SCHRES-06323; No of Pages 7 Schizophrenia Research xxx (2015) xxx–xxx

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Inflammatory markers are associated with general cognitive abilities in schizophrenia and bipolar disorder patients and healthy controls Sigrun Hope a,b,⁎, Eva Hoseth a,d, Ingrid Dieset a,d, Ragni H. Mørch a,d, Monica Aas a,d, Pål Aukrust c,f,h,i, Srdjan Djurovic a, Ingrid Melle a,d, Torill Ueland a,g, Ingrid Agartz a,e, Thor Ueland c,h,i, Lars T. Westlye a,d,g, Ole A. Andreassen a,d,h a

NORMENT, KG Jebsen Centre for Psychosis Research, University of Oslo, Oslo, Norway Department of Neuro Habilitation, Oslo University Hospital, Ullevål, Oslo, Norway c Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway d Division of Mental Health and Addiction, Oslo University Hospital, Ullevål, Oslo, Norway e Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway f Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Norway g Department of Psychology, University of Oslo, Oslo, Norway h Institute of Clinical Medicine, University of Oslo, Oslo, Norway i KG Jebsen Inflammatory Research Center, University of Oslo, Oslo, Norway b

a r t i c l e

i n f o

Article history: Received 4 September 2014 Received in revised form 25 March 2015 Accepted 7 April 2015 Available online xxxx Keywords: Severe mental disorders Inflammation Wechsler Abbreviated Scale of Intelligence (WASI) Cognitive sTNF-R1 IL-1Ra Osteoprotegerin IL-6 hsCRP Von Willebrand factor

a b s t r a c t Background: The mechanisms underlying cognitive impairment in schizophrenia and bipolar disorders are largely unknown. Immune abnormalities have been found in both disorders, and inflammatory mediators may play roles in cognitive function. We investigated if inflammatory markers are associated with general cognitive abilities. Methods: Participants with schizophrenia spectrum (N = 121) and bipolar spectrum (N = 111) disorders and healthy controls (N = 241) were included. General intellectual abilities were assessed using the Wechsler Abbreviated Scale of Intelligence (WASI). Serum concentrations of the following immune markers were measured: Soluble tumor necrosis factor receptor 1 (sTNF-R1), interleukin 1 receptor antagonist (IL-1Ra), osteoprotegerin, von Willebrand factor, C-reactive protein, interleukin-6 and CD40 ligand. Results: After adjusting for age, sex and diagnostic group, significant negative associations with general cognitive function were found for sTNF-R1 (p = 2 × 10−5), IL-1Ra (p = 0.002) and sCD40 ligand (p = 0.003). Among patients, the associations remained significant (p = 0.006, p = 0.005 and p = 0.02) after adjusting for possible confounders including education, smoking, psychotic and affective symptoms, body mass index, cortisol, medication and time of blood sampling. Subgroup analysis, showed that general cognitive abilities were significantly associated with IL-1Ra and sTNF-R1 in schizophrenia patients, with sCD40L and IL-1Ra in bipolar disorder patients and with sTNF-R1 in healthy controls. Conclusion: The study shows significant negative associations between inflammatory markers and general cognitive abilities after adjusting for possible confounders. The findings strongly support a role for inflammation in the neurophysiology of cognitive impairment. © 2015 Published by Elsevier B.V.

1. Introduction Schizophrenia spectrum disorder (SCZ) and bipolar spectrum disorder (BD) affect 2% of the population and cause marked decrements in quality of life and life expectancy (Whiteford et al., 2013). The core characteristic of SCZ is psychotic symptoms, while affective symptoms are at the core of BD. There is however, an overlap in these symptoms, as described in continuum hypotheses of the two disorders (Craddock and Owen, 2010). It has been increasingly recognized that cognitive deficits ⁎ Corresponding author at: NORMENT, KG Jebsen Centre, Oslo University Hospital, Ullevål, 0407 Oslo, Norway.

are among the core symptoms in both disorders, persistent across acute and chronic phases and associated with reduced functional outcome (Simonsen et al., 2010, 2011; Bourne et al., 2013). Recently, the NIMH Research Criteria Project suggested that cognition should be one of five core research domains in the field of psychiatric diseases (Morris and Cuthbert, 2012). SCZ and BD are highly heritable disorders (Lichtenstein et al., 2009) with complex genetic and environmental interactions involved (Burmeister et al., 2008). Several lines of research indicate that the immune system may be involved in these interactions (Kinney et al., 2010) and it has been suggested that mononuclear phagocyte cells including microglial cells may play a key role in their pathogenesis.

http://dx.doi.org/10.1016/j.schres.2015.04.004 0920-9964/© 2015 Published by Elsevier B.V.

Please cite this article as: Hope, S., et al., Inflammatory markers are associated with general cognitive abilities in schizophrenia and bipolar disorder patients and healthy co..., Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.04.004

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Increased macrophage/monocyte inflammatory activation and enhanced immune gene expression in circulating monocytes have been described in both BD and SCZ (Beumer et al., 2012; Bergink et al., 2014). Altered cytokine levels with elevated activity in the immunological signal pathways of tumor necrosis factor (TNF), and interleukin (IL)-1, IL-2, IL-4 and IL-6 have also been found in both disorders (Potvin et al., 2008; Drexhage et al., 2010; Munkholm et al., 2013). These elevations are of importance as animal studies suggest that elevated inflammatory signals may directly influence neuronal synaptic dynamics and neurotransmission and have a negative impact on cognitive abilities (Boulanger, 2009; Shatz, 2009; Havik et al., 2011). Levels of inflammatory markers are determined by both genetic and environmental factors (Neijts et al., 2013), and could be regarded as partly trait and state characteristics. Stress hormones such as cortisol and changes in the hypothalamic–pituitary–adrenal axis may have a marked effect on both inflammation and cognition (Himmerich et al., 2006; Kinney et al., 2010). We have previously measured the activity in three cytokine pathways described to play major roles in a cytokine model of cognition (McAfoose, 2009): the IL-1 receptor antagonist (IL-1Ra), soluble TNF receptor 1 (sTNF-R1) and IL-6 as markers of TNF, IL-1 and IL-6 activity. In addition we measured the activity in von Willebrand factor (vWf) as a marker of endothelial cell activation, osteoprotegerin (OPG) as a marker of calcium related vascular inflammation, soluble CD40 ligand as platelet activation (sCD40L), and C-reactive protein (CRP) as a reliable down-stream marker of inflammation mainly produced in the liver. We found elevated levels of inflammatory markers in SCZ and BD (Hope et al., 2009, 2010). Subsequent studies showed that higher levels of proinflammatory cytokines were associated with increased psychotic symptoms (Hope et al., 2011b, 2013), affective state and degree of affective symptoms in BD (Hope et al., 2011a), and brain morphology (Dieset et al., 2014). Enhanced immune activation, as measured by markers of inflammation has been found to correlate with poorer cognitive function in patients with neurological diseases and in healthy persons (Cunningham et al., 2009b; Patanella et al., 2010; Balldin et al., 2012; Bettcher and Kramer, 2014; Rocha et al., 2014). In SCZ, a systematic literature review investigating the relationship between cognition and inflammation found evidence of a negative association between high sensitivity CRP and cognition (Ribeiro-Santos et al., 2014), and in addition, a recent study showed a positive correlation between IL-2 and non-verbal intelligence (Asevedo et al., 2014). However, all studies measured activity in a single proinflammatory marker and none controlled for possible confounders e.g. smoking, body mass index, medication, or clinical severity measures. In BD, a recent meta-analysis found two studies that had found an association between a central inflammatory marker and cognition (Bauer et al., 2014) and in addition, a recent study in older patients found an association between inflammation and cognitive function (Lotrich et al., 2013). However, none of the studies measured activity in more than one of the central inflammatory pathways, nor did they control for possible confounding factors such as autoimmune disease, education or clinical severity measures. As several studies have reported that affective symptoms are associated with inflammatory markers (Hope et al., 2011b), affective states should be included as possible covariates. Thus, in both BD and SCZ, there are a lack of studies investigating how markers of different inflammatory pathways relate to general cognition after adjusting for both clinical severity measures and somatic characteristics. A person's general cognitive abilities are relatively stable up to 60 years of age (Hedden and Gabrieli, 2004), and may be measured through general intelligence quotient (IQ) tests (Gottfredson, 1998). The Wechsler Abbreviated Scale of Intelligence (WASI) is a neuropsychological test battery that estimates a full scale IQ (FSIQ) that correlates highly with IQ estimates obtained through the Wechsler Adult Intelligence Scale (WAIS-III) FSIQ (Ryan et al., 2003; Bosnes, 2009). The WASI also estimates performance IQ (fluid intelligence) and verbal IQ (crystallized intelligence), and has been validated across psychiatric

patient groups (Hays et al., 2002). Based on the proposed role of inflammatory markers in the pathophysiology of severe mental illness, we hypothesized that increased levels would be related to reduced general cognitive abilities as measured with the WASI. The role of immunerelated factors has been better documented in SCZ than in BD (Altamura et al., 2014; Andreassen et al., 2014) and possibly stronger associations may be present in SCZ than in BD. This has not been investigated before. Furthermore, inflammatory mediators may reflect physiological processes also in the absence of a severe mental illness (Boulanger, 2009; Shatz, 2009; Havik et al., 2011), and we wanted to investigate if associations between inflammatory markers and cognition could be found also in healthy volunteers. The aim of the current study was to determine how markers of different proinflammatory pathways (sTNF-R1, IL-6, IL-1Ra, OPG, vWf, sCD40L and hsCRP) relate to general cognitive abilities in large wellcharacterized samples of SCZ and BD patients and healthy controls after adjusting for disease severity measures and somatic characteristics and other possible confounding factors. 2. Methods 2.1. Participants The current sample has been described in previous publications (Hope et al., 2009, 2013; Simonsen et al., 2011). Briefly, patients from the catchment area of Oslo University Hospital and collaborating hospitals to the ongoing Thematically Organized Psychosis (TOP) Study in Oslo, Norway were included. Most patients received outpatient treatment. Inclusion criteria were as follows: Caucasian patients registered in the psychiatric services of Oslo University Hospital and collaborating hospitals; 18 to 63 years of age; and meeting DSM-IV criteria for SCZ or BD. Exclusion criteria were as follows: First language other than Norwegian, organic psychosis, neurological disorder, head injury with electroencephalogram (EEG)-, computer tomography (CT)- or magnetic resonance imaging (MRI)-scanned abnormalities following the injury, intellectual disability, autoimmune disease or use of non-steroid anti-inflammatory drugs (NSAIDs). The participants were included between 2003 and 2008. Included in the current analyses were 226 consecutively referred patients of whom 121 patients had a schizophrenia spectrum disorder (SCZ) (schizophrenia [93], schizophreniform [N = 8] and schizoaffective disorder [N = 20]), and 111 patients had a bipolar spectrum disorder (BD) (bipolar I disorder [N = 65], bipolar II disorder [N = 40] and BD not otherwise specified [N = 6]). Healthy controls from the same catchment area as the patients (Oslo and suburbs) were randomly selected from statistical records (www. ssb.no) and invited by letter. Included in the study were 241 persons without a history of medical diseases, severe psychiatric disorders, including alcohol or illicit substance abuse, or SCZ or BD in first-degree relatives. Both patients and healthy controls were assessed by trained psychiatrists or clinical psychologists. The Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) was used for diagnostic purposes. Inter-rater reliability was good, with an overall kappa score of 0.77 (95% confidence interval: 0.60–0.94) for diagnoses (Ringen et al., 2008). Clinical characteristics were assessed with the Positive and Negative Syndrome Scale (PANSS), General Assessment of Functioning (GAF), Young Mania Rating Scale (YMRS), and Inventory of Depressive Symptomatology (IDS)/Calgary Depression Scale for Schizophrenia (CDSS). Affective state was based on scores on YMRS and IDS/CDSS, as described previously (Hope et al., 2011b). For all participants, daily smoking, number of alcohol units and episodes of substance abuse during the last 2 weeks prior to assessment were recorded, as well as level of education, duration of illness and scores on the National Adult Reading Test (NART) (Russell et al., 2000). All participants gave written informed

Please cite this article as: Hope, S., et al., Inflammatory markers are associated with general cognitive abilities in schizophrenia and bipolar disorder patients and healthy co..., Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.04.004

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consent, and the study was approved by the Regional Committee for Medical Research Ethics (‘REK’) and by the Norwegian Data Inspectorate (‘Datatilsynet’).

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sTNF-R1, vWF and OPG, 100% of the sample had values above the detection limit. 2.3. Cognitive measures

2.2. Biochemical and immunological measures Blood sampling was performed between 8 am and 2 pm (in patients) and between 8 am and 5 pm (healthy controls) on the same day as cognitive testing. The analysis of clinical chemistry parameters was performed at Department of Clinical Chemistry, Oslo University Hospital, Oslo, Norway, on an Integra 800 from Roche Diagnostics (Basel, Switzerland) using standard methods. The rationale for selection of the inflammation parameters was to represent distinct inflammatory pathways with stable markers showing little diurnal fluctuations. For immunological analysis, blood was drawn on EDTA vials, and plasma was extracted and stored at −80 °C. Plasma levels of sTNF-R1, IL-1Ra, OPG and IL-6 were measured by enzyme immunoassays (EIAs) obtained from R&D systems (Minneapolis MN, USA), sCD40L was measured using an EIA obtained from Bender Medsystem (Vienna Austria) while hsCRP and vWf were measured using EIA antibodies from Dakocytomation (Oslo, Norway). Intra- and interassay coefficients of variance were less than 10%. The range of detected values was Il-6: 0.10–3.85 ng/ml; IL-1Ra: 0.02–5.91 ng/ml; sCD40L: 0.10–7.31 ng/ml; hsCRP: 0.10–19 mg/l; sTNF-R1: 0.38– 2.24 ng/ml; OPG: 0.33–10.40 ng/ml; and vWf: 15–280%. Values above the detection limit were found in the following percentage of the sample: IL-6: 64%, hsCRP: 72%, IL-1Ra: 96%, and sCD40L: 97%, while for

Four tests from the Wechsler Abbreviated Scale of Intelligence Scale (WASI) (Hays et al., 2002) including two subtests for verbal cognition (Similarities and Vocabulary) and two tests for performance abilities (Block design and Matrix reasoning) were used to assess general cognitive abilities. The test was administered by trained clinical psychologists. Blood for immune measures was routinely collected on the same day as the cognitive testing. 2.4. Statistical analysis Statistical analyses were conducted using the SPSS software package for Windows version 15.0 (SPSS, Chicago, IL). We utilized linear regression models and analysis of covariance (ANCOVA) to test for associations between cytokines and cognition. In order to achieve normally distributed residuals, IL-1Ra, OPG, IL-6 and hsCRP were log transformed prior to analysis. Raw scores from the four WASI subtests were independently Z-normalized (mean = 0, SD = 1) based on the total sample, and a mean Z-score across subtests was calculated for each individual and this composite score was used as a proxy for general cognitive abilities. For completeness and in order to demonstrate comparability with previous studies, we tested for main effects of diagnosis on cognitive abilities and on each of the markers of inflammation using ANCOVAs, covarying for age and sex.

Table 1 Demographic and clinical parameters.

WASI IQ score (mean, SD) Age (mean, SD) Female sex (%) Education, years (mean, SD) Smoking (%) Alcohol intake (mean, SD) Substance abuse (mean, SD) Body mass index (mean, SD) Diabetes/CVD (%) Creatinine (mean, SD) ALT (mean, SD) Cholesterol (mean, SD) Glucose (mean, SD) Cortisol Time of blood sampling Psychiatric medication (%) Antipsychotic (%) Mood stabilizer (%) Antidepressant (%) PANSS GAF YMRS IDS Disease duration (years) sTNF-R1 (mean, SD) OPG (mean, SD) vWf (mean, SD) IL-1Ra (mean, SD) IL-6 (mean, SD) hsCRP (mean, SD) sCD40L (mean, SD)

SCZ N = 121

BD N = 111

Healthy controls N = 241

Total group N = 467

Group differences

113 (9) 36 (10) 55 14 (2.5) 20a 9 (10)b 0.0 24.4 (3) 0 72 (11) 26 (17) 5.2 (1.0) 5.0 (0.8)

104 (15) 33 (10) 46 13 (2.3) 51 9 (19) 0.09 (0.4) 25.7 (5) 4.1 71 (13) 28 (19) 5.2 (1.0) 5.1 (1.2) 412 (138) 9.6 (1) 91 87 20 31 60 (5) 44 (11) 5.5 (5) 16 (11) 4.6 (6) 1.06 (0.31) 2.6 (1.38) 106 (50) 0.82 (1.2) 0.34 (0.45) 0.69 (1.9) 2.1 (1.7)

109 (12) 36 (12) 61 14 (2.2) 52 13 (23) 0.09 (0.4) 25.7 (4) 2.8 72 (18) 27 (20) 5.3 (1.2) 5.1 (1.2) 402 (164) 9.6 (1) 87 44 56 41 45 (10) 58 (12) 2.9 (3) 15 (12) 5.6 (7) 1.04 2.9 103 (56) 0.56 (0.76) 0.36 (55) 1.10 (2.5) 1.7 (1.3)

110 (12) 35 (11) 54 14 (2.4) 39 10 (17) 0.05 (0.3) 25.0 (4) 2 72 (13) 26 (18) 5.2 (1) 5.1 (1) 406 (150) 11.2 (3) 43 33 18 17 53 (7) 51 (13) 4.2 (4) 16 (12) 5.0 (7) 1.00 (0.29) 2.6 (0.97) 95 (52) 0.65 (0.96) 0.33 (0.43) 0.85 (1.6) 1.9 (1.4)

SCZ b BD b HC BD N SCZ & HC NS SCZ b BD &HC SCZ & BD N HC NS SCZ & BD N HC SCZ & BD N HC SCZ & BD N HC NS NS NS NS NS SCZ & BD b HC SCZ & BD b HC SCZ N BD BD N SCZ BD = SCZ SCZ N BD SCZ b BD BD N SCZ BD N SCZ NS SCZ & BD N HC BD N SCZ & HC SCZ &BD N HC NS NS NS NS

12.7 (3) 0 0 0 0

0.95 (0.25) 2.5 (0.93) 87 (49) 0.60 (0.87) 0.31 (0.34) 0.80 (1.3) 1.8 (1.3)

WASI: Wechsler Abbreviated Scale of Intelligence; SCZ: schizophrenia spectrum disorder; BD: bipolar spectrum disorder; HC: healthy controls; substance abuse: number of episodes last 2 weeks; alcohol intake: units of alcohol last two weeks; CVD: cardiovascular disease/hypertension; ALT: alanine transaminase; psychiatric medication: antipsychotics, mood stabilizer or antidepressants; PANSS: Positive and Negative Syndrome Scale; GAF: Global Assessment of Functioning; YMRS: Young Mania Rating Scale; IDS: Inventory of Depressive Symptomatology; sTNF-R1: tumor necrosis factor receptor 1; OPG: osteoprotegerin; vWf: von Willebrand factor; IL-1Ra: interleukin receptor antagonist; IL-6: interleukin 6; hsCRP: high sensitivity C-reactive protein; sCD40L: cluster of differentiation 40 ligand. a Missing 78. b Missing 28.

Please cite this article as: Hope, S., et al., Inflammatory markers are associated with general cognitive abilities in schizophrenia and bipolar disorder patients and healthy co..., Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.04.004

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Table 2 Variance in general cognitive abilities explained by inflammatory markers in the total sample, after adjustment for age, gender, diagnostic group and interaction between diagnostic group and inflammatory marker. Inflammatory marker

F

Partial Eta2 %

Significance

sTNF-R1 IL-1Ra sCD40L OPG IL-6 vWf hsCRP

15 10 9 3 3 2 3

4.2 2.1 1.9 0.7 0.5 0.4 0.1

2 × 10−5 0.002 0.003 0.07 0.13 0.17 0.59

General cognitive abilities: composite score of four WASI tests; diagnostic group: schizophrenia spectrum or bipolar disorder spectrum disorder patients or healthy controls; partial Eta2: proportion of variance in cognition explained by the variable; sTNF-R1: soluble tumor necrosis factor receptor 1; sCD40L: soluble CD40 ligand; OPG: osteoprotegerin; vWf: von Willebrand factor; IL-1Ra: interleukin 1 receptor antagonist; hsCRP: high sensitivity C-reactive protein; IL-6: interleukin 6.

The main effects of inflammatory markers on general cognitive abilities were investigated with ANCOVAs. General cognitive abilities were also set as the dependent variable, while sex and diagnostic group (SCZ and BD patients and healthy control) were fixed factors, and age and inflammatory markers were included as continuous variables. In order to evaluate possible differential effects between diagnostic groups, we also included interactions between diagnosis and inflammation on general cognitive abilities. In order to minimize the risk for Type I errors, we applied Bonferroni corrections for multiple testing (seven tests, one per inflammatory marker, adjusted alpha = p b 0.007). 2.4.1. Control for confounding factors Levels of inflammation may be influenced by possible confounding factors such as age, sex, smoking, medication with antipsychotics, antidepressants, or mood stabilizers, alcohol intake, substance abuse, stress hormones, kidney and liver function, body mass index (BMI), cholesterol, glucose and blood sampling. General cognitive abilities may be influenced by several of the same factors (e.g. age) in addition to factors such as education, affective state, disease duration and degree of psychotic, depressive and manic symptoms. In order to minimize the impact of such possible confounders on the main effects, we included these factors as additional covariates in the ANCOVAs. In the subsample analyses of SCZ patients, BD patients and healthy controls, associations were investigated through linear regression analysis: General cognitive ability was set as the dependent variable, while the inflammatory marker and possible confounding factors were set as independents with variable entered backwards and missing values replaced with mean. Accordingly, only covariates with a significant effect are shown in the subgroup regression models. 3. Results Table 1 summarizes cognitive, demographic, and inflammatory markers in patients with SCZ and BD and healthy controls. The sample has a mean age of 35 years, and the mean IQ estimate was 104 in SCZ patients, 109 in BD patients, and 113 in healthy controls. Compared to healthy controls, the patients had a mean IQ score that was 7 points lower, were one year younger, had a higher percentage of smokers, consumed slightly more alcohol, had more frequent substance abuse, more frequently suffered from cardiovascular diseases (CVD)/diabetes, and had a slightly higher BMI. As shown previously (Hope et al., 2009), the main effects of diagnosis on the following inflammatory markers, after covarying for age and sex, were observed: sTNF-R1 (p = 0.001), vWf (p = 0.0001) and OPG (p = 0.04), indicating increased levels in the SCZ and BD groups compared to healthy controls, and with no significant differences between

BD and SCZ in any of the inflammatory markers. All ANCOVAs revealed significant effects of diagnosis on general cognitive abilities, with lower general cognitive abilities in SCZ than BD patients (p b 0.001), and with both SCZ and BD patients having lower cognitive abilities than healthy controls, co-varying for age, sex, and inflammation (p b 0.005). Table 2 presents the results from the ANCOVAs testing for associations between general cognitive abilities and inflammatory markers, after adjusting for age, sex, diagnostic group and interaction between diagnostic group and inflammation. Highly significant negative associations were found for sTNF-R1 (F = 15, p = 2 × 10−5, η2 = 4.1%), IL-1Ra (F = 10, p = 0.002, η2 = 2.1%) and sCD40L (F = 9, p = 0.003, η2 = 1.9%). As seen in Table 2, there was also a non-significant trend of associations between cognitive abilities and OPG (p = 0.07). No significant associations were found between cognitive abilities and the other markers. In the total sample, there was a significant interaction effect between sTNF-R1 and IL-1Ra and diagnostic group (sTNFR1 × diagnostic group: p = 0.04; IL-1Ra × diagnostic group: p = 0.04), indicating different coefficients in the three groups, while for the other markers there were no significant interactions. 3.1. Control for possible confounding factors The variance in general cognitive abilities in patients explained by sTNF-R1, IL-1Ra and sCD40L after adjustment for potential confounders are shown in Table 3. sTNF-R1 and IL-1Ra remained significantly associated with general cognitive abilities also after adding possible confounders in the ANCOVA, accounting for 5.5% (p = 0.006) and 5.7% (p = 0.005) of the variance. There was also a trend of sCD40L being associated after control of these confounders, explaining 2.7% of the variance (p = 0.054). When possible confounders were adjusted for, there were no interaction effects between diagnostic category (SCZ/BD) and sTNF-R1 or IL-1Ra on general cognitive abilities (sTNF-R1 × diagnostic group: p = 0.33, IL1Ra × diagnostic group: p = 0.47), indicating that different associations between the inflammatory marker and cognition in SCZ and BD may be due to random factors. To control for the possible confounding effect of diurnal fluctuations of inflammatory markers at different blood sampling times, we performed analysis in a subsample that had taken their blood sample between 9 and 11 am (N = 257), and controlled for age, sex, time of blood sampling, diagnostic group and interaction between diagnostic group and inflammation. The results showed that the variance in general cognitive abilities explained by inflammatory markers remained significant: (sTNF-R1: η2 = 7.5%, p = 1 × 10−5; IL-1Ra: η2 = 4.1%, p = 0.001; sCD40L: η2 = 4.3%, p = 0.001). NART scores were added as a covariate into the ANCOVAS shown in Table 2, and the markers sTNF-R1 (p = 0.04) and sCD40L (p = 0.006) were still significantly associated with cognition, while IL-1Ra (p = 0.13) lost significance. NART was also added into analysis of the patient sample, controlling for all covariates shown in Table 3, and IL1Ra and sTNF-R1 were still significantly associated (p b 0.05) with cognition. 3.2. Subgroup analysis In the SCZ group, associations between general intellectual abilities and sTNF-R1 (p = 0.01) and IL-1Ra (p = 0.04), were significant after controlling for many possible confounders (Supplementary Table 1), while associations with sCD40L were not. In the BD group there was significant association between general cognitive abilities and IL-1Ra (p = 0.03) and sCD40L (p = 0.03) after controlling for confounders (see Supplementary Table 2), while not with sTNF-R1. In healthy controls, there was a significant association between cognition and sTNF-R1, present after adjusting for possible confounders (p = 0.01) (see Supplementary

Please cite this article as: Hope, S., et al., Inflammatory markers are associated with general cognitive abilities in schizophrenia and bipolar disorder patients and healthy co..., Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.04.004

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Table 3 ANCOVAs showing the proportion of variance in patients' general cognitive abilities explained by sTNF-R1, IL-1Ra, sCD40L and possible confounders. F

Corrected M Intercept Age Sex Education (years) SCZ vs BD GAF PANSS Disease duration Affective state YMRS Depression BMI Smoking Alcohol units Substance abuse Antipsychotic Mood stabilizer Anti-depressant Diabetes/CVD Creatinine ALT Cholesterol Glucose Cortisol Time of blood sampling Inflammatory marker × diagnostic group Inflammatory marker

sTNF-R1

IL-1Ra

sCD40L

F

Eta2

Sig

F

Eta2

Sig

F

Eta2

Sig

3.3 1.4 6.9 .29 22.8 .59 .95 1.2 .86 2.2 2.5 3.4 .20 .97 1.1 .23 .81 4.0 .09 1.3 .005 .85 2.32 .84 .16 1.41 .93 7.79

40.8 1.1 4.9 0.2 14.4 0.4 0.7 0.9 0.6 4.8 1.9 2.5 0.1 0.7 0.9 0.2 0.6 2.9 0.1 0.9 0.0 0.6 1.7 0.6 0.1 1.0 0.7 5.4

.00 .23 .009 .59 .000 .44 .33 .27 .35 .08 .11 .06 .65 .32 .28 .63 .36 .05 .75 .25 .94 .35 .12 .36 .68 .23 .33 .006

3.3 .000 10.4 0.07 33.9 1.07 .75 .27 .06 2.3 1.8 3.9 .07 .12 .69 .006 .97 4.4 .81 .79 .58 .85 .99 .76 .00 .12 .52 8.04

40.8 .0 7.2 0.1 20.1 00.8 0.6 0.2 0.0 4.9 1.3 2.9 0.1 0.1 0.5 0.0 0.7 3.2 0.6 0.6 0.4 0.6 0.7 0.6 0.0 0.1 0.4 5.6

.000 .99 .002 .79 .000 .30 .38 .600 .81 .08 .18 .05 .79 .73 .41 .94 .32 .04 .37 .37 .44 .36 .32 .38 .99 .72 .47 .005

2.9 .09 7.1 .02 26.4 .11 .06 .48 .49 2.3 1.4 2.3 .02 .29 .12 .11 .77 3.9 .38 .75 .50 1.0 1.1 1.4 .002 .31 .045 3.78

37.7 0.1 5.0 0.0 16.3 0.1 0.0 0.4 0.4 5.0 1.0 1.7 0.0 0.2 0.1 0.1 0.6 2.8 0.3 0.6 0.4 0.7 0.8 .1.1 0.0 0.2 0.0 2.7

.000 .76 .008 .912 .000 .73 .80 .48 .48 .07 .23 .13 .90 .59 .72 .73 .38 .05 .53 .38 .47 .31 .28 .22 .96 .57 .83 .05

General cognitive abilities: composite score of four WASI test results; F: F-test; Eta2: proportion of variance in cognition explained by the variable; sTNF-R1: soluble tumor necrosis factor receptor 1; IL-1Ra: interleukin receptor antagonist; sCD40L: soluble CD40 ligand; GAF: General Assessment of Functioning; PANSS: Positive and Negative Syndrome Scale; YMRS: Yong Mania Rating Scale; BMI: body mass index; ALT: alanine amino transferase; CVD: cardiovascular disease.

Table 3), while there were no associations between cognition and IL1Ra and sCD40L. 3.3. Associations between inflammatory markers and different cognitive domains Inflammatory markers were negatively associated with both perceptual organization (sTNF-R1: p = 0.00003, IL-1Ra: p = 0.02, sCD40L: p = 0.006 and OPG: p = 0.03) and verbal comprehension (sCD40L: p = 0.04) (see Supplementary Table 4). 4. Discussion The main result of the current study is that increased serum levels of three inflammatory markers, sTNF-R1, IL-1Ra and sCD40L, were negatively associated with general cognitive abilities across SCZ and BD patients and healthy controls. The variance explained by the variables was approximately equal to the variance explained by age, which is considered to have a substantial influence on cognition. The markers were associated with both verbal and non-verbal abilities, with more associations with the latter domain. They also explained more of the variance than clinical severity measures. The results remained significant after adjusting for a range of possible confounders, including education, clinical severity measures and cortisol. The sub-group analysis revealed that in SCZ patients, there were significant associations between general intellectual abilities and IL-1Ra and sTNF-R1, in BD patients, intellectual abilities were significantly associated with IL-1Ra and sCD40L, while in healthy controls, general cognitive abilities were associated with sTNF-R1. After controlling for confounders there were no significant interactions between diagnostic group (SCZ or BD) and inflammatory markers, indicating that different correlation coefficients between the diagnostic entities may be due to different distributions of covariates or random factors.

This is the first study to show an association between sTNF-R1 and IL-1Ra and cognition in SCZ. The findings were highly significant, and in line with previous findings in older BD patients (Lotrich et al., 2013), and in Parkinson's and Alzheimer's disease (Laske et al., 2013; Rocha et al., 2014) supporting that the associations may not be disease specific. This is also the first study to show that the concentration of sCD40L, a platelet derived factor also expressed in neurons, is associated with cognitive function. The marker showed the highest correlation with cognitive function in BD. We did not find any significant associations between general cognitive abilities and vWf or OPG, although patients had elevated levels of these markers. However, OPG was negatively associated with perceptual reasoning, and vWf had a trendlevel significant negative association with verbal function (p = 0.07), indicating poorer cognitive function with higher levels of these inflammatory markers also. As for hsCRP and IL-6, we did not find these markers elevated in our previous studies nor associated with symptom severity (Hope et al., 2011c). The present study revealed no association with general cognitive abilities, which is in contrast to the findings of two previous studies of SCZ and BD patients, but in line with findings in young healthy controls (Dickerson et al., 2007, 2013; Jonker et al., 2014). One explanation for the lack of association may be that values above the detection limit were found in 64% for IL-6 and in 72% for hsCRP, while the other markers were detectable in 96% of the sample or more. This reduction in the statistical power to detect associations may be partly responsible for the lack of associations with these two markers. The roles of the inflammatory markers in the brain are still uncertain, and it is difficult to pinpoint results from single studies. One mechanism by which TNF and IL-1Ra mediate their effects in the brain is through influence on glutamate, a neurotransmitter involved in the pathological mechanisms of SCZ and BD (Moghaddam and Javitt, 2012). IL-1Ra also plays a role in mediation of response to social stress (Arakawa et al., 2009), while TNF has a central role in the hippocampus a brain region important for memory function (Golan et al., 2004; Baune

Please cite this article as: Hope, S., et al., Inflammatory markers are associated with general cognitive abilities in schizophrenia and bipolar disorder patients and healthy co..., Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.04.004

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et al., 2012). The role of sCD40L in cognition is less described that that of IL-1Ra and sTNF-R1, but animal research suggests that sCD40L signaling is necessary for physiological neuronal function and that elevated levels may be a marker of dementia (Buchhave et al., 2009). The mechanisms underlying the association between inflammation and cognitive function are uncertain, and whether inflammation is a cause or a consequence of cognitive impairments has not been clarified (Manu et al., 2014). Support for a causal influence is found in recent experimental studies in humans showing that acute systemic inflammation induces cognitive changes (Harrison et al., 2014; Kullmann et al., 2014; Szabo et al., 2014) and in animal studies where inflammation has been found to accelerate neurodegenerative disease (Cunningham et al., 2009a). Evidence for the opposite, that high inflammation is a consequence of pathological neuronal activity is supported by the finding that epileptic neurological activity increases the release of IL-1β (Librizzi et al., 2012). Recent findings support a role of immunerelated molecules also in normal brain development and synaptic function, independent of brain tissue inflammation or infection (Boulanger, 2009). The association between inflammation and cognition found in healthy controls supports a role involved in normal physiological neurotransmission (McAfoose, 2009). A limitation of the current study is its cross-sectional nature, which makes it impossible to draw conclusions about causation. Inflammation may be both a cause and a consequence of brain effects manifested as cognitive abilities. It could also be a limitation that blood samples were collected at different times, and not all subjects were fasting, but as we controlled for timing and glucose levels, we believe the impact of differences should be limited. Another limitation may be that patients were not unmedicated. However, the results were adjusted for antipsychotic, antidepressant and mood stabilizing medication, in order to reduce the risk of such medications as confounders. According to recent studies, these medications tend to have anti-inflammatory properties rather than proinflammatory (Horowitz et al., 2014; Mondelli and Howes, 2014), and if so, the associations could probably have been stronger if all patients had been unmedicated. This if further supported by the fact that associations were found also among healthy volunteers, suggesting that the associations are not merely due to confounding by medication. There was a low detection limit of IL-6 and hsCRP which may have reduced the probability of finding significant associations with these markers. General cognitive abilities were measured with the WASI, a short form of the WAIS, and the use of the full version of the WAIS-III could have strengthened the study. Conclusively, the present results support that systemic inflammation markers are negatively associated with general cognitive abilities, and show that some inflammatory markers are associated with cognitive function in SCZ and BD patients and in healthy controls, also after controlling for a range of possible confounders. Longitudinal studies are needed to determine if individuals with high levels of sTNF-R1, IL-1Ra or sCD40L are at risk of cognitive decline.

Role of the funding source The study was supported by grants from the Research Council of Norway (#213694, #223273), the South-East Norway Health Authority (#2013-123, #2007-050) and the KG Jebsen Foundation. The funding source did not have any role in the study design, the interpretation of data or in the publication of the study.

Contributors Drs. Hope and Andreassen conceived the study and its design and contributed to data acquisition. Drs. Aukrust and Ueland contributed to study conception, data analysis and interpretation of results. Drs. Hope and Westlye performed the statistical analysis. Drs. Hoseth, Dieset, Mørch, Aas, Ueland, Melle, Djurovic and Agartz contributed to data acquisition and interpretation of the results. Drs. Hope, Andreassen and Westlye wrote the manuscript, which was reviewed by all other authors. All authors approved the final version of the manuscript.

Conflict of interest No authors reported any biomedical financial interests or potential conflicts of interest relevant to the subject matter of the manuscript.

Acknowledgments The authors thank the patients and controls for participating in the study, and TOP study group members for contributing to data collection.

Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.schres.2015.04.004.

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