Environmental Determinants of Pathological Brain Aging in WHI Memory Studies

痴呆症，包括阿尔茨海默病（AD），女性比男性负担更多，影响数百万人的老龄化 美国人和他们的家人虽然继续寻求有效的预防，但科学证据表明， 可改变的痴呆症风险因素仍然不确定。在过去的二十年里，令人信服的数据 在接触环境空气污染物的动物和人类中记录了显著的神经毒性。 毒性病理学研究显示大脑加速老化的证据（例如，β-淀粉样蛋白积聚）和 可能的神经变性（例如，神经元缠结）。虽然流行病学数据也支持， 环境空气污染物可能代表了一种新的和可改变的病理性大脑的环境决定因素 关于老龄化问题，拟议的纵向研究将解决以下关键的知识差距。第一，令人信服 仍然缺乏将环境空气污染与痴呆症风险增加联系起来的前瞻性队列数据。二是多数 已发表的空气污染神经流行病学研究正在研究晚年（年龄> 65岁）暴露;是否/如何 晚年前的暴露塑造了神经心理功能的轮廓，并决定了随后的风险。 对痴呆症的影响还没有被研究过。第三，机制介导的不利影响和人类 受空气污染物干扰的大脑结构仍然难以捉摸。第四，对PM暴露知之甚少 影响大脑老化的来源/成分。具体来说，这个应用程序是建立在两个良好的特点， 参与妇女健康倡议的绝经后和老年妇女的地理分布不同的队列 (WHI)记忆研究（WHIMS;1995-2007; n=7479，年龄65-80）和年轻女性的WHIMS（WHIMS-Y; n=1326，年龄50-55）。得到初步结果的支持，并利用长期后续行动 在WHIMS+ WHIMS-Y中，我们将更新神经认知结果数据库（痴呆亚型;每年 神经心理学评估;结构脑MRI），直到2016年。该应用程序还利用了最近 时空建模的进展，以丰富居民暴露数据库的NO2/臭氧/PM10（1993年- PM2.5（1993-1999年; 1999-2016年）。在目标1中，我们将确定 长期暴露对痴呆/AD发病率的影响。目标2将研究空气污染对 内部验证的神经心理学生物标志物的潜在轨迹，与估计的 从50-55岁开始接触，并持续到晚年。在目标3中，我们将使用结构方程 模型来评估假设的调解情绪障碍，减少边缘脑容量， 神经血管损伤增加是空气污染的神经毒性作用的基础。在目标4中，我们将探索 PM暴露源/成分与脑老化之间的关系。我们组建了一个 多学科团队共同致力于这一新兴领域的环境神经科学在大脑老化。 预期从R 01获得的新知识将大大提高我们对空气作用的理解 污染导致老年痴呆症/AD的神经心理过程和机制。

Dementia, including Alzheimer's disease (AD), burdens more women than men and affect millions of aging Americans and their families. While the search for effective prevention continues, scientific evidence on modifiable risk factors for dementia remains uncertain. In the last two decades, compelling data have documented significant neurotoxicity in animals and humans exposed to ambient air pollutants. Toxicopathological studies show evidence of accelerated brain aging (e.g., β-amyloid accumulation) and possible neurodegeneration (e.g., neuro-fibrillary tangles). Although epidemiologic data also support that ambient air pollutants may represent a novel and modifiable environmental determinant of pathological brain aging, the proposed longitudinal study will address the following critical knowledge gaps. First, convincing prospective cohort data linking ambient air pollution to increased dementia risks are still lacking. Second, most published air pollution-neuroepidemiologic studies were studying late-life (aged > 65) exposures; whether/how exposures before late life shape the profile of neuropsychological functions and determine the subsequent risk for dementia has not been studied. Third, mechanistic mediators underlying the adverse effects and human brain structures perturbed by air pollutants remain elusive. Fourth, very little is known about the PM exposure sources/compositions affecting brain aging. Specifically, this application is built on two well-characterized and geographically-diverse cohorts of postmenopausal and older women participating in Women's Health Initiative (WHI) Memory Study (WHIMS;1995-2007; n=7479, aged 65-80) and WHIMS of Younger Women (WHIMS-Y; n=1326, aged 50-55) since 1996. Supported by the preliminary results and drawing on the extended follow-up of WHIMS+ WHIMS-Y, we will update the neurocognitive outcome database (dementia subtype; annual neuropsychological assessment; structural brain MRI) until 2016. This application also leverages recent advances in spatiotemporal modeling to enrich the residential exposure database for NO2/ozone/PM10 (1993- 2016 monthly) and PM2.5 (1993-1999 yearly; 1999-2016 monthly). In Aim 1, we will determine the impact of long-term exposures on dementia/AD incidence. Aim 2 will examine the adverse effects of air pollution on latent trajectories of internally validated neuropsychological biomarkers, putatively associated with estimated exposures starting at age of 50-55 and continuing into later life. In Aim 3, we will use structural equation models to evaluate the hypothesized mediation by emotional disturbance, reduced limbic brain volume, and increased neurovascular damages underling the neurotoxic effects of air pollution. In Aim 4, we will explore the associations between PM exposure sources/compositions and brain aging. We have assembled a multidisciplinary team working together on this emerging field of environmental neurosciences in brain aging. Expected new knowledge gained from this R01 will greatly improve our understanding of the role of air pollution in contributing to neuropsychological processes and mechanisms of dementia/AD in late life.