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Magnetic resonance imaging of glutamate

Nature Medicine volume 18, pages 302–306 (2012)Cite this article

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Abstract

Glutamate, a major neurotransmitter in the brain, shows a pH- and concentration-dependent chemical exchange saturation transfer effect (GluCEST) between its amine group and bulk water, with potential for in vivo imaging by nuclear magnetic resonance. GluCEST asymmetry is observed ∼3 p.p.m. downfield from bulk water. Middle cerebral artery occlusion in the rat brain resulted in an ∼100% elevation of GluCEST in the ipsilateral side compared with the contralateral side, predominantly owing to pH changes. In a rat brain tumor model with blood-brain barrier disruption, intravenous glutamate injection resulted in a clear elevation of GluCEST and a similar increase in the proton magnetic resonance spectroscopy signal of glutamate. GluCEST maps from healthy human brain were also obtained. These results demonstrate the feasibility of using GluCEST for mapping relative changes in glutamate concentration, as well as pH, in vivo. Contributions from other brain metabolites to the GluCEST effect are also discussed.

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Figure 1: GluCEST: pH dependence and sensitivity.
Figure 2: GluCEST images at 7T of a phantom consisting of test tubes with different concentrations of glutamate (pH 7.0) immersed in a beaker containing PBS.
Figure 3: GluCEST mapping of healthy and ischemic rat brain.
Figure 4: GluCEST images and 1H MRS of rat brain with a tumor, before and after injection of glutamate.
Figure 5: GluCEST imaging and 1H MRS from a healthy human brain acquired at 7T.

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Acknowledgements

We gratefully acknowledge stimulating discussions with R.N. Bryan, M.D. Schnall, J.D. Glickson and W.S. Englander. We thank W. Liu and S. Pickup for their technical assistance in using the 9.4 T research scanners, W.R.T. Witschey for technical support, P. Waghray for experimental help and D. Reddy, K. Nath and T. Hiraki for help with animal models. This work was carried out at a US National Institutes of Health–supported resource, with funding from P41RR002305.

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Author notes

  1. Kejia Cai, Mohammad Haris and Anup Singh: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Radiology, Center for Magnetic Resonance and Optical Imaging, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Kejia Cai, Mohammad Haris, Anup Singh, Feliks Kogan, Hari Hariharan, John A Detre & Ravinder Reddy

  2. Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Joel H Greenberg & John A Detre

  3. Department of Radiology, Center for Functional Neuroimaging, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    John A Detre

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Contributions

K.C., M.H. and A.S. designed and performed experiments, analyzed data and wrote the manuscript; F.K. did experiments and helped with manuscript editing; J.H.G. helped with rat studies and manuscript editing; J.A.D. advised on neuroimaging aspects and contributed to the manuscript editing; H.H. provided pulse sequence design and technical guidance and contributed to the manuscript writing; R.R. provided conception and overall experimental design and contributed to manuscript writing and editing.

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Correspondence to Ravinder Reddy.

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Cai, K., Haris, M., Singh, A. et al. Magnetic resonance imaging of glutamate. Nat Med 18, 302–306 (2012). https://doi.org/10.1038/nm.2615

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