循环脑富集 microRNAs 作为神经退行性疾病检测和鉴别诊断的新型生物标志物。

Circulating brain-enriched microRNAs as novel biomarkers for detection and differentiation of neurodegenerative diseases.

机构信息

DiamiR LLC, Princeton, NJ, 08540, USA.

Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

出版信息

Alzheimers Res Ther. 2017 Nov 9;9(1):89. doi: 10.1186/s13195-017-0316-0.

DOI:10.1186/s13195-017-0316-0

PMID:29121998

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5679501/

Abstract

BACKGROUND

Minimally invasive specific biomarkers of neurodegenerative diseases (NDs) would facilitate patient selection and disease progression monitoring. We describe the assessment of circulating brain-enriched microRNAs as potential biomarkers for Alzheimer's disease (AD), frontotemporal dementia (FTD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).

METHODS

In this case-control study, the plasma samples were collected from 250 research participants with a clinical diagnosis of AD, FTD, PD, and ALS, as well as from age- and sex-matched control subjects (n = 50 for each group), recruited from 2003 to 2015 at the University of Pennsylvania Health System, including the Alzheimer's Disease Center, the Parkinson's Disease and Movement Disorders Center, the Frontotemporal Degeneration Center, and the Amyotrophic Lateral Sclerosis Clinic. Each group was randomly divided into training and confirmation sets of equal size. To evaluate the potential of circulating microRNAs enriched in specific brain regions affected by NDs and present in synapses as biomarkers of NDs, the levels of 37 brain-enriched and inflammation-associated microRNAs in the plasma of all participants were measured using individual qRT-PCR. A "microRNA pair" approach was used for data normalization.

RESULTS

MicroRNA pairs and their combinations (classifiers) capable of differentiating NDs from control and from each other were defined using independently and jointly analyzed training and confirmation datasets. AD, PD, FTD, and ALS are differentiated from control with accuracy of 0.89, 0.90, 0.88, and 0.83 (AUCs, 0.96, 0.96, 0.94, and 0.93), respectively; NDs are differentiated from each other with accuracy ranging from 0.77 (AUC, 0.87) for AD vs. FTD to 0.93 (AUC, 0.98) for AD vs. ALS. The data further indicate sex dependence of some microRNA markers. The average increase in accuracy in distinguishing ND from control for all and male/female groups is 0.06; the largest increase is for ALS, from 0.83 for all participants to 0.92/0.98 for male/female participants.

CONCLUSIONS

The work presented here suggests the possibility of developing microRNA-based diagnostics for detection and differentiation of NDs. Larger multicenter clinical studies are needed to further evaluate circulating brain-enriched microRNAs as biomarkers for NDs and to investigate their association with other ND biomarkers in clinical trial settings.

摘要

背景

微创特定的神经退行性疾病（NDs）生物标志物将有助于患者选择和疾病进展监测。我们描述了循环脑丰富的 microRNAs 作为阿尔茨海默病（AD）、额颞叶痴呆（FTD）、帕金森病（PD）和肌萎缩侧索硬化症（ALS）的潜在生物标志物的评估。

方法

在这项病例对照研究中，从 2003 年至 2015 年，在宾夕法尼亚大学健康系统（包括阿尔茨海默病中心、帕金森病和运动障碍中心、额颞叶变性中心和肌萎缩侧索硬化症诊所）招募了 250 名有临床诊断的 AD、FTD、PD 和 ALS 的研究参与者和年龄和性别匹配的对照组参与者（每组 50 名），采集了他们的血浆样本。每个组被随机分成训练集和验证集，大小相等。为了评估在受 NDs 影响的特定脑区富集并存在于突触中的循环 microRNAs 作为 NDs 生物标志物的潜力，使用个体 qRT-PCR 测量了所有参与者血浆中 37 种脑富集和炎症相关 microRNAs 的水平。采用“microRNA 对”方法进行数据归一化。

结果

使用独立和联合分析的训练和验证数据集，定义了能够将 NDs 与对照和彼此区分的 microRNA 对及其组合（分类器）。AD、PD、FTD 和 ALS 与对照的区分准确率分别为 0.89、0.90、0.88 和 0.83（AUCs，0.96、0.96、0.94 和 0.93）；NDs 彼此之间的区分准确率范围为 0.77（AUC，0.87）的 AD 与 FTD 至 0.93（AUC，0.98）的 AD 与 ALS。数据进一步表明，一些 microRNA 标记具有性别依赖性。所有和男性/女性组中，将 ND 与对照区分开来的准确率平均提高了 0.06；最大的提高是 ALS，从所有参与者的 0.83 提高到男性/女性参与者的 0.92/0.98。