COGNITION, STEROIDS AND IMAGING IN CUSHINGS DISEASE

库欣病中的认知、类固醇和影像学

• 批准号: 2410084
• 负责人: MONICA N STARKMAN
• 金额: $ 21.36万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-27 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2410084
• 关键词: Cushing's syndrome; brain mapping; clinical research; cognition disorders; cortisol; encephalography; hippocampus; hormone regulation /control mechanism; human subject; hypercortisolism; hypothalamic pituitary axis; learning; magnetic resonance imaging; memory; neuroendocrine system; neuropsychological tests; neuropsychology; pituitary adrenal axis

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.

描述（改编自申请人的摘要）： 下丘脑-垂体-肾上腺轴导致的高皮质醇血症是 存在于很大一部分老年人和神经精神疾病中 阿尔茨海默病和重度抑郁症等疾病。 然而，这种失调与临床症状的关系是 还是理解不够。 CD 患者表现出高皮质醇血症 并出现情绪、睡眠、性欲和认知障碍。 这 研究人员的假设是，这些不同的类固醇水平升高 条件具有重要的神经活性影响。 调查者的目的 是通过以下方式检查类固醇在行为病理生理学中的作用 利用 CD 患者是一个独特的模型这一事实，提供 持续暴露于高浓度的内源性类固醇超过 长期。 这些研究建议重点关注认知异常。 动物研究表明皮质类固醇升高会导致毒性 到海马体。 这是一种可能的机制 糖皮质激素会引起认知功能障碍。 调查员建议 使用大脑 MRI 和神经心理学 (NP) 测试来 研究人类的这种机制。 越来越多的证据表明其他 雄激素等类固醇在调节神经元方面发挥着关键作用 兴奋性。 在许多 CD 患者中，睾酮和 脱氢表雄酮（DHEA）也显着升高。 这 研究者的具体目标是： 1) 详细研究认知 使用敏感、特定的分级测试来检测 CD 患者的功能障碍 探索微妙和容易引出的困难程度 异常。 2) 在治疗前检查 MRI 确定的海马 CD 患者的形成 (HF) 体积，并与年龄体积进行比较， 性别和教育程度与正常对照相匹配。 调查员将检查 通过测量和比较尾状核的体积来确定区域的特异性 头部（CH）、额叶和前颞叶（ATL）。 3）检查 高皮质醇血症严重程度、NP 损伤和心力衰竭之间的关联 体积。 CH、额叶和 ATL 的体积将用作比较 地区。 4) 治疗后一年和两年重复 NP 测试和 MRI CD，以确定认知和高频音量的变化是否 可逆。 音量变化与认知测试之间的关联 将研究分数。 5) 检查潜在的调节作用 雄激素睾酮和 DHEA 与皮质醇共同分泌，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，并且发生在一些重要的疾病中 神经精神疾病。 拟议的研究将有助于增进知识 关于糖皮质激素皮质醇在机制中的作用 在这些情况下认知功能障碍。 开发理由 保护性药物，例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会增强。