SA82. Extracellular Free Water and Glutathione in First-Episode Psychosis: A Multimodal Investigation of an Inflammatory Model for Psychosis

Abstract

Background: Evidence has been accumulating for an immune-based component to the etiology of psychotic disorders. Advancements in diffusion magnetic resonance imaging (MRI) have enabled estimation of extracellular free water (FW), a putative biomarker of neuroinflammation. Furthermore, there is evidence that neuroimmune activation may alter brain levels of metabolites (e.g., glutathione [GSH]) that can be measured noninvasively with proton magnetic resonance spectroscopy (1H-MRS). Consequently, we sought to test the hypothesis that patients with first-episode psychosis (FEP) have increased FW and decreased GSH when compared to healthy controls (HC). Methods: FEP (n = 32) participants were identified based on an SCID (DSM-IV) diagnosis of Schizophrenia, Schizoaffective Disorder, Schizophreniform Disorder, or Bipolar Disorder with psychotic features. HC (n=27) had no family history of a psychotic disorder and no current or lifetime Axis 1 psychiatric disorder. All participants underwent a diffusion MRI scan on a Siemens 3T scanner in which multiple b-value shells were acquired. MPRAGE images were segmented and aligned to the diffusion-weighted images to compute mean FW values for gray and white matter whole-brain masks. 1H-MRS was acquired using a GSH-optimized MEGA-PRESS editing sequence and GSH–creatine ratios were calculated for voxels within the DLPFC and visual cortex. The addition of visual cortex GSH analyses represent new data that has not previously been presented and allow for identification of regionally specific GSH differences. Results: FEP demonstrated significantly elevated FW in whole-brain gray (P < .05) with no difference in white matter (P = .06). There were no significant group differences in GSH within the DLPFC (P = .1) or visual cortex (P = .41). There was a significant negative correlation between DLPFC GSH and both gray and white matter FW in FEP (r = −.35 and −.4, respectively; both P < .05). No relationships emerged between visual cortex GSH levels and either gray or white matter FW in the FEP sample. Finally, no relationships were identified between GSH and FW in the HC sample. Conclusion: These data provide compelling convergent evidence for the presence of neuroinflammatory processes in FEP. The inverse relationship between GSH and FW implies a common linkage to neuroinflammatory processes that may be present in FEP. Importantly, GSH measurements may be complicated by a genetic polymorphism that affects GSH synthesis, which will need to be accounted for in future studies. Nevertheless, these data suggest that FW and GSH show promise as neuroinflammatory biomarkers and could potentially provide tractable treatment targets for pharmacological intervention.