Petkus Andrew J, Salminen Lauren E, Wang Xinhui, Driscoll Ira, Millstein Joshua, Beavers Daniel P, Espeland Mark A, Braskie Meredith N, Thompson Paul M, Casanova Ramon, Gatz Margaret, Chui Helena C, Resnick Susan M, Kaufman Joel D, Rapp Stephen R, Shumaker Sally, Younan Diana, Chen Jiu-Chiuan
Department of Neurology, University of Southern California, Los Angeles, California, 90033, United States.
Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, 90033, United States.
medRxiv. 2023 Nov 29:2023.11.29.23299144. doi: 10.1101/2023.11.29.23299144.
Exposure to ambient air pollution, especially particulate matter with aerodynamic diameter <2.5 μm (PM) and nitrogen dioxide (NO), are environmental risk factors for Alzheimer's disease and related dementia. The medial temporal lobe (MTL) is an important brain region subserving episodic memory that atrophies with age, during the Alzheimer's disease continuum, and is vulnerable to the effects of cerebrovascular disease. Despite the importance of air pollution it is unclear whether exposure leads to atrophy of the MTL and by what pathways. Here we conducted a longitudinal study examining associations between ambient air pollution exposure and MTL atrophy and whether putative air pollution exposure effects resembled Alzheimer's disease-related neurodegeneration or cerebrovascular disease-related neurodegeneration. Participants included older women (n = 627; aged 71-87) who underwent two structural brain MRI scans (MRI-1: 2005-6; MRI-2: 2009-10) as part of the Women's Health Initiative Memory Study of Magnetic Resonance Imaging. Regionalized universal kriging was used to estimate annual concentrations of PM and NO at residential locations aggregated to 3-year averages prior to MRI-1. The outcome was 5-year standardized change in MTL volumes. Mediators included voxel-based MRI measures of the spatial pattern of neurodegeneration of Alzheimer's disease (Alzheimer's disease pattern similarity scores [AD-PS]) and whole-brain white matter small-vessel ischemic disease (WM-SVID) volume as a proxy of global cerebrovascular damage. Structural equation models were constructed to examine whether the associations between exposures with MTL atrophy were mediated by the initial level or concurrent change in AD-PS score or WM-SVID while adjusting for sociodemographic, lifestyle, clinical characteristics, and intracranial volume. Living in locations with higher PM (per interquartile range [IQR]=3.17μg/m) or NO (per IQR=6.63ppb) was associated with greater MTL atrophy (β = -0.29, 95% confidence interval [CI]=[-0.41,-0.18]; β =-0.12, 95%CI=[-0.23,-0.02]). Greater PM was associated with larger increases in AD-PS (β = 0.23, 95%CI=[0.12,0.33]) over time, which partially mediated associations with MTL atrophy (indirect effect= -0.10; 95%CI=[-0.15, -0.05]), explaining approximately 32% of the total effect. NO was positively associated with AD-PS at MRI-1 (β=0.13, 95%CI=[0.03,0.24]), which partially mediated the association with MTL atrophy (indirect effect= -0.01, 95% CI=[-0.03,-0.001]). Global WM-SVID at MRI-1 or concurrent change were not significant mediators between exposures and MTL atrophy. Findings support the mediating role of Alzheimer's disease-related neurodegeneration contributing to MTL atrophy associated with late-life exposures to air pollutants. Alzheimer's disease-related neurodegeneration only partially explained associations between exposure and MTL atrophy suggesting the role of multiple neuropathological processes underlying air pollution neurotoxicity on brain aging.
暴露于环境空气污染，尤其是空气动力学直径小于2.5微米的颗粒物（PM）和二氧化氮（NO），是阿尔茨海默病及相关痴呆症的环境风险因素。内侧颞叶（MTL）是一个对情景记忆起重要作用的脑区，其会随着年龄增长、在阿尔茨海默病进程中发生萎缩，并且易受脑血管疾病影响。尽管空气污染很重要，但尚不清楚暴露是否会导致MTL萎缩以及通过何种途径。在此，我们进行了一项纵向研究，以检验环境空气污染暴露与MTL萎缩之间的关联，以及假定的空气污染暴露效应是否类似于阿尔茨海默病相关的神经退行性变或脑血管疾病相关的神经退行性变。参与者包括老年女性（n = 627；年龄71 - 87岁），她们作为女性健康倡议磁共振成像记忆研究的一部分，接受了两次脑部结构MRI扫描（MRI - 1：2005 - 2006年；MRI - 2：2009 - 2010年）。使用区域化通用克里金法来估计在MRI - 1之前汇总为3年平均值的居住地点的PM和NO年浓度。结果指标是MTL体积的5年标准化变化。中介变量包括基于体素的MRI测量的阿尔茨海默病神经退行性变空间模式（阿尔茨海默病模式相似性评分[AD - PS]）以及作为全球脑血管损伤指标的全脑白质小血管缺血性疾病（WM - SVID）体积。构建结构方程模型以检验暴露与MTL萎缩之间的关联是否由AD - PS评分或WM - SVID的初始水平或同期变化介导，同时调整社会人口统计学、生活方式、临床特征和颅内体积。居住在PM浓度较高（每四分位数间距[IQR]=3.17μg/m）或NO浓度较高（每IQR = 6.63ppb）的地区与更大程度的MTL萎缩相关（β = -0.29，95%置信区间[CI]=[-0.41, -0.18]；β = -0.12，95%CI=[-0.23, -0.02]）。随着时间推移，更高的PM与AD - PS更大幅度的增加相关（β = 0.23，95%CI=[0.12, 0.33]），这部分介导了与MTL萎缩的关联（间接效应 = -0.10；95%CI=[-0.15, -0.05]），解释了总效应的约32%。在MRI - 1时，NO与AD - PS呈正相关（β = 0.13，95%CI=[0.03, 0.24]），这部分介导了与MTL萎缩的关联（间接效应 = -0.01，95%CI=[-0.03, -0.001]）。MRI - 1时的全球WM - SVID或同期变化在暴露与MTL萎缩之间不是显著的中介变量。研究结果支持阿尔茨海默病相关神经退行性变在与晚年暴露于空气污染物相关的MTL萎缩中起中介作用。阿尔茨海默病相关神经退行性变仅部分解释了暴露与MTL萎缩之间的关联，这表明空气污染对脑老化的神经毒性作用存在多种神经病理过程。
