Age-related changes in anterior cingulate cortex glutamate in schizophrenia: A 1H MRS Study at 7Tesla

Brandt, Allison; Unschuld, Paul G.; Pradhan, Subechhya; Lim, Issel Anne L.; Churchill, Gregory; Harris, Ashley D.; Hua, Jun; Barker, Peter B.; Ross, Christopher A.; Zijl, Peter C.M. van; Edden, Richard A.E.; Margolis, Russell L.

doi:10.1016/j.schres.2016.02.017

Cited by 68 publications

(54 citation statements)

References 72 publications

(40 reference statements)

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“…Current evidence has shown that Glu have also considerable potential as biomarker of disease progression (Brandt et al 2016), although the implications of changes in Glu on neuronal function are still not clear (Wijtenburg et al 2015). Given the tight metabolic relationship between glutamate and both NAA and Gln, changes in Glu levels that are not accompanied by NAA or Gln changes are surprising.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…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]. However, two out of the four found a trend toward reduced glutathione in schizophrenia [24,25] and in one, lowered levels of glutathione were associated with negative symptoms [24].…”

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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“…In vivo magnetic resonance spectroscopy (MRS) is an analytical technique used to measure levels of brain metabolites [30]. Successful application of MRS has shown alterations in brain glutamate (Glu) and γ-aminobutyric acid (GABA) levels in SZ patients [31-34]. In contrast, the data for GSH have been less consistent [19, 35, 36].…”

Section: Introductionmentioning

confidence: 99%

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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Age-related changes in anterior cingulate cortex glutamate in schizophrenia: A 1H MRS Study at 7Tesla

Cited by 68 publications

References 72 publications

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

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

Glutathione and glutamate in schizophrenia: a 7T MRS study

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

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