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.

我们建议研究儿童早期和晚年接触金属和 神经病理性阿尔茨海默病和相关痴呆(ADRD)以及临床痴呆症，以及 在不同种族的大范围内，早期接触金属是否会改变晚年接触金属的影响 这将使我们能够按种族和性别分开看待人口。我们还将评估金属和金属之间的关系 暴露和脑内基因表达谱(基因表达)及其与神经病理性ADRD的可能关系 和痴呆症，特别是专注于AD相关基因，发现在早期生活中铅暴露会改变 动物研究。我们将在巴西尸检中心的死者中进行这项工作，这些人看到 作为政府强制进行尸检的一部分，每年有超过5,000人死亡，导致 总体样本。我们将利用另一项正在进行的研究(PADOS)，该研究正在从 进行全基因组测序和广泛的神经病理学。还收集了其他数据 来自见多识广的线人，包括临床痴呆症评分。对于目前的研究，我们将另外 从1,000只帕多斯犬的遗体中收集骨骼、牙齿和额外的脑组织，这些遗体平均分配给怀特 和黑人/混血种族，以及65岁以上的男性和女性死者。儿童早期接触到的 将通过测量牙齿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)。将使用X射线荧光来评估晚年金属暴露 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，以及执行全基因组测序，以 早期生命和晚期生命金属暴露的个体水平生物标记物以及大脑基因表达数据。 这一研究环境使我们能够拥有前所未有的能力来检查早期生命金属暴露是否 与ADRD有关--这是动物研究中提出的金属暴露假说，但极难实现 在没有尸检时收集的牙齿可以提供的如此早期暴露的生物标志物的情况下在人类身上进行测试。 类似地，虽然一些人类文献表明成人接触金属在痴呆症风险中起到了作用， 几乎不存在使用单个累积暴露生物标记物的情况，而我们的切除骨样本将 提供，没有人去看神经病理学。