Chronic early-life obesity linked to childhood impulsivity predicts long-term psychosis trajectory through dose-dependent cerebellar dysmaturation in 22q11.2 Deletion Syndrome
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Background
Recent epidemiological evidence links early-life obesity and metabolic dysregulation to adult psychosis vulnerability, though a causal relationship remains unclear. Establishing causality in highly heritable psychotic disorders requires: 1) demonstrating that early-life metabolic factors mediate between genetic vulnerability and psychosis trajectory, 2) dissecting mechanisms leading to early-life obesity in genetically vulnerable individuals, and 3) clarifying downstream neurodevelopmental pathways linking early-life obesity to psychosis symptoms.
Methods
To address these key issues, we investigated bidirectional pathways linking behavioral, BMI, and neurodevelopment trajectories in a unique longitudinal cohort of 184 individuals at high genetic risk for psychosis, due to 22q11.2 Deletion Syndrome (22q11DS), and 182 neurotypical controls, followed-up since childhood. We combined repeated BMI measurements with clinical/neurocognitive phenotyping and neuroimaging. We investigated the relationship between BMI trajectories with risk of psychosis and tested whether altered cortical or cerebellar development could underlie this association.
Results
Childhood behavioral impulsivity predicted early and progressive deviations in BMI trajectories. In turn, pubertal BMI-increases were associated with concomitant worsening of depressive symptoms, while chronic BMI-increases emerging during childhood predicted the subsequent emergence of psychosis during late-adolescence/early-adulthood. The duration of increased BMI-status was associated with emergence of motor and cognitive disorganization, a key schizophrenia symptom domain, which was linked to progressive gray matter volume reductions in posterior-inferior cerebellum.
Conclusions
These findings suggest that metabolic dysregulation associated with obesity may link childhood behavioral impulsivity to psychosis vulnerability in 22q11DS, by influencing cerebellar maturation. These findings might support preventive interventions targeting early-life metabolic trajectories in individuals at risk of psychosis.
