Frontal hypo perfusion effects on antidepressant outcomes in geriatric depression

描述(由申请人提供)：一项重要的工作涉及到血管对老年抑郁症的发病机制的贡献。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低灌流为特征的血管病理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低灌注量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，以确定药物改善脑血流灌注是否可能是有效的抗抑郁药物增强策略。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。血管病变，如动脉管腔减少、扩张性降低和内皮功能障碍，导致自我调节过程维持稳定脑血流的能力降低，从而导致脑低灌流。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所见的背部系统代谢的改善。然而，这些人可能会从改善脑血流灌注的方法中受益。作为这一系列研究的第一步，当前建议的目标是确定抑郁症老年人的血管反应性降低和额叶低灌注量是否预测并持续抗抑郁药无效。我们将继续我们的主要目标来验证我们的假设，即反应性和低灌注率降低，特别是在背侧前额叶皮质和背侧前扣带回皮质，可以预测抗抑郁药的无效。我们的方法是招募40名抑郁症老年人，他们将在舍曲林为期12周的开放标签抗抑郁药物试验之前和之后完成临床、认知和MRI评估。使用动脉自旋标记(ASL)在a)休息时，b)在情绪古怪的任务期间，以及c)高碳酸刺激时评估反应性，来评估局部脑血流灌注。这将使我们能够检查反应性降低和额叶血流灌注是否预示着抗抑郁药的无效。这一建议是创新的，因为它从机械上研究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晚年抑郁症发病机制的理解，如果我们的假设是正确的，那么它将支持检验商业上可获得的改善脑血流灌注的药物的抗抑郁特性的研究。

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.