Pesticides, Olfaction, and Neurodegeneration Among US Farmers

摘要 我们提出了有史以来最全面的研究，以描述杀虫剂在与年龄相关的疾病中的作用。 嗅觉障碍(OI)及其与神经退行性变前驱体发育的相关性 阿尔茨海默病(AD)和帕金森氏病(PD)等疾病。大约15%-25%的美国老年人 有不同程度的OI，这是一种大多数人甚至没有意识到自己有的感觉障碍。尽管如此，Oi 独立预测短期和长期死亡率，并对营养、安全性和质量产生不利影响 生活。OI也是AD和PD最重要的早期症状之一。接触农药无处不在，而且 与帕金森病和潜在的阿尔茨海默病的风险更高有关，但对#年杀虫剂暴露的可靠评估 以人口为基础的研究一直是推动这一领域科学发展的主要障碍。我们的多学科 流行病学家、生物统计学家、暴露评估专家、临床科学家和 神经毒理学家将在这一领域开辟新的天地，通过剖析与年龄有关的杀虫剂之间的联系 OI和神经退行性疾病。我们将利用世界上最大的人类集合的资源 关于急性和慢性农药暴露的数据，农业健康研究(AHS)，成立于1993年，至今仍 正在进行中。大多数AHS参与者现在都是60岁的≥，因此有患神经退行性疾病的风险。通过 客观测试~2700名AHS农民的嗅觉并进行家庭临床评估 大约600名农民，我们希望为拟议的研究和以后的研究建立一个巨大、独特和持久的资源。 我们的具体目标是：1)描述农民长期接触农药与OI的关系； 2)分析高农药暴露事件与OI的关系；以及3)评估OI是否是重要的中介因素 在与农药相关的AD和PD中。该项目的科学严谨性由大样本量、最新状态保证。 -科学暴露和结果评估，精心规划的统计分析，以及非常有经验的 多学科、多机构的研究团队。创新：该项目将显著推进我们的 对长期接触农药的神经感觉和神经变性后果的了解 在具有良好特征的农业人口中培养20年的广泛数据收集。意义：我们将 对农药暴露与OI的关系有了新的认识，增加了对OI的理解 作为与农药暴露相关的阿尔茨海默病和帕金森病的早期预警标志。这个项目将 为未来生物标志物的纵向研究奠定坚实的基础(例如，基于神经成像或基于流体) 目的：明确各种农药在老年性OI和神经退行性变中的作用和机制。

Abstract We propose the most comprehensive study ever undertaken to delineate roles of pesticides in age-related olfactory impairment (OI), and to examine their relevance to prodromal development of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). About 15-25% of older US adults have various levels of OI, a sensory impairment that most do not even realize they have. Nonetheless, OI independently predicts short-term and long-term mortality, and adversely affects nutrition, safety, and quality of life. OI is also one of the most important early symptoms of AD and PD. Pesticide exposure is ubiquitous and has been linked to a higher risk of PD and potentially to AD, but reliable assessment of pesticide exposure in population-based studies has been a major hurdle to advancing the science in this field. Our multidisciplinary team of epidemiologists, biostatisticians, exposure assessment experts, clinical scientists, and a neurotoxicologist will break new ground in this area by dissecting the connections among pesticides, age-related OI, and neurodegenerative diseases. We will leverage resources from the world's largest collection of human data on acute and chronic pesticide exposure, the Agricultural Health Study (AHS), established in 1993 and still ongoing. Most AHS participants are now aged ≥60 years and thus at risk for neurodegenerative diseases. By objectively testing the sense of smell of ~2,700 AHS farmers and conducting in-home clinical assessments for ~600 farmers, we expect to build a large, unique, and lasting resource for the proposed research and beyond. Our Specific Aims are to: 1) delineate the associations of chronic exposure to pesticides with OI among farmers; 2) analyze high pesticide exposure events in relation to OI; and 3) assess whether OI is an important mediator in pesticide-related AD and PD. The Scientific Rigor of this project is assured by the large sample size, state-of- the-science exposure and outcome assessments, carefully planned statistical analyses, and a very experienced multidisciplinary and multi-institutional research team. Innovation: This project will significantly advance our knowledge of long-term neurosensory and neurodegenerative consequences of pesticide exposures by cultivating 20 years of extensive data collection in a well-characterized farming population. Significance: We will bring new insights into the relationship between pesticide exposure and OI, and increase understanding of OI as an early warning marker for AD and PD development in association with pesticide exposure. This project will lay a solid foundation for future longitudinal research with biomarkers (e.g., neuroimaging-based or fluid-based) to conclusively define roles and mechanisms of various pesticides in age-related OI and neurodegeneration.