GLUCOCORTICOID RESPONSIVITY IN VETERANS

退伍军人的糖皮质激素反应

• 批准号: 7718186
• 负责人: RACHEL YEHUDA
• 金额: $ 0.06万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7718186
• 关键词: Affect; Amygdaloid structure; Anterior; Area; Attention; Auditory; Bosnia-Herzegovina; Brain; California; Centers for Disease Control and Prevention (U.S.); Characteristics; Chronic; Chronic Disease; Cognition; Cognitive; Computer Retrieval of Information on Scientific Projects Database; Condition; Confidence Intervals; Corticotropin; Data; Depressed mood; Dexamethasone; Digit structure; Dose; Double-Blind Method; Exposure to; Fatigue; Feeling; Funding; Glucocorticoid Receptor; Glucocorticoids; Grant; Gulf War; Health; Hippocampus (Brain); Hydrocortisone; Infusion procedures; Ingestion; Institution; Kosovo; Letters; Link; Literature; Low Prevalence; Lymphocyte; Major Depressive Disorder; Measures; Mediating; Medical; Memory; Moods; Musculoskeletal; Neuroanatomy; Neuropsychological Tests; Neurosecretory Systems; Numbers; Performance; Placebo Control; Placebos; Post-Traumatic Stress Disorders; Procedures; Process; Rate; Regulation; Research; Research Personnel; Resources; Role; Savings; Short-Term Memory; Sleep; Source; Stress; Symptoms; System; Testing; Thinking; Trauma; Traumatic Stress Disorders; United States National Institutes of Health; Verbal Learning; Veterans; War; base; brain volume; cognitive function; cohort; day; design; dexamethasone suppression test; hypothalamic-pituitary-adrenal axis; improved; indexing; memory retention; response; visual memory

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Many Gulf War Veterans (GWV) suffer from unexplained medical symptoms known collectively as Chronic Multi-symptom Illness (CMI), presumed to have their origin in some aspect of deployment. As defined by the CDC, the illness is a chronic multi-system illness (CMI), reflecting a disturbance in mood and cognition, characterized by feeling depressed, moody or anxious, and having difficulty remembering, concentrating, finding words or sleeping as well as musculoskeletal symptoms and fatigue.1 These symptoms may also be present in psychiatric conditions associated with stress such as major depressive disorder (MDD) and posttraumatic stress disorder (PTSD). Not surprisingly, PTSD is prominent among veterans with CMI, and conversely, many GWV with PTSD have symptoms of CMI. The association between symptoms of CMI and PTSD has led our group to examine GWV using a similar neuroendocrine battery to that which we developed to elucidate neuroendocrine aspects of PTSD, and to a lesser extent, MDD, in other combat veterans with PTSD. An analysis of our data demonstrated that glucocorticoid-related alterations in GWV appeared to be strongly associated with the presence of health symptoms (i.e., of CMI), independently from their associations with PTSD. These findings raised the possibility of an interaction between PTSD and CMI with respect to glucocorticoid-related characteristics and the underlying brain alterations and cognitive processes that might be mediated by them. Although CMI has been associated with exposure to the Gulf, it is not unique to Gulf War veterans; it has also been found, at lower prevalence rates in veterans of Kosovo and Bosnia and is anticipated to similarly affect veterans of OIF/OEF . The unique neuroendocrine alterations in PTSD, and their likely associations with CMI, provide a rationale for using the double-blind placebo-controlled hCORT challenge test to study PTSD and CMI in veterans of recent wars (the first Gulf War, Bosnia, Kosovo, OIF, OEF). In our funded MERIT grant, we focused on the hippocampus because the hippocampus is an area rich in both Type I and Type II glucocorticoid receptors (GR), , and much excitement had been generated by the findings of smaller hippocampal volumes in PTSD. , , , , , , Our pilot data will support that such enthusiasm was warranted, as the hippocampus does appear to be more responsive to hCORT in VV with PTSD compared to those without PTSD. However, the hippocampus is not the only area of the brain with large concentrations of GR, nor is it the only region implicated in memory performance, or PTSD. In view of the possibility of an interaction between PTSD and CMI with respect to glucocorticoid-related characteristics, the proposed study is a 2 x 2 design (PTSD+, PTSD- and CMI+, CMI-) in which the functional neuroanatomy of glucocorticoid responsiveness and its relationship to memory performance will be evaluated in four groups (PTSD+CMI+, PTSD+CMI-, PTSD-CMI+, PTSD-CMI-), each comprised of 16 trauma-exposed veterans. We focus on glucocorticoid responsiveness because of the importance of the hypothalamic-pituitary-adrenal (HPA) axis in the regulation of psychiatric symptoms related to mood and PTSD,18 and also its role in physical and somatic processes and cognition. Two neuroendocrine challenges will be performed to assess glucocorticoid responsiveness: a double-blind placebo-controlled (17.5 mg) hCORT challenge procedure during which neuroendocrine, functional neuroanatomic, and memory performance indices will be assessed, and the low dose (0.50 mg) dexamethasone (DEX) suppression test (DST). Measures of glucocorticoid responsiveness, memory performance, and brain volumes and rGMR of several ROI's including the anterior cingulate, amygdala and hippocampus, will be obtained on the placebo and hCORT challenge days. To date, there is almost no information on the neuroendocrine characteristics associated with CMI subdivided on the basis of presence or absence of PTSD, or on how these characteristics are linked with either functional neuroanatomy, poor memory performance, which is a major symptom domain of CMI, and a frequently complaint among those with PTSD, or both. Aim 1: To investigate the effects of CMI and PTSD and their interaction in responsiveness to glucocorticoids at baseline and in response to hCORT and DEX challenge. In the hCORT challenge procedure, the critical measure of glucocorticoid responsiveness will be the maximum decrease from pre-infusion levels of ACTH (i.e., ACTH suppression) following placebo and 17.5 mg hCORT administration. In the DEX challenge, glucocorticoid responsiveness will be estimated by the percent suppression of cortisol, ACTH, and lymphocyte GR number in response to 0.5mg DEX ingestion. For Aims 1-3, the overall effects of CMI (with or without PTSD) and of PTSD (with or without CMI) will be assessed by analysis of covariance (ANCOVA). The interaction of CMI and PTSD refers to the difference between the effects of CMI in the absence or presence of PTSD, and, equivalently, the difference of the effects of PTSD in the absence or presence of CMI. Based on the literature on PTSD in other veteran cohorts and on our pilot data, we hypothesize that PTSD will be associated with greater ACTH suppression in response to hCORT, and greater percent suppression or cortisol, ACTH and lymphocyte GR number in response to DEX. There is much less literature on CMI on which to base hypotheses, but based on our pilot data, we hypothesize that CMI will be associated with decreased ACTH suppression in response to hCORT and reduced percent suppression or cortisol, ACTH and lymphocyte GR number in response to DEX. Aim 2: To investigate the effects of CMI and PTSD and their interaction in baseline memory performance following placebo and hCORT administration. At baseline, we will assess immediate and delayed auditory and visual memory, retention, implicit and explicit memory, and proactive and retroactive interference, since these components of memory are thought be sensitive to hippocampal damage. , , The cognitive functions will be measured using the California Verbal Learning Test (CVLT) and the WAIS and WMS. . Following placebo and hCORT infusions, we will measure verbal learning, attention, and working memory using three neuropsychological tests of explicit memory shown to be vulnerable to glucocorticoid administration. , , Verbal learning, as measured by immediate and delayed paragraph recall (measured by percent savings at delay, a measure of retention), will be tested using the Wechsler Memory Scale (WMS-III). Attention will be assessed using the Digit Span Forward (DSF) subtest of the WMS-III. Working memory will be measured by the Digit Span Backwards (DSB), and the Letter-Number Sequence (LNS) subtests of the WMS-III. Based on our pilot data in GWV with PTSD, we hypothesize that PTSD will be associated with greater decrements in measures of recall and attention in response to hCORT than GWV without PTSD. Other aspects of cognitive performance, such as attention, may not be affected or may even improve. We do not have pilot data in CMI on which to base hypotheses for this measure; however, if CMI is associated with less glucocorticoid responsiveness, as suggested by our pilot data, it may be associated with less of a decrement in memory performance in response to Hcort. Aim 3: To correlate simultaneously obtained measures of glucocorticoid responsiveness, hippocampal volume, and memory performance, within groups of subjects with and without PTSD and with and without CMI. For each pair of variables, the correlation will pool results within each of the four groups of subjects. This differs from the correlation that would result from including all subjects in a single analysis, since it excludes from consideration the group mean differences assessed in Aims 1 and 2. A 95% confidence interval will also be obtained for each correlation. We will also test whether relationship between changes in these measures depend on the levels of the variables at baseline. We hypothesize that simultaneously obtained measures of glucocorticoid responsiveness and of memory performance will be highly correlated. Based on the literature, we also hypothesize that PTSD will be associated with smaller hippocampal volumes. To the extent that poor memory performance in PTSD is a reflection of altered glucocorticoid responsiveness and/or smaller hippocampal volume, we hypothesize that correlations among these measures will be higher in the PTSD group. II. BACKGROUND & SIGNIFICANCE

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 许多海湾战争退伍军人 (GWV) 患有不明原因的医学症状，统称为慢性多症状疾病 (CMI)，推测其根源在于部署的某些方面。 根据 CDC 的定义，该疾病是一种慢性多系统疾病 (CMI)，反映情绪和认知障碍，其特征是感到抑郁、喜怒无常或焦虑，难以记忆、集中注意力、找词或睡眠，以及肌肉骨骼症状和疲劳。1 这些症状也可能出现在与压力相关的精神疾病中，例如重度抑郁症 (MDD) 和创伤后应激障碍 （创伤后应激障碍）。 毫不奇怪，PTSD 在患有 CMI 的退伍军人中很突出，相反，许多患有 PTSD 的 GWV 也有 CMI 的症状。 CMI 和 PTSD 症状之间的关联促使我们小组使用与我们开发的类似的神经内分泌电池来检查 GWV，以阐明 PTSD 的神经内分泌方面，并在较小程度上阐明其他患有 PTSD 的退伍军人的 MDD。 对我们数据的分析表明，与糖皮质激素相关的 GWV 变化似乎与健康症状（即 CMI）的存在密切相关，独立于其与 PTSD 的关联。这些发现提出了 PTSD 和 CMI 之间在糖皮质激素相关特征以及可能由它们介导的潜在大脑改变和认知过程方面相互作用的可能性。 尽管 CMI 与接触海湾有关，但它并不是海湾战争退伍军人所独有的。研究还发现，科索沃和波斯尼亚退伍军人的患病率较低，预计 OIF/OEF 退伍军人也会受到同样的影响。 PTSD 中独特的神经内分泌改变及其与 CMI 的可能关联，为使用双盲安慰剂对照 hCORT 挑战测试来研究近期战争（第一次海湾战争、波斯尼亚、科索沃、OIF、OEF）退伍军人的 PTSD 和 CMI 提供了理论依据。 在我们资助的 MERIT 资助中，我们重点关注海马体，因为海马体是富含 I 型和 II 型糖皮质激素受体 (GR) 的区域，并且 PTSD 中海马体体积较小的发现引起了人们的极大兴奋。 , , , , , , 我们的试验数据将支持这种热情是有道理的，因为与没有 PTSD 的 VV 相比，患有 PTSD 的 VV 中海马体似乎确实对 hCORT 更敏感。 然而，海马体并不是大脑中唯一具有大量 GR 的区域，也不是唯一与记忆表现或 PTSD 相关的区域。 鉴于 PTSD 和 CMI 之间在糖皮质激素相关特征方面可能存在相互作用，拟议的研究采用 2 x 2 设计（PTSD+、PTSD- 和 CMI+、CMI-），其中糖皮质激素反应性的功能神经解剖学及其与记忆表现的关系将分四组进行评估（PTSD+CMI+、 PTSD+CMI-、PTSD-CMI+、PTSD-CMI-），每个组由 16 名遭受过创伤的退伍军人组成。 我们关注糖皮质激素反应性，因为下丘脑-垂体-肾上腺 (HPA) 轴在调节与情绪和 PTSD 相关的精神症状中的重要性，18 及其在身体和躯体过程和认知中的作用。 将进行两次神经内分泌挑战来评估糖皮质激素反应性：双盲安慰剂对照（17.5 mg）hCORT挑战程序，在此过程中将评估神经内分泌、功能性神经解剖学和记忆表现指数，以及低剂量（0.50 mg）地塞米松（DEX）抑制试验（DST）。 将在安慰剂和 hCORT 挑战日获得糖皮质激素反应性、记忆表现、脑容量和几个 ROI（包括前扣带回、杏仁核和海马体）的 rGMR 测量值。 迄今为止，几乎没有关于根据是否存在 PTSD 来细分与 CMI 相关的神经内分泌特征的信息，也没有关于这些特征如何与功能性神经解剖学、记忆力差（这是 CMI 的主要症状领域）以及 PTSD 患者经常抱怨的问题或两者相关的信息。 目标 1：研究 CMI 和 PTSD 的影响以及它们在基线糖皮质激素反应以及 hCORT 和 DEX 挑战反应中的相互作用。 在 hCORT 激发程序中，糖皮质激素反应性的关键指标是安慰剂和 17.5 mg hCORT 给药后 ACTH 输注前水平的最大降低（即 ACTH 抑制）。在 DEX 挑战中，糖皮质激素反应性将通过对 0.5mg DEX 摄入的反应对皮质醇、ACTH 和淋巴细胞 GR 数量的抑制百分比来估计。 对于目标 1-3，CMI（有或没有 PTSD）和 PTSD（有或没有 CMI）的总体影响将通过协方差分析 (ANCOVA) 进行评估。 CMI 和 PTSD 的相互作用是指在不存在或存在 PTSD 的情况下 CMI 的影响之间的差异，以及同等地，在不存在或存在 CMI 的情况下 PTSD 的影响的差异。 根据其他退伍军人队列中关于 PTSD 的文献以及我们的试点数据，我们假设 PTSD 将与 hCORT 反应中的更大的 ACTH 抑制相关，以及 DEX 反应中的皮质醇、ACTH 和淋巴细胞 GR 数量更大的抑制百分比相关。 关于 CMI 的文献较少，但根据我们的初步数据，我们假设 CMI 与 hCORT 反应中 ACTH 抑制减少以及 DEX 反应中皮质醇、ACTH 和淋巴细胞 GR 数量抑制百分比降低有关。 目标 2：调查服用安慰剂和 hCORT 后 CMI 和 PTSD 的影响及其对基线记忆表现的相互作用。 在基线时，我们将评估即时和延迟的听觉和视觉记忆、保留、内隐和外显记忆以及前摄和追溯干扰，因为记忆的这些组成部分被认为对海马损伤敏感。 , , 认知功能将使用加州言语学习测试 (CVLT) 以及 WAIS 和 WMS 进行测量。 。 在注射安慰剂和 hCORT 后，我们将使用三项外显记忆神经心理学测试来测量语言学习、注意力和工作记忆，这些测试显示外显记忆容易受到糖皮质激素的影响。 , , 口头学习，通过立即和延迟段落回忆（通过延迟节省百分比来衡量，保留的衡量标准）进行测量，将使用韦克斯勒记忆量表（WMS-III）进行测试。 将使用 WMS-III 的数字跨度向前 (DSF) 子测试来评估注意力。 工作记忆将通过 WMS-III 的数字跨度向后 (DSB) 和字母数字序列 (LNS) 子测试来测量。 根据我们在患有 PTSD 的 GWV 中的试点数据，我们假设与没有 PTSD 的 GWV 相比，PTSD 与 hCORT 反应引起的回忆和注意力测量的更大下降相关。 认知表现的其他方面，例如注意力，可能不会受到影响，甚至可能会有所改善。 我们没有 CMI 的试点数据来作为这项措施的假设基础；然而，如果正如我们的试验数据所表明的那样，CMI 与较低的糖皮质激素反应性相关，那么它可能与 Hcort 引起的记忆性能下降较少相关。 目标 3：将患有和不患有 PTSD 以及患有和不患有 CMI 的受试者组内同时获得的糖皮质激素反应性、海马体积和记忆表现测量值关联起来。 对于每对变量，相关性将汇集四组受试者中每一组的结果。 这与将所有受试者纳入单一分析所产生的相关性不同，因为它排除了目标 1 和 2 中评估的组平均差异。每个相关性还将获得 95% 置信区间。 我们还将测试这些指标变化之间的关系是否取决于基线变量的水平。我们假设同时获得的糖皮质激素反应性和记忆表现的测量值将高度相关。根据文献，我们还假设 PTSD 与较小的海马体积有关。在某种程度上，PTSD 患者的记忆表现不佳是糖皮质激素反应性改变和/或海马体积变小的反映，我们假设这些指标之间的相关性在 PTSD 组中会更高。 二. 背景及意义