Effects of Glucocorticoids on Cognitive Functioning in HIV-infected Women

糖皮质激素对 HIV 感染女性认知功能的影响

• 批准号: 9566301
• 负责人: Leah Helane Rubin
• 金额: $ 48.23万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9566301
• 关键词: Address; Adverse effects; Affect; Alcohol or Other Drugs use; Area; Basic Science; Binding; Biological Markers; Brain; Chronic stress; Circadian Rhythms; Clinical; Cognition; Cognitive; Cognitive deficits; Comorbidity; Cross-Over Studies; Data; Dose; Double-Blind Method; Enrollment; Epidemiology; Genomics; Glucocorticoid Receptor; Glucocorticoids; Goals; HIV; Hippocampus (Brain); Hour; Hydrocortisone; Impaired cognition; Individual; Inflammation; Inflammatory; Intervention; Investigation; Link; Literature; Measures; Mediator of activation protein; Memory; Memory impairment; Mental Health; Molecular Chaperones; National Institute of Mental Health; Neurologic; Performance; Pilot Projects; Placebos; Population; Population Characteristics; Post-Traumatic Stress Disorders; Prefrontal Cortex; Randomized; Recording of previous events; Reporting; Research; Research Priority; Risk; Risk Factors; Safety; Sampling; Short-Term Memory; Stress; Targeted Research; Time; Trauma; Verbal Learning; Viral; Visuospatial; Woman; antiretroviral therapy; cerebral atrophy; clinically significant; cognitive ability; cognitive benefits; cognitive function; cognitive performance; cognitive testing; design; effective therapy; experience; hypothalamic pituitary axis; hypothalamic-pituitary-adrenal axis; immune activation; improved; meetings; monocyte; negative affect; neuroimaging; new therapeutic target; non-genomic; novel; novel strategies; pill; psychologic; receptor expression; receptor function; receptor sensitivity; response; stressor; treatment strategy

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.]

项目摘要/摘要 尽管有效的抗逆转录病毒疗法可获得，但在感染HIV的认知缺陷仍然很普遍 （HIV+）个人。艾滋病毒+女性在言语学习和记忆中表现出明显的缺陷，压力是主要的 这些缺陷的贡献者。实际上，我们已经表明，压力对言语记忆的影响更大 艾滋病毒+女性比在艾滋病毒未感染的（HIV-）妇女中。我们的结构和功能性神经影像学发现链接 这些与艾滋病毒+女性在前额叶皮质萎缩的与压力相关的记忆障碍，前额叶降低 Cortex（PFC）功能。皮质醇，一种糖皮质激素，在压力源后释放，并升高 慢性应激，已知会影响海马和PFC功能。临床上，这很重要，因为 LDH可以以低剂量氢化可的松（LDH）的形式外源，安全地给药。健康 个人，LDH会损害认知，但在创伤后应激障碍（PTSD）的个体中LDH增强 认识。最近，我们在一项单剂量LDH（10mg）的试点研究中将这一LDH研究线扩展到HIV。 在艾滋病毒+妇女中，患有高水平的压力，但没有当前的精神病合并症。值得注意的是，口头 与安慰剂相比，LDH治疗后4小时的学习和记忆改善了。虽然 导致这种效应的机制尚不清楚，LDH将应力诱导的变化归一化 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 这些发现的临床意义在较大的艾滋病毒+女性样本中，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。妇女会议招生标准 将完成三项认知评估。第一和第二评估将嵌入双重 盲人，安慰剂对照的，单一的LDH给药（药丸形式10毫克）与安慰剂的交叉研究 （目标n = 100）。常见共同点的受试者内设计控制（例如，心理风险因素， 物质使用史）可能会使HIV+女性人群中对LDH影响的解释复杂化。我们 剂量后将测量30分钟4小时的认知表现，因为新兴文献显示 LDH的认知作用取决于剂量后评估的时间。 30分钟的评估 解决LDH后最大皮质醇水平如何影响认知。这种即时评估是 压力和认知研究的标准，可以与更广泛的文献进行比较。更多新颖 临床上重要的是峰值后的4小时评估，当皮质醇水平更稳定时 LDH之后的状态和典型的每日皮质醇概况的典型状态。第三次评估将在4号之后进行 用LDH或安慰剂治疗数周。该评估解决了临床意义和安全性 长期LDH治疗。最后，我们将探索糖皮质激素和炎症和免疫激活 LDH可能会影响认知的机制。 [这项新型研究将是第一个针对心理健康相关的研究 机制（例如HPA轴功能障碍）增强HIV+女性认知的机制。如果在5年内，该研究验证 并扩展了我们最初的发现，即LDH增强了艾滋病毒+女性认知 进行进一步临床和机械研究的治疗靶标。]