A Life Course Approach to Integrating Trauma and Cognitive Aging: A Cohort of 9/11 Responders

摘要 阿尔茨海默病（AD）在2017年造成超过11万人死亡，使其成为第六大常见原因 死亡之在美国人口中，估计终生风险为40%，估计护理费用超过 2000亿美元的ADRD对个人及其家庭来说是沉重的负担，对社会来说代价高昂。虽然工作是 越来越多地确定ADRD的风险和弹性因素，对临床前AD的原因知之甚少。 生命历程研究人员认为，一生的压力源可以积累，导致发病率增加 与临床前AD一致的症状，包括记忆和认知功能早期阶段的变化 损伤在创建第一个也是唯一一个对世贸中心应急人员的认知监测研究时， (R01 AG 049953; PI，Clouston），我们假设慢性创伤后应激障碍（PTSD），一个相对 一种常见的精神障碍，其特征是对过去创伤的侵入性记忆， 压力反应，可能有助于提供一种独特的机制，将终生压力源与后来的发病联系起来 认知能力下降让人联想到ADRD这些数据旨在研究童年时期 暴露、中年暴露、遗传差异和晚年健康变化将有助于解释 世界贸易中心反应者的临床前AD认知症状。虽然我们现在知道创伤后应激障碍 预测与临床前AD一致的认知和身体症状的风险增加， 该协会的行动仍然不透明。在最近的一项试点研究中，我们发现，世贸中心的反应， 增加的血浆神经递质-光和血浆tau（其在该样品中与记忆相关），和 还确定了PTSD和血浆淀粉样蛋白-b负荷变化之间的强相关性。我们现在 创伤后应激障碍可能会导致阿尔茨海默病的病理级联反应，其中一个结果是认知功能障碍， 包括记忆在内的流体认知领域。本研究旨在利用纵向数据， 创伤后应激障碍可能引发AD神经病理级联反应然而，由于响应者非常年轻， 如果患者正在经历ADRD，我们还假设PSTD可能会降低认知储备， 放大了现存神经病理学的影响。最后，我们提出了一个替代假设， 吸入的纳米颗粒物暴露，一些响应者报告说，而在世贸中心可能有 增加了已知神经毒素的负担，结果之一是增加了神经病理学变化的风险 包括增加的tau蛋白病。 !

Abstract Alzheimer’s disease (AD) caused more than 110,000 deaths in 2017 making it the sixth most common cause of death. With an estimated lifetime risk of 40% in the U.S. population and an estimated cost of care exceeding $200 billion, ADRD is burdensome for individuals and their families, and costly to society. While work is increasingly determining risk and resilience factors for ADRD, little is known about causes of preclinical AD. Life course researchers have posited that a lifetime of stressors can accumulate to cause increased incidence of symptoms consistent with preclinical AD including changes to memory and early stages of cognitive impairment. In creating the first and only cognitive monitoring study of World Trade Center responders (R01 AG049953; PI, Clouston), we posited that chronic posttraumatic stress disorder (PTSD), a relatively common disorder characterized by intrusive memories of past trauma accompanied by a heightened stress response, might help to provide a unique mechanism linking lifetime stressors with later onset of cognitive decline reminiscent of ADRD. Those data sought to examine the extent to which childhood exposures, midlife exposures, genetic differences, and later-life changes in health would help to explain cognitive symptoms of preclinical AD in World Trade Center responders. While we now understand that PTSD predicts increased risk of cognitive and physical symptoms consistent with preclinical AD, the mechanisms of action for this association remain opaque. In a recent pilot study, we found that WTC responders have increased plasma neurofilament-light and plasma tau (which was associated with memory in this sample), and also identified a strong association between PTSD and changes to plasma amyloid-b burden. We now posit that PTSD may either cause an Alzheimer’s pathological cascade with one result being cognitive dysfunction in domains of fluid cognition including memory. This study seeks to examine, using longitudinal data, the extent to which PTSD might trigger an AD neuropathological cascade. However, since responders are very young to be experiencing ADRD, we additionally hypothesize that PSTD may reduce cognitive reserve thereby amplifying the effects of extant neuropathology. Finally, we propose an alternative hypothesis stating that inhaled nanoparticulate matter exposures, which some responders reported while at the WTC may have increased the burden of a known neurotoxin with one result being increased risk of neuropathological changes including increased tauopathy. !