Genetic Polymorphism Associated Prefrontal Glutathione and Its Coupling With Brain Glutamate and Peripheral Redox Status in Early Psychosis

Xin, Lijing; Mekle, Ralf; Fournier, Margot; Baumann, Philipp S.; Ferrari, Carina; Alameda, Luis; Jenni, Raoul; Lu, Huanxiang; Schaller, Benoît; Cuénod, Michel; Conus, Philippe; Gruetter, Rolf; Q., Kim

doi:10.1093/schbul/sbw038

Cited by 89 publications

(112 citation statements)

References 61 publications

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“…Although GCLC GAG TNR polymorphism reportedly influences GSH levels in the European Caucasian population [78], we reported that specific genotypes may not have affected the levels in our study population (the group of North Americans that include African Americans) [79]. It remains elusive which genetic and/or environmental factors potentially influence the sulforaphane response in GSH levels.…”

Section: Discussionmentioning

confidence: 83%

Sulforaphane Augments Glutathione and Influences Brain Metabolites in Human Subjects: A Clinical Pilot Study

et al. 2017

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Schizophrenia and other neuropsychiatric disorders await mechanism-associated interventions. Excess oxidative stress is increasingly appreciated to participate in the pathophysiology of brain disorders, and decreases in the major antioxidant, glutathione (GSH), have been reported in multiple studies. Technical cautions regarding the estimation of oxidative stress-related changes in the brain via imaging techniques have led investigators to explore peripheral GSH as a possible pathological signature of oxidative stress-associated brain changes. In a preclinical model of GSH deficiency, we found a correlation between whole brain and peripheral GSH levels. We found that the naturally occurring isothiocyanate sulforaphane increased blood GSH levels in healthy human subjects following 7 days of daily oral administration. In parallel, we explored the potential influence of sulforaphane on brain GSH levels in the anterior cingulate cortex, hippocampus, and thalamus via 7-T magnetic resonance spectroscopy. A significant positive correlation between blood and thalamic GSH post- and pre-sulforaphane treatment ratios was observed, in addition to a consistent increase in brain GSH levels in response to treatment. This clinical pilot study suggests the value of exploring relationships between peripheral GSH and clinical/neuropsychological measures, as well as the influences sulforaphane has on functional measures that are altered in neuropsychiatric disorders.

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Section: Discussionmentioning

confidence: 83%

Sulforaphane Augments Glutathione and Influences Brain Metabolites in Human Subjects: A Clinical Pilot Study

et al. 2017

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“…Firstly, given the evidence that glutathione and glutamate levels in the brain are affected by a risk variant of the gene coding for the glutathione synthesis enzyme, the role of genetic influences should be investigated [22]. Secondly, although we controlled for current antipsychotic medication intake and metabolite concentrations, possible confounding effects of long-term medication use should be considered.…”

Section: Discussionmentioning

confidence: 99%

“…One MRS study found reduced glutathione in the medial prefrontal cortex (mPFC) in schizophrenia patients compared with healthy controls [21]. Another recent study reported reduced glutathione only in schizophrenia patients carrying a risk variant of the gene coding for the ratelimiting enzyme in glutathione synthesis [22]. Four other studies reported no statistically significant differences in glutathione levels in the posterior medial frontal cortex [23], mPFC [24] or anterior cingulate cortex (ACC) [25,26].…”

Section: Introductionmentioning

confidence: 99%

Glutathione and glutamate in schizophrenia: a 7T MRS study

et al. 2018

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In schizophrenia, abnormal neural metabolite concentrations may arise from cortical damage following neuroinflammatory processes implicated in acute episodes. Inflammation is associated with increased glutamate, whereas the antioxidant glutathione may protect against inflammation-induced oxidative stress. We hypothesized that patients with stable schizophrenia would exhibit a reduction in glutathione, glutamate, and/or glutamine in the cerebral cortex, consistent with a post-inflammatory response, and that this reduction would be most marked in patients with "residual schizophrenia", in whom an early stage with positive psychotic symptoms has progressed to a late stage characterized by long-term negative symptoms and impairments. We recruited 28 patients with stable schizophrenia and 45 healthy participants matched for age, gender, and parental socio-economic status. We measured glutathione, glutamate and glutamine concentrations in the anterior cingulate cortex (ACC), left insula, and visual cortex using 7T proton magnetic resonance spectroscopy (MRS). Glutathione and glutamate were significantly correlated in all three voxels. Glutamine concentrations across the three voxels were significantly correlated with each other. Principal components analysis (PCA) produced three clear components: an ACC glutathione-glutamate component; an insula-visual glutathione-glutamate component; and a glutamine component. Patients with stable schizophrenia had significantly lower scores on the ACC glutathione-glutamate component, an effect almost entirely leveraged by the sub-group of patients with residual schizophrenia. All three metabolite concentration values in the ACC were significantly reduced in this group. These findings are consistent with the hypothesis that excitotoxicity during the acute phase of illness leads to reduced glutathione and glutamate in the residual phase of the illness.

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“…Unsuppressed water 1H MR spectra were used as an internal reference for the absolute quantification of metabolite concentrations. Tissue composition inside the MRS volume used for water content calculation and partial volume correction was calculated based on the segmentation of magnetization-prepared rapid gradientecho (MPRAGE) (Mugler and Brookeman 1990) images (TE/TR = 2.98/2300 ms, TI = 900 ms, flip angle = 9 degree, FOV = 240 × 256 mm2, matrix = 240 × 256, slice thickness = 1.2 mm) MPRAGE images using an in-house software (more details are reported elsewhere, Xin et al 2016). …”

Section: Spectral Quantificationmentioning

confidence: 99%

Cannabis use in early psychosis is associated with reduced glutamate levels in the prefrontal cortex

et al. 2017

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Rationale Recent studies have shown that cannabis may disrupt glutamate (Glu) signaling depressing Glu tone in frequent users. Current evidence have also consistently reported lower Glu-levels in various brain regions, particularly in the medial prefrontal cortex (mPFC) of chronic schizophrenia patients, while findings in early psychosis (EP) are not conclusive. Since cannabis may alter Glu synaptic plasticity and its use is a known risk factor for psychosis, studies focusing on Glu signaling in EP with or without a concomitant cannabis-usage seem crucial.Objective We investigate the effect of cannabis use on prefrontal Glu-levels in EP users vs. both EP non-users and healthy controls (HC). Methods Magnetic resonance spectroscopy was used to measure [Glu mPFC ] of 35 EP subjects (18 of whom were cannabis users) and 33 HC. For correlative analysis, neuropsychological performances were scored by the MATRICS-consensus cognitive battery. Results [Glu mPFC ] was lower in EP users comparing to both HC and EP non-users (p < 0.001 and p = 0.01, respectively), while no differences were observed between EP non-users and HC. A greater [Glu mPFC ]-decline with age was observed in EP users (r = −.46; p = 0.04), but not in EP non-users or HC. Among neuropsychological outcomes, working memory was the only domain that differentiates patients depending on their cannabis use, with users having poorer performances. Conclusions Cannabis use is associated with reduced prefrontal [Glu mPFC ] and with a stronger Glu-levels decline with age. Glutamatergic abnormalities might influence the cognitive impairment observed in users and have some relevance for the progression of the disease.

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Genetic Polymorphism Associated Prefrontal Glutathione and Its Coupling With Brain Glutamate and Peripheral Redox Status in Early Psychosis

Cited by 89 publications

References 61 publications

Sulforaphane Augments Glutathione and Influences Brain Metabolites in Human Subjects: A Clinical Pilot Study

Sulforaphane Augments Glutathione and Influences Brain Metabolites in Human Subjects: A Clinical Pilot Study

Glutathione and glutamate in schizophrenia: a 7T MRS study

Cannabis use in early psychosis is associated with reduced glutamate levels in the prefrontal cortex

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