Elevated peripheral cytokines characterize a subgroup of people with schizophrenia displaying poor verbal fluency and reduced Broca's area volume

Abstract

Previous studies on schizophrenia have detected elevated cytokines in both brain and blood, suggesting neuroinflammation may contribute to the pathophysiology in some cases. We aimed to determine the extent to which elevated peripheral cytokine messenger RNA (mRNA) expression: (1) characterizes a subgroup of people with schizophrenia and (2) shows a relationship to cognition, brain volume and/or symptoms. Forty-three outpatients with schizophrenia or schizoaffective disorder and matched healthy controls were assessed for peripheral cytokine mRNAs (interleukin (IL)-1β, IL-2, IL-6, IL-8 and IL-18), intelligence quotient, memory and verbal fluency, symptom severity and cortical brain volumes integral to language (that is, Broca's and Wernicke's areas). IL-1β mRNA levels were 28% increased in schizophrenia compared with controls (t(82)=2.64, P<0.01). Using a two-step clustering procedure, we identified a subgroup of people displaying relatively elevated cytokine mRNA levels (17/43 people with schizophrenia and 9/42 controls). Individuals with schizophrenia in the elevated cytokine subgroup performed significantly worse than the low-cytokine subgroup on verbal fluency (F(1,40)=15.7, P<0.001). There was a 17% volume reduction of the left pars opercularis (POp) (Broca's area) in patients with elevated cytokines compared with patients with lower cytokines (F(1,29)=9.41, P=0.005). Negative linear relationships between IL-1β mRNA levels and both verbal fluency and left POp volume were found in schizophrenia. This study is among the first to link blood biomarkers of inflammation with both cognitive deficits and brain volume reductions in people with schizophrenia, supporting that those with elevated cytokines represent a neurobiologically meaningful subgroup. These findings raise the possibility that targeted anti-inflammatory treatments may ameliorate cognitive and brain morphological abnormalities in some people with schizophrenia.

Figure 1

Cytokine mRNA expression levels in leukocyte cells from the blood of people with schizophrenia (red) and matched controls (blue). A significant increase was observed in IL-1β mRNA expression in schizophrenia. Other cytokines were not significantly changed but showed substantial expression variability. Horizontal bars represent the median values. Note the different scales on the y axes (**P<0.01).

Figure 2

A recursive two-step clustering analysis of the mRNA levels of four cytokines (IL-1β, IL-18, IL-8, IL-2 in order of contribution) yields two subgroups in the optimal model. Each cytokine mRNA expression is significantly elevated over the mean of all controls with the standard error (represented by bars) increasing as contribution weight decreases (a). One subgroup contains elevated levels of cytokine mRNA expression (dark colors) and the other subgroup has lower levels compared with the control average (light colors). The elevated cytokine subgroups comprise 40% of the schizophrenia group (red) and 21% of the control group (blue) (b).

Figure 3

Z-Scores for the 10 neurocognitive domains tested. Significance levels for diagnosis are indicated on the upper portion of the figure. All tests with the exception of the Controlled Oral Word Association Test (COWAT) and the similarities subtest of the WAIS-III were significantly changed between schizophrenia and control groups when covaried for premorbid IQ (Wechsler Test of Adult Reading). The COWAT revealed significantly poorer performance in individuals with schizophrenia who have elevated cytokine levels compared with those with low cytokine levels as shown by the bracket in the lower portion of the figure. Error bars indicate standard error (T; P=0.06, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001, *****P<0.0000001).

Figure 4

Language-related brain areas influenced by elevated cytokine levels in schizophrenia. Significant volumetric changes in areas associated with verbal fluency were found in the left hemisphere (a). The pars opercularis, part of Broca's area, showed significantly diminished volume in individuals with schizophrenia compared with controls (upper brackets). There was also a significantly decreased average brain volume in the elevated cytokine schizophrenia group as compared with the low-cytokine group in this brain area (lower brackets). The supramarginal gyrus in the right hemisphere showed a significant interaction effect between diagnosis and cytokine group, but there were no significant differences between diagnostic group or cytokine group. Error bars indicate calculated standard error (*P<0.05, **P<0.01). Increases in IL-1β mRNA in schizophrenia are a significant predictor of poorer COWAT scores (b). Similarly, increases in IL-1β mRNA also predict decreased volumes of the left hemisphere pars opercularis in schizophrenia (c). Individuals in the elevated cytokine group are represented by dark red points and those in the low-cytokine group indicated by lighter red points.