Air Pollution and Alzheimer's Dementia: Neuropathologic and Olfactory Mechanisms in Multi-Ethnic Longitudinal Cohorts

空气污染和阿尔茨海默氏痴呆：多种族纵向队列的神经病理学和嗅觉机制

• 批准号: 9975463
• 负责人: JAYANT M PINTO
• 金额: $ 83.7万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9975463
• 关键词: Affect; Aging; Air; Air Pollutants; Air Pollution; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Anatomy; Animals; Autopsy; Biological Markers; Blood Vessels; Brain; Cerebrovascular Disorders; Clinical; Cognition; Cognitive; Cohort Studies; Collaborations; Data; Deltastab; Dementia; Deposition; Deterioration; Development; Disease; Elderly; Electron Microscopy; Evaluation; Exposure to; Foundations; Functional disorder; Geography; Goals; Human; Image; Impaired cognition; Impairment; Individual Differences; Inflammation; Investigation; Knowledge; Latino; Link; Longitudinal Studies; Longitudinal cohort; Longitudinal cohort study; Measures; Medical; Medical Records; Memory; Metals; Microscopy; Minority; Modeling; Nervous system structure; Neurocognitive; Neurologic; Nitrogen Oxides; Olfactory Pathways; Olfactory tract; Outcome; Participant; Particulate Matter; Pathologic; Pathology; Pathway interactions; Physiological; Play; Population; Process; Public Health; Records; Resources; Risk Factors; Role; Smell Perception; Societal Factors; Specimen; Testing; Tissues; Toxic Environmental Substances; base; cerebrovascular; coarse particles; cognitive function; cognitive performance; cohort; dementia risk; disorder risk; neuropathology; novel marker; olfactory bulb; pollutant; predictive modeling; public health intervention; religious order study; research study

ABSTRACT Exposure to air pollution may play a role in the development of Alzheimer's disease and related dementias (ADRD), but how it affects neurocognitive aging is largely unknown. Major barriers to understanding include: inadequate assessment of cognitive decline, over-reliance on medical records and claims data to measure dementia status, sparse information on the connection of air pollution exposure to dementia pathology, and poor understanding of underlying mechanisms, including cerebrovascular and olfactory pathways as well as particulate matter (PM) access to the brain. Here, we will remedy these deficiencies by investigating air pollution and ADRD in a setting that: entails regular and systematic longitudinal evaluation of cognitive function and dementia in all participants, postmortem neuropathologic assessments with extensive cerebrovascular detail, and a far-reaching evaluation of the olfactory system, which is uniquely susceptible to airborne insults, as a direct pathway for environmental toxicants to reach the brain and cause ADRD. Covered in this evaluation will be assessments of olfaction, neuropathology of the olfactory bulb, and PM embedded in the olfactory bulb. We take advantage of 5 large, diverse ongoing, harmonized, well-characterized longitudinal cohort studies of neurologic aging that have collected rich clinical information on >4000 older adults: the Memory and Aging Project, the Minority Aging Research Study, the Religious Orders Study, the Latino CORE Study, and the Clinical Core. The data collected include annual assessments of cognition, dementia status, and olfaction, as well as brain specimens at autopsy (N>1600): the Memory and Aging Project, the Minority Aging Research Study, the Religious Orders Study, the Latino CORE Study, and the Clinical Core. We will estimate participants' long-term air pollution exposures using models previously developed by the MESA Air and MESA Coarse projects and use state-of-the-art, advanced microscopy to measure directly PM in the olfactory bulb, a first. We will assess 3 important underlying mechanisms: the olfactory pathway, inflammation (microglial activation), and cerebrovascular disease. Thus, we will be able to determine the effect of air pollution exposure on neurocognitive outcomes, and examine how resultant neuropathology and direct PM deposition explains these relationships. Our goal is to rigorously test the hypothesis that exposure to air pollution impairs cognitive function and accelerates ADRD via PM deposition in the olfactory system resulting in increased AD neuropathology. This project will generate pivotal new information on the contribution of air pollution to ADRD, raising the prospect of reduction of the burden of ADRD on a population scale via public health interventions.

摘要 暴露于空气污染可能在阿尔茨海默病和相关痴呆症的发展中发挥作用 （ADRD），但它如何影响神经认知衰老在很大程度上是未知的。理解的主要障碍包括： 对认知能力下降的评估不足，过度依赖医疗记录和索赔数据来衡量 痴呆状态，关于空气污染暴露与痴呆病理学联系的信息很少， 了解潜在的机制，包括脑血管和嗅觉通路，以及 颗粒物（PM）进入大脑。在这里，我们将通过调查空气污染来弥补这些缺陷 和ADRD的设置：需要定期和系统的认知功能的纵向评估， 所有参与者均患有痴呆症，尸检神经病理学评估具有广泛的脑血管细节， 以及对嗅觉系统的深远评价，嗅觉系统是唯一容易受到空气污染的系统， 环境毒物到达大脑并导致ADRD的途径。本评价将涵盖 评估嗅觉、嗅球的神经病理学和嗅球中嵌入的PM。 我们利用5个大型的、多样化的、持续的、协调的、特征良好的纵向队列， 神经老化研究收集了超过4000名老年人的丰富临床信息：记忆和 老龄化项目，少数民族老龄化研究，宗教秩序研究，拉丁美洲核心研究， 临床核心。收集的数据包括认知、痴呆状态和嗅觉的年度评估， 以及尸检时的大脑标本（N>1600）：记忆与衰老项目，少数民族衰老研究 研究，宗教秩序研究，拉丁美洲核心研究和临床核心。 我们将使用先前开发的模型估计参与者的长期空气污染暴露， 梅萨Air和梅萨Coarse项目，并使用最先进的先进显微镜直接测量 嗅球中的PM，第一次。我们将评估3个重要的潜在机制：嗅觉通路， 炎症（小胶质细胞活化）和脑血管疾病。因此，我们将能够确定 空气污染暴露对神经认知结果的影响，并研究由此产生的神经病理学和直接PM 沉积解释了这些关系。 我们的目标是严格检验暴露于空气污染会损害认知功能的假设， 通过PM在嗅觉系统中沉积加速ADRD，导致AD神经病理学增加。这 该项目将产生关于空气污染对ADRD贡献的关键新信息，提高以下前景： 通过公共卫生干预措施减轻ADRD在人口规模上的负担。