Measuring cerebral enzymatic activity, brain pH and extracranial muscle metabolism with hyperpolarized 13C-pyruvate

Hyperpolarized carbon-13 (C-13) magnetic resonance imaging (MRI) has shown promise for non-invasive assessment of the cerebral metabolism of [1-C-13]pyruvate in both healthy volunteers and patients. The exchange of pyruvate to lactate catalysed by lactate dehydrogenase (LDH) and that of pyruvate flux to bicarbonate through pyruvate dehydrogenase (PDH) are the most widely studied reactions in vivo. Here we show the potential of the technique to probe additional enzymatic activity within the brain. Approximately 50 s after intravenous injection of hyperpolarized pyruvate, high-flip-angle pulses were used to detect cerebral C-13-labelled carbon dioxide ((CO2)-C-13), in addition to the C-13-bicarbonate ((HCO3)-C-13 (-)) subsequently formed by carbonic anhydrase (CA). Brain pH measurements, which were weighted towards the extracellular compartment, were calculated from the ratio of (HCO3)-C-13 (-) to (CO2)-C-13 in seven volunteers using the Henderson-Hasselbalch equation, demonstrating an average pH +/- SD of 7.40 +/- 0.02, with inter-observer reproducibility of 0.04. In addition, hyperpolarized [1-C-13]aspartate was also detected, demonstrating irreversible pyruvate carboxylation to oxaloacetate by pyruvate carboxylase (PC) and subsequent transamination by aspartate aminotransferase (AST), with the average flux being on average 11% +/- 3% of that through PDH. A hyperpolarized [1-C-13]alanine signal was also detected, but this was localized to extracranial muscle tissue in keeping with skeletal alanine aminotransferase (ALT) activity. The results demonstrate the potential of hyperpolarized C-13-MRI to assess cerebral and extracerebral [1-C-13]pyruvate metabolism in addition to LDH and PDH activity. Non-invasive measurements of brain pH could be particularly important in assessing cerebral pathology given the wide range of disease processes that alter acid-base balance.