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.

Neuroinflammation and Oxidative Stress in Psychosis and Psychosis Risk

“…In addition, contradictory or ambiguous results may result in part from heterogeneity in the pathogenesis and biochemical profile of different psychosis subgroups. For example, a recent landmark paper showed evidence of a correlation between inflammatory markers in schizophrenia and specific structural and functional alterations, likely reflecting an etiologic subgroup of patients [113]. This may point towards the need for a staging system based not only on clinical symptomatology, but also on underlying pathology and endophenotypes [114].…”

The Relationship between Cytokines and Verbal Memory in Individuals with Schizophrenia and Their Unaffected Siblings

“…We did not find a correlation between EVM and TNF-α or IL-6, but these cytokines may be correlated to other cognitive domains. Second, we did not measure other cytokines such as IL-1β and eotaxin [42, 43]. Furthermore, we did not analyze the potential influence of antipsychotics on cytokine levels.…”

Nuclear Receptors and Neuroinflammation in Schizophrenia

“…With RXRB and RARG mRNAs being lower in the low inflammation schizophrenia group, it is unclear whether the change in expression of the retinoid receptors is leading to a change in inflammatory status or whether a change in inflammatory status is driving the changes in receptor expression. Previous work from our group has demonstrated reduced cognitive performance in individuals with schizophrenia with high inflammation [60], thus it appears that high inflammatory peripheral activity may have functional consequences for the brain. Here, our data do not support the hypothesis that decreased signalling via lower retinoid receptor levels is a likely contributor to the high inflammation in schizophrenia, but in fact we find increased retinoid receptors in high inflammation schizophrenia, perhaps reflecting an attempt to compensate for putative tissue damage during neuroinflammatory processes, as suggested by grey matter volume reductions [46] and elevated astrogliosis in those with schizophrenia and high inflammation [61].…”