Evidence for Cytokine Dysregulation in Schizophrenia Spectrum Disorders: A Comparison of Cerebrospinal Fluid and Blood Samples

Abstract

AbstractIntroductionAbnormalities in immune function have been described in schizophrenia. Cytokines, key signaling molecules of the immune system, have been investigated in peripheral blood samples of patients with schizophrenia though few studies have investigated cytokines in cerebrospinal fluid (CSF). Moreover, very few studies with schizophrenia subjects have investigated the relationships between CSF and blood cytokine levels or investigated sex differences.MethodsIn this cross-sectional study, subjects with schizophrenia spectrum disorder (SSD) diagnosis and healthy volunteers (HV) underwent a lumbar puncture, a blood draw, and psychopathology ratings. CSF and plasma levels of IL-1ß, IL-2, IL-4, IL-6, IL-8 and TNFα were determined by enzyme-linked immunosorbent assay (ELISA) and a high-sensitivity MilliplexTM Multiplex kit. Cytokine levels were square root transformed and compared between both groups using bivariate tests and a multivariate regression analysis. CSF and plasma cytokine levels were compared as were the effects of sex.ResultsThirty SSD and 23 HV were included in the study. In bivariate analysis, CSF TNFα and IL-4 levels were significantly increased in SSD subjects compared to HV. Multivariate regression analysis also showed increases in TNFα and IL-4 after adjusting for sex, age and body mass index. There were no significant differences in plasma cytokine levels between groups, and there were no correlations between CSF and plasma cytokine levels. CSF levels of TNFα and IL-4 were negatively correlated with speed of processing. Stratified analysis by sex showed significantly increased levels of TNFα and IL-4 in SSD vs. HV in males but not in females, although sample sizes were small after stratification.DiscussionThe present findings provide evidence of dysregulation of TNFα and IL-4 in CSF of schizophrenia and suggest that peripheral cytokine levels are not reflective of CSF levels. We also provide further evidence of the association between cytokine levels and impairment of certain cognitive domains. These results identify elevated CSF TNFα levels as a potential biomarker relevant to the neuropathophysiology of schizophrenia.