Attenuation of Corticosteroid-Induced Hippocampal Changes

描述（由申请人提供）：皮质类固醇过量与记忆和海马结构的变化有关。在皮质类固醇暴露期间或压力之后的一致发现是陈述性记忆任务的表现下降（例如，单词列表、段落回忆）。在库欣病导致皮质类固醇过量的患者中，以及我们的研究组在接受处方皮质类固醇治疗的内科疾病患者中，已经报告了陈述性记忆受损和海马萎缩。这些发现对情绪障碍患者具有重要意义，因为患有重度抑郁症和双相情感障碍的一部分人显示出HPA轴激活和皮质醇升高的证据。在动物模型中，皮质类固醇继发的海马变化可以用调节兴奋性氨基酸的药物减弱。谷氨酸释放抑制剂或N-甲基-D-天冬氨酸（NMDA）受体拮抗剂可以预防动物的组织学变化。在过去的15年里，我们的小组已经开发了一个研究项目，使用在医疗环境中接受处方皮质类固醇的患者（例如，泼尼松）疗法作为模型系统来探索皮质醇升高对人脑的影响。这也是一个庞大且具有临床重要性的患者人群，经常出现与皮质类固醇治疗相关的记忆障碍以及情绪症状。我们已经报道了抑郁症，陈述性记忆缺陷，N-乙酰天冬氨酸（NAA，神经元活力的标志物）的变化，以及慢性暴露于泼尼松期间海马体积的减少。我们进行了一项安慰剂对照的概念验证研究的NMDA受体拮抗剂美金刚在皮质类固醇治疗的患者，并发现统计学显着改善陈述性记忆。一个更大和更长的美金刚的最终试验，现在提出使用神经影像学以及记忆作为结果的措施。我们提出了一个随机，双盲，安慰剂对照的交叉试验美金刚在50例门诊哮喘患者接受慢性口服慢性皮质类固醇治疗。我们假设接受美金刚胺治疗的一组相对于安慰剂组在陈述性记忆（主要结果测量）方面有所改善。我们还将获得结构MRI和HMRS，以检查海马和杏仁核体积以及NAA和谷氨酸水平的变化。我们组建了一个研究团队，他们拥有情绪障碍、神经内分泌学、临床试验、神经心理学、哮喘和统计学方面的专业知识来进行这项研究。这些发现将对患有情绪障碍、物质使用障碍、痴呆、库欣氏病的患者以及每年数百万接受处方皮质类固醇治疗的患者产生影响。

DESCRIPTION (provided by applicant): Corticosteroid excess is associated with changes in memory and hippocampal structure. A consistent finding during corticosteroid exposure or following stress is a decline in performance on declarative memory tasks (e.g., word lists, paragraph recall). Impairment in declarative memory and hippocampal atrophy have been reported in patients with corticosteroid excess due to Cushing's disease, and, by our group, in medically ill patients receiving prescription corticosteroid therapy. These findings have important implications for patients with mood disorders, as a subset of people with major depressive disorder and bipolar disorder show evidence of HPA axis activation and elevated cortisol. In animal models, hippocampal changes secondary to corticosteroids can be attenuated with agents that modulate excitatory amino acids. Histological changes in animals can be prevented with glutamate release inhibitors or N-methyl-D-aspartate (NMDA) receptor antagonists. Over the past 15 years, our group has developed a research program using patients in medical settings receiving prescription corticosteroid (e.g., prednisone) therapy as a model system to explore the effects of cortisol elevations on the human brain. This is also a large and clinically important patient population that frequently has memory impairment as well as mood symptoms related to corticosteroid therapy. We have reported depressive symptomatology, deficits in declarative memory, changes in N-acetyl aspartate (NAA, a marker of neuronal viability), and reduction in hippocampal volume during chronic exposure to prednisone. We conducted a placebo-controlled proof-of-concept study of the NMDA receptor antagonist memantine in corticosteroid-treated patients and found statistically significant improvement in declarative memory. A larger and longer definitive trial of memantine is now proposed using neuroimaging as well as memory as outcome measures. We propose a randomized, double-blind, placebo-controlled crossover trial of memantine in 50 outpatients with asthma receiving chronic oral chronic corticosteroid therapy. We hypothesize that the group receiving memantine will show improvement in declarative memory (primary outcome measure) relative to the placebo group. We will also obtain structural MRI and HMRS to examine changes in hippocampal and amygdalar volumes and levels of NAA and glutamate. We have assembled a research team with expertise in mood disorders, neuroendocrinology, clinical trials, neuropsychology, asthma, and statistics to conduct the study. The findings will have implications for patients with mood disorders, substance use disorders, dementias, Cushing's disease, and the millions treated each year with prescription corticosteroids.