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

阿尔茨海默病的早期检测（MCI 阶段）：血浆游离 miRNA 分析

• 批准号: 8830766
• 负责人: SAMUIL R UMANSKY
• 金额: $ 71.62万
• 依托单位: DIAMIR, LLC
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8830766
• 关键词: Affect; Age; Alzheimer disease detection; Alzheimer disease screening; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Apoptosis; Area; Biological Markers; Blood; Blood specimen; Brain; Brain region; Cells; Cerebrospinal Fluid; Characteristics; Clinical Trials; Data Analyses; Deltastab; Dementia; Diagnostic; Diagnostic tests; Disease; Disease Progression; Early Diagnosis; Enrollment; Family; Goals; Guidelines; Health; Health Care Costs; Hippocampus (Brain); Image; Inflammation; Lobe; Marketing; MicroRNAs; Midbrain structure; Monitor; Motor Neurons; Neurites; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathology; Patient Monitoring; Patients; Phase; Plasma; Plasma Cells; Population; Prevention; Process; Progressive Disease; Prospective Studies; Registries; Research Personnel; Respondent; Retrospective Studies; Sampling; Small Business Innovation Research Grant; Staging; Surveys; Synapses; Technology; Testing; Universities; Validation; Washington; base; circulating microRNA; cohort; commercial application; cost effective; innovation; mild cognitive impairment; neuroimaging; novel; phase 1 study; phase 2 study; prospective; response; screening; tool

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.

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）。目前美国有 540 万 AD 患者；相关的医疗保健费用为每年 $200B。 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 AD 的疾病缓解疗法，但对最近临床试验数据的分层分析显示，早期患者的结果有希望。因此，非常需要用于初级筛查的准确无创且具有成本效益的诊断。 DiamiR 基于对血浆中循环的大脑富集 microRNA (miRNA) 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，能够以高达 96% 的准确度区分 MCI 和年龄匹配对照。在 SBIR 第一阶段研究中，另外几个 miRNA 对显示出预测 MCI 向 AD 转变以及 MCI 和 AD 与帕金森病 (PD) 的分化的前景。目前的 SBIR II 期研究旨在测试 DiamiR 在来自前瞻性和回顾性研究的较大、特征明确、异质患者群体的血浆样本中鉴定的候选 miRNA 生物标志物，从而验证用于 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检测早期 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 生物标志物与现有 AD 生物标志物（神经影像和脑脊液生物标志物）的相关性；以及验证生物标志物 miRNA 特征，以区分 AD 与其他 ND——PD、额颞叶痴呆 (FTLD) 和肌萎缩侧索硬化症 (ALS)。 DiamiR 生物标志物发现方法的假设如下：由于 ND 早期阶段的特点是不同大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 早期阶段、预测 MCI 前和 MCI 进展为痴呆以及区分 AD 与其他 ND 的 miRNA 生物标志物可以使用生物标志物 miRNA 对来定义，每个 一对由 (1) miRNA 组成，这些 miRNA 富含于受病理影响的大脑区域（AD 的海马、PD 的中脑、ALS 的运动神经元等），并且也存在于神经突和突触中； (2) 存在于与病理无关的细胞和大脑区域中的其他大脑富集的 miRNA，用作正常化因子，以补偿与病理无关的因素。其他潜在有用的 miRNA 对由未在大脑中富集但参与疾病进展阶段（例如炎症、细胞凋亡）特征的 miRNA 组成；以及富含大脑的 miRNA。基于此处验证的 miRNA 特征的实验室开发测试 (LDT) 将根据 CLIA 指南进行开发，并用于筛选临床试验患者。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。