Comparing the reproducibility of commonly used magnetic resonance spectroscopy techniques to quantify cerebral glutathione

Wijtenburg, S. Andrea; Near, Jamie; Korenic, Stephanie A.; Gaston, Frank; Chen, Hongji; Mikkelsen, Mark E.; Chen, Shuo; Kochunov, Peter; Hong, L. Elliot; Rowland, Laura M.

doi:10.1002/jmri.26046

Cited by 33 publications

(45 citation statements)

References 39 publications

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“…Despite this fact, the findings of this study indicate moderate to strong reliability of GSH measures in the DLPFC and M1 using the unedited MP‐off and SP methods, thus suggesting that conventional, unedited measures of GSH may have good precision. This finding is supported by a recent study which found good test–retest reproducibility for short echo‐time MRS measures of GSH . Correlations for the MP‐diff measures of GSH were generally poor, suggesting that quantification of the co‐edited GSH signal in GABA‐editing experiments is not reliable.…”

Section: Discussionsupporting

confidence: 55%

“…This finding is supported by a recent study which found good test-retest reproducibility for short echo-time MRS measures of GSH. 45 Correlations for the MP-diff measures of GSH were generally poor, suggesting that quantification of the co-edited GSH signal in GABA-editing experiments is not reliable. Nonetheless, all three methods tested tended to be in agreement that GSH levels were higher in the DLPFC than in M1.…”

Section: Discussionmentioning

confidence: 99%

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Validation of in vivo MRS measures of metabolite concentrations in the human brain

et al. 2019

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Purpose In vivo magnetic resonance spectroscopy (MRS) is the only technique capable of non‐invasively assessing metabolite concentrations in the brain. The lack of alternative methods makes validation of MRS measures challenging. The aim of this study is to assess the validity of MRS measures of human brain metabolite concentrations by comparing multiple MRS measures acquired using different MRS acquisition sequences. Methods Single‐voxel SPECIAL and MEGA‐PRESS MR spectra were acquired from both the dorsolateral prefrontal cortex and primary motor cortices in 15 healthy subjects. The SPECIAL spectrum, as well as both the edit‐off and difference spectra of MEGA‐PRESS were each analyzed in LCModel to obtain estimates of the absolute concentrations of total choline (TCh; glycerophosphocholine + phosphocholine), total creatine (TCr; creatine + phosphocreatine), N‐acetylaspartate (NAA), N‐acetylaspartylglutamate (NAAG), NAA + NAAG, glutamate (Glu), glutamine (Gln), Glu + Gln, scyllo‐inositol (Scyllo), myo‐inositol (Ins), glutathione (GSH), γ‐aminobutyric acid (GABA), lactate (Lac) and aspartate (Asp). Then, having obtained up to three independent measures of each metabolite per brain region per subject, correlations between the different measures were assessed. Results The degree of correlation between measures varied greatly across both the metabolites and sequences tested. As expected, metabolites with the most prominent spectral peaks (TCh, TCr, NAA + NAAG, Ins and Glu) had the most well‐correlated measures between methods, while metabolites with less prominent spectral peaks (Lac, Gln, GABA, Asp, and NAAG) tended to have poorly‐correlated measures between methods. Some metabolites with relatively less prominent spectral peaks (GSH, Scyllo) had fairly well‐correlated measures between some methods. Combining metabolites improved the agreement between methods for measures of NAA + NAAG, but not for Glu + Gln. Conclusions Given that the ground truth for in vivo MRS measures is never known, the method proposed here provides a promising means to assess the validity of in vivo MRS measures, which has not yet been explored widely.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Validation of in vivo MRS measures of metabolite concentrations in the human brain

et al. 2019

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“…GGT expression is accordingly higher in cancer, including in high-grade primary glioblastoma, and non-invasive analysis of GGT activity, therefore, is associated with tumor antioxidant levels. Here we quantified GSH ex vivo, however prior work has used optimized 1 H MRS sequences to separate GSH from the overlapping glutamate and glutamine peaks and assess steady-state GSH levels in patients in vivo [52][53][54] . Consistent with our preclinical findings, these studies showed that in brain tumors GSH levels were higher than in normal-appearing brain 55,56 .…”

Section: Discussionmentioning

confidence: 99%

In vivo detection of γ-glutamyl-transferase up-regulation in glioma using hyperpolarized γ-glutamyl-[1-13C]glycine

Batsios

Najac

Cao

et al. 2020

Sci Rep

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Glutathione (GSH) is often upregulated in cancer, where it serves to mitigate oxidative stress. γ-glutamyl-transferase (GGT) is a key enzyme in GSH homeostasis, and compared to normal brain its expression is elevated in tumors, including in primary glioblastoma. GGT is therefore an attractive imaging target for detection of glioblastoma. The goal of our study was to assess the value of hyperpolarized (HP) γ-glutamyl-[1-13 C]glycine for non-invasive imaging of glioblastoma. Nude rats bearing orthotopic U87 glioblastoma and healthy controls were investigated. Imaging was performed by injecting HP γ-glutamyl-[1-13 c]glycine and acquiring dynamic 13 C data on a preclinical 3T MR scanner. The signal-to-noise (SNR) ratios of γ-glutamyl-[1-13 C]glycine and its product [1-13 c]glycine were evaluated. Comparison of control and tumor-bearing rats showed no difference in γ-glutamyl-[1-13 C]glycine SNR, pointing to similar delivery to tumor and normal brain. In contrast, [1-13 c]glycine SnR was significantly higher in tumor-bearing rats compared to controls, and in tumor regions compared to normal-appearing brain. Importantly, higher [1-13 C]glycine was associated with higher GGT expression and higher GSH levels in tumor tissue compared to normal brain. Collectively, this study demonstrates, to our knowledge for the first time, the feasibility of using HP γ-glutamyl-[1-13 c]glycine to monitor GGt expression in the brain and thus to detect glioblastoma.Redox homeostasis is essential for managing oxidative stress and ensuring cell survival. Cancer cells, in particular, are often characterized by high levels of oxidative stress. This oxidative stress is the result of reactive oxygen species (ROS) that accumulate due to a variety of factors, including rapid cell proliferation, hypoxia, metabolic reprogramming and oncogenic signaling. The tripeptide glutathione (L-γ-glutamyl-L-cysteinyl-glycine, GSH) is the most abundant, non-enzymatic antioxidant molecule present in mammalian cells and plays a crucial role in regulating tumor oxidative stress due to its role in reducing ROS 1,2 . Several tumor types, including primary glioblastomas (GBMs), are characterized by elevated GSH levels, especially under hypoxic conditions 3 . Elevated GSH levels and reduced oxidative stress have also been linked to resistance to chemotherapy in GBMs 4 .GSH import is a critical step in the maintenance of both intracellular and extracellular redox status 5,6 . Although GSH can be transported out of cells and into the extracellular environment, most cells are incapable of importing intact GSH 7 . Instead, GSH is first degraded to its constituent amino acids 7,8 and the released amino acids are then transported into the cell and used as substrates for de novo GSH synthesis 6 . Specifically, GSH degradation is initiated by cleavage of the gamma-glutamyl bond 9 via the cell surface-bound glycoprotein gamma-glutamyl transpeptidase (GGT) whose catalytic site faces the extracellular environment 7,10-12 . After removal of the glutamyl group from GSH, cysteinylg...

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“…Proton magnetic resonance spectroscopy with H 1 -MRS quantifies various cerebral metabolites in vivo (Wiebenga et al 2014) and has been utilized in the evaluation of a variety of diseases including neurodegenerative (Alzheimer's disease; amyotrophic lateral sclerosis), psychiatric diseases (schizophrenia; depression) (Wijtenburg et al 2019), and brain trauma (Wu et al 2016). Cerebral metabolites are believed to correlate with cerebral cellular changes and/or injury.…”

Section: Spectroscopy (H 1 -Mrs)mentioning

confidence: 99%

“…Cerebral metabolites are believed to correlate with cerebral cellular changes and/or injury. Reproducibility of H 1 -MRS is high (Busch et al 2015;McGuire et al 2017b;Wijtenburg et al 2019).…”

Section: Spectroscopy (H 1 -Mrs)mentioning

confidence: 99%

Structural Brain Changes Associated with Space

McGuire¹

2020

Handbook of Space Pharmaceuticals

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Space flight occurs in an extremely hostile environment, one for which man is inherently poorly adapted. As the duration of flight increases, more clinical syndromes and cerebral structural changes are being described, suggesting a direct relationship to time of exposure. There is now emerging evidence for involvement of the neuro-ocular system, cerebrospinal fluid, gray matter, and white matter. A definitive pathophysiological mechanism remains elusive with investigation hampered by the limited number of study subjects, the logistical restrictions of examination during flight, the lack of terrestrial analogues, and the possible variability of individual susceptibility to the environmental challenge. The common underlying thread appears to be duration of exposure to a microgravity environment although anticipated future mission activities including frequent extravehicular activities may pose additional challenges, potentially

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Comparing the reproducibility of commonly used magnetic resonance spectroscopy techniques to quantify cerebral glutathione

Abstract: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018.

Cited by 33 publications

References 39 publications

Validation of in vivo MRS measures of metabolite concentrations in the human brain

Validation of in vivo MRS measures of metabolite concentrations in the human brain

In vivo detection of γ-glutamyl-transferase up-regulation in glioma using hyperpolarized γ-glutamyl-[1-13C]glycine

Structural Brain Changes Associated with Space

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