Association of sFlt-1 and worsening psychopathology in relatives at high risk for psychosis: A longitudinal study

Abstract

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.

VEGFA GENE variation influences hallucinations and frontotemporal morphology in psychotic disorders: a B-SNIP study

“…However, our findings align with animal studies, which have shown that VEGFA , VEGF receptor 1 (VEGFR1/Flt-1), and VEGF receptor 2 (VEGFR2/KDR) signaling affect working memory primarily by modulating neuroplasticity at the hippocampus or through peripheral neurotrophic effects 1 – 6 , 33 . Our findings are further supported by human studies, which have demonstrated that the effects of psychotic symptoms are mixed 34 , whereas VEGR1/Flt-1 and VEGFR2/KDR dysregulation were associated with worse psychotic symptoms in a prospective familial high risk for psychosis study 35 , 36 , a post mortem SZ study 10 , and in case reports of systemic VEGFR1/Flt-1 administration 19 , 20 , 37 . Additionally, treatment with antipsychotic or antidepressant medications has been shown to modulate VEGF levels and is associated with improved treatment outcomes in SZ, bipolar and major depressive disorder 38 – 41 .…”

Cerebral ischemia-induced genes are increased in acute schizophrenia: an opportunity for clinical translation of genomic research findings

“…in their plasma. 38,39 Our findings are not at variance with the results from the postmortem expression studies performed by other global down-regulation of mitochondrial genes. 42 Hakak et al (2001) discovered differential expression of myelination-related genes in schizophrenia suggesting a disruption of oligodendrocyte function 43 , a finding that has been confirmed by other expression and proteomic studies 44 .…”

Are the Cognitive Alterations Present in Children Born From Preeclamptic Pregnancies the Result of Impaired Angiogenesis? Focus on the Potential Role of the VEGF Family

“…At the central nervous system level, the precise role of sFlt-1 in modifying neuroanatomical and vascular architecture, and circulatory characteristics in the brain is unknown. Interestingly, high circulating levels of sFlt-1 are associated with adult psychiatric and neurological alterations ( Kim et al, 2007 ; Fulzele and Pillai, 2009 ; Emanuele et al, 2010 ; Lee et al, 2010 ; Lizano et al, 2016 , 2017 ; Pillai et al, 2016 ) and studies also reveal a reduction in total frontal lobe volume in patients with schizophrenia/schizoaffective disorder ( Pillai et al, 2016 ). Whether this association is the result of alterations in microvascular development in those patients is unknown, however, gene transfer of sFlt-1 in rats leads to a reduction in brain edema and in blood brain barrier permeability, suggesting a direct effect on brain endothelium ( Kumai et al, 2007 ).…”