Increase in glutamate as a sensitive indicator of extracellular matrix integrity in peritumoral edema: a 3.0-tesla proton magnetic resonance spectroscopy study

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Object

The authors of previous studies based on diffusion tensor imaging have indicated that there are two types of peritumoral edema—namely, edema with preserved structural integrity of the glial matrix and edema with compromised glial matrix. The authors of this study hypothesized that functionality of the glutamate (Glu)–glutamine shuttle, a vital neuron–glia interaction, may be differentially affected by peritumoral edema. They tested this hypothesis using proton magnetic resonance (MR) spectroscopy on a 3.0-tesla system that is capable of quantifying Glu without need of editing.

Methods

Twenty-three patients, each with a single brain tumor mass and peritumoral edema (nine high-grade gliomas, eight metastatic brain tumors, and six meningiomas), and nine healthy individuals participated in this study. Single-voxel proton MR imaging targeting the region of peritumoral edema was performed using a 3.0-tesla system.

Glutamate levels in the peritumoral edema of nonglial tumors was significantly elevated (p < 0.01) compared with edema associated with glial tumors or normal white matter. The finding confirmed that peritumoral edema in nonglial tumors is distinct from that of glial tumors, as previously indicated in diffusion tensor imaging studies. The authors hypothesized that the former condition represents a compensatory increase in activities of the Glu–glutamine shuttle brought about by simple expansion of the extracellular space due to edema.

Conclusions

The assessment of Glu concentrations in peritumoral edema using 3.0-tesla proton MR spectroscopy may be developed into an objective index of the structural integrity of the glial matrix.

Abbreviations used in this paper:Cho = choline; Cr = creatine; Glu = glutamate; MR = magnetic resonance; NAA = N-acetylaspartate.

Article Information

Current address for Dr. Kimura: Department of Neurosurgery, Abashiri Neurosugical Rehabilitation Hospital, Abashiri-shi, Hokkaido, Japan.

Address reprint requests to: Tsutomu Nakada, M.D., Ph.D., Center for Integrated Human Brain Science, Brain Research Institute, University of Niigata, 1 Asahimachi, Niigata 951-8585, Japan. email: tnakada@bri.niigata-u.ac.jp.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    Representative proton MR spectroscopy spectra of normal white matter and peritumoral edema associated with high-grade glioma, metastatic cancer, and meningioma. Asterisk indicates another resonance for NAA.

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    Summary of quantitative analysis. Areas of representative resonances for NAA, Cho compounds, and Glu were determined by integration and normalized to that of the Cr resonance. To correlate previously reported findings based on diffusion tensor imaging, peritumoral edema was categorized into two groups: glial and nonglial tumor. Glutamate (A; Glu/Cr) is significantly higher in the nonglial tumor group compared with normal and glial tumor groups (p < 0.01). The level of NAA (B; NAA/Cr) is significantly reduced in edema of both glial and nonglial tumors (p < 0.01). Choline compounds (C; Cho/Cr) are not associated with any significant differences among the three groups, but have a higher mean concentration in the glial tumor group. Bars indicate the range of standard deviations. WM = white matter.

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    Schematics of the Glu–glutamine shuttle. A: Normal. Excitation of glutamatergic neurons releases Glu into synaptic clefts. Termination of glutamatergic neurotransmission relies on specific transporters that clear the synaptic cleft. Glutamate transporters are present in neurons (shown as EAAC) and astrocytes ensheathing the synapses (shown as GLT). Under normal conditions, astrocytic Glu transporters play an essential, if not singular, role in clearing Glu out of synaptic clefts. Glutamate is then converted into glutamine, which is delivered into the extracellular space, and enters the neuron to be converted to Glu. B: Peritumoral edema around nonglial tumors. In simple expansion of the synaptic cleft due to vasogenic edema with relatively intact Glu–glutamine shuttle, a compensatory increase in Glu release occurs. Subsequently, Glu accumulation, and to some extent glutamine as well, results within the expanded extracellular space. C: Peritumoral edema around high-grade glioma. Glioma cells infiltrate into normal brain tissue and disrupt the structural integrity of the glial matrix. Because glioma cells have only trace levels of Glu transporter and lack significant glutamine synthetase activity, the Glu concentrations remain low. ATP = adenosine triphosphate; SAT = system A transporter; SN = system N transporter; TCA = tricarboxylic acid cycle.

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