Identification and Validation of Immuno-Inflammatory Neuroimaging Markers Across Major Psychiatric Disorders.

BACKGROUND

Neuroimaging-based subtypes have been increasingly identified across major psychiatric disorders (MPDs), but their clinical utility in guiding mechanism-targeted, stratified therapies remains limited. In this study, we aimed to identify biologically annotated neuroimaging markers by integrating brain connectome and DNA methylation profiles in patients with MPDs.

METHODS

The study was conducted in 2 stages with 2 cohorts. Stage I: A cross-sectional cohort from Shenyang included 329 patients with MPDs and 169 healthy control participants. Functional connectomes and whole-genome DNA methylation profiles in peripheral blood were obtained. Stage II: A longitudinal cohort from Nanjing included 554 patients with MPDs, with baseline functional connectomes, clinical data, and peripheral immune cell profiles collected at baseline, week 2, and discharge.

RESULTS

In stage I, we identified 2 methylation-derived biotypes, including an immuno-inflammatory biotype characterized by hypermethylation of adaptive immunity genes combined with hypomethylation of innate immunity genes. This subtype further exhibited altered epigenetic inflammation score, elevated neutrophils, and reduced lymphocytes. Immuno-inflammatory functional connectivity markers were identified through the integration of DNA methylation and functional connectome data. In stage II, longitudinal analyses confirmed the clinical utility of these neuroimaging markers, stratifying patients into immuno-inflammatory and non-immuno-inflammatory biotypes. Blood markers, including elevated neutrophils, decreased lymphocytes, and higher neutrophil-to-lymphocyte ratio and systemic immune-inflammatory index, aligned with the immuno-inflammatory biotype, which was linked to poorer responses to conventional therapies compared with the non-immuno-inflammatory biotype.

CONCLUSIONS

Our findings establish noninvasive, cost-effective neuroimaging markers of brain inflammation in MPDs, supporting biomarker-guided, stratified anti-inflammatory therapies in psychiatric practice.