Commentary to "Task activation results in regional 13C-lactate signal increase in the human brain"

Abstract

Metabolism is fundamental to functional brain imaging. While functional MRI (fMRI) has greatly benefited neuroscience, ¹³C-MRS measures coupling between neuroenergetics and neurotransmission. However, a hyperpolarized ¹³C-MRI study in human brain shows increased ¹³C-lactate (i.e., cytosolic aerobic glycolysis) with no ¹³C-bicarbonate change (i.e., mitochondrial oxidation) within fMRI-defined activated areas. We discuss (dis)advantages of hyperpolarized vs. non-hyperpolarized ¹³C experiments and metabolic implications regarding the lactate increase: Is lactate a fuel for oligodendrocytes, astrocytes, or neurons? Is lactate a neuromodulator or a vasomodulator? Is lactate a byproduct of astrocytic glycogenolysis? Caveats aside, there is great enthusiasm for hyperpolarized ¹³C-fMRI.

Keywords: Calibrated fMRI; excitation; glucose; glycogen; inhibition; lactate; oxygen.

Figure 1.

Schematic of a hyperpolarized ¹³C experiment. (a) Process of dissolution dynamic nuclear polarization (dDNP) in a polarizer (e.g., SPINlab by GE), involving transferring polarization from an electron-rich compound (electron paramagnetic agent) to ¹³C-pyruvate under conditions of absolute zero (∼1 K) in presence of a strong magnetic field (3.35–7T) during microwave irradiation. Hyperpolarized ¹³C-pyruvate is mixed with heated water and (b) injected intravenously for (c) imaging in an MRI scanner. (d) Hyperpolarized ¹³C-pyruvate is transported by monocarboxylate transporters (MCTs) across compartments to undergo metabolism, forming ¹³C-lactate by lactate dehydrogenase (LDH) in cytosol of neurons/astrocytes, whereas in mitochondria ¹³CO₂ is generated by pyruvate dehydrogenase (PDH) activity and ¹³C-bicarbonate is made by carbonic anhydrase (CA) of neurons/astrocytes. Despite transitory nature of hyperpolarized ¹³C signals, some downstream metabolites in tricarboxylic acid (TCA) cycle are detectable due to pyruvate carboxylase (PC) activity, which in the brain is located within astrocytes. (e) Spectrum of typical hyperpolarized ¹³C signals, where ¹³C-alanine (catalyzed by alanine aminotransferase) and ¹³C-pyruvate hydrate (metabolically inactive) were not imaged by Uthayakumar et al. (f). Kinetic profiles of hyperpolarized ¹³C signals, all of which must be measured within 2 minutes of the bolus injection. Figures A, E, F are from Vaeggemose et al., which allows sharing of all content because it is an open access article.