Determine the role of atmospheric particulate matter pollutants in contributing to Lewy Body Dementia

项目摘要 环境污染物是阿尔茨海默病相关痴呆的危险因素已达成共识 (ADRD)。新出现的证据表明，环境应激源(例如，城市和路边空气污染) 会导致痴呆症。我们支持的流行病学结果已经确定了年平均颗粒物 在美国，物质(PM)污染与首次住院风险的增加显著相关， 阿德勒。我们发现，在PM浓度较低时，浓度-反应关系具有很强的线性关系 大于16μg/m3(PM分布的第95个百分位数)。PM污染物可以针对中枢神经系统(CNS)。 然而，哪些特定的PM污染物与痴呆症有关，其潜在机制尚不清楚 为人所知。最常见的痴呆症之一被称为“路易体痴呆症(LBD)”，其典型特征是 αS病理，包括路易体痴呆和帕金森病痴呆。 LBD患者患有认知和记忆障碍、行为和情绪症状(例如， 抑郁、焦虑等)，影响到美国140万个人及其家人。此外，30% 在患有α的阿尔茨海默病(AD)患者中，S的病理通常表现出更快的认知速度 比单独患有AD的受试者下降。Braak等人的大量尸检研究。αS到场展示 病理在嗅球(OB)和胃肠道中初始化，并在以下情况下传播到大脑 陈旧的解剖学阶段，导致自主神经、神经精神和认知功能障碍。此外 据临床观察，新出现的证据表明，致病αS的传播是认知的主触发因素 用重组αS预制纤维(PFF)接种致脑损伤(CI)。与S有关的大多数α案件 痴呆症(LBD和⅓AD)是散发性的，原因很多。布拉克的理论很好地支持了这一假说 当外来应激源(例如PM污染物)通过鼻子/肠道进入人体时，αS相关性痴呆可能开始， 诱导αS聚集，继而病毒样病变扩散至中枢神经系统，导致多药耐药。 虽然流行病学研究表明ADRD与空气污染物有关的研究相对较多， 显然，对更多机械化研究的需求尚未得到满足。这一知识对于实现完整的 理解LBD的病因，并将这些知识转化为新的预防和治疗方法 战略。这对于了解ADRD社会经济不平等的原因尤其重要，以及 重要的是，环境毒物风险因素可能是可以改变的。

Project Summary There is a consensus that environmental pollutants are a risk factor for Alzheimer's Disease Related Dementias (ADRD). Emerging evidence has shown that environmental stressors (e.g., urban and roadside air pollution) contribute to dementia. Our supporting epidemiological results have determined that annual mean particulate matter (PM) pollution in the USA is significantly associated with an increased risk of first hospital admission with ADRD. We found strong evidence of linearity in concentration-response relationship at PM concentration less than 16 μg/m3 (95th percentile of the PM distribution). PM pollutants can target the central nervous system (CNS). However, what specific PM pollutants are associated with dementia and the underlying mechanisms are poorly known. One of the most common dementia is called “Lewy Body Dementia (LBD)” with the typical hallmark of αS pathology, including Dementia with Lewy body (DLB) and Parkinson's Disease with Dementia (PDD). Patients with LBD suffer from cognition and memory dysfunction, behavioral and mood symptoms (e.g., depression, anxiety, and etc.), affecting 1.4 million individuals and their families in the USA. Furthermore, 30% of the Alzheimer's disease (AD) subjects with αS pathology generally exhibit a more rapid rate of cognitive decline than subjects with AD alone. Substantial postmortem studies by Braak et al. showed the presence of αS pathology was initialized in the olfactory bulb (OB) and gastrointestinal tract, and spread to the brain following stereotypical anatomical stages, resulting in autonomic, neuropsychiatric, and cognitive dysfunction. In addition to clinical observations, emerging evidence has shown pathogenic αS spreading is a master trigger to cognitive impairment (CI) by using inoculation of recombinant αS preformed fibrils (PFF). The majority cases of αS-related dementia (LBD and ⅓ AD) are sporadic and have many causes. Braak's theory well supports the hypothesis that αS-related dementia may begin when foreign stressor (e.g., PM pollutants) enter the body via the nose/gut, induce αS aggregation and subsequent prion-like pathology spreading into the CNS, which results in ADRD. While epidemiological studies demonstrating an association of ADRD with air pollutants are relatively abundant, there is a clear unmet need for more mechanistic research. This knowledge is critical for achieving a complete understanding of the etiology of LBD and the translation of such knowledge to novel prevention and treatment strategies. This is especially important for understanding the causes of socioeconomic inequities in ADRD, and importantly, environmental toxicant risk factors are potentially modifiable.