MR spectroscopic imaging of glutathione in the white and gray matter at 7 T with an application to multiple sclerosis

doi:10.1016/j.mri.2009.06.008

Magnetic Resonance Imaging

Volume 28, Issue 2, February 2010, Pages 163-170

https://doi.org/10.1016/j.mri.2009.06.008 Get rights and content

Abstract

Detection of glutathione (GSH) is technically challenging at clinical field strengths of 1.5 or 3 T due to its low concentration in the human brain coupled with the fact that conventional single-echo acquisitions, typically used for magnetic resonance (MR) spectroscopy acquisitions, cannot be used to resolve GSH given its overlap with other resonances. In this study, an MR spectral editing scheme was used to generate an unobstructed detection of GSH at 7 T. This technique was used to obtain normative white (WM) and gray matter (GM) GSH concentrations over a two-dimensional region. Results indicated that GSH was significantly higher (P<.001) in GM relative to WM in normal subjects. This finding is consistent with previous radionuclide experiments and histochemical staining and validates this 7 T MR spectroscopy technique. To our knowledge, this is the first study to report normative differences in WM and GM glutathione concentrations in the human brain. Glutathione is a biomarker for oxidative status and this non-invasive in vivo measurement of GSH was used to explore its sensitivity to oxidative state in multiple sclerosis (MS) patients. There was a significant reduction (P<.001) of GSH between the GM in MS patients and normal controls. No statistically significant GSH differences were found between the WM in controls and MS patients. Reduced GSH was also observed in a MS WM lesion. This preliminary investigation demonstrates the potential of this marker to probe oxidative state in MS.

Introduction

Detection of glutathione (GSH) at clinical field strengths of 1.5 or 3 T has been difficult due to its low concentration (1–5 mM) in the normal brain. In a proton MR spectrum, the GSH resonance overlaps strongly with N-acetyl-aspartate (NAA), creatine, glutamate, lipids and macromolecular compounds so that even with increased frequency dispersion at 7 T, it cannot be isolated with single echo acquisitions. Studies using spectral editing schemes, such as MEGA-PRESS J-difference editing have been used for the detection of GSH at 4 T from a single voxel [1] spectrum.

The performance of spectral editing techniques improves with field strength due to increased frequency separation between metabolites allowing greater selectivity of the metabolite of interest. Recent studies using 7 T 1H MRS have reported linear gains in signal-to-noise ratio (SNR) with field strength. While the spectral linewidth, when measured in Hz increases with field strength due to T2 line broadening, there is a decrease in the ppm spectral linewidth [2]. Improved spectral resolution of the multiplet structure has been shown to enhance the quantification precision of myoinositol at 3 T relative to 1.5 T [3]. Increasing field strength also enhances the quantification of metabolites [4]. Hence, here, we develop a technique for GSH measurement at 7 T.

The motivation to develop this technique is that GSH is an indicator of oxidative status in the human brain. The antioxidant GSH (γ-glutamyl-cysteinyl glycine) is essential for detoxification of reactive oxygen species in brain cells [5]. The GSH S-transferase (GST) supergene family encodes isoenzymes such as GSH that are critical in the protection of cells against products of oxidative stress [6]. It has been shown that long-term prognosis and disability in multiple sclerosis (MS) is influenced by a genetically determined ability to remove toxic products of oxidative stress [7]. Genetic markers of GST were differentially expressed in chronic and acute plaque tissue relative to MS white matter (WM) [8]. Recent studies [9] have shown an increase in GSH is stimulated by extra-cellular glutamate indicating that GSH might also have a neuroprotective role to minimize Glutamate toxicity, which is a known mechanism of neurodegeneration. Hence, it is relevant to have a noninvasive measure of GSH that could be used as a marker for disease phenotype in MS.

In this study we report the unobstructed in vivo detection and quantification of GSH at 7 T over a two-dimensional region with proton MR spectroscopic imaging (MRSI) using a spectral editing scheme called band selective inversion with gradient dephasing (BASING) [10]. Normative estimates of GSH in WM and gray matter (GM) in normal subjects were compared to estimates of GSH in the normal-appearing WM (NAWM) and normal-appearing GM (NAGM) in a group of patients with MS.

Section snippets

Study population

Data from six normal volunteers and seven patients with MS are reported in this study. Two normal subjects were scanned twice to determine the reproducibility of the overall technique.

Study protocol

All experiments were performed on a 7 T GE Signa scanner (GE Healthcare, Waukesha) using an eight-channel phased-array (Nova Medical, Wilmington, MA, USA) receive coil. High-resolution anatomical images (512×512, 18 cm FOV, NEX=3, TE/TR=11/250 ms, 2/6-mm slice/gap) were acquired to prescribe the single spectral

Results

Fig. 1 shows the inversion profile of the spectral editing pulse that was used to selectively suppress the CH-GSH at 4.56 ppm on alternate scans and refocus the CH2-GSH resonance at 2.95 ppm. The sharp transition width of this pulse ensures that the application of this pulse has negligible affect on passband metabolites under investigation. This pulse was incorporated into the PRESS acquisition (Fig. 2) to generate the spectral editing acquisition used in this study. Fig. 3 demonstrates the

Discussion

In this study we report the unobstructed detection of GSH at 2.95 ppm that is well resolved from Creatine. Two-dimensional spectroscopic imaging allows a more accurate investigation of GSH in both the WM and GM. To our knowledge, this is the first study to report normative differences in WM and GM GSH concentrations in the human brain and also the first study to probe oxidative stress in MS using in vivo MR spectroscopy of GSH, an important biomarker for oxidative status in the human brain.

Conclusions

Spectral editing proton MR spectroscopic imaging technique was used to provide an unobstructed detection of GSH at 7 T over a two-dimensional region of interest. High SNR of detection of a low concentration metabolite like GSH demonstrates the sensitivity and potential of 7T MRSI. This technique was used in normal subjects to report significant elevation in GSH concentrations in the normal GM relative to WM. This finding is consistent with radionuclide experiments and demonstrates the validity

Acknowledgments

The author (R.S.) would like to thank Dr. Douglas Kelley (GE Healthcare) for helping with issues related to the 7 T system. This study was supported by the UC Industry-University Cooperative Research Program, ITL-BI004-10148, sponsored by the State of California in conjunction with GE Healthcare, National MS Society pilot grant (PP1182) and NIH/NCRR UCSF-CTSI Grant Number UL1 RR024131-01 and the UCSF Research Evaluation and Allocation Committee (REAC) grant.

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MR spectroscopic imaging of glutathione in the white and gray matter at 7 T with an application to multiple sclerosis

Abstract

Introduction

Section snippets

Study population

Study protocol

Results

Discussion

Conclusions

Acknowledgments

Brain Res Mol Brain Res

J Magn Reson

JMagn Reson

J Magn Reson

Neuroimage

J Neurol Sci

Measurement of reduced glutathione (GSH) in human brain using LCModel analysis of difference-edited spectra

Magn Reson Med

Signal-to-noise ratio and spectral linewidth improvements between 1.5 and 7 Tesla in proton echo-planar spectroscopic imaging

Magn Reson Med

A comparative study of myo-inositol quantification using LCmodel at 1.5T and 3.0T with 3D 1H proton spectroscopic imaging of the human brain

MRI

Glutathione pathways in the brain

Biol Chem

Glutathione S-transferase polymorphisms and their biological consequences

Pharmacology

Glutathione S-transferase polymorphisms in MS: their relationship to disability

Neurology

Glutamate induces release of glutathione from cultured rat astrocytes — a possible neuroprotective mechanism?

J Neurochem

Improved water and Lipid suppression for 3D PRESS CSI using RF band selective inversion with gradient dephasing (BASING)

Magn Reson Med

Imaging of the active B1 field in vivo

Magn Reson Med