Reversing Corticosteroid-Induced Memory Impairment

逆转皮质类固醇引起的记忆障碍

基本信息

批准号：
8208138
负责人：
E SHERWOOD BROWN
金额：
$ 23.57万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-20 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8208138
关键词：
Address Adrenal Cortex Hormones Adult Age Alcohol dependence Alzheimer&apos s Disease Amygdaloid structure Animal Experimentation Animal Model Animals Area Aspirate substance Asthma Atrophic Attention Attenuated Behavior Therapy Biological Biological Markers Biological Models Bipolar Disorder Brain Brain Diseases Calcium Channel Chronic Clinical Clinical Trials Cognition Cognitive Corticosterone Data Disease Dose Double-Blind Method Endocrine Gland Neoplasms Excitatory Amino Acids Exposure to Frequencies Functional disorder Glutamates Goals Hippocampus (Brain)Hormones Human Hydrocortisone Image Impairment Intervention Learning Life Literature Magnetic Resonance Imaging Major Depressive Disorder Manic Measures Mediating Medical Memory Memory impairment Modeling Mood Disorders Moods N-Methyl-D-Aspartate Receptors N-acetylaspartate National Institute of Mental Health Neurocognitive Neurons Neuropsychology Neurosecretory Systems Oral Outcome Outpatients Patient Self-Report Patients Performance Pharmaceutical Preparations Phenytoin Physiology Pilot Projects Pituitary-dependent Cushing&apos s disease Placebo Control Placebos Play Population Prednisone Prefrontal Cortex Prevention strategy Psychopathology Quality of life Randomized Randomized Controlled Trials Rare Diseases Relative (related person)Reporting Research Role Safety Secondary to Severities Short-Term Memory Sodium Channel Spectrum Analysis Speed Stress Structure Symptoms Systemic Lupus Erythematosus Translating Translational Research active method base clinically relevant clinically significant depressive symptoms effective therapy executive function extracellular hippocampal atrophy improved inhibitor/antagonist instrument lamotrigine medically necessary care neuroimaging neurotoxicity novel open label placebo controlled study prednisolone prevent programs public health relevance research and development statistics therapy development web site

项目摘要

DESCRIPTION (provided by applicant): In animals and humans, stress and corticosteroid excess is associated with changes in memory and hippocampal structure. A consistent finding during corticosteroid exposure is a decline in performance on declarative memory tasks. The human literature is quite limited. However, impairment in declarative memory and hippocampal atrophy, have been reported in patients with corticosteroid excess due to Cushing's disease, and, more recently by our group, in medically ill patients receiving prescription corticosteroid therapy. These have important implications to patients with mood disorders, as a subset of people with major depressive disorder and bipolar disorder have elevated cortisol levels. In animals, hippocampal changes secondary to corticosteroids can be attenuated with agents that modulate excitatory amino acids. Histological changes can be prevented and reversed with phenytoin, a glutamate release inhibitor, or an N-methyl-D-aspartate (NMDA) receptor antagonist. 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. In prior studies, we have documented 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. Lamotrigine is an antiseizure and bipolar disorder medication that decreases glutamate release through interactions with sodium and calcium channels. We conducted both open-label and placebo-controlled trials of lamotrigine in corticosteroid-treated patients finding statistically and clinically significant improvement in declarative memory. A larger and longer definitive trial is now proposed. We propose a randomized, double-blind, placebo-controlled pilot study of lamotrigine in 50 outpatients with asthma receiving chronic oral corticosteroid therapy. We hypothesize that the group receiving lamotrigine will show improvement in declarative memory relative to the placebo group. We will also assess NAA and glutamate using spectroscopy and hippocampal and amygdala volume using structural magnetic resonance imaging. We have assembled a research team with expertise in mood disorders, clinical trials, neuropsychology, asthma, statistics, hippocampal physiology, spectroscopy, and the neuroendocrine system to conduct the study. The findings will have implications for patients with major depressive disorder and the millions treated each year with prescription corticosteroids. PUBLIC HEALTH RELEVANCE: A large literature in animals suggests that stress hormones (corticosteroids) are associated with reversible and irreversible changes in the hippocampus, a brain structure that plays a critical role in learning and memory. In animal models, agents that inhibit the release of excitatory amino acids appear to block the effects of stress hormones on the hippocampus. In the proposed study, a randomized, controlled trial of lamotrigine, a medication that inhibits the release of excitatory amino acids, is proposed in a group of patients taking medically necessary prescription corticosteroids for asthma. The impact of lamotrigine on memory, mood, quality of life, structural imaging, and spectroscopy will be examined.

描述（由申请人提供）：在动物和人类中，压力和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的一致发现是陈述性记忆任务的表现下降。人类的文学作品相当有限。然而，由于库欣病导致皮质类固醇过量的患者以及最近我们小组在接受处方皮质类固醇治疗的疾病患者中报告了陈述性记忆受损和海马萎缩。这些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人的一部分皮质醇水平升高。在动物中，继发于皮质类固醇的海马变化可以通过调节兴奋性氨基酸的药物来减弱。可以使用苯妥英、谷氨酸释放抑制剂或 N-甲基-D-天冬氨酸 (NMDA) 受体拮抗剂来预防和逆转组织学变化。我们的小组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（例如泼尼松）治疗的患者作为模型系统，以探索皮质醇升高对人脑的影响。在之前的研究中，我们记录了长期暴露于泼尼松期间陈述性记忆的缺陷、N-乙酰天冬氨酸（NAA，神经元活力的标志物）的变化以及海马体积的减少。拉莫三嗪是一种抗癫痫和双相情感障碍药物，通过与钠和钙通道的相互作用减少谷氨酸的释放。我们对接受皮质类固醇治疗的患者进行了拉莫三嗪的开放标签和安慰剂对照试验，发现陈述性记忆在统计学上和临床上都有显着改善。现在提议进行更大规模、时间更长的最终试验。我们提议对 50 名接受长期口服皮质类固醇治疗的门诊哮喘患者进行拉莫三嗪的随机、双盲、安慰剂对照初步研究。我们假设，相对于安慰剂组，接受拉莫三嗪组的陈述性记忆会有所改善。我们还将使用光谱学评估 NAA 和谷氨酸，并使用结构磁共振成像评估海马和杏仁核体积。我们组建了一支在情绪障碍、临床试验、神经心理学、哮喘、统计学、海马生理学、光谱学和神经内分泌系统方面具有专业知识的研究团队来进行这项研究。这些发现将对重度抑郁症患者以及每年接受处方皮质类固醇治疗的数百万人产生影响。公共健康相关性：大量关于动物的文献表明，应激激素（皮质类固醇）与海马体的可逆和不可逆变化有关，海马体是一种在学习和记忆中发挥关键作用的大脑结构。在动物模型中，抑制兴奋性氨基酸释放的药物似乎可以阻止应激激素对海马体的影响。在这项拟议的研究中，建议对一组服用医学上必要的处方皮质类固醇治疗哮喘的患者进行拉莫三嗪（一种抑制兴奋性氨基酸释放的药物）的随机对照试验。将检查拉莫三嗪对记忆、情绪、生活质量、结构成像和光谱学的影响。