Novel methodology for studing oxidative metabolism

描述（由申请人提供）：耗氧量提供了有关神经元活动的重要信息。神经系统疾病如阿尔茨海默病、帕金森病和精神分裂症与催化氧化代谢反应的酶活性受阻有关。耗氧量也有可能用于检测脑缺血后存活组织的区域。脑耗氧量的定量绘图有助于更好地理解几种神经系统疾病的病理生理学。目前用于这种测量的方法是正电子发射断层扫描（PET），其提供低分辨率图像并且涉及放射性同位素。目前基于17 O磁共振成像（MRI）的方法具有局限性，例如灵敏度低、需要侵入性程序和需要超高磁场。这些限制，加上17O2气体的高成本，限制了直接17O MRI方法在小动物研究中的适用性。因此，没有将安全性与高空间和时间分辨率结合起来的非侵入性方法来测量人体体内的耗氧量。 该提案涉及一种综合方法的开发，该方法将有效的17O2气体输送系统与用于计算脑耗氧代谢率（CMRO2）的改进的非侵入性MRI策略相结合。具体地，将设计和优化用于大型动物和人类的有效17O2气体输送系统，其将17O2气体需求降低一个数量级。将在猪模型上测试该系统的有效性。将设计MRI方法来测量代谢产生的水（mph 217 O）和脑血流量的动脉输入功能。最后，上述系统和MRI技术将被集成到一个改进的MRI策略，用于测量mph 217 O，以计算在体内大脑中的CMRO 2。一旦目标实现，一种非侵入性工具将可用于测量具有高空间分辨率的CMRO2，这可以立即扩展到体内人体研究。这种方法将对神经系统疾病的科学和临床研究以及新疗法的开发和评估产生重大影响。

DESCRIPTION (provided by applicant): Oxygen consumption provides vital information about neuronal activity. Neurological disorders such as Alzheimer's disease, Parkinson's disease, and schizophrenia are associated with hampered enzymatic activity that catalyzes the reaction of oxidative metabolism. Oxygen consumption also has the potential for detecting regions of viable tissue following cerebral ischemia. Quantitative mapping of cerebral oxygen consumption contributes to the better understanding of the patho-physiology of several neurological disorders. A current method for such measurements is positron emission tomography (PET), which provides a low-resolution image and involves radioactive isotopes. Current 17O magnetic resonance imaging (MRI) based methods, have limitations such as low sensitivity and requirement of invasive procedure and requirement of ultra-high magnetic fields. These limitations, coupled with the high cost of 17O2 gas, limit the applicability of direct 17O MRI methods to small animal studies. Consequently, there are no non-invasive methods for measuring oxygen consumption in humans in vivo combining safety with high spatial and temporal resolution. This proposal deals with the development of an integrated approach that combines an efficient 17O2 gas delivery system with improved, noninvasive, MRI strategies for computing cerebral metabolic rate of oxygen consumption (CMRO2). Specifically, an efficient 17O2 gas delivery system, that reduces the 17O2 gas requirement by an order of magnitude will be designed and optimized for use on large animals and in humans. Efficacy of this system will be tested on a swine model. MRI methods will be designed to measure arterial input function of metabolically produced water (mpH217O) and cerebral blood flow. Finally, the above-mentioned system and MRI techniques will be integrated into an improved MRI strategy for measuring mpH217O to compute CMRO2 in the brain in vivo. Once the aims are accomplished, a noninvasive tool will become available to measure CMRO2 with high spatial resolution, which can be immediately extended to in vivo human studies. This approach will have substantial impact on the both scientific and clinical studies of neurological disorders and in the development and evaluation of novel therapies.