Elevated peripheral cytokines characterize a subgroup of people with schizophrenia displaying poor verbal fluency and reduced Broca’s area volume (2015)

Elevated peripheral cytokines characterize a subgroup of people with schizophrenia displaying poor verbal fluency and reduced Broca’s area volume (2015)

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.

“Group comparisons of peripheral circulating cytokines (signaling peptides of the immune system mediating the inflammation response) between individuals with schizophrenia and controls have consistently identified higher mean levels of interleukin (IL)-6, IL-1β, tumor necrosis factor and other cytokines in schizophrenia and even greater elevations during acute psychosis. We have recently provided evidence of central immune activation with cytokine messenger RNAs (mRNAs) for IL-6, IL-8 and IL-1β upregulated in brain tissue of ~40% of individuals who were chronically ill with schizophrenia. Demonstrating that a proportion of individuals with schizophrenia have abnormal cytokine profiles in blood, similar to what was previously described in post-mortem brain samples, would further support the relevance of inflammation to pathophysiology in a subgroup of those with the disease.”

“Our study found evidence for a biological subgroup of people with schizophrenia who display elevated peripheral cytokine mRNA levels, poor verbal fluency and decreased Broca’s area brain volumes. Our finding that ~40% of individuals in a community clinical sample had a pattern of relatively elevated cytokine expression in peripheral blood is consistent with our previous post-mortem brain tissue observations, in which we found that ~40% had elevated cytokines in the prefrontal cortex. Peripheral cytokine changes appear to be related to brain dysfunction given that the elevated cytokine subgroup with schizophrenia showed worse verbal fluency and a more pronounced volumetric reduction of Broca’s area. Our results suggest that there may be a meaningful biotype of patients with schizophrenia and increased cytokines who can be identified using easily accessible markers; however, as our study is a proof of concept, independent replication in larger samples will be required.”

“Out of all of the cytokine mRNAs that we measured peripherally, only IL-1β was significantly elevated in schizophrenia. IL-1β is a powerful classical proinflammatory cytokine, which has been described as a master regulator of other immune cells and immune processes. Our cluster analysis concurs with this in that individuals with elevated IL-1β tend to also have elevations in other cytokines forming a fingerprint, or a pattern. The possibility that patients with schizophrenia are abnormally sensitive to immune activation mediated by IL-1β is supported by our findings of robust correlations between elevated IL-1β mRNA levels, lower verbal fluency scores and reduced Broca’s area volumes.”

To conclude:

“Our finding that decreased verbal fluency and Broca’s area volume is related to immune activation suggests that targeted treatment of some individuals with schizophrenia displaying the elevated cytokine biotype with anti-inflammatory agents may be beneficial for cognitive deficits, especially verbal fluency. As current treatments have little beneficial effect on language dysfunction in schizophrenia, anti-inflammatory agents may yield greater efficacy on this prominent deficit of the illness. In support of this, although Alzheimer’s disease is a different disorder and any comparison with schizophrenia must be treated with caution, it is noteworthy that anti-inflammatory treatment resulted in a decrease in cytokine levels and improved verbal fluency.”

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