Impact of Combat Exposure on Structural and Functional Brain Connectivity and Risk forAlzheimer's Disease in Aging Veterans

青年时期的兵役通常伴随着各种各样的战斗暴露 已知会增加认知障碍和阿尔茨海默病（AD）的风险， 晚年生活（如高血压、糖尿病、高胆固醇血症和体重指数）。虽然 战斗暴露的重大医疗保健和社会成本是有据可查的， 这些初级的年轻成年期暴露可能还促进了后来的生活次级 这些情况现在才被发现。查明造成 老年退伍军人老年疾病的高风险提供了测试和 启动可能减缓这些疾病进展的治疗。此外，这些数据可以 被用来通知照顾年轻的，当代退伍军人，包括启动 生活方式和医疗变化，可能会改善病情的进展，促进以后 生活认知和行为状况。有可能在年轻的成年期， 启动了“不健康老龄化”的轨迹，生物风险逐渐升高， 促进结构和功能大脑网络的老化相关神经“断开”。 然而，到目前为止，有限的工作已经完成，将年轻的成年人战斗暴露与 老年退伍军人神经结构和功能的改变。此外，无论战斗- 在年轻的成年期暴露与晚期生命生物标志物的积累有关， AD，被称为淀粉样蛋白，tau，神经变性（A-T-N）框架，目前尚不清楚。 因此，将青年期与晚年风险联系起来的中介机制必须 接受检查。在大型创伤性脑损伤和应激障碍转化研究中心， （TRACTS）队列研究，我们发现，年轻的退伍军人与战斗暴露和症状， 此外，1）全身生物学风险升高; 2）关键脑功能改变 网络电路，如杏仁核和默认模式网络（DMN）;和3）显示加速 结构连通性和白色物质微观结构的老化趋势。我们的目标是在概念上 将这些发现与拟议的工作联系起来。我们建议，晚期生命风险首先通过 从青年期开始的全身健康状况的升高（即“累积生物学效应”） 风险“），导致关键的大脑连接受损。累积生物学效应的综合效应 风险加速了大脑结构和功能网络的恶化， 认知功能，包括记忆系统和/或补偿系统， 认知储备在面对AD病理。我们将测试一种与战斗有关的模型， 杏仁核网络失调促进青年期全身健康风险这 累积的生物风险反过来又会导致神经和认知功能的退化， 在老年退伍军人中，这项工作将阐明机制，有助于提高 暴露于战斗的退伍军人中认知障碍的风险，并可用于告知 老年退伍军人的治疗，但也可能告知年轻退伍军人的预防措施， 晚年神经系统疾病的风险。

Military service in young adulthood is typically accompanied by a variety of combat exposures that are known to increase the risk for cognitive impairment and Alzheimer’s disease (AD) in later life (e.g. hypertension, diabetes, hypercholesterolemia, and body mass index). Although the significant healthcare and societal costs of combat exposure are well documented, it is possible that these primary young adulthood exposures additionally promote later life secondary conditions that are only now being uncovered. Identification of factors that contribute to advanced risk for diseases of aging in older Veterans provides the opportunity to test and initiate treatments that may slow progression of these conditions. Additionally, these data could be used to inform care for the younger, current generation of veterans, including the initiation of lifestyle and medical changes that may ameliorate progression of conditions that promote later life cognitive and behavioral conditions. It is possible that combat-exposure in young adulthood initiates a trajectory of ‘unhealthy aging’ with progressive elevation in biological risk that promotes aging-related neural ‘disconnection’ of structural and functional brain networks. However, limited work to date has been performed linking young adulthood combat exposure to alterations in neural structure and function in older Veterans. Additionally, whether combat- exposure in young adulthood is related to the accumulation of late life biomarker hallmarks of AD, known as the amyloid, tau, neurodegeneration (A-T-N) framework, is currently unknown. Thus, intermediary mechanisms linking young adulthood combat exposure to late life risk must be examined. In the large Translational Research Center for TBI and Stress Disorders (TRACTS) cohort study, we find that younger Veterans with combat exposures and symptoms additionally 1) have elevations in systemic biological risk; 2) show alterations in critical brain network circuitry such as amygdala and default mode network (DMN); and 3) show accelerated aging trends in structural connectivity and white matter microstructure. We aim to conceptually link these findings in the proposed work. We propose that late life risk is conferred first through elevation in systemic health conditions starting in young adulthood (i.e. ‘cumulative biological risk’) that lead to damage to critical brain connections. Combined effects of cumulative biological risk accelerate the deterioration of structural and functional brain networks that support higher cognitive function, including memory systems and/or compensatory systems that provide cognitive reserve in the face of AD pathology. We will test a model of combat-associated amygdala network dysregulation promoting systemic health risk in young adulthood. This cumulative biological risk in turn contributes to neural and cognitive deterioration that is pronounced in older Veterans. This work will elucidate mechanisms that contribute to elevated risk for cognitive impairment in combat exposed military Veterans and can be used to inform treatments in older Veterans but also may inform preventative measures for young Veterans at risk for later life neurological disorders.