Chronic early-life obesity linked to childhood impulsivity predicts long-term psychosis trajectory through dose-dependent cerebellar dysmaturation in 22q11.2 Deletion Syndrome

Article Article scientifique Article Chronic early-life obesity linked to childhood impulsivity predicts long-term psychosis trajectory through dose-dependent cerebellar dysmaturation in 22q11.2 Deletion Syndrome eng 2025-09-08 author Sandini Corrado 0000-0003-2933-1607 846736 Département de psychiatrie (PSYAT) author Reich Natacha Laura 0009-0004-1628-4981 941582 Département de psychiatrie (PSYAT) author Delavari Farnaz 0000-0003-2990-4372 930325 author Pajic Lara Mariana 957741 author Escelsior Andrea author Forrer Silas 406113 Département de psychiatrie (PSYAT) author Imparato Andréa 413221 Département de psychiatrie (PSYAT) author Kojovic Nada 0000-0003-0116-2485 776933 Département de psychiatrie (PSYAT) author Latreche Caren 0000-0002-6812-2907 906679 Département de psychiatrie (PSYAT) author Parlatini Valeria 0000-0002-4754-2494 author Cortese Samuele 0000-0001-5877-8075 author Schneider Maude 0000-0001-7147-8915 594384 Section de psychologie (PSICO) author Eliez Stéphan 0000-0002-8269-3028 39336 Département de psychiatrie (PSYAT) 10.1016/j.bpsc.2025.08.014 40930217 2451-9022 https://www.sciencedirect.com/science/article/pii/S2451902225002629 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: Here we investigated bidirectional pathways linking behavioral, body mass index (BMI), and neurodevelopmental 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 control individuals, 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, mediating the effects of 22q11DS vulnerability to early-life obesity. Chronic BMI increases manifesting during childhood predicted the subsequent emergence of psychosis during late adolescence/early adulthood, mediating the effects of behavioral impulsivity. A dose-effect relationship linked duration of increased BMI status to worsening of motor and cognitive disorganization, a key schizophrenia symptom domain, which was mediated by 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. ADHD BMI Cerebellum Inflammation Obesity Schizophrenia Dewey 616.89 Dewey 150 Dewey 576.5 Swiss National Science Foundation Swiss VCFS Cohort: a 10-year longitudinal investigation from genes to brain to cognition for understanding psychosis proneness in 22q11.2 deletion 144260 CH Swiss National Science Foundation The Swiss 22q11DS longitudinal cohort: understanding psychosis proneness through negative symptoms 179404 CH Swiss National Science Foundation Cross-sectional and longitudinal predictors of real-life social functioning in schizophrenia using the Experience Sampling Method (ESM) 162006 CH Swiss National Science Foundation Towards an ecological characterization of affective and sleep co-morbidities in ADHD, through temporal network analysis 209096 CH Swiss National Science Foundation NCCR SYNAPSY: The synaptic bases of mental diseases (phase I) 125759 CH European Commission EPIGENETIC-GENETIC-MENTAL HEALTH CASCADE BASED PERSONALISED PREVENTION OF NON-COMMUNICABLE DISEASE IN ADOLESCENTS DIAGNOSED WITH AUTISM (ETHEREAL) 101095568 ETHEREAL EU HE 60 Département de psychiatrie 225 108 Section de psychologie 71 135 Département de médecine génétique et développement 21D false 421 Laboratoire d'imagerie et de psychopathologie développementale 693 1360 Autism Brain and Behavior Lab 1033 1302 Unité de psychologie clinique des situations de handicap Biological psychiatry. Cognitive neuroscience and neuroimaging a1014137-d963-4858-b67c-8d74495852b7 Article (Published version) Public 1-s2.0-S2451902225002629-main.pdf 5171957 application/pdf CC BY-4.0 9948eac462e0d4f64552cc099366dfd377691e924eb60dfb735e28013a7d7b4d d20b801c-09fc-40b8-92c9-28de1655927d Supplemental data Public 1-s2.0-S2451902225002629-mmc1.pdf 14349964 application/pdf f64e207be0856fef91f87bab96a26186c69bf743c973aafced6cb46315846344 openAccess Faculté de médecine / Section de médecine clinique / Département de psychiatrie Faculté de psychologie et des sciences de l'éducation / Section de psychologie Faculté de médecine / Section de médecine fondamentale / Département de médecine génétique et développement

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Chronic early-life obesity linked to childhood impulsivity predicts long-term psychosis trajectory through dose-dependent cerebellar dysmaturation in 22q11.2 Deletion Syndrome	Biological psychiatry. Cognitive neuroscience and neuroimaging			2025	20	106

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