Glutathione and glutamate in schizophrenia: a 7T MRS study

Abstract

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.

Longitudinal changes in brain metabolites in healthy subjects and patients with first episode psychosis (FEP): a 7-Tesla MRS study

“…Glu is the primary excitatory neurotransmitter in the adult human brain. The reduction of Glu in the pathological trajectory of patients with psychosis, including those with FEP, has been reported by multiple groups (7,9,11). Although there are reports that compared brain metabolite levels between young and aged populations (34), we believe that this study is the first to report that a longitudinal change in young adulthood occurs in healthy subjects.…”

“…Tesla (T) MRS offers a more precise measurement of metabolite levels (4)(5)(6). To date, there have only been a handful of 7T MRS studies using either first episode psychosis (FEP) (7) or schizophrenia (SZ) patients (8)(9)(10)(11)(12)(13). However, all of these studies were cross-sectional and most of them used a fairly small number of subjects.…”

Influence of prior beliefs on perception in early psychosis: effects of illness stage and hierarchical level of belief

“…It has been proposed that glutamatergic abnormalities may be prominent in the early stages of psychotic illness (Merritt et al 2016, Kumar et al 2018), and that these may be key in driving pathophysiology of illness, predictive processing dysfunction, and psychopathology (Corlett et al, 2009 & 2011; Sterzer et al 2018). We did not find a significant relationship between glutamate levels in the anterior cingulate cortex and the strength of the perceptual and cognitive priors across all participants.…”

Dopamine and glutamate in schizophrenia: biology, symptoms and treatment

“…Higher field strength has greater sensitivity, enabling greater separation of glutamate and glutamine peaks, and allowing for more accurate quantification. Two studies in first‐episode patients have shown reduced glutamate concentrations in the anterior cingulate cortex, while another only found this in a subset of patients with predominantly negative symptoms. No difference has been observed in several other investigations.…”