Novel 31P MRS Approach for Measuring Abnormal Bioenergetics in Schizophrenia

描述（由申请人提供）：精神分裂症是一种慢性、严重和致残的脑部疾病，会导致严重的社会或职业功能障碍，如长期失业、贫困和无家可归。先前的研究表明，通过测量高能含磷酸盐化合物（HEP）的稳态浓度，大脑生物能量学异常与精神分裂症有关。线粒体能量产生系统对神经元功能、突触和神经可塑性至关重要，这些功能与学习、记忆以及情绪、认知和感觉运动功能的适应性变化有关。因此，检测线粒体能量代谢率将为更好地理解神经元功能的改变提供关键信息。尽管研究深入，但与精神分裂症病因和病理生理相关的异常脑能代谢机制仍不明确。我们最近在麻醉大鼠脑中的研究表明，与稳态HEP浓度相比，通过31P磁化转移（MT）光谱测量肌酸激酶（CK）和atp酶催化的脑能代谢率，可以更灵敏和定量地测量生理或病理状态下脑生物能量及其与脑活动变化相关的变化。因此，我们认为动态评估精神分裂症患者肌酸激酶（CK）和atp酶的化学反应活性将为反映精神分裂症相关线粒体功能障碍提供更直接、更灵敏的功率计。然而，用传统的31P MT光谱法测量人类精神病人的CK和atp酶反应活性是极其困难的。由于许多方法上的挑战，这方面的进展几十年来一直受到阻碍。因此，本研究旨在开发一种新的31P MT方法，以提高空间分辨率、灵敏度和可靠性，无创、快速检测精神分裂症患者的生物能量异常。已建立的MR方法和关于精神分裂症的初步发现将提供一个重要的框架，解决与精神分裂症相关的具体病理生理学问题，对潜在的医学诊断和药物开发至关重要。

DESCRIPTION (provided by applicant): Schizophrenia is a chronic, severe, and disabling brain disorder which causes significant social or occupational dysfunction, such as long-term unemployment, poverty and homelessness. The previous studies indicate abnormal cerebral bioenergetics associated with schizophrenia by measurements of the steady-state concentrations of high energy phosphate-containing compounds (HEP: PCr and ATP) and in-organic phosphate (Pi) using 1H or 31P MRS. Mitochondrial energy production system is of enormous importance for neuron function, synapses and neuroplasticity which is associated with learning, memory, as well as with adaptive changes in emotional, cognitive and sensorimotor function. Therein detecting mitochondrial energy metabolic rate would provide the crucial information for better understanding the altered function of the neuron. Despite intensive research, the mechanism of abnormal cerebral energy metabolism linked to the etiology and pathophysiology of schizophrenia has remained elusive. Our recent studies in anesthetic rats' brains demonstrate that measurements of cerebral energy metabolic rates catalyzed by the creatine kinase (CK) and ATPase enzymes by 31P magnetization transfer (MT) spectroscopy provide more sensitive and quantitative measures of brain bioenergetics and its changes associated with brain activity changes under physiological or pathological condition as compared to the measurements of the steady-state HEP concentration. Thus, we believe that dynamically assessing the chemical reaction activities of creatine kinase (CK) and ATPase enzymes in schizophrenic patients would provide direct and more sensitive power meter to reflect mitochondria dysfunction associated with schizophrenia. However, it is extremely difficult to measure CK and ATPase reaction activities in human psychiatric patients by the conventional 31P MT spectroscopy. The progress in this development has been hampered for several decades due to many methodological challenges. Therefore, the current studies aim to develop a novel 31P MT methodology to noninvasively and rapidly detect abnormal bioenergetics in schizophrenia with the increased spatial resolution, higher sensitivity and reliability. The established MR methodology and preliminary findings about schizophrenia would provide an important framework which addresses the questions regarding to specific pathophysiology associated with schizophrenia and is essential for potential medical diagnosis and drug developments. PUBLIC HEALTH RELEVANCE: Schizophrenia is a chronic, severe, and disabling brain disorder that causes significant social or occupational dysfunction. The current project aims to develop a novel magnetic resonance methodology to noninvasively and rapidly detect abnormal bioenergetics in schizophrenia. It should provide an important framework to address questions regarding the specific pathophysiology associated with schizophrenia.