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: 10291778
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10291778
• 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）是一种复发率高的慢性精神疾病。BD是一种高度流行的精神病 疾病，尤其是退伍军人。超过130，000名退伍军人在退伍军人事务部（VA）医疗保健系统 一直在寻求BD的治疗。患有BD的人的生活质量可能会下降 这是由于该病症表现出的症状的特征。自杀是一个主要问题 在VA医疗保健系统中，患有BD的退伍军人自杀的风险很高。 尽管BD的流行和广泛的研究努力，其病理生理学仍然是 复杂而晦涩。虽然已经开发了各种治疗方式，但大约三分之一的人 BD患者对治疗反应不足。迫切需要将 BD的神经生物学机制和临床表现之间的差距。过去的研究表明 磁共振波谱（MRS）在BD患者中是一种有效的方法，以了解更多关于 BD的性质。 氧化应激诱导的神经元线粒体功能障碍已被牵连作为一个有力的原因 BD基于大量的前期研究。此外，据报道，氧化应激可能是 在高海拔地区会因低压缺氧而加重。这可能会导致BD的自杀率增加超过2，000 根据最近出版的几篇文章，英尺高度。此外，动物研究也支持 海拔高度对BD的影响暴露于模拟低压缺氧的大鼠表现出类似于 除了表现出抑郁行为的增加外，在患有BD的个体中也可以看到。 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成分存在差异 与生活在低海拔（海平面）的人相比;然而，我们没有发现生物能量的差异， BD受试者和健康对照之间的代谢产物。在这项研究中，我们将比较 BD退伍军人与健康对照组相比，他们的大脑如何补偿 能量耐受缺氧条件下使用MRS技术。共计划88例受试者 招募：44名患有BD的退伍军人和44名健康对照。所有受试者将接受MRS脑部扫描， 测量呼吸中的大脑生物能量学（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英尺和海平面处的氧气）。 据推测，应对由于缺氧而导致的能量产生减少可能会减少 相对于健康对照，在BD受试者中有效。目前拟议方案的预期成果 这项研究将阐明BD中的氧化应激，并为BD提出新的治疗靶点。