Urban Air Pollution and Pathological Brain Aging: A Nationwide Twin Study in Men

大量证据表明，接触室外空气污染物可能会加速认知衰老。 来自动物模型的新数据也表明，阿尔茨海默病 (AD) 的风险可能会增加 以及与交通相关空气污染物（TRAP）暴露相关的痴呆症。 TRAP动物模型展示 神经毒性的有力证据，但 TRAP 对人脑衰老的神经毒性作用的现有研究 重要的知识差距：1）长期地址历史数据很少； 2）关于晚前暴露效果的数据很少 生活； 3）关于认知的数据有限，特别是轻度认知障碍（MCI）或AD； 4）有限的神经影像学 措施； 5) 没有检查潜在的早期生活混杂因素：6) 对老年人的研究主要集中在 妇女； 7）需要更好地理解基因与环境的相互作用。项目2，建立在NIA- 资助的纵向越南时代孪生衰老研究（VETSA；R01 AG018386 和 AG022381），非常适合 解决这些差距。其中包括 VETSA 1 中年龄为 51-60 岁的男性双胞胎 (n=1291) 和 VETSA 2 中年龄为 55-66 岁的男性双胞胎 （n=1205）。 VETSA 是来自 49 个州的地理多样化群体，在 TRAP 方面具有很大的可变性 曝光。受试者每次都有 10-12 小时的神经心理学、心理社会和健康/医疗数据 时间点； 545 和 447 分别在 VETSA 1 和 2 处进行结构磁共振成像 (MRI)。我们 将通过收集 1993 年以来的居住历史数据并进行地理编码来解决第一个问题 环境暴露核心 C，创建 TRAP 累积指数。然后我们就可以直接解决 间隙2-7。 TRAP 的特点是估计环境中 NO2（一种气体替代物）水平， PM2.5 的元素碳 (EC) 成分（柴油机尾气颗粒的标志）以及预测的来源概况 PM2.5。 VETSA 受试者的年龄是晚年之前检查 TRAP 效应的理想年龄。我们检查 以下目标： 目标 1. 评估 TRAP 对大脑结构/功能的影响：主要影响。我们预测陷阱 暴露与较高的 AD 相关脑特征评分、脑灌注不足有关（平行 小鼠项目 4) 和白质高信号。 TRAP 暴露会导致认知能力较差 随着时间的推移，功能和认知能力会进一步下降。目标 2. 评估 TRAP 对认知和认知的影响 大脑老化：中介。我们将研究 TRAP 与特定认知测量之间的关联 重点关注情景记忆、执行功能和处理速度，以及特定的中介作用 大脑措施。脑微观结构的弥散张量成像（DTI）指数尚未在 之前的研究。我们将检查内侧颞叶和额叶灰质和白质的平均扩散率 地区。目标 3. 检查基因与环境 (GE) 的相互作用。 3a) 我们假设不利的 TRAP 对大脑和认知能力下降的影响将根据 APOE-ε4 和 AD 的多基因风险评分而有所不同， 炎症处理和 tau 代谢/处理。 3b) 我们将使用 MZ 配对内差异分析 作为阐明遗传和环境影响如何协同作用的另一种方法。

Substantial evidence indicates that exposure to outdoor air pollutants may accelerate cognitive aging. Emerging data from animal models also point to a possible increase in the risk of Alzheimer's disease (AD) and related dementias with exposure to traffic-related air pollutants (TRAP). Animal models of TRAP show strong evidence of neurotoxicity, but existing studies of neurotoxic effects of TRAP on human brain aging have important knowledge gaps: 1) little long-term address history data; 2) little data on exposure effects before late life; 3) limited data on cognition, particularly mild cognitive impairment (MCI) or AD; 4) limited neuroimaging measures; 5) no examination of potential confounding early-life factors: 6) studies of older adults mostly on women; and 7) need for better understanding of gene-environment interactions. Project 2, built on the NIA- funded longitudinal Vietnam Era Twin Study of Aging (VETSA; R01 AG018386 & AG022381), is ideal for addressing these gaps. It includes male twins ages 51-60 at VETSA 1 (n=1291) and 55-66 at VETSA 2 (n=1205). VETSA is a geographically-diverse cohort from 49 states, offering great variability in TRAP exposure. Subjects have 10-12 hours of neuropsychological, psychosocial, and health/medical data at each timepoint; 545 and 447 have structural magnetic resonance imaging (MRI) at VETSA 1 and 2, respectively. We will address gap #1 by collecting and geocoding residential history data back to 1993, and in conjunction with Environmental Exposures Core C, create cumulative indices of TRAP. We will then be able to directly address gaps 2-7. TRAP will be characterized by the estimated ambient levels of NO2 (a gaseous surrogate), elemental carbon (EC) component of PM2.5 (a marker of diesel exhaust particle), and predicted source profiles of PM2.5. The age of VETSA subjects is ideal for examining TRAP effects before late life. We examine the following aims: Aim 1. Assess TRAP effects on brain structure/function: Main effects. We predict TRAP exposure will be associated with higher AD-related brain signature scores, cerebral hypoperfusion (paralleling Mouse Project 4), and white matter hyperintensities. TRAP exposure will be associated with poorer cognitive function and greater cognitive decline over time. Aim 2. Assess the impact of TRAP on cognitive and brain aging: Mediation. We will examine associations between TRAP and specific measures of cognition with a focus on episodic memory, executive function, and processing speed, as well its mediation by specific brain measures. Diffusion tensor imaging (DTI) indices of brain microstructure have not been examined in prior studies. We will examine mean diffusivity in both grey and white matter in medial temporal and frontal regions. Aim 3. Examine gene-environment (GE) interaction. 3a) We hypothesize that adverse TRAP effects on brain and cognitive decline will differ as a function of APOE-ε4, and polygenic risk scores for AD, inflammatory processing, and tau metabolism/processing. 3b) We will use MZ within-pair difference analysis as another approach to shed light on how genetic and environmental influences work in tandem.