Imaging Brain Deoxyglucose Uptake and Metabolism by Glucocest MRI

Abstract

1,4,52-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. Keywords: 2-deoxyglucose; glucose; glucoCEST; magnetic resonance imaging; metabolism INTRODUCTIONThe rate of glucose uptake and its conversion into subsequent metabolites are important biomarkers of cellular function. Since the seminal work of Sokoloff et al, 1 isotopically labeled 2-deoxy-Dglucose (2DG) has been established as a way to measure glucose metabolism; this is based on the observation that 2DG enters cells by the same transporters as glucose (e.g., mostly GLUT-1 and GLUT-3 in the brain). It is phosphorylated by hexokinase into 2DG-6-phosphate (2DG6P) but only minimally metabolized further via glucose-6-phosphate dehydrogenase in the oxidative pentose phosphate pathway, and glucose-6-phosphate isomerase in the glycolytic pathway, because of the lack of a hydroxyl group on carbon atom 2 (C2). As the amount of glucose-6-phosphatase that catalyzes the hydrolysis of 2DG6P to 2DG is low in mammalian brain, and having low membrane permeability 2DG6P becomes trapped in brain cells for many hours.2 By quantifying the amount of 2DG and 2DG6P, the glucose metabolic rate can be estimated via compartmental modeling.

Advanced MR Methods in Differential Diagnosis of Brain Tumors

“…Consequently, most applications on human brain tumors are focused on mobile proteins and polypeptides, measuring either their concentrations or tumor environmental changes which can modify the exchange rate (Zhou et al 2003a;Togao et al 2014). Amino and hydroxyl protons usually fall in the slow to medium exchange regime (Δω/k exchange ~ 1), but it has been shown that glucose and glycogen can be detected with CEST in animal models at high magnetic field strengths (>9 T, (Chan et al 2012;Nasrallah et al 2013;van Zijl et al 2007)). Recently it was proposed that spin-locking (SL) techniques are more suited for the intermediate exchange regime (Lin et al 2011;Jin et al 2012) and pilot studies could detect myoinositol (Haris et al 2011) and glutamate (Cai et al 2012) using this method.…”

“…An increased uptake of glucose in PET is a typical finding in malignant brain tumors. First results indicate that glucose concentrations can be detected by CEST via the hydroxyl protons (glucoCEST) (Nasrallah et al 2013). Significant enhancement of the glucoCEST signal has been found upon systemic glucose infusion in an experimental study with breast cancer cells (Chan et al 2012).…”

“…A CEST effect is observed when the off-resonance frequency matches the MR frequency of a metabolite proton which is exchanging with the water protons at an appropriate rate. By varying the frequency, power, and timing of the saturation pulses, CEST contrast can be tuned to signals from endogenous mobile proteins and peptides (amide proton transfer, APT) (Zhou et al 2003a, b) to amino protons of glutamate (gluCEST) (Cai et al 2012) or to hydroxyl protons like those from glucose (glucoCEST) (Chan et al 2012;Nasrallah et al 2013). Since the basic principle of the contrast relies on proton exchange with the solvent and therefore depends on the concentration of solvent protons, the method allows to measure tissue pH (Zhou et al 2003b).…”

Multiparametrische und molekulare Bildgebung von Brusttumoren mit MRT und PET‑MRT

“…apoptotischen und/oder nekrotischen Tumorarealen und aktivem Tumor mög-lich [41]. Nach intravenöser Applikation von Glukose kann mit CEST-(glucoCEST-)ähnlicher FDG-PET eine nichtinvasive Evaluation des Gewebsglukosestoffwechsels vorgenommen werden [42]. Es sind jedoch weitere Studien notwendig, um das wahre Potenzial der CEST-Bildgebung in der Mammadiagnostik zu erforschen.…”

Imaging and spectroscopic approaches to probe brain energy metabolism dysregulation in neurodegenerative diseases

“…saturation intensity, offset and duration), it is possible to probe different exchanging protons. CEST offers the possibility to detect metabolites such as glutamate 91 , glucose 92,93 and myo-inositol 94 . These endogenous molecules can be used to explore energy metabolism in ND as non-invasive biomarkers, as they are involved in many biological pathways.…”