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

描述（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；相关的医疗成本为每年2000亿美元。65岁以上人群中有10-20%患有轻度认知障碍（MCI），其中估计每年有15%进展为痴呆症。尽管目前还没有针对阿尔茨海默病的疾病修饰疗法，但对近期临床试验数据的分层分析显示，早期患者的治疗结果很有希望。因此，有很大的需求，准确的非侵入性成本效益诊断初级筛查。基于对血浆中循环的脑富集microrna （mirna）的分析，DiamiR开发了用于早期检测和监测AD和其他ndds的创新测试。最近，我们鉴定并验证了6对miRNA（“miR-132”和“miR-134”家族）的生物标志物特征，这些miRNA能够将MCI与年龄匹配的对照组区分开来，准确率高达96%。在SBIR I期研究中，一些额外的miRNA对显示出了预测MCI到AD的转变以及MCI和AD从帕金森病（PD）分化的希望。目前的SBIR II期研究旨在测试来自前瞻性和回顾性研究的更大、特征明确、异质性的患者血浆样本中在DiamiR中鉴定的候选miRNA生物标志物，从而验证生物标志物miRNA特征对阿尔茨海默病的早期特异性检测。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前期和MCI到AD的进展；评估miRNA生物标志物与AD现有生物标志物（神经影像学和脑脊液生物标志物）的相关性；并验证AD与其他NDs - PD、额颞叶痴呆（FTLD）和肌萎缩侧索硬化症（ALS）区分的生物标志物miRNA特征。DiamiR的生物标志物发现方法的假设如下：自早期阶段的特点是在不同的脑区和神经轴突和突触的破坏类型,我们假设microrna标志物检测AD的早期阶段,预测pre-MCI和MCI发展为痴呆和分化的广告从其他NDs可以定义使用生物标志物microrna的对,每一对(1)组成的microrna丰富的大脑区域受到一个病理学(海马的广告,中脑PD, ALS运动神经元,等)，也存在于神经突和突触中；(2)存在于与病理无关的细胞和脑区域中的其他富含大脑的mirna，用作正常化剂，以补偿与病理无关的因素。其他潜在有用的miRNA对包括在大脑中不富集的miRNA，但参与疾病进展阶段的特征过程（例如炎症、细胞凋亡）；以及大脑富集的mirna。基于本文验证的miRNA特征的实验室开发测试（LDTs）将根据CLIA指南开发，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轻度认知损伤，并预测轻度认知损伤是否会发展为AD或其他ndds。

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.