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: 10653000
• 负责人: Marc G Weisskopf
• 金额: $ 53.47万
• 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/10653000
• 关键词: Ablation; Address; Adult; 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; Health; Human; Impaired cognition; Individual; Inductively Coupled Plasma Mass Spectrometry; Intervention; Lasers; Late Effects; 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; cognitive development; cognitive function; cognitive testing; cost estimate; early childhood; early detection biomarkers; early life exposure; economic cost; extracellular vesicles; human old age (65+); human study; in utero; lead exposure; men; 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、产后早期和成人接触金属和 老年认知功能，以及早期生活暴露是否会改变成人暴露的影响。我们还将 探讨这些暴露和认知结果是否与血液来源的变化相关 细胞外囊泡 (EV) 微小 RNA 表达 (miRNA)，可以代表表观遗传机制 底层关联。我们将对原始圣路易斯的一部分参与者进行队列研究 乳牙（SLBT）研究谁在 20 世纪 50 年代和 1960 年代捐赠了乳牙。根据我们的试点工作，我们 预计能够轻松招募 1,000 名前 SLBT 参与者（500 名男性和 500 名女性），他们将 完成问卷和认知功能测试，我们将从他们身上采集血液进行 miRNA 分析和重复脚趾甲样本以进行成人金属分析。产前和产后早期接触 将通过测量乳牙釉质中的金属来评估几种金属（使用激光烧蚀感应 耦合等离子体质谱法）。将使用 X 射线荧光来评估成人金属暴露 测量脚趾甲样本中的金属。将从血液样本中分离出 EV 并进行 EV 分析 miRNA 表达水平。 SLBT 提供了一个独特的环境，使我们能够拥有个人水平 我们可以对其进行认知功能的老年人早期生命和成年金属暴露的生物标志物 测试。这种研究环境使我们能够拥有前所未有的能力来检验早期生活暴露是否 与晚年认知健康有关——动物研究中提出的金属暴露假设，但是 如果没有如此早期暴露的生物标志物，就很难在人类身上进行测试，因为已经收集到的婴儿 SLBT 中的牙齿可以提供。