Air Particulate, Metals, and Cognitive Performance in an Aging Cohort- Roles of Circulating Extracellular Vesicles and Non-coding RNAs

空气颗粒物、金属和衰老人群的认知表现——循环细胞外囊泡和非编码 RNA 的作用

基本信息

批准号：
10226996
负责人：
Joel D Schwartz
金额：
$ 72.57万
依托单位：
HARVARD SCHOOL OF PUBLIC HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2023-07-31
项目状态：
已结题

项目摘要

As the U.S. population ages, there is growing concern about the loss of mental acuity associated with aging. Even small deficits are considered intermediates between normal cognitive attrition and severe conditions, such as Alzheimer’s disease. Mild cognitive impairment, which affects ~10% of those ≥65 years, has a 56% conversion rate to dementia over 4 years. Because of dementia’s strong age dependence, merely delaying its onset could have a dramatic impact. A 5-year delay in the onset of Alzheimer’s disease would lead to ~4 million fewer cases in the U.S. The lack of biomarkers that reflect adverse exposures and preclinical effects dramatically limits opportunities for effective targeted prevention. Environmental exposures that augment systemic inflammation, such as ambient air pollution and metals, have been shown to hasten cognitive aging by as much as 5 years. We also recently showed that long term exposure to air pollution is associated with Alzheimer's disease incidence. Our goal is to identify new biomarkers that reflect environmental influences and predict the risk of impaired cognition. We will leverage experimental and clinical evidence on extracellular vesicles (EVs)—i.e., tiny membrane-bound vesicles actively released by tissue cells into the bloodstream—and of their bioactive cargo of micro (miRNAs) and long (lncRNAs) noncoding RNAs, which can signal inflammatory responses via their potent capacity for gene regulation. Animal and human studies have shown that environmental exposures induce the release of pro-inflammatory EVs into the bloodstream. Recent clinical data also show that changes in blood EV biomarkers precede and predict cognitive impairment. In particular, a small, but highly suggestive, case-control study identified EV-miRNAs in patients with Alzheimer’s disease, relative to controls, which were used—by means of a machine learning model (which we will also employ)—to identify early preclinical risk of Alzheimer’s disease. In the proposed studies, we will leverage the resources of well-phenotyped longitudinal cohorts. First, in the Normative Aging Study, we will access ready-to-use longitudinal collections of biospecimens, exposure data, and cognitive function measurements from four serial visits over 12 years of follow up. We hypothesize that environmental exposures to air pollution and metals, individually and as mixtures, will be associated with significantly higher numbers of EVs and differential EV size (Aim 1). We further hypothesize that the levels of and longitudinal changes in EV-encapsulated miRNAs and lncRNAs reflect current and past environmental exposures and predict subsequent cognitive decline (Aim 2). Finally, we will use machine learning and mediation analysis to determine the roles of circulating EVs and their noncoding RNA cargo on the biological pathways linking environmental exposures to cognitive decline (Aim 3). We will validate all findings in the KORA cohort, which has similar design and data. Our work may yield a model for other potentially modifiable risk factors for impaired cognition and Alzheimer’s disease, as well as for additional age-related diseases.

随着美国人口老龄化，人们越来越担心与衰老相关的精神敏锐度的丧失，即使是很小的缺陷也被认为是介于正常认知减退和严重疾病（例如阿尔茨海默病）之间的一种现象，这种疾病影响了大约 10% 的人。 ≥65 岁，4 年内有 56% 转化为痴呆症，因为痴呆症具有很强的年龄依赖性，仅延迟其发病即可产生巨大影响。阿尔茨海默病将导致美国病例减少约 400 万例。缺乏反映不良暴露和临床前影响的生物标志物极大地限制了有效有针对性预防的机会。环境暴露会加剧全身炎症，例如环境空气污染和金属，已被证明会加速认知衰老长达 5 年。我们最近还发现，长期暴露于空气污染与阿尔茨海默病的发病率有关。以确定反映环境影响并预测认知受损风险的新生物标志物，我们将利用细胞外囊泡（EV）的实验和临床证据，即由组织细胞主动释放到脑中的微小膜结合囊泡。动物和人类研究表明，环境暴露会诱导促炎性 EV 的释放。最近的临床数据还表明，血液 EV 生物标志物的变化先于并预测认知障碍，特别是，一项小型但具有高度启发性的病例对照研究在阿尔茨海默病患者中发现了 EV-miRNA。控制，通过机器学习模型（我们也将使用）来识别阿尔茨海默病的早期临床前风险。在拟议的研究中，我们将利用表型良好的纵向队列的资源，首先，在规范老化研究中，我们将获得来自四次连续访视的即用型纵向收集的生物样本、暴露数据和认知功能测量结果。经过 12 年的跟踪，我们发现，空气污染和金属的环境暴露（无论是单独的还是混合的）与电动汽车数量和电动汽车尺寸差异的显着增加有关（目标 1）。 EV 封装的 miRNA 和 lncRNA 的变化反映了当前和过去的环境暴露并预测随后的认知能力下降（目标 2）。最后，我们将使用机器学习和中介分析来确定循环 EV 及其非编码 RNA 在生物途径中的作用。将环境暴露与认知能力下降联系起来（目标 3）。我们将验证 KORA 队列中的所有发现，该队列具有类似的设计和数据，我们的工作可能会为认知受损和阿尔茨海默病的其他潜在可改变的风险因素提供一个模型。疾病，以及其他与年龄相关的疾病。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Intermediate and long-term exposure to air pollution and temperature and the extracellular microRNA profile of participants in the normative aging study (NAS).

规范衰老研究 (NAS) 参与者的中长期暴露于空气污染和温度以及细胞外 microRNA 谱。

DOI：
10.1016/j.envres.2023.115949
发表时间：
2023
期刊：
Environmental research
影响因子：
8.3
作者：
DaneshYazdi,Mahdieh;Nassan,FeibyL;Kosheleva,Anna;Wang,Cuicui;Xu,Zongli;Di,Qian;Requia,WeeberbJ;Comfort,NicoleT;Wu,Haotian;Laurent,LouiseC;DeHoff,Peter;Vokonas,Pantel;Baccarelli,AndreaA;Schwartz,JoelD
通讯作者：
Schwartz,JoelD

Short-term air pollution and temperature exposure and changes in the extracellular microRNA profile of Normative Aging Study (NAS) participants.

DOI：
10.1016/j.envint.2023.107735
发表时间：
2023-01
期刊：
Environment international
影响因子：
11.8
作者：
Mahdieh Danesh Yazdi;F. Nassan;A. Kosheleva;Cuicui Wang;Zongli Xu;Q. Di;W. Réquia;Nicole T. Comfort;Haotian Wu;L. Laurent;P. Dehoff;P. Vokonas;A. Baccarelli;J. Schwartz
通讯作者：
Mahdieh Danesh Yazdi;F. Nassan;A. Kosheleva;Cuicui Wang;Zongli Xu;Q. Di;W. Réquia;Nicole T. Comfort;Haotian Wu;L. Laurent;P. Dehoff;P. Vokonas;A. Baccarelli;J. Schwartz