MRI/MRSI Studies of Bipolar Treatment Response

双相情感障碍治疗反应的 MRI/MRSI 研究

• 批准号: 7097384
• 负责人: PERRY FRANKLIN RENSHAW
• 金额: $ 43.15万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7097384
• 关键词: antidepressants; behavioral /social science research tag; bioenergetics; bioimaging /biomedical imaging; bipolar depression; brain imaging /visualization /scanning; brain morphology; clinical research; drug screening /evaluation; gamma aminobutyrate; glutamates; glutamine; gray matter; human subject; human therapy evaluation; lactates; lithium; magnetic resonance imaging; mental disorder chemotherapy; mitochondrial disease /disorder; neurochemistry; neuropathology; paroxetine; patient oriented research; uridine

DESCRIPTION (provided by applicant): This is a second revision to a competing renewal for 5 years of funding to extend a research program entitled "MRI/MRSI Studies of Bipolar Treatment Response." The original application was funded for a 3-year period and the project was conducted both at Harvard/McLean Hospital and the University of Washington. Major findings during the prior period of funding include (1) observation of a diffuse pattern of neurochemical change consistent with mitochondrial dysfunction (increased gray matter lactate and glutamate/glutamine/GABA (Glx)) in untreated patients with bipolar disorder; (2) measured changes toward normal values in brain Glx were associated with lithium treatment, but not valproic acid therapy; and (3) neuroanatomic alterations identified using voxel based morphometry and shape analyses were associated with a bipolar disorder diagnosis. This revised application is focused on the role that mitochondrial dysfunction plays in bipolar disorder. In addition to our prior MRSI findings, recent, independent, post-mortem data suggests that "pronounced and extensive decrease in the expression of genes regulating oxidative phosphorylation" is present in brain tissue from individuals with bipolar disorder (Konradi et al., 2004). To support the hypothesis that these energetic abnormalities may create a novel therapeutic target for the treatment of bipolar disorder, extensive new preliminary data on the effects of cytidine on mood and brain chemistry is provided. Clinically, cytidine was more effective than placebo in improving the symptoms of bipolar depression when added to divalproex. Intriguingly, in contrast to the effects of lithium, cytidine appears to reduce both Glx and brain lactate levels. All studies proposed in this revised application will be performed at the McLean Hospital Brain Imaging Center. Studying in total of 130 subjects with bipolar disorder and 60 healthy comparison subjects, 3 specific lines of research will be pursued. Specific projects are designed to (1) further characterize changes in brain chemistry related to altered mitochondrial function in bipolar disorder using multinuclear (phosphorus-31 and hydrogen-1) magnetic resonance spectroscopic imaging at high-field; (2) evaluate the therapeutic efficacy and the neurochemical effects of uridine, a neurochemical to which cytidine is converted in man, compared to paroxetine in lithium treated bipolar subjects; and (3) utilize novel morphometric methods to better understand neuroanatomic correlates of disease manifestation and treatment effects.

描述（由申请人提供）：这是对一项名为“双相治疗反应的MRI/MRSI研究”的5年研究项目的竞争性续期的第二次修订。最初的申请获得了为期3年的资助，该项目在哈佛/麦克莱恩医院和华盛顿大学进行。在先前资助期间的主要发现包括：(1)观察到未经治疗的双相情感障碍患者中与线粒体功能障碍一致的弥漫性神经化学变化模式（灰质乳酸和谷氨酸/谷氨酰胺/GABA （Glx）增加）；(2)脑Glx向正常值的变化与锂治疗有关，而与丙戊酸治疗无关；(3)使用基于体素的形态测量和形状分析确定的神经解剖学改变与双相情感障碍诊断相关。这个修订后的应用集中在线粒体功能障碍在双相情感障碍中所起的作用。除了我们之前的核磁共振成像发现之外，最近的独立尸检数据表明，双相情感障碍患者的脑组织中存在“调节氧化磷酸化的基因表达明显而广泛的减少”（Konradi et al., 2004）。为了支持这些能量异常可能为治疗双相情感障碍创造新的治疗靶点的假设，提供了关于胞苷对情绪和脑化学影响的大量新的初步数据。临床上，与双丙戊酸联合使用胞苷在改善双相抑郁症状方面比安慰剂更有效。有趣的是，与锂的作用相反，胞苷似乎降低了Glx和脑乳酸水平。本修订申请中提出的所有研究将在McLean医院脑成像中心进行。总共研究了130名双相情感障碍患者和60名健康对照受试者，将进行3个具体的研究方向。具体项目旨在：(1)利用高场多核（磷-31和氢-1）磁共振光谱成像，进一步表征双相情感障碍患者与线粒体功能改变相关的脑化学变化；(2)与帕罗西汀相比，评估尿苷的治疗效果和神经化学作用，尿苷是胞苷在人体内转化为的一种神经化学物质；(3)利用新的形态计量学方法更好地了解疾病表现和治疗效果的神经解剖学相关性。