Frontal hypo perfusion effects on antidepressant outcomes in geriatric depression

描述（由申请人提供）：一项重要的研究表明血管在晚年抑郁症发病机制中的作用。然而，这种关系背后的机制尚未被清楚地证明。我们认为，以中枢血管反应性受损和脑灌注不足为特征的血管病理学可能是导致老年抑郁症临床、认知和放射学表现的潜在因素。这一研究的长期目标是确定血管反应性降低和额叶灌注不足是否与抗抑郁药不缓解有关。如果正确，这将指导未来的研究，以确定脑灌注的药理学改善是否可能是一种有效的抗抑郁增强策略。该项目的基本原理是，在老年人群中，血管疾病与抑郁症状、认知缺陷和高强度病变的发展密切相关。血管病理，如动脉管腔减少、扩张性降低和内皮功能障碍，导致维持脑血流稳定的自我调节过程能力下降，导致脑灌注不足。这种灌注不足可能导致抗抑郁药无反应，因为它们会阻碍抗抑郁药治疗对背系统代谢的改善。然而，这些个体可能从改善脑灌注的方法中获益。作为这条研究路线的第一步，当前建议的目的是确定老年抑郁症患者血管反应性降低和额叶灌注不足是否预示着抗抑郁药物的不缓解并持续存在。我们将追求我们的主要目标，验证我们的假设，即反应性降低和灌注不足，特别是在背外侧前额叶皮层和背前扣带皮层，预测抗抑郁药不缓解。我们的方法是招募40名患有抑郁症的老年人，他们将在为期12周的开放标签抗抑郁药物舍曲林试验前后完成临床、认知和MRI评估。在a)休息时，b)情绪异常任务时，c)高碳刺激时评估反应性，将使用动脉自旋标记（ASL）评估局部脑灌注。这将使我们能够检查反应性降低和额叶灌注是否预示抗抑郁药未缓解。这个建议是创新的，因为它机械地检查了血管失调如何影响晚年抑郁症的结果。这项研究意义重大，因为它将提高我们对老年抑郁症发病机制的理解，如果我们的假设是正确的，它将支持对改善脑灌注的市售药物抗抑郁特性的研究。

DESCRIPTION (provided by applicant): A significant body of work implicates a vascular contribution to the pathogenesis of late-life depression. However, the mechanisms underlying this relationship have not been clearly demonstrated. We propose that vascular pathology, characterized by impaired central vascular reactivity and cerebral hypoperfusion, may be the underlying contributor to the clinical, cognitive, and radiological findings in late-life depressio. The long-term goal of this line of research is to determine if decreased vascular reactivity and frontal hypoperfusion is associated with antidepressant nonremission. If correct, this will guide future studies to determine if pharmacological improvement of cerebral perfusion may be a valid antidepressant augmentation strategy. The rationale for this project is that in older populations, vascular disease is strongly associated with the development of depressive symptoms, cognitive deficits, and hyperintense lesions. Vascular pathology, such as decreased arterial lumens, reduced distensibility, and endothelial dysfunction result in the decreased ability of autoregulatory processes to maintain stable cerebral blood flow, resulting in cerebral hypoperfusion. Such perfusion deficits could contribute to antidepressant nonresponse as they would hinder improvements in dorsal system metabolism seen with antidepressant treatment. However, such individuals might receive benefit from approaches that improve cerebral perfusion. As the first step in this line of research, the objective of the current proposal is to determine if decreased vascular reactivity and frontal hypoperfusion in depressed elders predicts and persists with antidepressant nonremission. We will pursue our primary aim testing our hypothesis that decreased reactivity and hypoperfusion, specifically in the dorsolateral prefrontal cortex and dorsal anterior cingulate cortex, predict antidepressant nonremission. Our approach is to enroll 40 depressed elders who will complete clinical, cognitive, and MRI assessments before and after a 12-week open-label antidepressant trial of sertraline. Regional cerebral perfusion will be assessed using arterial spin labeling (ASL) at a) rest, b) during an emotional oddball task, and c) with a hypercarbic challenge to assess reactivity. This will allow us to examine if reduced reactivity and frontal perfusion is predictive of antidepressant nonremission. This proposal is innovative as it mechanistically examines how vascular dysregulation influences late-life depression outcomes. It is significant as it will improve our understanding of the pathogenesis of late-life depression and, if our hypotheses are correct, support studies examining the antidepressant properties of commercially available drugs that improve cerebral perfusion.