Sex Differences in Cognitive Response to a Hydrocortisone Challenge in HIV

描述(由申请人提供)：尽管有有效的艾滋病毒治疗方法，但认知缺陷仍然存在。新的数据表明，与男性相比，迟发性记忆障碍是艾滋病毒女性认知障碍的一个主要特征。此外，压力与HIV血清状态相互作用，特别是对言语记忆产生负面影响。这项申请建议调查应激相关的糖皮质激素(GC)增加，作为艾滋病毒妇女言语记忆缺陷的潜在贡献者。GCS在应激源后释放，是非HIV感染者压力和记忆功能障碍之间关系的关键中介。相关证据表明，健康的女性比健康的男性更容易受到GC的认知影响。在这里，我们建议将这项研究扩展到HIV，并具体研究GCs反应对认知功能的因果作用。具体地说，我们建议通过一项双盲、安慰剂对照的交叉研究，在82名HIV成年人(41名男性，41名女性)中调查氢化可的松对HIV认知功能影响的性别差异。这一设计的一个创新特征建立在最近的证据基础上，即GC对认知的影响取决于与应激激素暴露相关的认知评估的时间。因此，我们建议研究GC如何对认知功能产生剧烈影响(干预后30分钟)和延迟后(干预后240分钟)。我们假设，与HIV男性相比，HIV女性言语记忆的急性和延迟性损害的程度将更大。据我们所知，这将是第一个阐明GCs在HIV中的认知效应的药理学挑战研究。这样的演示将为与压力相关的GC增加提供关键的见解，作为HIV女性语言记忆明显比男性更大缺陷的一种机制。确定这一机制是设计临床试验的关键的第一步，目的是降低压力和GCs，以改善认知功能，特别是在艾滋病毒妇女中。

DESCRIPTION (provided by applicant): Cognitive deficits persist despite the availability of effective therapies for HIV. New data indicates that, in contrast to men, delayed memory impairments are a central feature of cognitive impairment in HIV+ women. Furthermore, stress interacts with HIV serostatus to negatively impact verbal memory in particular. This application proposes to investigate stress-associated increases in glucocorticoids (GCs) as a potential contributor to verbal memory deficits in HIV+ women. GCs are released after a stressor and are the key mediator of the relationship between stress and memory dysfunction in non-HIV-infected individuals. Correlational evidence suggests that healthy women are more vulnerable to the cognitive effects of GCs than healthy men. Here we propose to extend this research to HIV and specifically examine the causal role of GCs response on cognitive function. Specifically, we propose to investigate sex differences in the impact of hydrocortisone on cognitive function in HIV in a double-blind, placebo-controlled, cross-over study in 82 HIV+ adults (41 men, 41 women). An innovative feature of this design builds on recent evidence that the effects of GCs on cognition depends on the timing of the cognitive assessment in relation to stress hormone exposure. Therefore, we propose to examine how GCs impact cognitive function both acutely (30 minutes post- intervention) and after a delay (240 minutes post-intervention). We hypothesize that the magnitude of acute and delayed impairments on verbal memory will be greater in HIV+ women compared to HIV+ men. To the best of our knowledge, this will be the first pharmacologic challenge study to elucidate the cognitive effects of GCs in HIV. Such a demonstration will provide critical insights into stress-related increases in GCs as a mechanism underlying the apparent greater deficit in verbal memory in HIV+ women compared to men. Identifying this mechanism is a critical first step in the design of clinical trials aimed at lowerng stress and GCs in order to improve cognitive function, particularly in HIV+ women.