Brain vasculature disturbance in schizophrenia

Abstract

Purpose of reviewThe vascular hypothesis of schizophrenia (SZ) postulates that brain endothelial dysfunction contributes to brain pathophysiology. This review discusses recent evidence for and against this hypothesis, including data related to blood–brain barrier (BBB), brain endothelium, and brain blood supply, to provide a critical weighed update.Recent findingsDifferent studies report a consistent proportion of SZ patients showing increased BBB permeability, reflected by higher levels of albumin in the cerebral spinal fluid. Of note, this was not a result of antipsychotic medication. The high inflammatory profile observed in some SZ patients is strongly associated with increased BBB permeability to circulating immune cells, and with more severe cognitive deficiencies. Also, sex was found to interact with BBB integrity and permeability in SZ. The strongest independent genetic association with SZ has been identified in FZD1, a hypoxia-response gene that is 600-fold higher expressed in early development endothelium as compared to adult brain endothelium. Regarding brain blood supply, there is evidence to suggest alterations in proper brain perfusion in SZ. Nonetheless, ex-vivo experiments suggested that widely used antipsychotics favor vasoconstriction; thus, alterations in cerebral perfusion might be related to the patients′ medication.SummaryIn some patients with SZ, a vulnerable brain endothelium may be interacting with environmental stressors, such as inflammation or hypoxia, converging into a more severe SZ symptomatology. Gene expression and performance of human brain endothelium could vary along with development and the establishment of the BBB; therefore, we encourage to investigate its possible contribution to SZ considering this dynamic context.

It takes two to tango: Widening our understanding of the onset of schizophrenia from a neuro-angiogenic perspective

“…Interestingly, for many of the pathways analyzed, except for the WNT and mTOR pathways which seem to be consistently downregulated in SZ, different studies show variations with respect to the direction of this dysregulation regarding gene or protein expression. This may be a reflection of the high genetic heterogeneity present in SZ, especially in genes described as highly variable for this disease, rather than through gene expression or variant number ( Huang et al, 2020 ; Puvogel et al, 2022 ). Taking into consideration the variability in gene expression in SZ reviewed in this and other articles, we propose the existence of molecular patterns that may be related to specific symptoms, severity, and even responses to medication.…”

“…As in most neurological disorders, the main descriptions of SZ physiopathology have been focused on neuronal deficiencies. Altered cerebral connectivity and brain dynamics, abnormalities in the excitatory/inhibitory balance, as well as failure to specify specific neuron identities have been described ( Spencer, 2009 ; Kantrowitz and Javitt, 2010 ; Inan et al, 2013 ; Puvogel et al, 2022 ). In addition to these neuronal alterations, increasing evidence has linked SZ to vascular impairments.…”

“…In addition to these neuronal alterations, increasing evidence has linked SZ to vascular impairments. Hypoperfusion in several areas of the brain, reduced cerebral blood flow (CBF), and Blood-Brain Barrier (BBB) dysfunctions have been described ( Andreasen et al, 1997 ; Lopes et al, 2015 ; Katsel et al, 2017 ; Baruah and Vasudevan, 2019 ; Puvogel et al, 2022 ).…”

The role of the blood-brain barrier in psychiatric disorders

“…In recent years several studies identified BBB dysfunction and its increased permeability as potentially important factor in the development of psychiatric disorders [4,13,14].…”

“…The roles of neurotransmission disturbances, immune response, and low-grade inflammation ("low-grade encephalitis") have been all implied [18,19]. Recent data indicate that the oxidative stress associated with neuroinflammation and neurovascular endotheliopathy can lead to impairment of BBB integrity and decreased cerebral perfusion and disruption of neuronal homeostasis in patients with schizophrenia [13,19]. The damage to occluding compounds between endothelial cells of continuous BBB capillaries (i.e., decreased CLDN5 expression in the hippocampus) has been demonstrated in schizophrenia [20].…”