Blood-brain barrier pathology in patients with severe mental disorders: a systematic review and meta-analysis of biomarkers in case-control studies

Abstract

Background Blood-brain barrier (BBB) pathology may be associated with mental disorders. The aim of this systematic review and meta-analysis is to identify, evaluate and summarize available evidence on whether potential biomarkers of BBB pathology are altered in patients with schizophrenia spectrum disorders, major depression and bipolar disorder compared to healthy controls. Methods The primary outcome is blood S100B, while secondary outcomes include biomarkers in blood and/or cerebrospinal fluid, i.e. albumin ratio, fibrinogen, immunoglobulin G, glial fibrillary acidic protein, amyloid beta (Aβ), matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases, endothelial glycocalyx constituents, and cell adhesion molecules (CAMs). A systematic search in PubMed, Embase and PsycINFO resulted in 131 eligible studies, of which 93 were included in the meta-analysis. Meta- and subgroup analyses were undertaken using random-effects modelling. The protocol was a priori registered on PROSPERO (CRD42020152721). Results S100B was increased in schizophrenia spectrum disorders (24 studies; 1107 patients; standardized mean difference (SMD) ​= ​0.82; 95% confidence interval (CI) ​= ​0.51 to 1.13; I 2 ​= ​90%), major depression (13 studies; 584 patients; SMD ​= ​0.57; 95% CI ​= ​0.31 to 0.83; I 2 ​= ​73%) and bipolar disorder (4 studies; 142 patients; SMD ​= ​0.55; 95% CI ​= ​0.16 to 0.94; I 2 ​= ​48%). Similarly, numerous secondary outcomes, including albumin ratio, fibrinogen, Aβ, MMPs and CAMs, were altered. Results of the included studies varied considerably, and important confounders were often not accounted for. Conclusions The findings implicate occurrence of BBB pathology in patients with schizophrenia spectrum disorders, major depression and bipolar disorder compared to healthy controls. However, definite conclusions cannot be drawn, mainly because the investigated biomarkers are indirect measures of BBB pathology.

Long COVID and neuropsychiatric manifestations (Review)

“…The cytokine storm as part of the systemic hyperinflammatory state observed in acute COVID-19 infection, also plays a key role in persistent maladies, precipitated by changes in cerebral perfusion, an increased permeability of the blood-brain barrier, changes in astrocytes involved in synaptogenesis and the imbalance of neurotransmitters ( 115 ). These molecules dysregulate neurogenesis, causing neurons, oligodendrocytes and glial cells to lose their physiological function ( 116 ).…”

Blood-brain barrier dysfunction in bipolar disorder: Molecular mechanisms and clinical implications

“…BD has also been associated with a dysregulation of matrix metalloproteinases (MMPs), which are proteolytic enzymes that contribute to BBB dysfunction by breaking down basal lamina proteins, tight junctions, and the BBB extracellular matrix. Specifically, blood MMP-7 and MMP-2 levels were found to be elevated and decreased in BD, respectively, while the levels of MMP-1 and tissue inhibitors of metalloproteinase 1 did not differ between patients and controls in a recent meta-analysis ( Futtrup et al., 2020 ).…”

TNFα and MMP1 in brain microvascular endothelial cells regulate blood-brain barrier dysfunction in psychotic disorders

“…We had previously identified a high inflammatory subtype of psychosis in chronic and first episode psychosis patients using peripheral markers of inflammation and vascular disruption. Studies of postmortem tissue 7,30 , cerebral spinal fluid 31 , peripheral markers 32 , and in vivo brain imaging 16,33 suggest that BBB disruption exists is SZ and/or BD and that it can be identified in a subgroup of individuals with psychosis2/11/2022 4:32:00 PM. In order to identify patient subgroups with significantly higher levels of BBB (peak TEER) dysfunction, an outlier analysis was performed (based on the mean minus two standard deviations) in HC individuals and used to stratify the SZ and BD groups.…”

“…Studies suggest that peripheral inflammation may be causally related to psychosis 35 , but the source of inflammation is currently unknown. BMECs are a potential source of inflammation in psychotic disorders given their role in immune and inflammatory pathways 3,32,36,37 . In order to test the hypothesis that BMECs secrete factors that can alter BBB function, we performed cross-culture experiments to determine: 1) whether secreted factors from HC BMECs can improve BBB function (i.e., improve TEER) in BBB-deficit BMECs and 2) whether secreted factors from BBB-deficit BMECs can impair BBB function in HC BMECs.…”