Efficient in vivo 31P magnetization transfer approach for noninvasively determining multiple kinetic parameters and metabolic fluxes of ATP metabolism in the human brain

Abstract

ATP metabolism is controlled mainly by ATP synthase (ATP(ase)) and creatine kinase (CK) reactions that regulate cerebral ATP production, transportation, and utilization. These coupled reactions constitute a chemical exchange metabolic network of PCr<-->ATP<-->Pi characterized by two forward and two reverse reaction fluxes, which can be studied noninvasively by in vivo (31)P MRS combined with magnetization transfer (MT). However, it is still debated whether current MT approaches can precisely determine all of these fluxes. We developed and tested a modified in vivo (31)P MT approach based on a multiple single-site saturation (MSS) technique to study the entire PCr<-->ATP<-->Pi network in human occipital lobe at 7T. Our results reveal that 1) the MSS MT approach can explicitly determine all four reaction fluxes with a minimal number of (31)P spectra; 2) the three-spin exchange model accurately determines reverse reaction fluxes, resulting in equal forward and reverse fluxes for both CK and ATP(ase) reactions; and 3) the ATP synthesis rate (8.8 +/- 1.9 micromol/g/min, N = 11) measured in the human brain reflects cerebral oxidative phosphorylation. The MSS MT approach should provide an important modality for noninvasively studying the essential roles of ATP metabolism in brain bioenergetics, function, and diseases.