COGNITION, STEROIDS AND IMAGING IN CUSHINGS DISEASE

描述（改编自申请人摘要）： 下丘脑-垂体-肾上腺轴导致高皮质醇血症， 在老年人和神经精神病患者中存在显著比例 阿尔茨海默病和严重抑郁症等疾病。 然而，这种失调与临床症状的关系是 仍然没有被充分理解。 CD患者表现出高皮质醇血症 并在情绪、睡眠、性欲和认知方面出现障碍。 的 研究人员的假设是，在这些不同的类固醇水平升高， 条件具有重要的神经活性作用。 研究者的目标 是研究类固醇在行为病理生理学中的作用， 利用CD患者是一种独特的模型， 持续暴露于高浓度的内源性类固醇超过一年 长期的。 这些研究的重点是认知方面的异常。 动物研究表明，皮质类固醇激素水平升高会导致毒性 到海马体。 这是一种可能的机制， 糖皮质激素引起认知功能障碍。 研究者建议 使用大脑MRI和神经心理学（NP）测试， 在人类中研究这种机制。 越来越多的证据表明 类固醇如雄激素在调节神经元 兴奋性 在许多CD患者中， 脱氢表雄酮（DHEA）也明显升高。 的 研究者的具体目标是：1）详细研究认知 使用敏感性、特异性和分级试验评估CD患者功能障碍 探索微妙和容易引发的困难程度 异常 2)治疗前，检查MRI确定的海马 形成（HF）的CD患者的体积，并与年龄的体积相比， 性别和教育程度相匹配的正常对照。 调查员会检查 通过测量和比较尾状核体积的区域特异性 头部（CH）、额叶和前颞叶（ATL）。 3)审查 高皮质醇血症严重程度、NP损害与HF之间的关系 音量. CH、额叶和ATL的体积将用作比较 地区 4)治疗后1年和2年重复NP检测和MRI 的CD，以确定认知和HF体积的变化是否 可逆的 音量变化与认知测验的关系 分数将被研究。 5)检查潜在的调节作用， 雄激素睾酮和脱氢表雄酮，共同分泌的皮质醇，在测试， 注意力、学习和记忆。 高皮质醇血症随着年龄的增长而发生， 神经精神疾病 建议的研究将有助于增进知识 关于糖皮质激素皮质醇的作用， 认知功能障碍 发展的理由 保护性药物如位点特异性糖皮质激素受体拮抗剂 或兴奋性氨基酸抑制剂的作用会增强。

DESCRIPTION (Adapted from applicant's abstract): Dysregulation of the hypothalamic-pituitary-adrenal axis resulting in hypercortisolemia is present in a significant proportion of the aged and in neuropsychiatric conditions such as Alzheimer's Disease and Major Depressive Disorder. However, the relationship of this dysregulation to clinical symptoms is still insufficiently understood. Patients with CD exhibit hypercortisolemia and develop disturbances in mood, sleep, libido, and cognition. The investigator's hypothesis is that steroid elevations in these various conditions have important neuroactive effects. The investigator's objective is to examine the role of steroids in the pathophysiology of behavior by exploiting the fact that patients with CD are a unique model providing sustained exposure to high concentrations of endogenous steroids over a long-term period. The studies proposed focus on abnormalities in cognition. Studies in animals indicate that elevated corticosteroids result in toxicity to the hippocampus. This is one likely mechanism for the manner in which glucocorticoids elicit cognitive dysfunction. The investigator proposes to use MRI of the brain together with neuropsychologic (NP) testing to investigate such a mechanism in humans. Evidence is accumulating that other steroids such as androgens play key roles in modulating neuronal excitability. In many patients with CD, testosterone and dehydroepiandrosterone (DHEA) are also markedly elevated. The investigator's specific aims are to: 1) Study in fine detail cognitive dysfunction in patients with CD using sensitive, specific tests with graded levels of difficulty to probe for subtle as well as easily-elicited abnormalities. 2) Examine, prior to treatment, MRI-determined hippocampal formation (HF) volume in patients with CD, and compare to the volume of age, sex, and education-matched normal controls. The investigator will examine specificity for region by measuring and comparing the volumes of caudate head (CH), frontal lobe and anterior temporal lobe (ATL). 3) Examine associations between severity of hypercortisolemia, NP impairment and HF volume. The volumes of CH, frontal and ATL will be used as comparison regions. 4) Repeat NP testing and MRI one and two years following treatment of CD, in order to determine if changes in cognition and HF volume are reversible. Associations between changes in volume and cognitive test scores will be studied. 5) Examine the potential modulatory role of the androgens testosterone and DHEA, co-secreted with cortisol, on tests of attention, learning and memory. Hypercortisolemia occurs with aging and in several important neuropsychiatric diseases. The studies proposed will help advance knowledge about the role of the glucocorticoid cortisol in the mechanisms contributing to cognitive dysfunction in these conditions. The rationale for developing protective drugs such as site-specific glucocorticoid receptor antagonists or excitatory amino acid suppressors would be strengthened.