Effects of Glucocorticoids on Cognitive Functioning in HIV-infected Women

项目摘要/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。 (艾滋病毒)个人。艾滋病女性在言语学习和记忆方面表现出明显的缺陷，而压力是主要原因 造成这些赤字的因素。事实上，我们已经证明，压力对言语记忆有更深刻的影响 艾滋病毒妇女比未感染艾滋病毒(HIV-)的妇女。我们的结构和功能神经影像发现 这些与应激相关的记忆损害与HIV女性的前额叶皮质萎缩和前额叶减少有关 大脑皮层(PFC)功能。皮质醇，一种糖皮质激素，在应激源后释放，并升高 在慢性应激的情况下，已知会影响海马区和PFC功能。在临床上，这是相关的，因为 LDH可以外源性安全地以低剂量氢化可的松(LDH)的形式给予。在健康中 个体，LDH损害认知，但在患有创伤后应激障碍(PTSD)的个体中，LDH增强 认知力。我们最近在对单剂量(10毫克)乳酸脱氢酶的初步研究中，将这一乳酸脱氢酶研究扩展到艾滋病毒。 在艾滋病毒妇女中，有高水平的感觉到的压力，但目前没有精神共病。值得注意的是，口头上 与安慰剂相比，使用乳酸脱氢酶治疗4小时后，学习和记忆能力有所改善。尽管 导致这种效应的机制尚不清楚，LDH使应激诱导的脑组织改变正常化 下丘脑-垂体-肾上腺(HPA)轴与炎症。在这里，我们建议检查健壮性和 这些发现在更大样本的HIV女性中表现出认知功能障碍和 报告高水平的压力、创伤病史和心理健康风险因素。符合入学标准的女性 将完成三项认知评估。第一次和第二次评估将嵌入一个双重- 单次服用乳酸脱氢酶(10毫克药丸)与安慰剂对照的盲法、安慰剂对照交叉研究 (靶向n=100)。受试者内的设计控制共同的基础(例如，心理风险因素， 药物使用史)，这可能会使对艾滋病毒妇女人群中乳酸脱氢酶影响的解释复杂化。我们 将测量服药后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机。30分钟的评估 阐述LDH后最大皮质醇水平如何影响认知。这一直接评估是 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。更新奇 临床上重要的是在皮质醇水平更稳定的高峰期后进行4小时评估 这是腰椎间盘突出症后更广泛的皮质醇每日变化的典型状态。第三次评估将在4点后进行 用乳酸脱氢酶或安慰剂治疗数周。这项评估涉及临床意义和安全性。 长期LDH治疗。最后，我们将探讨糖皮质激素与炎症和免疫激活之间的关系 乳酸脱氢酶可能影响认知的机制。这项新的研究将是第一个针对心理健康相关的研究 增强艾滋病毒妇女认知的机制(例如，HPA轴失调)。如果在5年内，这项研究证实 并扩展了我们最初的发现，即乳酸脱氢酶增强了HIV女性的认知能力，那么我们将发现一种新的 作为进一步临床和机制研究的治疗目标。]

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.]