Frontal hypo perfusion effects on antidepressant outcomes in geriatric depression

描述（由申请人提供）：一个重要的机构的工作涉及血管的贡献，老年抑郁症的发病机制。然而，这种关系背后的机制还没有得到明确的证明。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老年抑郁症的临床、认知和放射学表现的潜在因素。这项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未缓解有关。如果正确，这将指导未来的研究，以确定是否药理学改善脑灌注可能是一个有效的抗抑郁药增强策略。该项目的基本原理是，在老年人群中，血管疾病与抑郁症状、认知缺陷和高信号病变的发展密切相关。血管病理学，如动脉管腔减少、扩张性降低和内皮功能障碍，导致自动调节过程维持稳定脑血流的能力降低，从而导致脑灌注不足。这种灌注缺陷可能导致抗抑郁药无反应，因为它们会阻碍抗抑郁药治疗中观察到的背侧系统代谢的改善。然而，这些人可能会从改善脑灌注的方法中获益。作为这一系列研究的第一步，目前的建议的目的是确定是否降低血管反应性和额叶灌注不足的老年抑郁症预测和持续抗抑郁药未缓解。我们将追求我们的主要目标，检验我们的假设，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侧前扣带皮层，预测抗抑郁药的非缓解。我们的方法是招募40名老年抑郁症患者，他们将在12周的舍曲林开放标签抗抑郁试验前后完成临床、认知和MRI评估。在a）休息时，B）情绪古怪任务期间，和c）高碳水化合物激发时，使用动脉自旋标记（ASL）评估局部脑灌注，以评估反应性。这将使我们能够检查是否减少反应性和额叶灌注是预测抗抑郁药不缓解。这个建议是创新的，因为它机械地检查血管失调如何影响晚年抑郁症的结果。这是重要的，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，支持研究检查市售药物的抗抑郁特性，改善脑灌注。

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.