Imaging brain deoxyglucose uptake and metabolism by glucoCEST MRI

Abstract

2-Deoxy-D-glucose (2DG) is a known surrogate molecule that is useful for inferring glucose uptake and metabolism. Although (13)C-labeled 2DG can be detected by nuclear magnetic resonance (NMR), its low sensitivity for detection prohibits imaging to be performed. Using chemical exchange saturation transfer (CEST) as a signal-amplification mechanism, 2DG and the phosphorylated 2DG-6-phosphate (2DG6P) can be indirectly detected in (1)H magnetic resonance imaging (MRI). We showed that the CEST signal changed with 2DG concentration, and was reduced by suppressing cerebral metabolism with increased general anesthetic. The signal changes were not affected by cerebral or plasma pH, and were not correlated with altered cerebral blood flow as demonstrated by hypercapnia; neither were they related to the extracellular glucose amounts as compared with injection of D- and L-glucose. In vivo (31)P NMR revealed similar changes in 2DG6P concentration, suggesting that the CEST signal reflected the rate of glucose assimilation. This method provides a new way to use widely available MRI techniques to image deoxyglucose/glucose uptake and metabolism in vivo without the need for isotopic labeling of the molecules.

Figures

Figure 1

Chemical exchange saturation transfer z-spectra of: (A) 2-deoxy-D-glucose (2DG); and (B) 2DG-6-phosphate (2DG6P) with concentrations (mmol/L) of 100 (red), 75 (blue), 50 (purple), 25 (green), 12.5 (gray), and 6.25 (black) in phosphate-buffered saline buffer (pH=7.4) measured at 37°C on the 400.13 MHz nuclear magnetic resonance spectrometer. The insets are the corresponding MTRasym plots. (C) The MTRasym of 2DG and 2DG6P at 1 p.p.m. increased linearly with concentration until ∼75 mmol/L and 100 mmol/L, respectively.

Figure 2

(A) Dynamic glucoCEST images of rat brains before and after a 1.0 (top) and 0.5 (bottom) g/kg 2-deoxy-D-glucose (2DG) injection showed high signal increases in the cortex and thalamus. The image intensity represents relative glucoCEST signal change from the baseline (color scale between ±100%). (B) Examples of 31P magnetic resonance spectra of a rat brain before and ∼38 minutes after injection of 1.0 g/kg 2DG. Especially note the resonance assigned to 2DG-6-phosphate (2DG6P) at 7.2 p.p.m.

Figure 3

Time courses of: (A) glucoCEST signal; (B) 2DG-6-phosphate measured by 31P magnetic resonance spectra and (C) arterial blood glucose after injection of 1.0 (red) and 0.5 (blue) g/kg 2-deoxy-D-glucose. The glucoCEST signal represents the difference of MTRasym integral around 1.0 p.p.m. from the baseline signal. Error bars denote standard error of the mean.

Figure 4

(A) Time series of glucoCEST images of rat brain under constant infusion of D-glucose (top), after bolus injection of 1 g/kg D-glucose (middle), and after bolus injection of 1 g/kg L-glucose (bottom). The image intensity represents relative glucoCEST signal change from the baseline. (B) Time courses of glucoCEST signal under the above three injection conditions in (A). The signal represents the difference of MTRasym integral around 1.0 p.p.m. from the baseline signal. (C) Arterial blood glucose with constant infusion (blue) and bolus injection (red) of D-glucose. Error bars denote standard error of the mean.

Figure 5

(A) Examples of glucoCEST images under 1.0%, 1.5%, and 2.0% isoflurane (top to bottom) anesthesia. Time courses of (B) glucoCEST signal, and (C) 2DG-6-phosphate measured by 31P magnetic resonance spectra after injecting 0.5 g/kg of 2-deoxy-D-glucose under 1.0% (blue), 1.5% (red), and 2.0% (green) isoflurane. Error bars denote standard error of the mean.

Figure 6

Time courses of: (A) glucoCEST signal; and (B) 2DG-6-phosphate measured by 31P magnetic resonance spectra after injecting 0.5 g/kg of 2-deoxy-D-glucose (2DG) under hypercapnia (red) and normocapnia (blue). (C) The MTRasym of 50 mmol/L 2DG in phosphate-buffered saline (blue), of human erythrocytes (red blood cells (RBCs); gray), of 50 mmol/L 2DG mixed with RBCs (green), 50 mmol/L of 2DG in RBCs (red), and 50 mmol/L of 2DG in plasma (orange). Error bars denote standard error of the mean.