From Micro Molecular to Functional Levels Through Macro Structures: Mediation of Structural Brain Changes on the Relationship Between Oxidative Stress and Cognition in Early Onset Psychosis.

BACKGROUND: Previous findings showed decreased frontal left gray matter (FLGM) volume predicted working memory impairments over 2 years after first-episode psychosis (FEP) in adolescents, as a function of age. However, the interplay between brain changes and cognitive development is not well understood. Oxidative stress (STOX), specifically lower baseline glutathione (GSH) levels, has been linked to greater FLGM volume loss and cognitive impairments in this same sample group. This study further investigated the relationship between baseline GSH levels, longitudinal brain changes, and cognitive impairments in FEP compared to healthy controls. We hypothesized that lower baseline GSH levels and accelerated FLGM volume loss underlie working memory deficits over time in adolescent FEP. METHODS: GSH levels were measured in peripheral blood at baseline. Regional FLGM volume was obtained using automated methods based on Talairach's. Mediation analyses were conducted using regression and bootstrapping techniques. RESULTS: We confirmed the association between lower GSH levels at the time of FEP and FLGM volume loss, and between decreased FLGM volume and decreased working memory over the first 2 years after onset. STOX had an indirect effect on impaired working memory in adolescent psychosis, where decreased FLGM was a mediator. No association was found in controls. CONCLUSIONS: Lower baseline GSH levels negatively impacted FLGM volume, contributing to working memory impairments in adolescent psychosis. Biomolecular and macrostructural alterations (lower GSH, FLGM atrophy) may underlie functional cognitive outcomes like working memory deficits longitudinally. These findings may elucidate how STOX relates to neuroanatomical changes that disrupt cognitive trajectories during adolescent brain maturation in FEP.