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）。为了了解将空气污染暴露和 在衰老期间，人类的ADRD提出了一种综合的纵向代谢组学方法 基于人群的墨西哥裔美国人依靠现实生活中的长期空气污染暴露 我们与Adrd建立了链接。代谢组学可以提供暴露和与疾病相关的扰动图 跨越相互联系的生物通路。它在了解疾病过程时特别有用 当重复的生物样本在诊断之前可用时提供有关启动和的新信息 认知障碍和ADRD的进展。具体而言，我们建议使用不靶向和针对性的 代谢组学以进一步理解长期暴露于空气污染和CI/ADRD 来自“萨克拉曼多地区拉丁裔衰老研究”的墨西哥裔美国人的老年人（莎莎） 1,789名拉丁裔参与者的5689个现有血样的优势是10年以上的 认知功能（7,696次重复认知考试），并通过多域神经心理电池进行了测试， 痴呆调整的临床和MRI评估。拉丁裔少数群体遭受分配 合并风险因素（例如糖尿病）的暴露率和高流行率。我们已经观察到很强 空气污染与事件相关的关联。以前，我们进行了空气监测活动 并将其与常规监视数据，土地使用，排放，流量数据和气象结合在一起 莎莎参与者的空气污染暴露（R01ES023451 MPI：RITZ/HAAN）。在这里，我们将与 埃默里（Emory）的琼斯（Jones）博士指导一个发展最前沿的高性能代谢分析的中心 方法。我们将利用这些独特的资源来确定空气污染的分子机制和CI/ADRD 在拉丁美洲人的纵向上，展示代谢组如何随着认知的下降和CI/ADRD的发展而变化， 空气污染的暴露如何通过随访而改变代谢组，以及脆弱性或韧性如何 有助于发展痴呆症的过程。我们还将评估空气污染对 以前与CI/ADRD相关的中间生物标志物，包括炎症，代谢和抗氧化剂 标记（TNF-A，IL6，CRP等）。最后，我们将研究已知的ADRD风险因素，例如APOE4，糖尿病， 体育活动或性别会通过重复措施和多种多样的措施影响空气污染相关的代谢组学特征 级别聚类以生成对CI/ADRD多因素病因的见解。我们还建议进行 使用来自同一平台，空气污染和认知评估的现有代谢组学进行复制分析 277名中部加利福尼亚人的数据。这项研究将提高我们对空气污染机制的理解 与CI/ADRD相关的毒性，此类途径可能会提供可行且可治疗的靶标。它也将帮助找到 最有风险和支持偶然性的人的循证生物标志物，并提出缓解方法。