Cognitive and inflammatory heterogeneity in severe mental illness: Translating findings from blood to brain.

Recent findings link cognitive impairment and inflammatory-immune dysregulation in schizophrenia (SZ) and bipolar (BD) spectrum disorders. However, heterogeneity and translation between the periphery and central (blood-to-brain) mechanisms remains a challenge. Starting with a large SZ, BD and healthy control cohort (n = 1235), we aimed to i) identify candidate peripheral markers (n = 25) associated with cognitive domains (n = 9) and elucidate heterogenous immune-cognitive patterns, ii) evaluate the regulation of candidate markers using human induced pluripotent stem cell (iPSC)-derived astrocytes and neural progenitor cells (n = 10), and iii) evaluate candidate marker messenger RNA expression in leukocytes using microarray in available data from a subsample of the main cohort (n = 776), and in available RNA-sequencing deconvolution analysis of postmortem brain samples (n = 474) from the CommonMind Consortium (CMC). We identified transdiagnostic subgroups based on covariance between cognitive domains (measures of speed and verbal learning) and peripheral markers reflecting inflammatory response (CRP, sTNFR1, YKL-40), innate immune activation (MIF) and extracellular matrix remodelling (YKL-40, CatS). Of the candidate markers there was considerable variance in secretion of YKL-40 in iPSC-derived astrocytes and neural progenitor cells in SZ compared to HC. Further, we provide evidence of dysregulated RNA expression of genes encoding YKL-40 and related signalling pathways in a high neuroinflammatory subgroup in the postmortem brain samples. Our findings suggest a relationship between peripheral inflammatory-immune activity and cognitive impairment, and highlight YKL-40 as a potential marker of cognitive functioning in a subgroup of individuals with severe mental illness.

Toxoplasma gondii infection associated with inflammasome activation and neuronal injury.

Toxoplasma gondii (TOXO) infection typically results in chronic latency due to its ability to form cysts in the brain and other organs. Latent toxoplasmosis could promote innate immune responses and impact brain function. A large body of evidence has linked TOXO infection to severe mental illness (SMI). We hypothesized that TOXO immunoglobulin G (IgG) seropositivity, reflecting previous infection and current latency, is associated with increased circulating neuron-specific enolase (NSE), a marker of brain damage, and interleukin-18 (IL-18), an innate immune marker, mainly in SMI. We included 735 patients with SMI (schizophrenia or bipolar spectrum) (mean age 32 years, 47% women), and 518 healthy controls (HC) (mean age 33 years, 43% women). TOXO IgG, expressed as seropositivity/seronegativity, NSE and IL-18 were measured with immunoassays. We searched for main and interaction effects of TOXO, patient/control status and sex on NSE and IL-18. In the whole sample as well as among patients and HC separately, IL-18 and NSE concentrations were positively correlated (p < 0.001). TOXO seropositive participants had significantly higher NSE (3713 vs. 2200 pg/ml, p < 0.001) and IL-18 levels (1068 vs. 674 pg/ml, p < 0.001) than seronegative participants, and evaluation within patients and HC separately showed similar results. Post-hoc analysis on cytomegalovirus and herpes simplex virus 1 IgG status showed no associations with NSE or IL-18 which may suggest TOXO specificity. These results may indicate ongoing inflammasome activation and neuronal injury in people with TOXO infections unrelated to diagnosis.

Sex differences in autonomic adverse effects related to antipsychotic treatment and associated hormone profiles.

Autonomic adverse effects of antipsychotic drugs (APs) cause clinical challenges, but few studies have investigated sex differences and their underlying biological pathways. Sex-specific regulation of relevant hormones could be involved. We investigated sex differences in autonomic adverse effects related to olanzapine, quetiapine, risperidone, and aripiprazole, and the role of hormones related to APs. Patients with severe mental disorders (N = 1318) were included and grouped based on AP monotherapy: olanzapine (N = 364), quetiapine (N = 211), risperidone (N = 102), aripiprazole (N = 138), and no AP (N = 503). Autonomic symptoms from the Udvalg for Kliniske Undersøgelser (UKU) side effect scale was analyzed with logistic regression, adjusting for age, diagnosis, and polypharmacy. Further, we analyzed associations between autonomic symptoms and hormones related to APs. We found associations between autonomic adverse effects and APs, with sex-specific risk for palpitations/tachycardia associated with hormonal changes related to APs. Results showed increased salivation associated with aripiprazole, reduced salivation with quetiapine, and nausea/vomiting and palpitations/tachycardia with olanzapine, and higher risk of nausea/vomiting, diarrhea, constipation, polyuria/polydipsia, and palpitations/tachycardia in females. Significant sex x AP interaction was found for palpitations/tachycardia, with higher risk in risperidone-treated males, which was associated with different hormone profiles of prolactin, cortisol, and insulin. Our findings implicate a role of several hormones in the sex-specific autonomic adverse effects related to APs.

Expression of ANK3 moderates the association between childhood trauma and affective traits in severe mental disorders.

Exposure to early life trauma increases the risk of psychopathology later in life. Here we investigated if ANK3 mRNA levels influence the relationship between childhood trauma experiences and clinical characteristics in mental disorders. A sample of 174 patients with bipolar disorder and 291 patients with schizophrenia spectrum disorder were included. Patients were diagnosed using the Structured Clinical Interview for DSM-IV, and childhood trauma was assessed using the childhood trauma questionnaire. Age at illness onset and number of psychotic and affective episodes were assessed from interview and medical records. Current depressive symptoms were measured using the calgary depression scale for schizophrenia and the inventory for depressive symptomatology. ANK3 expression was analyzed in whole blood using the Illumina HumanHT-12 v4 Expression BeadChip. Analyses were carried out with the Process adjusted for confounders. Within the total sample, patients with both high ANK3 expression and with the most severe childhood sexual abuse had more manic/hypomanic episodes and an earlier age at onset of the first episode. ANK3 mRNA levels also moderated the relationship between emotional neglect and manic/hypomanic episodes. Our results suggest that ANK3 expression levels moderate the association between specific types of childhood trauma and affective traits in mental disorders.

Telomere length and verbal learning in bipolar disorders.

INTRODUCTION: Recent studies indicate accelerated ageing processes, shorter telomere length and poorer cognitive functioning in patients with bipolar disorder. The neurobiology underlying cognitive function in bipolar disorder is yet to be established. We anticipated that accelerated ageing as indicated by shortened telomere length, would be associated with reduced cognitive performance in bipolar disorder, particularly for ageing sensitive functions such as memory and learning. METHODS: The study consisted of 647 participants (bipolar disorder [n = 246] and healthy controls [n = 401]). All participants underwent a standardized neuropsychological test battery, including working memory, executive functioning, processing speed, verbal learning, and verbal memory. Leucocyte telomere length was measured via blood and determined by quantitative real-time Polymerase Chain Reaction (qPCR) providing a telomere to single copy ratio (T/S ratio). The T/S ratio was used as an estimate of the mean telomere length of each participant. All analyses were adjusted for medication, Daily Defined Dose (DDD), chronological age, sex, and ethnicity. RESULTS: Patients had shorter telomere lengths than healthy controls (Cohen's d = 0.11, p = 0.01). Within patients', a positive association was observed for verbal learning and telomere length (ß = 0.14, p = 0.025), along with a trend for verbal memory and telomere length (ß = 0.11, p = 0.07). No other associations were observed for telomere length and cognitive functioning in the patient or the control group (p > 0.1). CONCLUSION: Our study may suggest poorer brain health in bipolar disorder as indexed by shorter telomere length and reduced learning correlates. However, the role of telomere length on cognitive functioning in bipolar disorder seems limited.

Elevated Systemic Levels of Markers Reflecting Intestinal Barrier Dysfunction and Inflammasome Activation Are Correlated in Severe Mental Illness.

BACKGROUND AND HYPOTHESIS: Gut microbiota alterations have been reported in severe mental illness (SMI) but fewer studies have probed for signs of gut barrier disruption and inflammation. We hypothesized that gut leakage of microbial products due to intestinal inflammation could contribute to systemic inflammasome activation in SMI. STUDY DESIGN: We measured plasma levels of the chemokine CCL25 and soluble mucosal vascular addressin cell adhesion molecule-1 (sMAdCAM-1) as markers of T cell homing, adhesion and inflammation in the gut, lipopolysaccharide binding protein (LBP) and intestinal fatty acid binding protein (I-FABP) as markers of bacterial translocation and gut barrier dysfunction, in a large SMI cohort (n = 567) including schizophrenia (SCZ, n = 389) and affective disorder (AFF, n = 178), relative to healthy controls (HC, n = 418). We assessed associations with plasma IL-18 and IL-18BPa and leukocyte mRNA expression of NLRP3 and NLRC4 as markers of inflammasome activation. STUDY RESULTS: Our main findings were: (1) higher levels of sMAdCAM-1 (P = .002), I-FABP (P = 7.6E-11), CCL25 (P = 9.6E-05) and LBP (P = 2.6E-04) in SMI compared to HC in age, sex, BMI, CRP and freezer storage time adjusted analysis; (2) the highest levels of sMAdCAM-1 and CCL25 (both P = 2.6E-04) were observed in SCZ and I-FABP (P = 2.5E-10) and LBP (3) in AFF; and (3), I-FABP correlated with IL-18BPa levels and LBP correlated with NLRC4. CONCLUSIONS: Our findings support that intestinal barrier inflammation and dysfunction in SMI could contribute to systemic inflammation through inflammasome activation.

Sex-specific associations between metabolic hormones, severe mental disorders and antipsychotic treatment.

BACKGROUND: Metabolic dysregulation has been associated with severe mental disorders (SMD) and with antipsychotic (AP) treatment, but the role of sex is unknown. To identify possible sex-related processes linked to SMD and AP treatment, we investigated sex differences in associations between hormones involved in metabolic regulation in patients with SMD compared to healthy controls (HC) and AP treatment. METHODS: We included patients with SMD (N = 1753) and HC (N = 1194) and measured hormones involved in metabolic regulation (insulin, cortisol, thyroid-stimulating hormone (TSH), thyroxine, leptin, adiponectin, testosterone, sex hormone-binding globulin (SHBG), prolactin). Patients were grouped according to use of first-generation AP (N = 163), second-generation AP (N = 1087) or no use of AP (N = 503). Hormones were used one by one as dependent variables in multiple regression analyses with interactions between sex and SMD patients versus HC, and between sex and AP treatment, followed by analyses in males and females separately. RESULTS: We found significant interactions between sex and SMD patients versus HC for testosterone, SHBG and adiponectin, with significantly higher testosterone and lower adiponectin levels in females. Furthermore, we found significant interaction between sex and AP groups for TSH, testosterone and insulin, with significantly lower TSH levels in AP-treated females, and lower testosterone and higher insulin levels in AP-treated males. CONCLUSIONS: Our findings suggest sex differences in metabolic hormones related to both SMD and AP treatment, indicating sex-dependent mechanisms. Clinicians should be aware of potential sex-specific metabolic changes during AP treatment and experimental studies are warranted to clarify the underlying mechanisms.