RESUMEN
BACKGROUND: Angiogenic dysfunction and abnormalities in psychopathology and brain structure have been reported in schizophrenia, but their relationships are mostly unknown. We recently demonstrated that sFlt-1, anti-angiogenic factor, was significantly elevated in patients at familial high-risk for psychosis (FHR). We hypothesized that elevated sFlt-1 correlates with baseline and longitudinal changes in psychopathology, cognition, and brain structure. METHODS: Plasma sFlt-1 in FHR (n=35) and HC (n=39) was obtained at baseline. Schizotypal, cognitive, soft neurologic signs, and structural brain imaging (1.5T T1-weighted MRI, FreeSurfer software) measures were obtained in both groups. Longitudinal clinical and brain structural measures were obtained in a subgroup of FHR patients. Baseline data analysis used correlations between sFlt-1 and clinical/imaging measures and adjusted for multiple corrections. Linear mixed-effects models described differences in trajectories between high sFlt-1 and low sFlt-1. RESULTS: Baseline sFlt-1 was significantly correlated with soft neurologic signs (r=0.27, p=0.02) and right entorhinal volume (r=0.50, p=0.02), but not other baseline clinical/brain structural measures. Longitudinal examination of the FHR group (sFlt-1 high, n=14; sFlt-1 low, n=14) demonstrated that high sFlt-1 was significantly associated with worsening schizotypal symptoms (t=2.4, p=0.018). Reduced right hippocampal/parahippocampal volume/thickness trajectories were observed in high versus low sFlt-1 groups. CONCLUSIONS: The findings from this FHR study demonstrate that peripheral markers of angiogenic dysfunction can predict longitudinal clinical and brain structural changes. Also, these findings further support the hypothesis of altered microvascular circulation in schizophrenia and those at risk.
Asunto(s)
Encéfalo/metabolismo , Trastornos del Conocimiento/etiología , Trastornos Psicóticos/sangre , Trastornos Psicóticos/complicaciones , Trastornos Psicóticos/patología , Receptor 1 de Factores de Crecimiento Endotelial Vascular/sangre , Adolescente , Adulto , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Trastornos del Conocimiento/diagnóstico por imagen , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Modelos Lineales , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Escalas de Valoración Psiquiátrica , Trastornos Psicóticos/diagnóstico por imagen , Estadística como Asunto , Adulto JovenRESUMEN
Schizophrenia (SZ) is a heterogeneous disorder that presents in adolescence, persists into adulthood, and has many clinical features. Recent evidence suggests that abnormalities in inflammatory, neurotrophic, and angiogenic processes may play a role in the etiology of SZ. The identification of molecular biomarkers early in the course of disease is crucial to transforming diagnostic and therapeutic avenues. We investigated 14 molecular analytes focusing on inflammatory, neurotrophic and angiogenic pathways from the plasma of antipsychotic-naïve familial high risk for SZ (FHR; n=35) and first-episode psychosis (FEP; n=45) subjects, in comparison to healthy controls (HC, n=39). We identified distinct alterations in molecular signatures in young relatives at FHR for SZ prior to psychosis onset and FEP subjects. Firstly, the expression of soluble fms-like tyrosine kinase (sFlt-1), an anti-angiogenic factor that binds vascular endothelial growth factor (VEGF), was significantly increased in the FHR group compared to HC, but not in FEP. Secondly, interferon gamma (IFNγ) was significantly reduced in the FEP group compared to HC. Thirdly, network analysis revealed a positive correlation between sFlt-1 and VEGF, suggesting an activation of the angiogenic cascade in the FHR group, which persists in FEP. Our results indicate an angiogenesis and immunological dysfunction early in the course of disease, shifting the balance towards anti-angiogenesis and inflammation.