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。一个一致的发现是，在皮质类固醇暴露或随后的压力下，陈述性记忆任务（例如，单词列表，段落回忆）的表现下降。在库欣病导致皮质类固醇过量的患者中，以及在接受处方皮质类固醇治疗的内科患者中，已经报道了陈述性记忆损伤和海马萎缩。这些发现对情绪障碍患者具有重要意义，因为重度抑郁症和双相情感障碍患者的一个子集显示HPA轴激活和皮质醇升高的证据。在动物模型中，皮质类固醇引起的海马变化可以通过调节兴奋性氨基酸的药物来减弱。动物的组织学变化可以通过谷氨酸释放抑制剂或n -甲基- d -天冬氨酸（NMDA）受体拮抗剂来预防。在过去的15年里，我们的团队开发了一项研究计划，使用在医疗环境中接受处方皮质类固醇（如强的松）治疗的患者作为模型系统，探索皮质醇升高对人类大脑的影响。这也是一个很大的和临床上重要的患者群体，经常有记忆障碍以及与皮质类固醇治疗相关的情绪症状。我们已经报道了慢性暴露于强的松期间的抑郁症状、陈述性记忆缺陷、n -乙酰天冬氨酸（NAA，神经元活力的标记物）的变化和海马体积的减少。我们在皮质类固醇治疗的患者中进行了一项NMDA受体拮抗剂美金刚的安慰剂对照概念验证研究，发现陈述性记忆有统计学上的显著改善。一个更大更长期的美金刚的决定性试验现在被提议使用神经成像和记忆作为结果测量。我们建议在50例接受慢性口服皮质类固醇治疗的哮喘门诊患者中进行一项随机、双盲、安慰剂对照的美金刚交叉试验。我们假设，相对于安慰剂组，接受美金刚的组在陈述性记忆（主要结果测量）方面表现出改善。我们还将获得结构MRI和HMRS来检查海马和杏仁体体积以及NAA和谷氨酸水平的变化。我们组建了一个研究团队，在情绪障碍、神经内分泌学、临床试验、神经心理学、哮喘和统计学方面具有专业知识，以开展这项研究。这一发现将对患有情绪障碍、物质使用障碍、痴呆、库欣病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.