Association of the in Utero Exposome with Life-Course Cognition and Prodromal Alzheimer's Disease in Midlife.

子宫内暴露体与中年终生认知和前驱阿尔茨海默病的关联。

• 批准号: 10597462
• 负责人: BARBARA A COHN
• 金额: $ 213.02万
• 依托单位: PUBLIC HEALTH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597462
• 关键词: Adolescence; Adolescent; Adult; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid beta-Protein; Anthropometry; Aromatic Polycyclic Hydrocarbons; Biological; Biological Markers; Biological Process; Birth; Blood; Blood Vessels; Cerebrospinal Fluid; Chemicals; Child Development; Child Health; Childhood; Cognition; Cysteine Metabolism Pathway; Data; Data Collection; Development; Digit structure; Energy Metabolism; Ensure; Environment; Environmental Exposure; Epidemiology; Exposure to; Foundations; Galactose Metabolism Pathway; Genotype; Glial Fibrillary Acidic Protein; Glutathione; Health Status; Image; Impaired cognition; Individual; Inflammatory; Intervention; Lead; Learning; Life; Life Cycle Stages; Light; Link; Longitudinal Studies; Mass Fragmentography; Measures; Mediating; Mediator of activation protein; Metabolic; Metals; Methionine Metabolism Pathway; Mitochondria; Nerve Degeneration; Neurocognitive; Outcome; Pathologic; Pathway interactions; Persons; Pesticides; Phenotype; Plasma; Prospective Studies; Pyrimidine; Reading; Resolution; Risk; Secure; Serum; Stress; Symptoms; Testing; Toxic Environmental Substances; Tyrosine Metabolism Pathway; Uridine Diphosphate Sugars; Vocabulary Test; Vulnerable Populations; base; cognitive function; cohort; design; environmental agent; follow-up; health disparity; human data; human study; in utero; innovation; metabolome; metabolomics; middle age; middle childhood; mild cognitive impairment; neurofilament; neurotoxicology; novel; offspring; prenatal; prenatal exposure; prevent; prodromal Alzheimer' s disease; prospective; pyrimidine metabolism; response; social factors; stressor; tau Proteins; tau-1

We propose to discover opportunities for Alzheimer’s Disease (AD) prevention at multiple points in the life- course: before birth, adolescence, and in midlife. We hypothesize that in utero exposure to environmental toxicants leads to cognitive dysfunction in midlife that is accompanied by changes in the serum metabolome and blood biomarkers associated with cognitive dysfunction and prodromal AD. We propose that metabolomics will reveal novel, actionable midlife biomarkers for AD prevention for persons at increased risk for AD. Our previous studies show that decline in cognition is linked to decline in plasma glutathione (GSH), which is best represented in stored plasma by associated changes in pyrimidine and mitochondrial energy metabolism; and that mild cognitive impairment is linked to GSH-related methionine and cysteine metabolism, pathways linked to UDP-sugars (pyrimidine and galactose metabolism) and tyrosine metabolism. Each of these pathways is actionable, providing a secure foundation to test these pathways as mechanisms for biological responses to environmental exposure which could mediate neurocognitive outcomes. This prospective study leverages a 50+ year follow-up of a subset of the Child Health and Development Studies (CHDS) birth cohort that was designed to investigate developmental origins of health disparities; N ~400 offspring were examined in midlife with prior follow-up in childhood and adolescence. This study has available maternal, prenatal, and offspring midlife biospecimens as well as life-course social factors, anthropometry, and health status, and is 40% black. We will use high resolution GC-MS and LC-MS to measure exposures and the metabolome in both targeted and untargeted analysis. This is an efficient use of existing data and biospecimens; no new human data collection is required. Our transdisciplinary team (Epidemiology, Cohn; Metabolomics & Exposomics, Jones; Neurotoxicology, Richardson) has collaborated previously ensuring feasibility. Aim 1 will identify associations of prenatal exposures (pesticides, PAHs, and novel exposures) with midlife 50-year AD-related outcomes and altered metabolic response. Aim 2 will identify potentially actionable biomarkers by identifying associations between altered midlife metabolome and AD-related outcomes. Aim 3 will determine if adolescent cognition: a) is associated with the prenatal exposome, b) predicts midlife AD- related outcomes, c) mediates associations of the prenatal exposome with midlife AD-related outcomes. This unique study can discover mechanisms that link the early life environment to AD and identify midlife interventions that may mitigate early life insults.

我们建议在生活中的多个点发现预防阿尔茨海默病（AD）的机会- 课程：出生前，青春期和中年。我们假设在子宫内暴露于环境中 有毒物质导致中年认知功能障碍，伴随着血清代谢组的变化 以及与认知功能障碍和前驱AD相关的血液生物标志物。我们认为代谢组学 将揭示新的，可操作的中年生物标志物，用于AD风险增加的人的AD预防。 我们以前的研究表明，认知能力的下降与血浆谷胱甘肽（GSH）的下降有关， 在储存的血浆中最好由嘧啶和线粒体能量代谢的相关变化表示; 轻度认知障碍与谷胱甘肽相关的蛋氨酸和半胱氨酸代谢途径有关， 与UDP-糖（嘧啶和半乳糖代谢）和酪氨酸代谢有关。这一切成功都 途径是可行的，提供了一个安全的基础，以测试这些途径作为生物学机制， 对环境暴露的反应可能介导神经认知结果。这项前瞻性 一项研究利用了对儿童健康与发育研究（CHDS）出生子集的50多年随访 队列研究旨在调查健康差异的发育起源; N ~400名后代 在中年进行检查，并在儿童和青少年期进行随访。这项研究有可用的产妇， 产前和后代中年生物标本以及生命过程中的社会因素，人体测量学， 健康状况，40%是黑人。我们将使用高分辨率GC-MS和LC-MS来测量暴露， 在靶向和非靶向分析中的代谢组。这是对现有数据的有效利用， 生物标本;不需要收集新的人体数据。我们的跨学科团队（流行病学，科恩; Metabolomics & Exposomics，Jones; Neurotoxicology，Richardson）以前曾合作， 可行性目标1将确定产前接触（农药、多环芳烃和新型接触）与 中年50岁AD相关结局和代谢反应改变。目标2将确定潜在的可操作性 通过识别中年代谢组改变与AD相关结果之间的关联来确定生物标志物。目标3 将决定青少年的认知：a）与产前疾病有关，B）预测中年AD- 相关结果，c）介导产前疾病与中年AD相关结果的关联。这 一项独特的研究可以发现将早期生活环境与AD联系起来的机制， 可以减轻早期生活伤害的干预措施。