711. Brain-Derived Exosomal MicroRNAs Predict Psychosis Onset in Clinical High-Risk Individuals: Externally Validated

Abstract

Abstract Background Clinical diagnostic criteria for the psychosis prodrome identify individuals with 10-20% two-year psychosis risk. While substantially higher than population-risk, this modest conversion rate impedes development and implementation of preventative interventions, creating an urgent need for biomarkers that improve prediction accuracy. The redox-hub, an integrated system encompassing oxidative-stress regulation, mitochondrial function, neuroinflammation, NMDAR-mediated neurotransmission, and blood-brain barrier integrity, plays a critical role in psychosis pathophysiology. MicroRNAs that regulate redox pathways are altered in psychosis and can be measured in brain-derived extracellular vesicles (EV)/exosomes isolated from peripheral blood, potentially providing a window into CNS pathology. Aims & Objectives We hypothesized that plasma levels of brain-derived exosomal miRNAs regulating redox-hub function would predict psychosis onset in clinical high-risk (CHR) individuals. Method We conducted a multicenter biomarker development and validation study across two independent cohorts. The EUGEI cohort comprised 268 CHR individuals and 57 healthy-controls recruited from 10 centers across Europe, South America, and Australia. The NAPLS3 cohort comprised 103 CHR individuals and 46 controls recruited from 9 centers in the United States. Clinical assessments were performed at baseline and follow-up (12 and 24 months). Blood samples collected at baseline were processed to isolate brain-derived exosomes, from which five miRNAs (miR-137,miR-132,miR-9,miR-941, and miR-34a) were quantified. These miRNAs were selected a priori based on their established roles in regulating mitochondrial processes, antioxidant activity, NMDAR function, BBB permeability, neurogenesis, and neural differentiation, all redox-sensitive processes implicated in psychosis. Target proteins were measured to validate biological relevance of miRNA alterations. A logistic regression model (LASSO) was developed in the EUGEI cohort, internally validated using repeated nested cross-validation, and externally validated in the independent NAPLS3 cohort. Primary outcomes were discrimination (C-index) and calibration (intercept and slope). Clinical utility was assessed using decision curve analysis. Post-hoc univariate analyses employed Mann-Whitney U-tests with Wilcoxon effect sizes. Results LASSO-model demonstrated excellent discriminative performance in both internal validation (C-index=0.948) and external validation (C-index=0.95), successfully distinguishing CHR participants who transitioned to psychosis from those who did not. Some miscalibration was observed, with risk underestimation at higher observed risk levels. Decision curve analysis indicated that implementing this model in clinical practice would identify an additional 21 psychosis cases early per 100 CHR individuals screened compared to current care strategies. Post-hoc analyses revealed that psychosis onset was associated with elevated miR-34a levels and reduced levels of miR-941,miR-9,miR-132,and miR-137. These patterns suggest coordinated dysregulation of redox-hub function preceding psychosis onset. Discussion & Conclusions This study provides the first externally validated evidence that circulating brain-derived exosomal-miRNAs regulating redox pathways can predict psychosis onset in CHR with high accuracy. The near-perfect discrimination across international cohorts demonstrates robust generalizability. Because these markers are derived from EV-brain-specific, they likely reflect central redox dysregulation. Assessment requires a blood sample, making implementation feasible in clinical practice. These findings support the clinical utility of redox-hub biomarkers for risk stratification and suggest that redox dysregulation may represent a therapeutic target for psychosis prevention. The convergence of predictive biomarker evidence with recent trials showing a redox-modulator prevents psychosis in high-risk individuals strengthens the mechanistic relevance of the redox-hub in psychosis pathophysiology and progression.