Upregulation of sICAM-1 and sVCAM-1 Levels in the Cerebrospinal Fluid of Patients with Schizophrenia Spectrum Disorders

Abstract

Immunological explanatory approaches are becoming increasingly important in schizophrenia research. In this context, the function of the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier (BCSFB) plays an essential role. Different adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), are key elements in sustaining the integrity of the BBB and BCSFB. The objectives of this study were to (1) compare the levels of different cell adhesion molecules in the CSF of patients with schizophrenia spectrum disorders to those of patients with unipolar depression and (2) analyze their association with the established markers of the BBB/BCSFB function (CSF total protein and albumin quotient (AQ)). Therefore, a total of 40 patients with schizophrenia spectrum disorder and 39 age- and sex-matched control patients with unipolar depression were analyzed. The levels of soluble ICAM-1 (s-ICAM-1), soluble VCAM-1 (s-VCAM-1), and plasminogen activator inhibitor 1 (PAI-1) in the CSF were measured using a magnetic bead multiplexing immunoassay. The levels of sICAM-1 (p < 0.001), sVCAM-1 (p < 0.001), and PAI-1 (p < 0.001) in the CSF were significantly higher in patients with schizophrenia spectrum disorder than in patients with unipolar depression. In addition, a significant correlation of sVCAM-1 levels with total protein concentrations (r = 0.454, p = 0.003) and AQ levels (r = 0.512, p = 0.001) in patients with schizophrenia spectrum disorders was observed. The results revealed that sICAM-1 and sVCAM-1 levels in the CSF were higher in patients with schizophrenia spectrum disorder than in those with depression. These circulating signaling molecules may indicate endothelial dysfunction causing impaired BBB/BCSFB function in patients with schizophrenia spectrum disorders. Consistent with this view, a highly significant correlation of sVCAM-1 with CSF protein and AQs was detected. Upregulation of these cell adhesion molecules might be indicative of a proinflammatory immune response underlying the BBB/BCSFB disturbance in a subgroup of patients with schizophrenia spectrum disorders. The significance of the study is limited by its retrospective research design and by the absence of a healthy control group. The assay used was not previously established for the measurement of CSF. Further translational and controlled studies of the role of different cell adhesion molecules in schizophrenia are needed.

Brain vasculature disturbance in schizophrenia

“…A meta-analysis indicated BBB leak in SZ, reflected by higher levels of CSF albumin [33 ▪▪ ]. Three subsequent studies corroborated this result and indicated BBB leakage across a relatively similar percentage of the patients (15.8% [52 ▪▪ ], 19% [53 ▪▪ ], 15% [34 ▪▪ ]). Reductions in the tight junction protein CLDN5 were reported in the hippocampus [43 ▪▪ ] and serum of the patients [42].…”

“…In SZ, CSF sICAM1 was also higher than reference control levels. Levels of these proteins were similar among first-episode and chronic SZ patients, suggesting that alterations were not a consequence of a degenerative process, nor of cumulative antipsychotic use [34 ▪▪ ]. Elevated serum levels of PAI-1 and other pro-inflammatory cytokines were also reported in another study with large samples, and levels were even higher in SZ patients that had experienced Acute Ischemic Stroke (SZ-AIS) (150 SZ, 150 SZ-AIS, and 150 controls) [59].…”

“…Plasminogen activator inhibitor-1 (PAI-1) is a pro-coagulant protein and its expression is enhanced in a pro-inflammatory environment [57], facilitating leukocyte migration across the endothe-lium [58]. Meixensberger et al, (2021) quantified CSF levels of endothelial cell adhesion molecules in SZ (40) and unipolar depression patients (39), and reported increased sICAM1, sVCAM1, and PAI-1 in SZ compared to the depressed patients. In SZ, CSF sICAM1 was also higher than reference control levels.…”

“…A meta-analysis found increased blood levels of S100B and MMP9, and increased CSF albumin (24–2 studies; 1107-69 SZ and 873-92 control subjects), suggesting BBB damage and increased barrier permeability in SZ [33 ▪▪ ]. A subsequent study also reported increased CSF albumin, as compared to reference control levels, but only in 15% of the patients with SZ (40 SZ) [34 ▪▪ ].…”

Unveiling the gut-brain axis: structural and functional analogies between the gut and the choroid plexus vascular and immune barriers

“…Different from the CSF which is characterize by CD4 + central memory T cells [ 122 , 123 ], the choroid plexus contains CD4 + effector memory T cells localized within the epithelium near to MHCII cells and with a pattern of receptors (TCR) peculiar and specific to CNS antigens [ 19 , 124 ].…”