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

基本信息

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
项目类别：
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

项目摘要

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.]

项目概要/摘要尽管有有效的抗逆转录病毒疗法，但艾滋病毒感染者的认知缺陷仍然普遍存在（艾滋病毒+）个人。 HIV+女性在语言学习和记忆方面表现出明显的缺陷，压力是一个主要因素这些赤字的贡献者。事实上，我们已经证明压力对言语记忆有更深远的影响。 HIV+ 女性与未感染 HIV（HIV-）的女性相比。我们的结构和功能神经影像学发现链接 HIV+女性中这些与压力相关的记忆障碍会导致前额皮质萎缩和前额皮质下降皮质（PFC）功能。皮质醇，一种糖皮质激素，在应激源后释放并升高众所周知，慢性压力会影响海马和 PFC 功能。在临床上，这是相关的，因为 LDH 可以以低剂量氢化可的松 (LDH) 的形式安全外源给药。在健康的情况下 LDH 会损害个体的认知能力，但在患有创伤后应激障碍 (PTSD) 的个体中，LDH 会增强认知能力认识。我们最近在单剂量 LDH（10 毫克）的试点研究中将 LDH 研究范围扩展到 HIV 患有高水平压力但目前没有精神合并症的艾滋病毒阳性女性。值得注意的是，言语与安慰剂相比，LDH 治疗后 4 小时学习和记忆力有所改善。虽然导致这种效应的机制尚不清楚，LDH 使压力引起的变化正常化下丘脑-垂体-肾上腺（HPA）轴和炎症。在这里，我们建议检查稳健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压力、创伤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双单次服用 LDH（10 毫克药丸形式）与安慰剂相比的盲法、安慰剂对照、交叉研究（目标 n=100）。受试者内设计控制了常见的共同因素（例如，心理风险因素、物质使用史），这可能会使 LDH 对 HIV 阳性女性群体的影响的解释变得复杂。我们将测量给药后 30 分钟和 4 小时的认知表现，因为一项新兴文献表明 LDH 的认知影响取决于给药后评估的时间。 30分钟评估讨论 LDH 后最大皮质醇水平如何影响认知。这个即时评估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。更新颖临床上重要的是在峰值后进行的 4 小时评估，此时皮质醇水平更加稳定 LDH 后更广泛的日常皮质醇分布的状态和典型。第三次评估将在 4 后进行 LDH 或安慰剂治疗数周。该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 LDH 影响认知的机制。 [这项新颖的研究将是第一个针对心理健康相关的研究增强 HIV+ 女性认知能力的机制（例如 HPA 轴失调）。如果 5 年后这项研究证实并扩展我们的初步发现，即 LDH 增强 HIV+ 女性的认知能力，那么我们将发现一种新的进一步临床和机制研究的治疗目标。]