Cerebrospinal fluid proteomic study of two bipolar disorder cohorts

The pathophysiology of bipolar disorder remains to be elucidated and there are no diagnostic or prognostic biomarkers for the condition. In this explorative proteomic study, we analyzed 201 proteins in cerebrospinal fluid (CSF) from mood stable bipolar disorder patients and control subjects sampled from two independent cohorts, amounting to a total of 204 patients and 144 controls. We used three Olink Multiplex panels, whereof one specifically targets immune biomarkers, to assess a broad set of CSF protein concentrations. After quality control and removal of proteins with a low detection rate, 105 proteins remained for analyses in relation to case-control status and clinical variables. Only case-control differences that replicated across cohorts were considered. Results adjusted for potential confounders showed that CSF concentrations of growth hormone were lower in bipolar disorder compared with controls in both cohorts. The effect size was larger when the analysis was restricted to bipolar disorder type 1 and controls. We found no indications of immune activation or other aberrations. Growth hormone exerts many effects in the central nervous system and our findings suggest that growth hormone might be implicated in the pathophysiology of bipolar disorder

High Survivin Levels Predict Poor Clinical Response to Infliximab Treatment in Patients with Rheumatoid Arthritis

Objective: To evaluate if the measurement of survivin in the blood of patients with rheumatoid arthritis (RA) undergoing infliximab treatment has predictive value for treatment response. Methods: The study included 87 consecutive RA patients (age 24-89 years, disease duration 18-526 months) treated with regular infusions of influximab. Survivin levels were measured by enzyme-linked immunosorbent assay and evaluated in relation to the total dose of infliximab, disease activity (DAS28), response to infliximab treatment (change in DAS28 > 1.2), and radiographic damage (vdH-Sharp score). Results: Thirty-seven percent of patients were survivin-positive (survivin > 0.9 ng/mL) and showed severe radiographic damage at the start of infliximab treatment compared with survivin-negative (P = 0.027). Patients with high survivin levels were unlikely to respond to infliximab treatment (OR 4.02 [1.22-14.61], P = 0.022) and achieve remission (OR 4.32[1.01-30.11], P = 0.048) compared with patients with low survivin levels. Conclusions: High survivin levels are associated with severe radiographic damage at the start of treatment and a poor response to infliximab. Survivin measurement should be considered an additional tool for aiding the selection and follow-up of antirheumatic treatment. (C) 2012 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 41:652-65

Lower complement C1q levels in first-episode psychosis and in schizophrenia

Recent evidence has implicated complement component (C) 4A in excessive elimination of synapses in schizophrenia. C4A is believed to contribute to physiological synapse removal through signaling within the C1q initiated classical activation axis of the complement system. So far, a potential involvement of C1q in the pathophysiology of schizophrenia remains unclear. In this study, we first utilized large-scale gene expression datasets (n = 586 patients with schizophrenia and n = 986 controls) to observe lower C1QA mRNA expression in prefrontal cortex tissue of individuals with schizophrenia (P = 4.8x10-05), while C1QA seeded co-expression networks displayed no enrichment for schizophrenia risk variants beyond C4A. We then used targeted liquid chromatography-mass spectrometry (LS-MS) to measure cerebrospinal fluid (CSF) levels of C1qA in 113 individuals with first-episode psychosis (FEP), among which 66 individuals was later diagnosed with schizophrenia, and 87 healthy controls. CSF concentrations of C1qA were lower in individuals diagnosed with FEP (P = 0.0001), also after removing subjects with a short-term prescription of an antipsychotic agent (P = 0.0005). We conclude that C1q mRNA and protein levels are lower in schizophrenia and that further experimental studies are needed to understand the functional implications

Cerebrospinal fluid concentration of complement component 4A is increased in first episode schizophrenia.

Postsynaptic density is reduced in schizophrenia, and risk variants increasing complement component 4A (C4A) gene expression are linked to excessive synapse elimination. In two independent cohorts, we show that cerebrospinal fluid (CSF) C4A concentration is elevated in patients with first-episode psychosis (FEP) who develop schizophrenia (FEP-SCZ: median 0.41 fmol/ul [CI = 0.34-0.45], FEP-non-SCZ: median 0.29 fmol/ul [CI = 0.22-0.35], healthy controls: median 0.28 [CI = 0.24-0.33]). We show that the CSF elevation of C4A in FEP-SCZ exceeds what can be expected from genetic risk variance in the C4 locus, and in patient-derived cellular models we identify a mechanism dependent on the disease-associated cytokines interleukin (IL)-1beta and IL-6 to selectively increase neuronal C4A mRNA expression. In patient-derived CSF, we confirm that IL-1beta correlates with C4A controlled for genetically predicted C4A RNA expression (r = 0.39; CI: 0.01-0.68). These results suggest a role of C4A in early schizophrenia pathophysiology