Metals and Developmental Origins of Late Life Cognitive Function

金属与晚年认知功能的发育起源

• 批准号: 10027714
• 负责人: Marc G Weisskopf
• 金额: $ 54.54万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-08 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10027714
• 关键词: Ablation; Accounting; Address; Adult; Age; Alzheimer' s Disease; American; Animal Experimentation; Animals; Biological Markers; Blood; Blood specimen; Cells; Child; Cognitive; Cognitive aging; Cohort Studies; Data; Dementia; Dental Enamel; Deposition; Development; Disease; Economic Burden; Elderly; Encapsulated; Enrollment; Environmental Exposure; Epigenetic Process; Exposure to; Fluorescence; Gene Expression; Genetic Transcription; Health; Human; Impaired cognition; Individual; Inductively Coupled Plasma Mass Spectrometry; Intervention; Lasers; Life; Link; Lipid Bilayers; Measures; Metal exposure; Metals; MicroRNAs; Modification; Neurons; Outcome; Participant; Pathology; Patients; Performance; Population; Prevention; Process; Public Health; Questionnaires; Risk; Risk Factors; Roentgen Rays; Role; Sampling; Serum; Signal Transduction; Structure of nail of toe; Testing; Time; Tooth structure; United States; Vulnerable Populations; Woman; Work; age related; aging brain; aging population; base; cognitive development; cognitive function; cognitive testing; cost estimate; early childhood; early detection biomarkers; early life exposure; economic cost; extracellular vesicles; human study; in utero; lead exposure; men; miRNA expression profiling; nanoscale; novel marker; particle; postnatal; prenatal; recruit

We propose to study the relation between prenatal, early postnatal, and adult exposure to metals and cognitive function in older age, and whether early life exposures modify effects of adult exposures. We will also explore whether those exposures and cognitive outcomes are associated with changes in blood-derived extracellular vesicle (EV) micro RNA expression (miRNA), which could represent epigenetic mechanisms underlying associations. We will conduct a cohort study among a subset of participants in the original St. Louis Baby Tooth (SLBT) study who donated their baby teeth in the 1950s and 1960s. Based on our pilot work, we anticipate easily being able to enroll 1,000 former SLBT participants (500 men and 500 women) who will have completed questionnaires and cognitive function testing, and from whom we will collect blood for miRNA analyses and repeated toenail samples for adult metal analyses. Prenatal and early postnatal exposure to several metals will be assessed by measuring metals in baby tooth enamel (using laser-ablation inductively coupled plasma mass spectrometry). Adult metal exposures will be assessed using X-Ray Fluorescence to measure metals in the toenail samples. EVs will be isolated from the blood samples and analyzed for EV miRNA expression levels. The SLBT provides a unique setting that will allow us to have individual-level biomarkers of early life and adult metal exposures in older adults on whom we can conduct cognitive function testing. This study setting allows us to have an unprecedented ability to examine whether early life exposures are related to late life cognitive health—a hypothesis suggested for metals exposure from animal research, but extremely hard to test in humans without the biomarker of such early exposure that the already collected baby teeth in the SLBT can provide.

我们建议研究产前、产后早期和成人暴露于金属之间的关系， 老年人的认知功能，以及早年接触是否会改变成年人接触的影响。我们还将 探索这些暴露和认知结果是否与血液来源的变化有关， 细胞外囊泡（EV）微RNA表达（miRNA），这可能代表表观遗传机制 潜在的关联我们将在最初圣路易斯的一部分参与者中进行队列研究。 婴儿牙齿（SLBT）研究谁捐赠了他们的婴儿牙齿在20世纪50年代和60年代。根据我们的试点工作，我们 预计可以轻松招募1,000名前SLBT参与者（500名男性和500名女性），他们将 完成问卷调查和认知功能测试，我们将从他们那里收集血液进行miRNA检测， 分析和重复的趾甲样本进行成人金属分析。产前和产后早期接触 通过测量婴儿牙釉质中的金属（使用激光消融感应 偶联等离子体质谱法）。成人金属暴露将使用X射线荧光进行评估， 测量脚趾甲样本中的金属含量将从血液样本中分离EV并分析EV miRNA表达水平。SLBT提供了一个独特的设置，使我们能够拥有个人级别的 我们可以对老年人的早期生命和成年金属暴露进行认知功能的生物标志物 试验.这项研究使我们有了前所未有的能力来检查生命早期的暴露是否 与晚年的认知健康有关--这是动物研究中提出的金属暴露假设， 如果没有这种早期暴露的生物标志物， 牙齿在SLBT可以提供。