Environmental Determinants of Cognitive Aging in the WHI Memory Study

描述（由申请人提供）：该项目的长期目标是更好地了解环境对大脑衰老的影响以及随后的认知障碍和痴呆症风险。具体来说，我们将调查晚年暴露于环境空气污染物作为新的环境因素的认知老化的易感人群的老年妇女。在过去的十年中，科学研究一再表明，环境空气污染会增加心血管疾病（CVD）的风险和死亡率。以前的研究发现，老年人，特别是女性，对空气污染物的这些不利健康影响更敏感。虽然心血管疾病是认知障碍和痴呆症的主要原因，但很少有人关注环境空气污染对老年人认知健康的潜在影响。在暴露于臭氧的动物模型中已经证明了记忆障碍。神经毒理学数据表明，暴露于环境空气污染物可诱导多个脑区的氧化应激和神经炎症，尤其是海马和前额区。空气污染毒性病理学研究还发现了大脑加速老化的证据（例如，2-淀粉样蛋白积聚伴或不伴营养不良性神经炎）。人体解剖研究和横断面流行病学分析分别将环境空气污染与脑老化或认知障碍的神经病理学联系起来。然而，关于环境空气污染是否以及如何导致大脑老化以及随后人类认知障碍和痴呆症风险的令人信服的队列研究仍然缺乏。因此，拟议的研究以具有成本效益的方式设计，以解决这一关键的知识差距，通过以下具体目标：（1）检查晚年暴露于空气污染是否预示着认知功能下降（2）调查长期暴露于空气污染是否会增加痴呆症的风险;（3）阐明认知障碍与暴露于空气污染之间的可能机制;（4）确定人群对空气污染的神经认知影响易感性的临床决定因素。该应用程序利用了在妇女健康倡议记忆研究（WHIMS）队列（N=7479;年龄65-80岁）中收集的高质量纵向结果数据。根据每个WHIMS参与者的居住地理编码，将通过时空建模方法估计颗粒物和臭氧的暴露，该方法将美国EPA监测系统的空气样本测量与空气质量模型的数据输出相结合。将使用多变量校正的考克斯模型、多水平混合效应模型和潜伏曲线结构模型分析数据。从这项研究中获得的知识将有助于国家努力更好地了解环境对认知健康的影响，解决环境神经学新兴领域的关键知识差距，并为环境公共卫生政策提供信息。

DESCRIPTION (provided by applicant): The long-term goal of this project is to better understand the environmental influence on brain aging and subsequent risk of cognitive impairment and dementia. Specifically, we will investigate later-life exposure to ambient air pollutants as novel environmental determinants of cognitive aging in a susceptible population of older women. Over the last decade, scientific research has repeatedly shown that ambient air pollution increases cardiovascular disease (CVD) risk and mortality. Previous studies have found that older people, especially women, are more sensitive to these adverse health effects of air pollutants. Although CVD is a major contributor to cognitive impairment and dementia, little attention has been directed to the potential impact of ambient air pollution on cognitive health of the elderly. Memory impairments have been demonstrated in animal models exposed to ozone. Neurotoxicological data have shown that exposures to ambient air pollutants induce oxidative stress and neuroinflammation in multiple brain regions, especially in hippocampus and prefrontal region. Air pollution toxicopathological studies also found evidence of accelerated brain aging (e.g., 2-amyloid accumulation with or without dystrophic neuritis) in canines. Human autopsy studies and cross-sectional epidemiologic analyses have related ambient air pollution to neuropathology of brain aging or cognitive impairment, respectively. Convincing cohort studies on whether and how ambient air pollution contributes to brain aging and subsequent risk of cognitive impairment and dementia in humans, however, are still lacking. The proposed study is thus designed in a cost-efficient manner to address this critical knowledge gap, through the following specific aims: (1) to examine whether later-life exposure to air pollution predicts declines in cognitive function (global; specific domains); (2) to investigate whether long-term air pollution exposure increases the risk of dementia; (3) to elucidate the possible mechanisms linking cognitive impairment with exposure to air pollution; and (4) to identify the clinical determinants of population susceptibility to the neurocognitive effects of air pollution. This application leverages the high-quality longitudinal outcome data collected in the well-characterized Women's Health Initiative Memory Study (WHIMS) cohort (N=7479; aged 65-80 years). Based on residential geocode of each WHIMS participant, exposures to particulate matter and ozone will be estimated by a spatiotemporal modeling approach, which integrates air-sample measurements from the U.S. EPA monitoring system with the data outputs of air quality models. Multivariable-adjusted Cox models, multilevel mixed-effect models, and latent curve structural models will be used to analyze the data. The knowledge gained from this study will contribute to national efforts to better understand the environmental influence on cognitive health, address a critical knowledge gap in the emerging area of environmental neurology, and inform the environmental public health policies.