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

战斗暴露对老年退伍军人大脑结构和功能连接以及阿尔茨海默病风险的影响

• 批准号: 10591407
• 负责人: DAVID H SALAT
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591407
• 关键词: Acceleration; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Amygdaloid structure; Amyloid; Behavioral; Biological; Biological Markers; Body mass index; Boston; Brain; Brain imaging; Caring; Center for Translational Science Activities; Cognition Disorders; Cognitive; Cohort Studies; Data; Dementia; Deterioration; Development; Diabetes Mellitus; Disease; Elderly; Equipment and supply inventories; Exposure to; Funding; Generations; Health; Health Care Costs; Healthcare Systems; Hypertension; Impaired cognition; Impairment; Life Style; Link; Maps; Measures; Mediator; Medical; Memory; Military Personnel; Modeling; Nerve Degeneration; Participant; Pathology; Pathway Analysis; Physiological; Post-Traumatic Stress Disorders; Prevalence; Preventive measure; Principal Investigator; Procedures; Proxy; Rest; Risk; Risk Factors; Sampling; Statistical Models; Stress; Structure; Symptoms; System; Testing; Trauma; Veterans; Visit; Waxes; Work; aged; associated symptom; cognitive function; cognitive performance; cognitive reserve; cohort; combat; disorder risk; emerging adult; follow-up; functional independence; hypercholesterolemia; insight; mild traumatic brain injury; military service; military trauma; military veteran; multimodality; nervous system disorder; neural; neural circuit; neuroimaging; neuromechanism; neuropathology; non-demented; resilience; serial imaging; societal costs; stress disorder; support network; tau Proteins; trend; white matter; young adult

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.

青年时期服兵役通常伴随着各种战斗经历 已知会增加认知障碍和阿尔茨海默病 (AD) 的风险 晚年生活（例如高血压、糖尿病、高胆固醇血症和体重指数）。虽然 战斗暴露造成的巨大医疗保健和社会成本都有据可查， 这些主要的青少年时期接触可能还会促进以后的生活继发性 直到现在才被发现的条件。识别促成因素 老年退伍军人老年疾病的高级风险提供了测试和 开始可能减缓这些病症进展的治疗。此外，这些数据可以 用于为当前年轻一代退伍军人提供护理信息，包括启动 生活方式和医疗的改变可能会改善随后病情的进展 生活认知和行为条件。成年早期的战斗经历可能 开启“不健康衰老”的轨迹，生物风险逐渐升高， 促进与衰老相关的大脑结构和功能网络的神经“断开”。 然而，迄今为止，将青年时期的战斗暴露与 老年退伍军人神经结构和功能的改变。此外，无论是战斗 成年早期的暴露与晚年生物标志物的积累有关 AD，称为淀粉样蛋白、tau 蛋白、神经变性 (A-T-N) 框架，目前尚不清楚。 因此，必须建立将青年时期的战斗暴露与晚年风险联系起来的中介机制。 被检查。在 TBI 和应激障碍大型转化研究中心 （TRACTS）队列研究，我们发现有战斗经历和症状的年轻退伍军人 另外 1) 系统性生物风险升高； 2）显示关键大脑的变化 网络电路，例如杏仁核和默认模式网络（DMN）； 3) 显示加速 结构连接性和白质微观结构的老化趋势。我们的目标是从概念上 将这些发现与拟议的工作联系起来。我们建议首先通过以下方式赋予晚年风险 从成年早期开始全身健康状况的升高（即“累积生物 风险”），导致关键的大脑连接受损。累积生物效应的综合效应 风险会加速支持更高功能的大脑结构和功能网络的恶化 认知功能，包括记忆系统和/或提供补偿的系统 面对 AD 病理的认知储备。我们将测试一个与战斗相关的模型 杏仁核网络失调会促进成年早期的系统性健康风险。这 累积的生物风险反过来会导致神经和认知功能恶化 在老年退伍军人中明显。这项工作将阐明有助于升高的机制 暴露在战斗中的退伍军人认知障碍的风险，可用于告知 老年退伍军人的治疗，也可能为年轻退伍军人的预防措施提供信息 晚年神经系统疾病的风险。