Noninvasive Study of Cerebral ATP Metabolism, Bioenergetics and Brain Function

描述(申请人提供)：能量新陈代谢是生命的基本过程。三磷酸腺苷(ATP)为静息和激活的大脑中的大多数细胞活动提供能量。最近发展起来的光学和磁共振(MR)神经成像方法使我们研究大脑的能力发生了革命性的变化，并重新激发了我们对涉及正常大脑功能和大脑疾病的脑生物能量学的兴趣。然而，这些方法依赖于由神经元活动引起的次级代谢和生理过程，并不提供细胞能量学的直接测量。在过去的几年里，我们开展了一系列的研究，证明了活体31P磁共振波谱与超高场磁化转移(MT)技术相结合直接测量大脑氧化磷酸化速率的能力和可行性。这些引人注目的发展形成了我们的核心假设：在体内，31P MT法适合测量和定量成像由PI和ADP合成的大脑ATP的净代谢率(CMRATP)，而MR测得的速率由氧化磷酸化速率主导，氧化磷酸化速率直接反映了线粒体中电子传递链与F1F0-ATPase反应的耦合效率与大脑耗氧速率(CMRO2)之间的乘积；体内这种方法的验证和建立，以及与CMRO2的直接测定结合使用，将为以非侵入性方式研究ATP氧化代谢在调节与大脑功能和功能障碍相关的神经能量学中的核心作用提供宝贵的神经成像手段。为了验证这一假设，我们建议：1)进一步改进超高场下动物脑中CMRATP的体内31P MT测量和定量方法；2)在静息脑中使用高场17O MRS成像方法同时测量CMRATP和CMRO2，以检查测量的31P MT是否与根据相应的CMRO2和P：O比率估计的净氧化磷酸化速率相匹配，以及它是否对大生理范围内的脑活动水平敏感；3)利用视觉刺激进行功能研究，以检查激活的视皮层中的CMRATP是否增加以支持更高的能量需求和刺激诱发的神经元活动；4)在静息和刺激的动物脑中进行细胞外神经元记录研究，并将电生理学结果与CMRATP结果进行关联，以提供对神经-ATP-代谢耦合关系的新见解。这项研究的意义在于两个层面：建立一种独特的神经成像模式来成像CMRATP：一种基本和直接的脑ATP能量测量方法；以及了解氧化ATP代谢在神经能量学和神经生理学中支持正常脑功能的可能作用。公共卫生相关性：线粒体中的氧化磷酸化缺陷与许多脑部疾病有关，特别是神经退行性和衰老问题。尽管这项建议的主要目的并不直接解决具体的临床问题，但这项研究项目的成功将为各种大脑疾病和神经退行性疾病的潜在临床研究和诊断提供一个强大的成像工具。

DESCRIPTION (provided by applicant): Energy metabolism is a fundamental process of life. Adenosine triphosphate (ATP) provides energy for most cellular activities in resting and activated brain. Recently developed optical and magnetic resonance (MR) Neuroimaging methods have revolutionized our ability to study the brain and renewed our interests in cerebral bioenergetics involving normal brain function and brain disease. However, these methods rely on secondary metabolic and physiologic processes invoked by neuronal activity and do not provide direct measure of the cellular energetics. In last few years, we have carried out a series of studies, which demonstrated the capability, and feasibility of the in vivo 31P MR spectroscopy in combined with magnetization transfer (MT) techniques at ultrahigh field for directly measuring the oxidative phosphorylation rate in the brain. These compelling developments have led to our central hypothesis: In vivo 31P MT approach is suitable for measuring and quantitatively imaging the net cerebral metabolic rate of ATP synthesis from Pi and ADP (CMRATP) and this MR measured rate is dominated by the rate of oxidative phosphorylation which directly reflects the product between the coupling efficiency of the electron transport chain to the F1F0-ATPase reaction in the mitochondria and the rate of cerebral oxygen consumption (CMRO2); the validation and establishment of this in vivo approach, and its use in conjunction with direct determinations of CMRO2 will provide an invaluable Neuroimaging modality for noninvasively studying the central role of oxidative ATP metabolism in regulating neuroenergetics associated with brain function and dysfunction. To test this hypothesis we propose: 1) to further improve in vivo 31P MT measurements and quantification methods for accurately determining CMRATP in animal brain at ultrahigh field; 2) to conduct concurrent measurements of CMRATP and CMRO2 using high-field in vivo 17O MRS imaging approach in resting brain to examine if the 31P MT measured CMRATP matches the net oxidative phosphorylation rate estimated from the corresponding CMRO2 and the P:O ratio, and if it is sensitive to the brain activity level under a wide physiological range; 3) to conduct functional studies using visual stimulation to examine if CMRATP increases in the activated visual cortex for supporting higher energy demand and stimulus-evoked neuronal activity; 4) to conduct extracellular neuron-recording studies in resting and stimulated animal brain, and to correlate electrophysiology results with CMRATP results for providing new insights into the neuro-ATP-metabolic coupling relationships. The significance of this research lies in two layers: to establish a unique Neuroimaging modality for imaging CMRATP: a fundamental and direct measure of brain ATP energy; and to understand the possible roles of oxidative ATP metabolism in neuroenergetics and neurophysiology for supporting normal brain function. PUBLIC HEALTH RELEVANCE: The oxidative phosphorylation deficit in mitochondria has been linked to numerous brain diseases, in particular, the neurodegenerative and aging problems. Although, the main objective of this proposal does not directly address specific clinical questions, the success of this research project would provide a powerful imaging tool for potential clinical research and diagnosis of various brain disorders and neurodegenerative diseases.