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| Author(s): |
Fabiana Maria das Graças Corsi Zuelli
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Ribeirão Preto. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) |
| Defense date: | 2024-08-09 |
| Examining board members: |
Cristina Marta Del Ben;
Niels Olsen Saraiva Câmara;
Clarissa Severino Gama;
Felipe Villela Gomes
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| Advisor: | Cristina Marta Del Ben |
| Abstract | |
Studies using a diverse range of methodologies highlight the contribution of the immuneinflammatory system to schizophrenia and other psychotic disorders. Modifiable risk factors, such as cannabis use and childhood maltreatment, have been associated with increased risk of psychosis. Hitherto, the involvement of these environmental risk factors in immuneinflammatory dysregulation in psychosis remains uncertain. Another complexity lies in the unclear relationship between peripheral immune-inflammatory dysregulation and central nervous system alterations in psychosis, and the contribution of such alterations to the occurrence of transdiagnostic multidimensional symptoms. Our study aimed to address these gaps in the literature. For Studies 1-3, we analysed data from a cross-sectional study of patients with first-episode psychosis (FEP), their unaffected siblings (except Study 1), and community controls, for both sexes, aged 16-64 years, and residing in the Ribeirão Preto-SP catchment area. Study 1 (published in Psychological Medicine): In FEP patients (n=153) and community controls (n=256), cannabis use, whether daily or during adolescence, was only significantly associated with increased odds of psychosis in participants with an inflammatory score at the mean or above the mean [computed using concentrations of pro- and anti-inflammatory plasma cytokines; interleukin (IL)-1β, IL-6, tumour necrosis factor (TNF)-α, interferon (IFN)-γ, IL-10, IL-4, transforming growth factor (TGF)-β; multiplex]. Study 2 (published in Translational Psychiatry): In FEP patients (n=78), age- and sex-matched community controls (n=78), and unaffected siblings (n=25), unsupervised clustering analyses showed that individuals with a history of childhood maltreatment exhibited an inflammatory profile (higher plasma levels of neutrophil extracellular traps, NETs and IL-6) compared to those who did not experience traumatic events in childhood, with this profile being significantly higher in patients with a positive history compared to the other groups. Additionally, young male Sprague-Dawley rats (post-natal day, PN24) exposed to the adolescent stress model (combination of daily inescapable foot shock during PN31-40, in addition to three restraint stress sessions on PD31, 32, and 40) showed higher serum levels of NETs and IL-6 (PN51), and a trend towards higher NETs released from the bone marrow compared to rats left undisturbed. Study 3 (published in Psychological Medicine): In FEP patients (n=110), community controls (n=200), and patients\' unaffected siblings (n=52), we observed significant associations between pro- and antiinflammatory mediators measured in plasma (IL-1β, IL-6, TNF-α, IFN-γ, IL-10, IL-4, TGF-β) with the transdiagnostic dimensions of psychosis (positive, negative, and depressive). Additionally, exploratory analysis demonstrated that a higher schizophrenia polygenic risk score moderated associations between cytokines and psychotic dimensions in the three groups. Study 4 (in submission): In early-stage psychosis patients (n=206, Manchester-UK) and chronic psychosis patients (n=104, Dublin and Galway, Republic of Ireland), increased IL-6 levels were associated with greater severity of depressive symptoms in early-onset patients and with greater severity of negative symptoms in chronic patients. However, Structural Equation Modelling revealed that such associations did not occur through the interrelationship between IL-6 concentrations with structural brain measures (volume and cortical thickness) and general cognitive performance. Study 5 (published in Neuroscience and Biobehavioral Reviews and Brain, Behavior, and Immunity - Health). In a critical narrative review of the literature, in vivo (PET scan) studies, post-mortem brain transcriptomic studies, and randomised clinical trials suggested reduced or no difference in microglial inflammation in psychosis, concomitantly to an increased astrocyte reactivity. Experimental studies in the field of neuroimmunology pointed the involvement of regulatory T cells in reducing peripheral inflammation and regulating microglia-astrocyte homeostasis, indicating a potential new therapeutical target for psychosis. Conclusion and clinical relevance of the studies. Understanding the immune-inflammatory system in the context psychosis offers a translational tool to identify individuals with greater biological vulnerability to psychosis when exposed to environmental risk factors. This understanding may be crucial to inform more personalized interventions and targeted treatments, contributing to more effective therapeutic approaches tailored to the needs of each individual. (AU) | |
| FAPESP's process: | 19/13229-2 - Inflammatory profile in the general population: transdiagnostic dimensions in the context of the psychosis continuum |
| Grantee: | Fabiana Maria das Graças Corsi Zuelli |
| Support Opportunities: | Scholarships in Brazil - Doctorate |