Brain Bioenergetic Response to Hypoxic Stress in Bipolar Disorder

双相情感障碍患者大脑对缺氧应激的生物能反应

• 批准号: 9856936
• 负责人: PERRY FRANKLIN RENSHAW
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9856936
• 关键词: Acute; Adenosine Triphosphate; Air; Altitude; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animals; Area; Atmospheric Pressure; Bioenergetics; Bipolar Disorder; Blood; Boston; Brain; Brain Chemistry; Brain Diseases; Brain scan; Breathing; Buffers; Cells; Cerebrum; Characteristics; Chronic; Cities; Clinical; Cognitive; Consumption; Coupled; Creatine Kinase; Data; Development; Diabetes Mellitus; Diagnostic; Disease; Education; Exhibits; Exposure to; Functional disorder; Genetic Transcription; Glucose; Goals; Healthcare Systems; Homeostasis; Huntington Disease; Hypoxia; Hypoxia Inducible Factor; Individual; Intervention; Learning; Life; Link; Magnetic Resonance Spectroscopy; Magnetism; Measures; Mental disorders; Messenger RNA; Methods; Mission; Mitochondria; Modality; Nature; Neurons; Obesity; Oxidative Phosphorylation; Oxidative Stress; Oxygen; Parkinson Disease; Partial Pressure; Patients; Peripheral; Phosphocreatine; Phosphorus; Photic Stimulation; Prevalence; Production; Progress Reports; Proteins; Publications; Quality of life; Rattus; Reaction; Relapse; Reporting; Research; Respiration; Respiratory Chain; Scanning; Sea; Serum; Site; Sodium Chloride; Source; Spectrum Analysis; Stress; Suicide; Symptoms; System; Techniques; Testing; Therapeutic; Thinness; Transcript; Transcriptional Regulation; Traumatic Brain Injury; United States Department of Veterans Affairs; Veterans; Veterans Health Administration; Visual Cortex; Work; base; clinical center; completed suicide; coping; depressive behavior; deprivation; design; falls; foot; high risk; improved; in vivo; insight; mitochondrial dysfunction; neurobiological mechanism; new therapeutic target; novel; pressure; recruit; response; severe mental illness; side effect; stem; suicidal behavior; suicidal risk; suicide rate; treatment response; treatment-resistant depression

Bipolar disorder (BD) is a chronic mental illness with high rates of relapse. BD is a highly prevalent psychiatric disorder, especially in veterans. More than 130,000 veterans in the Veterans Affairs (VA) healthcare system have been seeking treatment for BD. Individuals suffering with BD are likely to have diminished quality of life due to characteristics of symptoms which manifest as a result of the disorder. Suicide is a major concern within the VA healthcare system, and veterans suffering with BD are at high risk for committing suicide. Despite the prevalence of BD and widespread research efforts, its pathophysiology remains complicated and obscure. Although various therapeutic modalities have been developed, about one third of BD patients have demonstrated an inadequate response to treatment. There exists a critical need to bridge the gap between neurobiological mechanisms and clinical manifestations of BD. Past research has shown magnetic resonance spectroscopy (MRS) in patients with BD to be an effective approach to learn more about the nature of BD. Oxidative stress induced by neuronal mitochondrial dysfunction has been implicated as a potent cause of BD based on ample prior research. Moreover, it has been reported that oxidative stress could be aggravated by hypobaric hypoxia at altitude. This may result in an increased suicide rate in BD above 2,000 feet altitude according to several recent publications. Additionally, there are animal studies supporting altitude’s effects on BD. Rats exposed to simulated hypobaric hypoxia exhibited brain chemistry similar to that seen in individuals with BD, in addition to demonstrating increased depressive behavior. In our recent study, we found a difference in the brain chemistry of subjects living in moderate altitude compared to those living at low altitude (sea level); however, we found no difference in bioenergetic metabolites between BD subjects and healthy controls. In this proposed study, we will compare the difference in how veterans with BD compare to healthy controls in how their brains compensate for the shortage of energy enduring hypoxic conditions using MRS techniques. A total number of 88 subjects are planned for recruitment: 44 veterans with BD and 44 healthy controls. All subjects will undergo MRS brain scans to measure brain bioenergetics (phosphocreatine and adenosine triphosphates levels) in breathing 16% and 25% oxygen concentrations (equal to oxygen at 10,000 feet and sea level, respectively). It is hypothesized that coping with decreased energy production as a result of hypoxia may be less efficient in the subjects with BD, relative to healthy controls. The anticipated results of the current proposed study will elucidate the oxidative stress in BD and suggest new therapeutic targets for BD.

双相情感障碍（BD）是一种复发率很高的慢性精神疾病，是一种非常普遍的精神疾病。 疾病，尤其是退伍军人事务部 (VA) 医疗系统中超过 130,000 名退伍军人。 一直在寻求 BD 治疗的人的生活质量可能会下降。 由于该疾病所表现出的症状特征，自杀是一个主要问题。 在退伍军人管理局的医疗保健系统内，患有双相情感障碍的退伍军人自杀的风险很高。 尽管双相情感障碍很普遍并且研究工作也很广泛，但其病理生理学仍然存在 尽管已经开发出各种治疗方式，但大约有三分之一是复杂和模糊的。 BD 患者对治疗的反应不足，迫切需要弥补。 过去的研究已经表明BD的神经生物学机制和临床表现之间存在差距。 磁共振波谱 (MRS) 是了解 BD 患者更多信息的有效方法 BD 的本质。 神经元线粒体功能障碍引起的氧化应激被认为是一个潜在的原因 此外，据报道，氧化应激可能与 BD 相关。 海拔超过 2,000 时，低压缺氧会加剧这可能导致自杀率增加。 此外，根据最近的几篇出版物，还有动物研究支持。 海拔对 BD 的影响表现出与模拟低压缺氧相似的大脑化学反应。 除了表现出抑郁行为增加之外，还可见于双相障碍患者。 在我们最近的研究中，我们发现生活在中等海拔地区的受试者的大脑化学物质存在差异 然而，与生活在低海拔地区（海平面）的人相比，我们发现生物能量没有差异； 在这项拟议的研究中，我们将比较 BD 受试者和健康对照之间的代谢差异。 患有双相情感障碍的退伍军人与健康对照者相比，他们的大脑如何弥补双相情感障碍的不足 计划对总共 88 名受试者进行使用 MRS 技术的能量耐受缺氧条件。 招募：44 名患有 BD 的退伍军人和 44 名健康对照者所有受试者都将接受 MRS 脑部扫描。 测量呼吸时的大脑生物能量（磷酸肌酸和三磷酸腺苷水平）16% 和 25% 氧气浓度（分别等于 10,000 英尺和海平面的氧气）。 人们重新认识到，应对因缺氧而导致的能量产生减少可能会减少 相对于健康对照，BD 受试者的疗效是目前提出的预期结果。 研究将阐明 BD 中的氧化应激并提出 BD 的新治疗靶点。