Transdiagnostic neuroanatomical risk in schizophrenia: integrating regional vulnerability indices with anthropometric and fitness-based markers of cardiometabolic health

Schizophrenia is a multisystem disorder affecting both brain and body, with patients exhibiting substantial somatic comorbidities including obesity, reduced physical fitness, and elevated cardiometabolic risk. While neuroimaging-derived Regional Vulnerability Indices (RVIs) have quantified brain structural deviations from disorder-specific patterns, their relationship to physical health in schizophrenia remains largely unexplored. In this study, we combined RVIs with detailed anthropometric and fitness assessments in 42 schizophrenia patients and 43 matched healthy controls. Participants underwent MRI-based cortical thickness analyses to derive RVIs for nine psychiatric, neurological, and metabolic disorders, alongside measurements of body composition, cardiorespiratory fitness, handgrip strength, and jump performance. Patients exhibited significantly higher RVIs for schizophrenia (Cohen's D = -1.1), bipolar disorder (Cohen's D = -0.9), Alzheimer's (Cohen's D = -0.6) and Parkinson's disease (Cohen's D = -0.7), and type 2 diabetes (Cohen's D = -0.9). These overlapping neuroanatomical vulnerabilities across psychiatric, neurodegenerative, and metabolic conditions might reflect shared underlying genetic and physiological mechanisms. Principal component analysis revealed three latent dimensions: (1) general risk factors, (2) physical fitness deficits, and (3) psychosis-spectrum vulnerability, with the latter two showing significant differences between groups. These findings highlight that metabolic impairment and reduced physical fitness in schizophrenia are not merely secondary phenomena but constitute distinct dimensions of systemic vulnerability. Overall, our results support a brain-body conceptualization of schizophrenia, suggesting that RVIs may serve as biomarkers to guide precision medicine interventions integrating neuroprotective strategies with lifestyle management. Future research should incorporate longitudinal and multimodal assessments to clarify causal relationships and optimize individualized treatment approaches.