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A multimodal approach to studying the relationship between peripheral glutathione, brain glutamate, and cognition in health and in schizophrenia

Abstract

Involvement of oxidative stress in the pathophysiology of schizophrenia (SZ) is suggested by studies of peripheral tissue. Nonetheless, it is unclear how such biological changes are linked to relevant, pathological neurochemistry, and brain function. We designed a multi-faceted study by combining biochemistry, neuroimaging, and neuropsychology to test how peripheral changes in a key marker for oxidative stress, glutathione (GSH), may associate with central neurochemicals or neuropsychological performance in health and in SZ. GSH in dorsal anterior cingulate cortex (dACC) was acquired as a secondary 3T 1H-MRS outcome using a MEGA-PRESS sequence. Fifty healthy controls and 46 patients with SZ were studied cross-sectionally, and analyses were adjusted for effects of confounding variables. We observed lower peripheral total GSH in SZ compared to controls in extracellular (plasma) and intracellular (lymphoblast) pools. Total GSH levels in plasma positively correlated with composite neuropsychological performance across the total population and within patients. Total plasma GSH levels were also positively correlated with the levels of Glx in the dACC across the total population, as well as within each individual group (controls, patients). Furthermore, the levels of dACC Glx and dACC GSH positively correlated with composite neuropsychological performance in the patient group. Exploring the relationship between systemic oxidative stress (in particular GSH), central glutamate, and cognition in SZ will benefit further from assessment of patients with more varied neuropsychological performance.

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Fig. 1: Voxel placement and sample spectra from dorsal Anterior Cingulate Cortex (dACC).
Fig. 2: Comparison of plasma GSH between groups as well as evaluation of its relationship with other measured variables across and within groups.
Fig. 3: Comparison of dACC Glx and dACC GSH between groups as well as evaluation of their relationship across and within groups.

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Acknowledgements

This work was supported by the National Institute of Mental Health (MH-094268 Silvio O. Conte center, MH-092443, MH-105660, MH-107730) (AS), as well as grants from Stanley (AS), S-R (AS), RUSK (AS), NARSAD (JC and AS), and support of the Alexander Wilson Schweizer Fellowship (JC). This project also applies tools developed under P41 EB015909 (RE and PB) and R01 EB016089 (RE). The design, writing, and the decision of publication are only of the authors, who have no conflict of interest to declare. A fund from Mitsubishi Tanabe Pharma Corporation was partly used for recruitment of 11 healthy controls. The authors thank Drs. Kim Do and Michel Cuenod for kindly contributing to scientific discussions and feedback related to this work. They thank Dr. Laurent Younes and Dr. Brian Caffo for discussions regarding medical statistics and data analysis, and also sincerely thank Yukiko Lema for assistance in graphical design of the figures.

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Coughlin, J.M., Yang, K., Marsman, A. et al. A multimodal approach to studying the relationship between peripheral glutathione, brain glutamate, and cognition in health and in schizophrenia. Mol Psychiatry (2020). https://doi.org/10.1038/s41380-020-00901-5

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