Novel 31P MRS Approach for Measuring Abnormal Bioenergetics in Schizophrenia

描述（申请人提供）：精神分裂症是一种慢性、严重和致残性大脑疾病，可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。以往的研究表明，异常的大脑生物能量学与精神分裂症有关的测量稳态浓度的高能磷酸盐的化合物（HEP：PCr和ATP）和无机磷酸盐（Pi）。线粒体能量产生系统对于神经元功能、突触和与学习、记忆、以及情绪、认知和感觉运动功能的适应性变化。其中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。尽管进行了深入的研究，与精神分裂症的病因和病理生理学相关的脑能量代谢异常的机制仍然难以捉摸。我们最近在麻醉大鼠脑中的研究表明，与稳态HEP浓度的测量相比，通过31P磁化转移（MT）光谱测量由肌酸激酶（CK）和ATP酶催化的脑能量代谢率提供了更灵敏和定量的脑生物能量学及其与生理或病理条件下的脑活动变化相关的变化的测量。因此，我们认为，动态评估肌酸激酶（CK）和ATP酶的化学反应活性的精神分裂症患者将提供直接和更敏感的功率计，以反映线粒体功能障碍与精神分裂症。然而，它是非常困难的测量人类精神病患者的CK和ATP酶反应活性的常规31 P MT光谱。几十年来，由于许多方法上的挑战，这方面的进展一直受到阻碍。因此，目前的研究旨在开发一种新的31 P MT方法，以非侵入性和快速检测精神分裂症的异常生物能量学，具有更高的空间分辨率，更高的灵敏度和可靠性。已建立的MR方法和精神分裂症的初步研究结果将提供一个重要的框架，解决与精神分裂症相关的特定病理生理学的问题，是必不可少的潜在的医学诊断和药物开发。 公共卫生相关性：精神分裂症是一种慢性、严重和致残性的脑部疾病，可导致显著的社会或职业功能障碍。目前的项目旨在开发一种新的磁共振方法，以非侵入性和快速检测精神分裂症的异常生物能量学。它应该提供一个重要的框架来解决与精神分裂症相关的特定病理生理学问题。

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.