Effects of Glucocorticoids on Cognitive Functioning in HIV-infected Women

项目概要/摘要 尽管有有效的抗逆转录病毒疗法，但认知缺陷在艾滋病毒感染者中仍然普遍存在。 (HIV+）个人。艾滋病毒阳性妇女在语言学习和记忆方面表现出明显的缺陷，压力是主要的障碍。 造成这些赤字。事实上，我们已经证明，压力对非文字记忆的影响更为深远， 艾滋病毒阳性的妇女多于未感染艾滋病毒的妇女。我们的结构和功能神经影像学发现 HIV阳性女性的这些与压力相关的记忆障碍与前额叶皮质萎缩和前额叶皮质减少有关。 皮质（PFC）功能。皮质醇，一种糖皮质激素，在压力刺激后释放， 慢性应激，已知会影响海马和PFC功能。临床上，这是相关的，因为 LDH可以以低剂量氢化可的松（LDH）的形式安全地外源性给药。健康 LDH损害认知，但在创伤后应激障碍（PTSD）患者中，LDH增强 认知.我们最近将LDH的研究扩展到HIV，进行了单剂量LDH（10 mg）的初步研究。 在HIV阳性女性中，有高水平的感知压力，但目前没有精神病合并症。特别是口头上 与安慰剂相比，在用LDH治疗后4小时，学习和记忆改善。虽然 导致这种效应的机制尚不清楚，LDH使应激诱导的 下丘脑-垂体-肾上腺（HPA）轴和炎症。在这里，我们建议检查鲁棒性和 这些发现在表现出认知功能障碍的HIV阳性女性的较大样本中具有临床意义， 报告高水平的压力、创伤史和心理健康风险因素。符合入学标准的妇女 将完成三项认知评估第一次和第二次评估将被嵌入一个双重- LDH（10 mg，丸剂）与安慰剂单次给药的盲态、安慰剂对照、交叉研究 （目标n=100）。常见并发症的受试者内设计控制（例如，心理风险因素， 物质使用史），这可能使解释LDH在HIV+女性人群中的作用变得复杂。我们 将测量给药后30分钟和4小时的认知表现，因为一项新的文献显示， LDH的认知效应取决于给药后评估的时间。30分钟评估 解决了LDH后皮质醇最大水平如何影响认知。这一即时评估是 这是压力和认知研究的标准，并允许与更广泛的文献进行比较。更加新颖 临床上重要的是4小时的评估，发生在峰值后，当皮质醇水平更稳定时 状态和LDH后较广泛的每日皮质醇曲线的典型。第三次评估将在4点后进行。 LDH或安慰剂治疗周。该评估涉及以下方面的临床意义和安全性： 长期LDH治疗。最后，我们将探讨糖皮质激素和炎症和免疫激活， LDH可能影响认知的机制。[This新的研究将是第一个针对心理健康相关的 机构（例如，HPA轴失调），以提高艾滋病毒阳性妇女的认知能力。如果5年后这项研究证实 并扩展了我们最初的发现，LDH增强了HIV阳性女性的认知能力，那么我们将发现一种新的 用于进一步临床和机制研究的治疗靶点。

PROJECT SUMMARY/ABSTRACT Despite the availability of effective antiretroviral therapies, cognitive deficits remain prevalent in HIV-infected (HIV+) individuals. HIV+ women show prominent deficits in verbal learning and memory, and stress is a major contributor to these deficits. In fact, we have shown that stress has more profound effects on verbal memory in HIV+ women than in HIV-uninfected (HIV-) women. Our structural and functional neuroimaging findings link these stress-related memory impairments in HIV+ women to prefrontal cortical atrophy and decreased prefrontal cortex (PFC) functioning. Cortisol, a glucocorticoid that is released following a stressor and which is elevated with chronic stress, is known to influence both hippocampal and PFC function. Clinically, this is relevant because LDH can be administered exogenously and safely in the form of low-dose hydrocortisone (LDH). In healthy individuals, LDH impairs cognition, but in individuals with post-traumatic stress disorder (PTSD) LDH enhances cognition. We recently extended this line of LDH research to HIV in a pilot study of a single dose of LDH (10mg) in HIV+ women with high levels of perceived stress but no current psychiatric comorbidities. Notably, verbal learning and memory improved 4 hours following treatment with LDH compared to placebo. Although the mechanisms contributing to this effect are unknown, LDH normalizes stress-induced alterations in the hypothalamic-pituitary-adrenal (HPA) axis and inflammation. Here we propose to examine the robustness and clinical significance of these findings in a larger sample of HIV+ women demonstrating cognitive dysfunction and reporting high levels of stress, trauma history, and mental health risk factors. Women meeting enrollment criteria will complete three cognitive assessments. The first and second assessments will be embedded in a double- blind, placebo-controlled, cross-over study of a single administration of LDH (10 mg in pill form) versus placebo (targeted n=100). The within-subject design controls for common cofounds (e.g., psychological risk factors, substance use history) that could complicate interpretation of LDH effects in a population of HIV+ women. We will measure cognitive performance 30 minutes and 4 hours post-dosing, because an emerging literature shows that the cognitive effects of LDH depends on timing of the assessment post-dosing. The 30-minute assessment addresses how the maximal cortisol levels following LDH affect cognition. This immediate assessment is standard in studies of stress and cognition and allows for comparisons with the broader literature. More novel and clinically important is the 4-hour assessment which occurs post-peak, when cortisol levels are more steady state and typical of the broader daily cortisol profile following LDH. The third assessment will take place after 4 weeks of treatment with LDH or placebo. That assessment addresses the clinical significance and safety of longer-term LDH treatment. Lastly, we will explore glucocorticoids and inflammation and immune activation as mechanisms by which LDH might affect cognition. [This novel study will be the first to target mental health related mechanisms (e.g., HPA axis dysregulation) to enhance cognition in HIV+ women. If in 5-years this study verifies and extends our initial findings that LDH enhances cognition in HIV+ women then we will have identified a novel therapeutic target for further clinical and mechanistic investigations.]