC）、血浆/血清及其衍生物、外泌体;以及Aim 2，鉴定四个前导阵列分析和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II期，目标1扩展到200个MCI患者样本的更大队列，以建立追踪这4个家族的21个microRNA的第1阶段生物标志物训练数据集;目的2在我们研究中的22名MCI受试者的存档标本中建立了第2阶段生物标志物的库，其中12人在过去十年内转化为AD，通过对21种列出的miRNAs进行qPCR分析，并通过阵列分析来鉴定其他新的miRNAs，将新鲜收集的血液样本与来自转换者与非转换者的存档血液样本进行比较;目的3建立了与非AD痴呆相比，对AD特异的鉴定的生物标志物，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，这是前所未有的测试，用于监测疾病的发作，进展和新疗法的药物疗效，以延缓MCI向真正的AD的下降。