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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.]

项目总结/文摘