Pesticides, Olfaction, and Neurodegeneration Among US Farmers

摘要 我们建议进行有史以来最全面的研究，以确定农药在与年龄有关的疾病中的作用。 嗅觉障碍（OI），并检查其相关性前驱发展的神经退行性疾病 阿尔茨海默病（AD）和帕金森病（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的感觉障碍。然而， 独立预测短期和长期死亡率，并对营养，安全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。农药暴露无处不在， 与PD和AD的高风险有关，但对农药暴露的可靠评估表明， 以人口为基础的研究一直是推进这一领域科学的主要障碍。我们的多学科 由流行病学家、生物统计学家、暴露评估专家、临床科学家和 神经毒理学家将通过解剖杀虫剂之间的联系，年龄相关的， OI和神经退行性疾病。我们将利用世界上最大的人类资源 关于急性和慢性农药接触的数据，农业健康研究（AHS），建立于1993年， 日至今大多数AHS参与者现在年龄≥60岁，因此有神经退行性疾病的风险。通过 客观地测试2,700名AHS农民的嗅觉，并进行家庭临床评估， ~600农民，我们希望建立一个大的，独特的，和持久的资源，为拟议的研究和超越。 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; 3）评估OI是否是一个重要的媒介 与农药有关的AD和PD。该项目的科学严谨性是由大样本量，国家， 科学暴露和结果评估、精心策划的统计分析以及经验丰富的 多学科和多机构的研究团队。创新：该项目将大大推动我们的 了解农药接触的长期神经感觉和神经变性后果， 培养20年的广泛数据收集在一个良好的特征农业人口。意义：我们将 为农药暴露与OI之间的关系带来新的见解，并增加对OI的理解 作为与农药暴露相关的AD和PD发展的早期预警标志。该项目将 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） 最终确定各种农药在年龄相关性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.