COGNITION, STEROIDS AND IMAGING IN CUSHINGS DISEASE

描述(改编自申请人的摘要)： 导致高皮质醇血症的下丘脑-垂体-肾上腺轴 在相当大比例的老年人和神经精神病患者中存在 阿尔茨海默氏症和严重抑郁障碍等疾病。 然而，这种失调与临床症状的关系是 仍然没有得到充分的理解。CD患者表现为高皮质醇血症 并在情绪、睡眠、性欲和认知方面出现障碍。这个 研究人员的假设是，在这些不同的类固醇升高 条件对神经活动有重要的影响。调查员的目标 是通过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式提供 持续暴露于高浓度的内源性类固醇 长期的。这些研究建议关注认知方面的异常。 在动物身上的研究表明，皮质类固醇含量升高会导致毒性 到海马体。这是一种可能的机制，其方式是 糖皮质激素会导致认知功能障碍。调查员提议 使用脑部核磁共振结合神经心理学(NP)测试 在人类身上研究这种机制。越来越多的证据表明另一种 类固醇，如雄激素，在调节神经元方面起着关键作用 兴奋性。在许多CD患者中，睾酮和 脱氢表雄酮(DHEA)也明显升高。这个 调查员的具体目标是：1)详细研究认知 CD患者功能障碍的灵敏、特异的分级试验 探索微妙和容易引发的问题的难度级别 异常现象。2)治疗前检查MRI确定的海马区 CD患者的形成(HF)体积，并与年龄、 性别、教育程度相匹配的正常对照组。调查员将检查 通过测量和比较尾状核体积来确定区域的特异性 头部(CH)、额叶和前颞叶(ATL)。3)审查 高皮质醇血症严重程度、NP损害与心衰的关系 音量。将CH、Frontal和ATL的体积作为比较 地区。4)治疗后一年和两年复查NP和MRI 以确定认知和心衰体积的改变是否 可逆的。音量变化与认知测试之间的关系 分数将被研究。5)研究经济增长的潜在调节作用 雄激素、睾酮和脱氢表雄酮，与皮质醇共同分泌，在 注意力、学习和记忆。 高皮质醇血症随着年龄的增长而发生，并在几个重要的 神经精神疾病。建议的研究将有助于增进知识 关于糖皮质激素在发病机制中的作用 在这些情况下的认知功能障碍。开发的基本原理 保护性药物，如部位特异性糖皮质激素受体拮抗剂 否则兴奋性氨基酸抑制作用就会增强。

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.