Early detection of Alzheimer's (MCI stage): Analysis of plasma cell-free miRNA

描述（由申请人提供）：阿尔茨海默病（AD）是最常见的神经退行性疾病（ND）。目前在美国有540万AD患者;相关的医疗费用为每年2000亿美元。10-20%的65岁以上人群患有轻度认知障碍（MCI），其中估计每年有15%进展为痴呆症。虽然没有AD的疾病修饰疗法，但对最近临床试验数据的分层分析显示，早期患者的结果很有希望。因此，非常需要用于初级筛查的准确的非侵入性成本效益诊断。DiamiR基于对血浆中循环的脑富集microRNAs（miRNAs）的分析，开发了用于早期检测和监测AD和其他ND的创新测试。最近，我们鉴定并验证了6个miRNA对（“miR-132”和“miR-134”家族）的生物标志物特征，其能够以高达96%的准确度将MCI与年龄匹配的对照区分开。在SBIR I期研究中，几种额外的miRNA对已经显示出预测MCI向AD转变以及MCI和AD与帕金森病（PD）的区分的前景。目前的SBIR II期研究旨在测试来自前瞻性和回顾性研究的较大的、充分表征的、异质性患者队列的血浆样本中在DiamiR中鉴定的候选miRNA生物标志物，以验证用于AD早期特异性检测的生物标志物miRNA特征。具体目标包括确定如何早期检测MCI和AD，以及是否可以可靠地预测从MCI前和MCI到AD的进展;评估miRNA生物标志物与现有AD生物标志物的相关性。（神经成像和脑脊液生物标志物）;以及验证用于区分AD与其他ND- PD、额颞叶痴呆（FTLD）和肌萎缩侧索硬化（ALS）的生物标志物miRNA签名。DiamiR发现生物标志物的方法的基本假设如下：由于ND的早期阶段的特征在于在不同的脑区域和神经元类型中的神经突和突触破坏，我们假设用于检测AD的早期阶段、预测前MCI和MCI进展为痴呆以及将AD与其他ND区分开的miRNA生物标志物可以使用生物标志物miRNA对来定义，每对由（1）在受病理影响的脑区域（AD的海马、PD的中脑、ALS的运动神经元等）中富集的miRNA组成;并且也存在于神经突和突触中;和（2）存在于与病理学无关的细胞和脑区域中的其它脑富集的miRNA，用作标准化物，以补偿与病理学无关的因素。其他潜在有用的miRNA对由脑中未富集但参与进行性疾病阶段特征性过程（例如炎症、细胞凋亡）的miRNA和脑富集的miRNA组成。将根据CLIA指南开发基于本文验证的miRNA签名的实验室开发的测试（LDT），并用于筛选临床试验的患者。这些测试将帮助研究人员和临床医生检测MCI并预测MCI是否会进展为AD或其他ND。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common neurodegenerative disease (ND). Currently in the US there are 5.4M AD patients; associated healthcare cost is $200B per year. 10-20% of people age 65+ have Mild Cognitive Impairment (MCI) of which estimated 15% progress to dementia annually. Although no disease- modifying therapy for AD is available, stratified analysis of data from recent clinical trials revealed promising results for early stage patients. Thus, there is a great need for accurate noninvasive cost-effective diagnostics for primary screening. DiamiR develops innovative tests for early detection and monitoring of AD and other NDs based on analysis of brain-enriched microRNAs (miRNAs) circulating in plasma. Recently we identified and validated a biomarker signature of 6 miRNA pairs ("miR-132" and "miR-134" families) capable of differentiating MCI from age-matched control with up to 96% accuracy. In the SBIR Phase I study several additional miRNA pairs have shown promise for prediction of MCI to AD transition and differentiation of MCI and AD from Parkinson's disease (PD). The present SBIR Phase II study aims to test candidate miRNA biomarkers identified at DiamiR in plasma samples from larger, well-characterized, heterogeneous cohorts of patients from both prospective and retrospective studies, so as to validate biomarker miRNA signatures for early specific detection of AD. Specific aims include determining how early MCI and AD can be detected, and whether progression from pre-MCI and MCI to AD can be reliably predicted; assessing correlation of the miRNA biomarkers with existing biomarkers of AD (neuroimaging and cerebrospinal fluid biomarkers); and validation of biomarker miRNA signatures for differentiation of AD from other NDs - PD, Frontotemporal Lobe Dementia (FTLD), and Amyotrophic Lateral Sclerosis (ALS). The hypothesis underlying DiamiR's approach to biomarker discovery is as follows: since early stages of NDs are characterized by neurite and synapse destruction in distinct brain areas and neuron types, we hypothesize that miRNA biomarkers for detection of early stages of AD, prediction of pre-MCI and MCI progression to dementia, and differentiation of AD from other NDs can be defined using biomarker miRNA pairs, with each pair consisting of (1) miRNAs which are enriched in brain regions affected by a pathology (hippocampus for AD, midbrain for PD, motor neurons for ALS, etc.) and also present in neurites and synapses; and (2) other brain-enriched miRNAs present in cells and brain regions not involved in the pathology, used as normalizers, so as to compensate for factors not re- lated to the pathology. Additional potentially useful miRNA pairs consist of miRNAs not enriched in the brain, but involved in the processes characteristic of progressive disease stages (e.g. inflammation, apoptosis); and of brain-enriched miRNAs. Lab-Developed Tests (LDTs) based on the miRNA signatures validated herein will be developed under CLIA guidelines and used to screen patients for clinical trials. The tests will assist researchers and clinicians with detecting MCI and predicting whether MCI will progress to AD or other NDs.