Air Pollution, Metabolome, and Alzheimer disease in Mexican Americans

墨西哥裔美国人的空气污染、代谢组和阿尔茨海默病

• 批准号: 10591306
• 负责人: Beate R Ritz
• 金额: $ 227.44万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591306
• 关键词: Affect; Aging; Air Pollution; Alzheimer' s Disease; Alzheimer' s disease related dementia; Antioxidants; Area; Biochemical Pathway; Biological; Biological Markers; Biological Process; Blood specimen; Body mass index; California; Clinical; Cognition; Cognitive; Cognitive deficits; Data; Dementia; Diabetes Mellitus; Diagnosis; Disease; Elderly; Environmental Exposure; Etiology; Exposure to; Funding; Gender; Genomics; Goals; High Pressure Liquid Chromatography; High Prevalence; Human; IL6 gene; Impaired cognition; Inflammatory; Latino; Latino Population; Life; Life Cycle Stages; Link; Longitudinal cohort; Magnetic Resonance Imaging; Maps; Measurement; Measures; Mental Depression; Metabolic; Metabolism; Meteorology; Methods; Mexican Americans; Minority Groups; Modeling; Molecular; Molecular Target; Monitor; Neurologic; Neuropsychology; Outcome; Participant; Pathogenesis; Pathologic; Pathway Analysis; Pathway interactions; Pattern; Performance; Persons; Physical activity; Physiological; Plasma; Population; Positioning Attribute; Prevention; Preventive; Process; Proteomics; Public Policy; Research; Resolution; Resources; Risk; Risk Factors; Sampling; System; TNF gene; Testing; Therapeutic; Time; Toxic effect; Variant; Visit; Work; adjudicate; adjudication; aging brain; air monitoring; base; biological systems; cognitive function; cognitive testing; cohort; comorbidity; dementia risk; epigenomics; evidence base; follow-up; improved; individual response; insight; land use; lifestyle factors; liquid chromatography mass spectrometry; member; metabolic abnormality assessment; metabolome; metabolomics; novel; population based; potential biomarker; resilience; response; sex; small molecule; transcriptomics

PROJECT ABSTRACT Air pollution is increasingly recognized as an important risk factor for cognitive impairment (CI) and Alzheimer’s and related dementias (ADRD). To gain insights into the biologic processes which link air pollution exposure and ADRD in humans during aging, we propose an integrative longitudinal metabolomics approach in a large population-based cohort of Mexican-Americans relying on real-life, long-term air pollution exposures for which we established links with ADRD. Metabolomics can provide a map of exposure and disease-related perturbations across interconnected biological pathways. It is especially useful in gaining understanding of disease processes when repeated biosamples are available before diagnosis to provide novel information about initiation and progression of cognitive impairment and ADRD. Specifically, we propose to use untargeted and targeted metabolomics to further mechanistic understanding of long-term exposures to air pollution and CI/ADRD in an elderly population of Mexican Americans from the “Sacramento Area Latino Study on Aging” (SALSA), taking advantage of 5689 existing blood samples from 1,789 Latino participants followed over 10 years, screened for cognitive function (7,696 repeated cognitive exams), and tested with multi-domain neuro-psychological batteries, clinical and MRI assessments for dementia adjudication. Latino minority populations suffer disparities in exposures and a high prevalence of comorbid risk factors, such as diabetes. We have already observed strong associations for air pollution exposure with incident ADRD. Previously, we conducted an air monitoring campaign and combined this with routine monitoring data, land use, emissions, traffic data, and meteorology to generate air pollution exposures for SALSA participants (R01ES023451 mPIs: Ritz/Haan). Here, we will collaborate with Dr. Jones at Emory who directs a Center that developed cutting edge high-performance metabolic profiling methods. We will employ these unique resources to identify molecular mechanisms of air pollution and CI/ADRD in Latinos longitudinally, to show how the metabolome is changing as cognition declines and CI/ADRD develops, how air pollution exposure changes the metabolome over follow-up, and how vulnerability or resilience contributes to the process of developing dementia. We will also evaluate the influence of air pollution on intermediate biomarkers previously linked to CI/ADRD, including inflammatory, metabolic, and antioxidant markers (TNF-a, IL6, CRP etc.). Finally, we will study how known ADRD risk factors such as APOE4, diabetes, physical activity, or gender affect air pollution related metabolomic profiles using repeated measures and multi- level clustering to generate insight into the multifactorial etiologies of CI/ADRD. We also propose to conduct replication analyses using existing metabolomics from the same platform, air pollution and cognitive assessment data in 277 elderly Central Californians. This study will improve our understanding of mechanisms of air pollution toxicity related to CI/ADRD, such pathways may provide actionable and treatable targets. It will also help find evidence-based biomarkers for those most at risk and support causality and suggest mitigation approaches.

项目摘要 空气污染越来越被认为是认知障碍 (CI) 和阿尔茨海默氏症的重要危险因素 和相关痴呆症 (ADRD) 深入了解与空气污染暴露和痴呆症相关的生物过程。 ADRD 在人类衰老过程中的应用，我们提出了一种综合纵向代谢组学方法 基于人口的墨西哥裔美国人群体，依赖于现实生活中的长期空气污染暴露 我们与 ADRD 建立了联系，可以提供暴露和疾病相关扰动的图谱。 它对于了解疾病过程特别有用。 当诊断前可获得重复的生物样本时，可以提供有关启动和治疗的新信息 具体来说，我们建议使用非针对性和针对性的治疗。 代谢组学，以进一步了解长期暴露于空气污染和 CI/ADRD 的机制 来自“萨克拉门托地区拉丁裔老龄化研究”（SALSA）的墨西哥裔美国人老年人口， 利用来自 1,789 名拉丁裔参与者的 5689 份现有血液样本，经过 10 多年的跟踪，筛选出 认知功能（7,696 次重复认知测​​试），并使用多域神经心理电池进行测试， 拉丁裔少数群体痴呆症裁决的临床和 MRI 评估存在差异。 我们已经观察到强烈的暴露和合并症危险因素（例如糖尿病）的高患病率。 此前，我们开展了一项空气监测活动。 并将其与常规监测数据、土地利用、排放、交通数据和气象相结合，生成 SALSA 参与者的空气污染暴露（R01ES023451 mPI：Ritz/Haan）。 埃默里大学的琼斯博士领导着一个开发尖端高性能代谢分析的中心 我们将利用这些独特的资源来确定空气污染和 CI/ADRD 的分子机制。 纵向研究拉丁美洲人，以显示代谢组如何随着认知能力下降和 CI/ADRD 发展而变化， 空气污染暴露如何改变后续的代谢组，以及脆弱性或恢复力如何 我们还将评估空气污染对痴呆症的影响。 先前与 CI/ADRD 相关的中间生物标志物，包括炎症、代谢和抗氧化剂 最后，我们将研究已知的 ADRD 危险因素，如 APOE4、糖尿病、 体力活动或性别通过重复测量和多因素影响空气污染相关的代谢组特征 我们还建议进行水平聚类，以深入了解 CI/ADRD 的多因素病因。 使用同一平台的现有代谢组学、空气污染和认知评估进行复制分析 277 名中加州老年人的数据这项研究将增进我们对空气污染机制的理解。 与 CI/ADRD 相关的毒性，此类途径可能提供可操作和可治疗的目标。 针对风险最高的人群的基于证据的生物标志物，支持因果关系并建议缓解方法。