31P magnetization transfer study of bipolar disorder

双相情感障碍的 31P 磁化转移研究

• 批准号: 7923151
• 负责人: Chun S Zuo
• 金额: $ 19.75万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7923151
• 关键词: Adenosine Diphosphate; Adenosine Triphosphate; Adult; Affect; Affective; Age; Americas; Antidepressive Agents; BB form creatine kinase; Bioenergetics; Bipolar Depression; Bipolar Disorder; Brain; Cerebrum; Chemicals; Code; Creatine; Creatine Kinase; Data; Depressed mood; Development; Disease; Disease model; Dose; Elderly; Energy Metabolism; Enzymes; Equation; Functional disorder; Genes; Genetic Transcription; Hippocampus (Brain); Human; Individual; Kinetics; Link; Lithium; Magnetic Resonance Spectroscopy; Maintenance; Measurement; Measures; Mental Depression; Messenger RNA; Metabolic Pathway; Methods; MgADP; Mitochondria; Molecular; Molecular Genetics; Moods; Nuclear; Pathology; Pathway interactions; Patient Recruitments; Patients; Phosphocreatine; Photic Stimulation; Play; Positron-Emission Tomography; Prefrontal Cortex; Prevalence; Principal Investigator; Proteins; Publishing; Reaction; Refractory; Relative (related person); Reporting; Resistance; Resources; Rodent; Role; Scheme; Selective Serotonin Reuptake Inhibitor; Severities; Signal Transduction; System; Technology; Temporal Lobe; Testing; Tissues; Valproic Acid; abstracting; base; brain electrical activity; cost; depressive symptoms; design; frontal lobe; glucose metabolism; healthy volunteer; improved; inorganic phosphate; insight; programs; public health relevance; reaction rate; sex; single photon emission computed tomography; socioeconomics; standard care; suicidal risk; treatment strategy

DESCRIPTION (provided by applicant): Magnetization Transfer Study of Bipolar Disorder Abstract The disease mechanism of bipolar disorder remains largely unknown. However, recent data suggest that pathogenic alterations in cerebral bioenergetics pathways may be linked to bipolar disorder, especially in patients expressing symptoms of depression. In such patients, magnetic resonance spectroscopy (MRS) studies have consistently found decreases in phosphocreatine (PCr) levels, PET and SPECT studies have often reported cerebral energetic alterations and mitochondrial pathology. Furthermore, molecular genetics studies have reported decreases in the mRNA expression of creatine kinase (CK), the enzyme that facilitates the reversible transfer of a phosphate group from PCr to ADP, resulting in ATP. While important, measurements of static concentrations of metabolites and mRNA expression alone are not sufficient for characterization of a dynamic metabolic pathway. Quantitative analysis of potentially retarded reaction rates and associated fluxes are needed to accurately describe the mechanisms of this energy system. We propose to non-invasively measure the forward rate constant (kfor) of brain CK in 36 patients suffering from bipolar depression using magnetization transfer-31P MRS. Age and sex matched healthy control subjects (n=18) will undergo the same measurement for comparison. To increase patient homogeneity while maintaining feasibility of patient recruitment, our exploratory study will be performed on type II bipolar patients who are on either divalproex or lithium in conjunction with either no or limited use of antidepressants. Our preliminary data demonstrate that we have the technologies and subject resources to complete the proposed study. We hypothesize that 1) CK enzymatic activity, measured as kfor, in the frontal lobe of depressed BPD subjects will be decreased relative to that of age and sex matched controls; 2) the kfor of CK will be negatively associated with depression severity in bipolar patients. Should the hypotheses prove to be correct, it will be of importance to the understanding of brain bioenergetic alterations as it relates to the disease mechanism of bipolar disorder. Furthermore, Positive results of the hypotheses on alterations in cerebral bioenergetics pathways could prompt the development of new treatment strategies. PUBLIC HEALTH RELEVANCE: Successful completion of this study will provide further insight into the disease mechanism of bipolar disorder, especially in older adults who are often treatment refractory bipolar patients, demonstrating the relevance of the altered bioenergtic model of the disease. Positive results of the hypotheses on alterations in cerebral bioenergetics pathways could prompt the development of new treatment strategies.

描述（由申请人提供）：躁郁症的磁化转移研究摘要躁郁症的疾病机制在很大程度上未知。但是，最近的数据表明，脑生物能途径的致病改变可能与躁郁症有关，尤其是在表达抑郁症状的患者中。在此类患者中，磁共振光谱（MRS）研究一直发现磷酸氨酸水平（PCR）水平降低，PET和SPECT研究经常报道大脑能量改变和线粒体病理学。此外，分子遗传学研究报告了肌酸激酶（CK）的mRNA表达降低，肌酸激酶（CK）是促进磷酸基团从PCR到ADP的可逆转移的酶，从而导致ATP。虽然重要，但单独的代谢物和mRNA表达的静态浓度的测量不足以表征动态代谢途径。需要对潜在智障反应速率和相关通量进行定量分析，以准确描述该能量系统的机制。我们建议使用磁化转移-31p MRS的36例患有躁郁症抑郁症患者的脑CK的前进速率常数（KFOR）。年龄和性别匹配的健康对照受试者（n = 18）将进行相同的测量以进行比较。为了增加患者同质性的同时维持患者招募的可行性，我们的探索性研究将对在Divalproex或Divalproex或锂的II型双极患者中进行，并与NO或有限使用抗抑郁药一起进行。我们的初步数据表明，我们拥有技术和主题资源来完成拟议的研究。我们假设1）在BPD受试者的额叶额叶中以KFOR测量的CK酶活性将相对于年龄和性别匹配的对照组而减少； 2）CK的KFOR将与双极患者的抑郁严重程度负相关。如果假设被证明是正确的，那么对于与双相情感障碍疾病机制有关的理解，这对于理解脑生物能改变至关重要。此外，关于脑生物能途径改变的假设的积极结果可能会促使发展新的治疗策略。公共卫生相关性：这项研究的成功完成将进一步了解双相情感障碍的疾病机制，尤其是在经常治疗难治性双相患者的老年人中，这表明了疾病改变生物联凝模型的相关性。关于脑生物能途径改变的假设的积极结果可以促使发展新的治疗策略。