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

基本信息

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
项目类别：
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&apos 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

项目摘要

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）：阿尔茨海默氏病（AD）是最常见的神经退行性疾病（ND）。目前在美国有540万名AD患者；相关的医疗保健费用为每年$ 200B。 10-20％的65岁以上的人患有轻度认知障碍（MCI），其中估计每年有15％的痴呆症进展。尽管没有可用于AD的疾病修改疗法，但是对最近临床试验的数据进行了分层分析，显示早期患者的结果有令人鼓舞的结果。因此，非常需要准确的非侵入性成本有效诊断来进行初级筛查。 Diamir基于在血浆中循环的脑增强的microRNA（miRNA）的分析，开发了对AD和其他NDS进行早期检测和监测的创新测试。最近，我们确定并验证了6个miRNA对（“ miR-132”和“ miR-134”家族）的生物标志物签名，能够将MCI与年龄匹配的控制区分开，最高为96％。在SBIR I期中，其他几个miRNA对显示了对MCI的AD过渡和MCI和AD分化的预测，从帕金森氏病（PD）进行了分化。本SBIR II期研究的目的是测试DIAMIR在DIAMIR中鉴定出的候选miRNA生物标志物，该血浆样品中的较大，良好的，良好的，异质的异质人群的前瞻性和回顾性研究患者的患者群体以验证生物标志物miRNA特定检测AD。具体目的包括确定如何检测到早期MCI和AD，以及是否可以可靠地预测从MCI和MCI到AD的进展；评估miRNA生物标志物与AD的现有生物标志物（神经成像和脑脊液生物标志物）的相关性；生物标志物miRNA签名的验证与其他NDS -PD，额叶叶痴呆（FTLD）和肌萎缩性侧向硬化症（ALS）分化。 DIAMIR对生物标志物发现的方法的假设如下：由于ND的早期阶段的特征是神经突和突触的特征是不同的大脑区域和神经元类型的突触破坏，因此我们假设MiRNA生物标志物可以检测到AD的早期预测，所以Pre-Mci的早期预测可以使用生物标志物miRNA对定义AD与其他ND的差异，并且AD与其他ND的分化，每对由（1）miRNA组成，这些miRNA富含受病理影响的大脑区域（AD的Hippocampus，Hippocampus for AD，Midbrain for PD，Motor，Motor ALS等神经元，也存在于神经突和突触中；（2）在不涉及病理学的细胞和脑区域中存在的其他富含脑部的miRNA，用作归一化剂，以补偿未与病理相关的因素。其他潜在有用的miRNA对由不富含大脑的miRNA组成，而是参与进行性疾病阶段的过程（例如炎症，凋亡）；和富含脑部的miRNA。基于本文验证的miRNA签名的实验室开发测试（LDT）将根据CLIA指南开发，并用于筛查患者进行临床试验。这些测试将帮助研究人员和临床医生检测MCI，并预测MCI是否会发展为AD或其他NDS。