Background In recent years, a role for the immune system in the pathogenesis of psychiatric diseases has gained increased attention. Although bipolar disorder appears to be associated with altered ...serum cytokine levels, a putative immunological contribution to its patho-physiology remains to be established. Hitherto, no direct analyses of cerebrospinal fluid (CSF) cytokines in patients with bipolar disorder have been performed. Methods We analyzed CSF cytokine concentrations in euthymic patients with diagnosed bipolar disorder type I ( n = 15) or type II ( n = 15) and healthy volunteers ( n = 30) using an immunoassay-based protein array multiplex system. Results The mean interleukin (IL)-1β level (4.2 pg/mL, standard error of the mean SEM 0.5) was higher and the IL-6 level (1.5 pg/mL, SEM 0.2) was lower in euthymic bipolar patients than in healthy volunteers (0.8 pg/mL, SEM 0.04, and 2.6 pg/mL, SEM 0.2, respectively). Patients with 1 or more manic/hypomanic episodes during the last year showed significantly higher levels of IL-1β (6.2 pg/mL, SEM 0.8; n = 9) than patients without a recent manic/hypomanic episode (3.1 pg/mL, SEM 1.0; n = 10). Limitations All patients were in an euthymic state at the time of sampling. Owing to the large variety of drugs prescribed to patients in the present study, influence of medication on the cytokine profile cannot be ruled out. Conclusion Our findings show an altered brain cytokine profile associated with the manifestation of recent manic/hypomanic episodes in patients with bipolar disorder. Although the causality remains to be established, these findings may suggest a pathophysiological role for IL-1β in bipolar disorder.
Background Patients with schizophrenia show elevated brain levels of the neuroactive tryptophan metabolite kynurenic acid (KYNA). This astrocyte-derived mediator acts as a neuroprotectant and ...modulates sensory gating and cognitive function. We measured the levels of KYNA in the cerebrospinal fluid (CSF) of patients with bipolar disorder and healthy volunteers to investigate the putative involvement of KYNA in bipolar disorder. Methods We obtained CSF by lumbar puncture from 23 healthy men and 31 euthymic men with bipolar disorder. We analyzed the samples using high-performance liquid chromatography. Results Patients with bipolar disorder had increased levels of KYNA in their CSF compared with healthy volunteers (1.71 nM, standard error of the mean SEM 0.13 v. 1.13 nM, SEM 0.09; p = 0.002. The levels of KYNA were positively correlated with age among bipolar patients but not healthy volunteers. Limitations The influence of ongoing drug treatment among patients cannot be ruled out. We conducted our study during the euthymic phase of the disease. Conclusion Brain KYNA levels are increased in euthymic men with bipolar disorder. In addition, KYNA levels increased with age in these patients. These findings indicate shared mechanisms between bipolar disorder and schizophrenia. Elevated levels of brain KYNA may provide further insight to the pathophysiology and progression of bipolar disorder.
AbstractBackgroundBipolar disorder (BD) is a highly heritable psychiatric disorder characterized by episodes of manic and depressed mood states, and associated with cortical brain abnormalities. ...Although the course of BD is often progressive, longitudinal brain imaging studies are scarce. It remains unknown whether brain abnormalities are static traits of BD, or result from pathological changes over time. Moreover, the genetic effect on implicated brain regions remains unknown. MethodsBD patients and healthy controls (HC) underwent structural magnetic resonance imaging at baseline (123 patients, 83 HC) and after six years (90 patients, 61 HC). Cortical thickness maps were generated using FreeSurfer. Using linear mixed effects models, we compared longitudinal changes in cortical thickness between BD and HC across the whole brain. We related our findings to genetic risk for BD, and tested for effects of demographic and clinical variables. ResultsPatients showed abnormal cortical thinning of temporal cortices, and thickness increases in visual/somatosensory brain areas. Thickness increases were related to genetic risk and lithium use. Patients, who experienced (hypo)manic episodes between timepoints revealed abnormal thinning in inferior frontal cortices. Cortical changes did not differ between the diagnostic subtypes I and II. ConclusionsIn the largest longitudinal BD study to date, we detected abnormal cortical changes with high anatomical resolution. We delineated regional effects of clinical symptoms, genetic factors and medication that may explain progressive brain changes in BD. Our study yields important insights into disease mechanisms and suggests that neuroprogression plays a role in BD.
Background Bipolar disorder is a common psychiatric mood disorder that is defined by recurrent episodes of abnormally elevated mood and depression. Progressive structural brain changes in individuals ...with bipolar disorder have been suggested to be associated with defects in the secretion of neurotrophic factors. We sought to assess how the regulated secretory pathway in the brain is affected in patients with bipolar disorder by measuring chromogranin B and secretogranin II, which are 2 cerebrospinal fluid (CSF) biological markers for this process. Methods We measured the concentrations of chromogranin B (peptide 439–451) and secretogranin II (peptide 154–165) in the CSF of patients with well-defined bipolar disorder and healthy controls. The lifetime severity of bipolar disorder was rated using the Clinical Global Impression (CGI) scale. Results We included 126 patients with bipolar disorder and 71 healthy controls in our analysis. Concentrations of secretogranin II were significantly lower in patients with bipolar disorder type I than in healthy controls. The reduction was most pronounced in patients with high CGI scores (i.e., severe disease). Limitations The cross-sectional design of the current study limits the ability to pinpoint the causalities behind the observed associations. Conclusion This study shows that the CSF marker secretogranin II has the potential to act as a biological marker for severe forms of bipolar disorder. Our findings indicate that patients with bipolar disorder possess defects in the regulatory secretory pathway, which may be of relevance to the progressive structural brain changes seen in those with severe forms of the disease.
Background Testosterone has been attributed importance for various aspects of behaviour. The aim of our study was to investigate the potential influence of 2 functional polymorphisms in the amino ...terminal of the androgen receptor on personality traits in men. Methods We assessed and genotyped 141 men born in 1944 recruited from the general population. We used 2 different instruments: the Karolinska Scales of Personality and the Temperament and Character Inventory. For replication, we similarly assessed 63 men recruited from a forensic psychiatry study group. Results In the population-recruited sample, the lengths of the androgen receptor repeats were associated with neuroticism, extraversion and self-transcendence. The association with extraversion was replicated in the independent sample. Limitations Our 2 samples differed in size; sample 1 was of moderate size and sample 2 was small. In addition, the homogeneity of sample 1 probably enhanced our ability to detect significant associations between genotype and phenotype. Conclusion Our results suggest that the repeat polymorphisms in the androgen receptor gene may influence personality traits in men.
Background Bipolar disorder is associated with medical comorbidities that have been linked to systemic inflammatory mechanisms. There is, however, limited evidence supporting a role of ...neuroinflammation in bipolar disorder. Here we tested whether microglial activation and associated tissue remodelling processes are related to bipolar disorder by analyzing markers in cerebrospinal fluid (CSF) and serum from patients and healthy controls. Methods Serum was sampled from euthymic patients with bipolar disorder and healthy controls, and CSF was sampled from a large subset of these individuals. The levels of monocyte chemoattractant protein-1 (MCP-1), YKL-40, soluble cluster of differentiation 14 (sCD14), tissue inhibitor of metalloproteinases-1 (TIMP-1) and tissue inhibitor of metalloproteinases-2 (TIMP-2), were measured, and we adjusted comparisons between patients and controls for confounding factors. Results We obtained serum samples from 221 patients and 112 controls and CSF samples from 125 patients and 87 controls. We found increased CSF levels of MCP-1 and YKL-40 and increased serum levels of sCD14 and YKL-40 in patients compared with controls; these differences remained after controlling for confounding factors, such as age, sex, smoking, blood–CSF barrier function, acute-phase proteins and body mass index. The CSF levels of MCP-1 and YKL-40 correlated with the serum levels, whereas the differences between patients and controls in CSF levels of MCP-1 and YKL-40 were independent of serum levels. Limitations The cross-sectional study design precludes conclusions about causality. Conclusion Our results suggest that both neuroinflammatory and systemic inflammatory processes are involved in the pathophysiology of bipolar disorder. Importantly, markers of immunological processes in the brain were independent of peripheral immunological activity.
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