Circulating Blood-Based Diagnostic for Mild Cognitive Impaired Victims

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）；从轻度认知损伤到全面阿尔茨海默病（AD）的转化风险。我们已经报道，在AD血液样本中可以识别出系统性足迹，即关键微RNA （miR）水平的增加；在这里，我们认为这也适用于MCI，即AD前阶段。我们最近的研究结果表明认知能力下降连续分为两个阶段：第一阶段，关键microrna从正常老年对照（NEC）的循环血液中增加到MCI患者，但没有进一步增加到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：1期循环microrna作为MCI特异性生物标志物，2期循环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：阶段1，miR-181b从NEC增加到MCI水平，但在AD血浆样品中没有进一步增加；阶段2，miR-34a和miR-34c水平升高，仅在MCI到AD中观察到，而在NEC到MCI血浆中没有观察到。这些结果表明MCI认知能力下降可能始于1期microrna表达的增加，2期microrna表达的增加加重了损伤；前者为mci特异性生物标志物，后者为mci特异性生物标志物

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.