Measuring extracellular human brain pH and amino acid metabolism with hyperpolarized pyruvate

Hyperpolarized carbon-13 MRI has shown promise for non-invasive assessment of the cerebral metabolism of [1-13C]pyruvate in both healthy volunteers and in patients. Exchange of pyruvate to lactate catalyzed by lactate dehydrogenase (LDH), and 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 other metabolic reactions in the human brain. Approximately 50 s after intravenous injection of hyperpolarized pyruvate, high flip angle pulses were used to detect cerebral 13C-labelled carbon dioxide (13CO2), in addition to the 13C-bicarbonate (H13CO2-) subsequently formed by carbonic anhydrase. Brain pH weighted towards the extracellular compartment was calculated from the ratio of H13CO3- to 13CO2 in seven volunteers using the Henderson-Hasselbalch equation, demonstrating an average pH {+/-} S.D. of 7.40 {+/-} 0.02, with inter-observer reproducibility of 0.04. In addition, hyperpolarized [1-13C]aspartate was also detected in four of nine volunteers demonstrating irreversible pyruvate carboxylation to oxaloacetate by pyruvate carboxylase (PC), and subsequent transamination by aspartate aminotransferase (AST), with this flux being approximately 6% of that through PDH. Hyperpolarized [1-13C]alanine signal was also detected within the head but this was localized to muscle tissue in keeping with skeletal alanine aminotransferase (ALT) activity. The results demonstrate the potential of hyperpolarized carbon-13 MRI to assess cerebral and extracerebral [1-13C]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.