Figure 5.

Simplified schematic of different metabolites and processes in the brain that can be interrogated using ¹H MRS, ³¹P MRS, ¹³C MRS, and DNP ¹³C MRS. ¹H and ³¹P MRS show endogenous metabolites; ¹³C MRS requires exogenous ¹³C-enriched substrate, while for DNP ¹³C MRS the exogenous ¹³C-enriched substrate is hyperpolarized before administration, transiently boosting ¹³C signal. Pathways include uptake of glucose that is metabolized via glycolysis in the cytosol [with a low yield of ATP per mole of glucose consumed] producing pyruvate. Pyruvate can enter mitochondria where it is converted into acetyl-CoA that enters the TCA cycle. Pyruvate remaining in the cytosol can be converted into lactate, simultaneously recycling NADH into NAD⁺ allowing glycolysis to continue. The rate of glucose uptake and glycolysis can be interrogated with ¹³C MRS (glucose and lactate appearance) whereas the relative flux of “anaerobic” metabolism vs. aerobic mitochondrial metabolism can be measured with DNP ¹³C MRS (lactate vs. ${\text{HCO}}_{\text{3}}^{-}$) and ¹H MRS (lactate). The TCA cycle drives the mitochondrial electron transport chain for high-yield ATP synthesis. The rate of the TCA cycle can be calculated by the rate of appearance of ¹³C labeled glutamate (Glu) (¹³C MRS) and ATP produced measured with ³¹P MRS (γ-ATP, β-ATP, and Pi). Neuronal integrity and mitochondrial function can be measured indirectly by detection of NAA with ¹H MRS (and ¹³C MRS). Neuronal–glial coupling is represented by Glu–glutamine (Gln) cycling detected by ¹³C MRS, whereas total combined Glu and Gln that may be raised in pathological excitotoxicity can be measured with ¹H MRS. Cell membrane integrity and damage and turnover may be represented by ¹H MRS (choline and lipid) and ³¹P MRS (PME/PDE ratio), which also can detect the balance and consumption of high-energy phosphates (ATP, PCr, and Pi). Further details of the above, and other MRS-detectable molecules (including creatine, myoinositol, glycogen, and nicotinamide-adenine dinucleotides), can be found in the text. Abbreviations: ADP, adenosine diphosphate; ATP, adenosine triphosphate; Cr, creatine; DNP, dissolution dynamic nuclear polarization; GABA, gamma-aminobutyric acid; NAA, N-acetylaspartate; MRS, magnetic resonance spectroscopy; NAD⁺, nicotinamide adenine dinucleotide oxidized form; NADH, nicotinamide adenine dinucleotide reduced form; PCr, phosphocreatine; PDE, phosphodiester; PME, phosphomonoester; Pi, inorganic phosphate; PPP, pentose phosphate pathway; TCA, tricarboxylic acid.