Neurovascular Mechanisms Underlying the Negative Effect of Stress in Cognitive Aging

压力会增加老年退伍军人认知能力下降的风险，但两者之间的机制联系 人们对压力和认知老化仍然知之甚少。此外，目前存在的与压力有关的干预措施 一般都是为了防止与压力相关的情绪和生理变化，并表现出非常 在缓解认知症状方面的效用有限。确定潜在的神经生物学机制 与压力相关的认知变化，特别是那些本质上可以改变的认知变化，将具有巨大的 对干预策略的影响。在这种情况下，几个潜在的可修改的生物系统 被牵连为感知压力和认知老化之间关系的中介，并持有很大 承诺作为治疗靶点，包括神经血管功能。重要的是，似乎有多重压力- 对大脑内皮细胞或内细胞有负面下游影响的相关通路 血管的衬里。反过来，内皮功能障碍被认为破坏了血脑屏障的完整性和 脑血流量(CBF)，对维持认知功能和大脑至关重要的神经血管过程 健康。鉴于在应激的病理生理学中涉及脑血流和内皮功能障碍的证据- 相关的认知障碍，再加上有证据表明这些过程可以通过 行为(例如，体力活动)和药物干预，令人惊讶的是，没有研究，对我们的 知识方面，已经直接探讨了CBF和内皮功能障碍作为中介之间的关系 压力和认知障碍。目前拟议的职业发展奖(CDA)旨在弥合这一点 GAP通过使用多模式和跨诊断方法来检查强健和 自我报告压力的综合测量，动脉自旋标记(ASL)MRI测量的CBF，基于血液 内皮功能障碍的生物标志物和100名老年人(65岁以上)的认知表现 受过创伤的退伍军人。参与者将接受核磁共振扫描、抽血、临床访谈和 神经心理电池。将利用多元回归和系列中介分析来确定 终生应激严重程度与血清血管黏附分子-1水平、中性粒细胞的关系 颞叶(MTL)和内侧前额叶皮质(MPFC)CBF和认知表现(记忆、执行 功能)。这项研究的主要目标将是检验神经血管功能障碍的假设 解释了压力的主观体验和认知之间的关系。结果将会有所改善 理解压力在认知老化中的作用。此外，这项研究是关键的第一步。 确定可修改的生物标记物，作为干预措施的治疗目标 减轻目前老年退伍军人中与压力有关的大脑和认知健康损害。 基于申请人先前在神经成像和认知老化方面的经验，拟议的CDA还 提供以血液为基础的压力相关研究方法的新实践培训机会 生物标志物、血管功能和高级统计分析。这与候选人的长期政策相吻合 职业目标是在压力和认知老化的交叉点上发展专业知识。来自该项目的数据将 为成功筹备退伍军人奖励计划提供关键的试点数据。总而言之，这项研究和培训 PLAN将很好地定位申请人过渡到退伍军人管理局系统内的独立临床研究人员。

Stress increase risk for cognitive decline among older Veterans, but the mechanistic link between stress and cognitive aging remains poorly understood. Further, currently existing stress-related interventions are generally aimed at preventing stress-related emotional and physiological changes, and have shown very limited utility in mitigating cognitive symptoms. Identification of the neurobiological mechanisms underlying stress-related cognitive change, particularly those that are modifiable in nature, would have enormous implications for intervention strategies. In this context, several potentially modifiable biological systems have been implicated as mediators of the relationship between perceived stress and cognitive aging and hold great promise as treatment targets, including neurovascular function. Importantly, there appear to be multiple stress- related pathways that have negative downstream effects on the cerebral endothelium, or the inner cellular lining of blood vessels. In turn, endothelial dysfunction is thought to disrupt blood brain barrier integrity and cerebral blood flow (CBF), neurovascular processes critical to the maintenance of cognitive function and brain health. Given the evidence implicating CBF and endothelial dysfunction in the pathophysiology of stress- related cognitive impairment, combined with evidence that these processes can be successfully modified by behavioral (e.g., physical activity) and pharmaceutical interventions, it is surprising that no study, to our knowledge, has directly explored CBF and endothelial dysfunction as mediators of the relationship between stress and cognitive impairment. The current proposed career development award (CDA) aims to bridge this gap by utilizing a multimodal and transdiagnostic approach to examine relationships among a robust and comprehensive measure of self-reported stress, arterial spin labeling (ASL) MRI-measured CBF, blood-based biomarkers of endothelial dysfunction, and cognitive performance among a sample of 100 older adult (65+) trauma-exposed Veterans. Participants will undergo an MRI scan, a blood draw, a clinical interview, and a neuropsychological battery. Multiple regression and serial mediation analyses will be utilized to determine relationships among lifetime stress severity, serum vascular adhesion molecule-1 (sVCAM-1) levels, medial temporal lobe (MTL) and medial prefrontal cortex (mPFC) CBF, and cognitive performance (memory, executive functioning). The primary goal of the study will be to test the hypothesis that the neurovascular dysfunction accounts for relationships among the subjective experience of stress and cognition. Results will improve understanding of the role of stress in cognitive aging. Moreover, this study represents the critical first step toward identifying modifiable biomarkers that can serve as treatment targets for interventions aimed at mitigating currently existing stress-related damage to brain and cognitive health among older Veterans. Building upon the applicant’s prior experience in neuroimaging and cognitive aging, the proposed CDA also provides opportunity for new hands-on training in stress-related research methodologies, blood-based biomarkers, vascular function, and advanced statistical analysis. This dovetails with the candidate’s long-term career goal of developing expertise at the intersection of stress and cognitive aging. Data from this project will provide critical pilot data for successful preparation of a VA Merit Award. Together, this research and training plan will well position the applicant for transition to an independent clinical researcher within the VA system.