Traffic-Related Air Pollutants and Alzheimer's Disease: Risk, Susceptibility and Mechanisms in Women

与交通相关的空气污染物和阿尔茨海默病：女性的风险、易感性和机制

• 批准号: 10456752
• 负责人: Jiu-Chiuan Chen
• 金额: $ 44.02万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456752
• 关键词: Address; Adverse effects; Affect; Age; Air; Air Pollutants; Air Pollution; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amygdaloid structure; Amyloid beta-Protein; Animals; Area; Biological; Biological Markers; Brain; Categories; Cerebrovascular Trauma; Classification; Clinical; Cognitive deficits; Communities; Complex; Computer Analysis; Data; Dementia; Deposition; Ecological Bias; Elderly; Environmental Risk Factor; Episodic memory; Equation; Exposure to; Funding; Geography; Heterogeneity; Hippocampus (Brain); Impaired cognition; Individual; Knowledge; Link; Literature; Magnetic Resonance Imaging; Measures; Medial; Mediating; Mediation; Memory; Modeling; Multi-Ethnic Study of Atherosclerosis; National Institute of Environmental Health Sciences; Neurobiology; Neuroepidemiology; Neuronal Injury; Nitrogen Dioxide; Ozone; Particulate Matter; Pathologic; Pathway interactions; Population; Predisposition; Prospective cohort; Publishing; Reporting; Research Personnel; Risk; Risk Factors; Role; Sampling; Scientist; Source; Structure; Surface; Temporal Lobe; Testing; White Matter Hyperintensity; Woman; Women' s Health; aged; aging brain; ambient air pollution; base; cognitive change; cohort; cost; dementia risk; design; early detection biomarkers; epidemiology study; executive function; experience; fine particles; gray matter; high dimensionality; human data; insight; magnetic resonance imaging biomarker; men; middle age; mild cognitive impairment; neuroimaging; neuropathology; neurotoxic; neurotoxicity; novel; older women; pre-clinical; predictive marker; prospective; sex; tool; traffic-related air pollution; urban setting; white matter; young woman

Project-1 is designed to investigate the contribution of traffic-related air pollution (TRAP) to the risk, susceptibility and mechanisms of Alzheimer’s disease (AD) and related dementias (ADRD) in a nationwide cohort of women from the Women’s Health Initiative (WHI) Memory Studies (WHIMS). ADRD affects more women than men, and increasing evidence indicates different risk factors by sex, pointing to the need to identify modifiable environmental factors separately for women and men. In the last two decades, compelling data have shown that exposure to outdoor air pollutants including TRAP is a novel environmental determinant of brain aging. Despite the strong evidence for TRAP-induced neurotoxicity (e.g., increased Aβ deposit shown in Project-3), human data on whether and how TRAP exposure effects brain aging remain limited and inconsistent. Previous studies had notable limitations: (1) lacking prospective evidence for an increased ADRD risk associated with TRAP; (2) not based on our current understanding of early cognitive change, biomarkers, and neurobiological classification of AD; (3) not studying AD risk resulting from TRAP effects before late life (e.g., aged < 55); and (4) providing limited insight on the brain structure and neuropathology linking TRAP to early cognitive deficits or an increased risk of AD. To address these knowledge gaps cost-efficiently, Project-1 builds on two well-characterized and geographically-diverse cohorts of mid-aged and older women in the WHIMS of Younger Women (WHIMS-Y; n=1346, inception age 50-54) and WHIMS-MRI (n=1403, inception age 65-80) followed annually since 1996, both with comparable longitudinal assessments on episodic memory and executive function. We further capitalize an NIEHS-funded R01 in WHIMS which employs sophisticated air pollution models developed by the MESA-Air ("Multi-Ethnic Study of Atherosclerosis and Air Pollution") team to estimate TRAP (NO2; PM2.5; exposure sources/components). Supported by the Core B1, we take the novel population neuroimaging approach to studying pathological brain aging in communities, drawing on both clinical and neuropathological classification of AD defined in very well-characterized samples from the Alzheimer’s Disease Neuroimaging Initiative with biomarkers of β-amyloid and neuronal injuries. State-of-the- art mediation and neurocomputational analyses will be conducted to examine the TRAP-affected brain structures and neuropathological pathways underlying the early cognitive deficits or MRI biomarkers of increased AD risk. Aim 1 will determine the impact of TRAP on early biomarkers predictive of increased risks for AD, mild cognitive impairment, and preclinical AD in older women. Aim 2 will examine the associations of cognitive decline reflecting early AD with TRAP exposure before/during late life. In Aim 3, we will take both targeted and agnostic approached with high-dimensional neurocomputation to elucidate the brain structure and neuropathology mediating the TRAP effects on pathological brain aging. Aim 4 will evaluate whether APOE4 and vascular brain injuries increase the susceptibility to the neurotoxic effects of TRAP exposure.

项目1旨在调查与交通相关的空气污染(陷阱)对风险的贡献， 阿尔茨海默病(AD)和相关痴呆(ADRD)在全国范围内的易感性和机制 妇女健康倡议(WHI)记忆研究(Whims)的妇女队列。ADRD影响更大 女性多于男性，越来越多的证据表明不同性别的风险因素不同，表明有必要 分别为女性和男性确定可更改的环境因素。在过去的二十年里，令人信服 数据表明，暴露于室外空气污染物(包括诱捕器)是一种新的环境决定因素。 大脑老化的症状。尽管有强有力的证据表明TRAP诱导的神经毒性(例如，显示增加的Aβ沉积 在项目3)中，关于陷阱暴露是否以及如何影响大脑老化的人类数据仍然有限， 前后不一致。以前的研究有明显的局限性：(1)缺乏增加ADRD的前瞻性证据 与陷阱相关的风险；(2)不是基于我们目前对早期认知变化的理解，生物标记物， 和AD的神经生物学分类；(3)晚年之前没有研究陷阱效应引起的AD风险 (例如，55岁)；以及(4)对脑部结构和神经病理学提供有限的洞察力。 早期认知缺陷或AD风险增加。为了经济高效地解决这些知识差距，Project-1 建立在两个具有良好特征且地理位置不同的中老年女性队列的基础上 年轻女性的奇想(Whims-Y；n=1346，开始年龄50-54岁)和Whims-MRI(n=1403，开始 65-80岁)，自1996年以来每年都进行跟踪，两者对情景记忆进行了类似的纵向评估 和执行功能。我们进一步利用了NIEHS资助的R01 in Whims，它使用了复杂的空气 由MESA-AIR(《动脉粥样硬化和空气污染的多种族研究》)团队开发的污染模型 估计陷阱(NO2；PM2.5；暴露源/成分)。在核心B1的支持下，我们把这部小说 人群神经成像方法研究社区病理性脑老化，两者都有 阿尔茨海默病的临床和神经病理分类由来自 阿尔茨海默病神经成像计划与β-淀粉样蛋白和神经元损伤的生物标记物。最新情况- ART调解和神经计算分析将被用来检查受陷阱影响的大脑 早期认知障碍或MRI生物标志物的结构和神经病理途径 增加AD风险。目标1将确定TRAP对预测风险增加的早期生物标志物的影响 对于AD，轻度认知障碍，以及老年女性的临床前AD。目标2将考察 认知功能减退反映了早期AD患者在晚年/之前暴露于陷阱。在《目标3》中，我们将两者兼得 目标和不可知论者通过高维神经计算阐明大脑结构和 神经病理学介导TRAP对病理性脑老化的影响。AIM 4将评估APOE4是否 血管脑损伤增加了对TRAP暴露的神经毒性效应的易感性。