Noninvasive Study of Cerebral ATP Metabolism, Bioenergetics and Brain Function

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.