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 空气污染日益被认为是认知障碍(CI)和阿尔茨海默病的重要危险因素 和相关痴呆症(ADRD)。为了深入了解空气污染暴露和 在人类衰老过程中的ADRD，我们提出了一种整合的纵向代谢组学方法 以人口为基础的墨西哥裔美国人队列依赖于真实的、长期的空气污染暴露 我们与ADRD建立了联系。代谢组学可以提供暴露和与疾病相关的扰动的图谱 跨越相互关联的生物路径。它在了解疾病过程方面特别有用。 当在诊断前有重复的生物样本可用来提供关于启动和 认知功能障碍和ADRD的进展。具体地说，我们建议使用非定向和定向 代谢组学对空气污染长期暴露和人群CI/ADRD的进一步机械性理解 来自“萨克拉门托地区拉丁裔老龄化研究”(SALSA)的墨西哥裔美国老年人口，采取 对1789名拉丁裔参与者的5689份现有血液样本进行了长达10年的跟踪调查，筛选出 认知功能(7696次重复认知测试)，并用多领域神经心理电池进行测试， 痴呆症判定的临床和MRI评估。拉美裔少数民族人口在以下方面存在差异 暴露和糖尿病等共病风险因素的高流行率。我们已经观察到了强烈的 空气污染暴露与ADRD事件的关联。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、土地使用、排放、交通数据和气象学相结合，生成 萨尔萨参与者的空气污染暴露(R01ES023451 MPIs：Ritz/Haan)。在这里，我们将与 埃默里的琼斯博士，他领导着一个开发尖端高性能代谢图谱的中心 方法：研究方法。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 在拉丁裔纵向上，为了显示代谢组如何随着认知能力的下降和CI/ADRD的发展而变化， 空气污染暴露如何改变后续代谢组，以及脆弱性或恢复力如何 有助于发展成痴呆症的过程。我们还将评估空气污染对 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 指标(肿瘤坏死因子-α、白介素6、C反应蛋白等)。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种方法影响与空气污染相关的代谢谱 水平聚类，以深入了解CI/ADRD的多因素病因。我们还建议进行 利用同一平台的现有代谢组学、空气污染和认知评估进行重复分析 277名中加州老年人的数据。这项研究将加深我们对空气污染机理的理解。 与CI/ADRD相关的毒性，这种途径可能提供可操作和可治疗的靶点。它还将帮助您找到 为风险最大的人提供基于证据的生物标记物，并支持因果关系和建议缓解方法。