title: Genetic Polymorphism Associated Prefrontal Glutathione and Its Coupling With Brain Glutamate and Peripheral Redox Status in Early Psychosis.
abstract: Oxidative stress and glutathione (GSH) metabolism dysregulation has been implicated in the pathophysiology of schizophrenia. GAG-trinucleotide repeat (TNR) polymorphisms in the glutamate-cysteine ligase catalytic gene (GCLC), the rate-limiting enzyme for GSH synthesis, are associated with schizophrenia. In addition, GSH may serve as a reserve pool for neuronal glutamate (Glu) through the γ-glutamyl cycle. The aim of this study is to investigate brain [GSH] and its association with GCLC polymorphism, peripheral redox indices and brain Glu.
  
  
  
  Magnetic resonance spectroscopy was used to measure [GSH] and [Glu] in the medial prefrontal cortex (mPFC) of 25 early-psychosis patients and 33 controls. GCLC polymorphism was genotyped, glutathione peroxidases (GPx) and glutathione reductase (GR) activities were determined in blood cells.
  
  
  
  Significantly lower [GSHmPFC] in GCLC high-risk genotype subjects were revealed as compared to low-risk genotype subjects independent of disease status. In male subjects, [GSHmPFC] and blood GPx activities correlate positively in controls (P = .021), but negatively in patients (P = .039). In GCLC low-risk genotypes, [GlumPFC] are lower in patients, while it is not the case for high-risk genotypes.
  
  
  
  GCLC high-risk genotypes are associated with low [GSHmPFC], highlighting that GCLC polymorphisms should be considered in pathology studies of cerebral GSH. Low brain GSH levels are related to low peripheral oxidation status in controls but with high oxidation status in patients, pointing to a dysregulated GSH homeostasis in early psychosis patients. GCLC polymorphisms and disease associated correlations between brain GSH and Glu levels may allow patients stratification.
authors.affiliation: Animal Imaging and Technology Core (AIT), Center for Biomedical Imaging (CIBM), Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland;
authors.forename: Lijing
authors.initials: L
authors.lastname: Xin
authors.affiliation: Physikalisch-Technische Bundesanstalt, Berlin, Germany;
authors.forename: Ralf
authors.initials: R
authors.lastname: Mekle
authors.affiliation: Unit for Research in Schizophrenia, Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital (CHUV), Lausanne, Switzerland;
authors.forename: Margot
authors.initials: M
authors.lastname: Fournier
authors.affiliation: Unit for Research in Schizophrenia, Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital (CHUV), Lausanne, Switzerland; Service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital (CHUV), Lausanne, Switzerland;
authors.forename: Philipp S
authors.initials: PS
authors.lastname: Baumann
authors.affiliation: Unit for Research in Schizophrenia, Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital (CHUV), Lausanne, Switzerland; Service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital (CHUV), Lausanne, Switzerland;
authors.forename: Carina
authors.initials: C
authors.lastname: Ferrari
authors.affiliation: Unit for Research in Schizophrenia, Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital (CHUV), Lausanne, Switzerland; Service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital (CHUV), Lausanne, Switzerland;
authors.forename: Luis
authors.initials: L
authors.lastname: Alameda
authors.affiliation: Unit for Research in Schizophrenia, Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital (CHUV), Lausanne, Switzerland; Service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital (CHUV), Lausanne, Switzerland;
authors.forename: Raoul
authors.initials: R
authors.lastname: Jenni
authors.affiliation: Institute of Surgical Technology and Biomechanics, University of Bern, Bern, Switzerland;
authors.forename: Huanxiang
authors.initials: H
authors.lastname: Lu
authors.affiliation: Laboratory of Functional and Metabolic Imaging, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland;
authors.forename: Benoit
authors.initials: B
authors.lastname: Schaller
authors.affiliation: Unit for Research in Schizophrenia, Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital (CHUV), Lausanne, Switzerland;
authors.forename: Michel
authors.initials: M
authors.lastname: Cuenod
authors.affiliation: Service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital (CHUV), Lausanne, Switzerland;
authors.forename: Philippe
authors.initials: P
authors.lastname: Conus
authors.forename: Rolf
authors.initials: R
authors.lastname: Gruetter
authors.affiliation: Unit for Research in Schizophrenia, Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital (CHUV), Lausanne, Switzerland; kim.do@chuv.ch.
authors.forename: Kim Q
authors.initials: KQ
authors.lastname: Do
mesh_terms: D000328:Adult; D005260:Female; D005838:Genotype; D005721:Glutamate-Cysteine Ligase / Q000235:genetics*; D018698:Glutamic Acid / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010084:Oxidation-Reduction; D058451:Oxidative Coupling; D011110:Polymorphism, Genetic; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging / Q000378:metabolism*; D011618:Psychotic Disorders / Q000000981:diagnostic imaging / Q000378:metabolism*; D055815:Young Adult
chemical_list: D018698:Glutamic Acid; D005979:Glutathione Peroxidase; C000609392:GCLC protein, human; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione
keywords: GCLC; MRS; glutamate; glutathione; glutathione peroxidase; oxidative stress; redox; schizophrenia