A Systems Biology Model Linking Peripheral NIMETOX Biomarkers to Multilevel Brain Structural and Functional Alterations Across Major Depression and Schizophrenia

Abstract

Peripheral lipid and antioxidant-related biomarkers may help contextualize brain abnormalities across psychiatric disorders, but their relationships with brain structure, intrinsic activity, and dimensional symptoms remain incompletely characterized. In this cross-sectional study, 93 adults were recruited: 38 with major depressive disorder, 29 with schizophrenia, and 26 healthy controls. Eighty-seven participants met resting-state functional MRI quality-control criteria. Assessments included structural and functional MRI, serum lipids, albumin, apolipoprotein A-I, childhood maltreatment, psychological resilience, and clinical symptoms. Exploratory analyses combined regional imaging measures, within-network connectivity, statistical mediation, and partial least squares structural equation modeling. Group-related functional abnormalities involved parietal, sensorimotor, cingulate, insular, and temporal regions. Peripheral lipid and antioxidant-related measures were associated with regional gray matter measures and intrinsic activity. Childhood maltreatment and resilience were associated with mood-related symptom burden, whereas lower connectivity and nodal strength within the selected 11-region network were associated with psychosis-related and overall illness severity. Exploratory structural equation models accounted for 66.4% of the variance in the mood-related composite and 25.3% of the variance in local intrinsic activity. These findings describe cross-sectional relationships among peripheral biological measures, regional brain characteristics, developmental adversity, and psychopathology. They provide a framework for further investigation rather than evidence of a causal blood-to-brain sequence. Independent replication with prospectively defined measures and longitudinal assessments is needed.