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

摘要 2017年，阿尔茨海默病(AD)导致超过11万人死亡，成为第六大常见原因 对死亡的恐惧。在美国人口中估计终身风险为40%，估计护理费用超过 ADRD耗资2000亿美元，对个人及其家庭来说是负担，对社会来说也是昂贵的。而工作则是 越来越多地确定ADRD的风险和复原力因素，对临床前AD的原因知之甚少。 生命历程研究人员假设，终生的压力源会累积，导致发病率增加。 符合临床前AD的症状，包括记忆和认知早期阶段的变化 减损。在创建第一个也是唯一一个对世贸中心响应者的认知监测研究中 (R01 AG049953；PI，Clouston)，我们假设慢性创伤后应激障碍(PTSD)，一种相对 一种常见疾病，其特征是对过去创伤的侵入性记忆，并伴有高度的 应激反应，可能有助于提供一种独特的机制，将终生应激源与较晚发病联系起来 认知功能减退让人想起ADRD。这些数据试图检验儿童时期 暴露、中年暴露、遗传差异和晚年健康变化将有助于解释 世贸中心应答者临床前AD的认知症状。虽然我们现在了解到创伤后应激障碍 预测与临床前AD一致的认知和身体症状的风险增加，其机制 针对这一关联的行动仍然不透明。在最近的一项初步研究中，我们发现WTC的应答者 增加血浆神经丝-光和血浆tau(在本样本中与记忆有关)，以及 还发现创伤后应激障碍与血浆淀粉样蛋白b负荷的变化有很强的相关性。我们现在假设 创伤后应激障碍可能会导致阿尔茨海默氏病的病理级联，其中一个结果是认知功能障碍 包括记忆在内的流动认知领域。这项研究试图使用纵向数据来检验 创伤后应激障碍可能会引发AD的神经病理级联反应。然而，由于响应人员非常年轻， 在经历ADRD时，我们另外假设PSTD可能因此降低认知储备 放大现有神经病理学的影响。最后，我们提出了另一种假设，即 吸入纳米颗粒物暴露，一些应答者报告在WTC时可能有 增加了已知的神经毒素的负担，结果之一是增加了神经病变的风险 包括紧张症的增加。 好了！

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. !