Neurovascular Mechanisms Underlying the Negative Effect of Stress in Cognitive Aging

压力增加了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

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.