Child and adult Metal exposures, gene expression and neuropathologically confirmed Alzheimer's Disease

儿童和成人金属暴露、基因表达和神经病理学证实的阿尔茨海默病

• 批准号: 10901032
• 负责人: Marc G Weisskopf
• 金额: $ 112.53万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10901032
• 关键词: Ablation; Address; Adult; Affect; Age Years; Aluminum; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; American; Amyloid; Ancillary Study; Animal Experimentation; Animals; Arsenic; Autopsy; Biocompatible Materials; Biological Markers; Black race; Brain; Brazil; Cadmium; Calcium; Cessation of life; Child; Clinical; Clinical dementia rating scale; Collection; Communities; Copper; DNA sequencing; Data; Dementia; Development; Disease; Elderly; Environment; Epidemiology; Exposure to; Female; Fluorescence; Gene Expression; General Population; Genes; Genotype; Government; Human; Individual; Inductively Coupled Plasma Mass Spectrometry; Interview; Ions; Iron; Lasers; Late Effects; Lead; Life; Link; Literature; Manganese; Measures; Mercury; Messenger RNA; Metal exposure; Metals; Methodology; Minority Groups; National Institute on Aging; Pathogenesis; Pathology; Perinatal; Persons; Physiological; Population; Population Heterogeneity; Proteins; Race; Risk Factors; Roentgen Rays; Role; Sampling; Strategic Planning; Testing; Therapeutic Intervention; Tissues; Tooth structure; Underrepresented Minority; United States; Vulnerable Populations; Work; Zinc; advanced disease; aging brain; beta-site APP cleaving enzyme 1; bone; brain tissue; cognitive function; cost estimate; dementia risk; disorder prevention; early childhood; early detection biomarkers; early life exposure; economic cost; examination questions; frontal lobe; genome sequencing; human study; informant; lead exposure; mRNA Expression; male; neuropathology; racial diversity; racial population; sex; socioeconomics; tau Proteins; transcriptomics; virtual; whole genome

We propose to study the relation between early childhood and late life exposure to metals and neuropathological Alzheimer’s Disease and Related Dementias (ADRD) as well as clinical dementia, and whether early life metal exposures modify effects of late life metal exposures in a large, racially diverse population that will allow us to look separately by race and sex. We will also assess the relation between metal exposures and brain mRNA profiles (gene expression) and their possible relation to neuropathological ADRD and dementia, focusing, in particular, on AD-related genes found to be modified by early life lead exposure in animal studies. We will conduct this work in a population of decedents from autopsy centers in Brazil that see over 5,000 decedents per year as part of a government mandate to conduct autopsies resulting in a general population sample. We will leverage another ongoing study (PARDoS) that is collecting biomaterial from decedents to conduct whole genome sequencing and extensive neuropathology. Additional data is collected from knowledgeable informants including clinical dementia rating. For the current study, we will additionally collect bone, teeth, and additional brain tissue from 1,000 of the PARDoS decedents split equally among White and Black/Mixed race, and male and female decedents over 65 years of age. Early childhood exposure to several metals will be assessed by measuring metals in the teeth (using laser-ablation inductively coupled plasma mass spectrometry). Late life metal exposures will be assessed using X-Ray Fluorescence to measure metals in the bone samples. Brain tissue (frontal cortex) will be analyzed for mRNA expression levels. This Brazilian autopsy setting provides a unique opportunity that will allow us to leverage an ongoing study that is documenting neuropathology and clinical dementia, as well as performing whole genome sequencing, to have individual-level biomarkers of early life and late life metal exposures as well as brain gene expression data. This study setting allows us to have an unprecedented ability to examine whether early life metal exposures are related to ADRD—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 teeth collected at autopsy can provide. Similarly, while some human literature exists suggesting a role for adult metal exposures in dementia risk, virtually none exists using individual biomarkers of cumulative exposure that our excised bone samples will provide, and none look at neuropathology.

我们建议研究幼儿期和晚年接触金属之间的关系， 神经病理性阿尔茨海默病和相关痴呆（ADRD）以及临床痴呆，和 早期生活中的金属暴露是否会改变晚期生活中金属暴露的影响， 这将使我们能够按种族和性别分别看待人口。我们还将评估金属之间的关系 暴露和脑mRNA谱（基因表达）及其与神经病理性ADRD的可能关系 和痴呆症，特别关注AD相关基因，这些基因被发现在早期生活中暴露于铅， 动物研究。我们将在巴西尸检中心的死者中进行这项工作， 每年有5，000多名死者死亡，这是政府授权进行尸检的一部分， 人口抽样我们将利用另一项正在进行的研究（PARDoS），该研究正在从 对死者进行全基因组测序和广泛的神经病理学检查。收集更多数据 包括临床痴呆症评级。在目前的研究中，我们还将 从1,000名PARDoS死者身上收集骨头、牙齿和其他脑组织，白色人平分 和黑人/混血儿，以及65岁以上的男性和女性死者。儿童早期接触 通过测量牙齿中的金属（使用激光烧蚀感应耦合 等离子体质谱法）。晚期金属暴露将使用X射线荧光进行评估， 骨头样本中的金属将分析脑组织（额叶皮质）的mRNA表达水平。这 巴西的尸检环境提供了一个独特的机会，使我们能够利用正在进行的研究， 记录神经病理学和临床痴呆症，以及进行全基因组测序， 早期生命和晚期生命金属暴露的个人水平生物标志物以及大脑基因表达数据。 这项研究使我们有了前所未有的能力来检查早期生活中的金属暴露是否是 与ADRD有关-动物研究中提出的金属暴露假设，但很难确定 在没有生物标记物的情况下进行人体测试，这些生物标记物可以提供尸检时收集的牙齿。 同样，虽然一些人类文献表明成年人接触金属在痴呆症风险中的作用， 事实上，使用累积暴露的个体生物标志物，我们切除的骨样本将 提供，没有人看神经病理学。