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和 神经病理性阿尔茨海默氏病和相关痴呆症 (ADRD) 以及临床痴呆症，以及 早年金属暴露是否会改变晚年金属暴露对大范围、种族多样化的影响 我们还将评估金属之间的关系。 暴露和大脑 mRNA 谱（基因表达）及其与神经病理学 ADRD 的可能关系 和痴呆症，特别关注与 AD 相关的基因，这些基因被发现因生命早期的铅暴露而改变 我们将在巴西尸检中心的死者群体中进行这项工作。 作为政府授权的一部分，每年对 5,000 多名死者进行尸检，从而得出一般结论 我们将利用另一项正在进行的研究（PARDoS），该研究正在收集生物材料。 死者进行全基因组测序和广泛的神经病理学收集额外的数据。 来自知识丰富的知情人，包括临床痴呆评级。对于当前的研究，我们还将另外提供。 从 1,000 名 PARDoS 死者身上收集骨头、牙齿和额外的脑组织，这些组织均分给白人 黑人/混血人种，以及 65 岁以上的男性和女性后裔。 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技术） 等离子质谱法）。将使用 X 射线荧光来测量晚期金属暴露。 将分析大脑组织（额叶皮层）中的金属的 mRNA 表达水平。 巴西尸检环境提供了一个独特的机会，使我们能够利用一项正在进行的研究 记录神经病理学和临床痴呆症，以及进行全基因组测序，以 早期和晚年金属暴露的个体水平生物标志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生命早期的金属暴露是否 与 ADRD 相关——动物研究中提出的金属暴露假设，但极难证实 在没有尸检时收集的牙齿可以提供的早期暴露生物标志物的情况下对人体进行测试。 同样，虽然一些人类文献表明成人金属暴露在痴呆风险中发挥着作用， 不存在使用我们切除的骨样本将累积暴露的几乎单独的生物标志物 提供，但没有人关注神经病理学。