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1.
  • Abé, Christoph, et al. (author)
  • Cortical thickness, volume and surface area in patients with bipolar disorder types I and II.
  • 2016
  • In: Journal of psychiatry & neuroscience : JPN. - : CMA Joule Inc.. - 1488-2434 .- 1180-4882. ; 41:4, s. 240-50
  • Journal article (peer-reviewed)abstract
    • Bipolar disorder (BD) is a common chronic psychiatric disorder mainly characterized by episodes of mania, hypomania and depression. The disorder is associated with cognitive impairments and structural brain abnormalities, such as lower cortical volumes in primarily frontal brain regions than healthy controls. Although bipolar disorder types I (BDI) and II (BDII) exhibit different symptoms and severity, previous studies have focused on BDI. Furthermore, the most frequently investigated measure in this population is cortical volume. The aim of our study was to investigate abnormalities in patients with BDI and BDII by simultaneously analyzing cortical volume, thickness and surface area, which yields more information about disease- and symptom-related neurobiology.
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2.
  • Abé, Christoph, et al. (author)
  • Longitudinal Cortical Thickness Changes in Bipolar Disorder and the Relationship to Genetic Risk, Mania, and Lithium Use.
  • 2020
  • In: Biological psychiatry. - : Elsevier BV. - 1873-2402 .- 0006-3223. ; 87:3, s. 271-281
  • Journal article (peer-reviewed)abstract
    • Bipolar 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.Patients with BD and healthy control (HC) subjects underwent structural magnetic resonance imaging at baseline (123 patients, 83 HC subjects) and after 6 years (90 patients, 61 HC subjects). Cortical thickness maps were generated using FreeSurfer. Using linear mixed effects models, we compared longitudinal changes in cortical thickness between patients with BD and HC subjects across the whole brain. We related our findings to genetic risk for BD and tested for effects of demographic and clinical variables.Patients 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 hypomanic or manic episodes between time points showed abnormal thinning in inferior frontal cortices. Cortical changes did not differ between diagnostic BD subtypes I and II.In 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.
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3.
  • Abé, Christoph, et al. (author)
  • Manic episodes are related to changes in frontal cortex: a longitudinal neuroimaging study of bipolar disorder 1.
  • 2015
  • In: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 138:Pt 11, s. 3440-8
  • Journal article (peer-reviewed)abstract
    • Higher numbers of manic episodes in bipolar patients has, in cross-sectional studies, been associated with less grey matter volume in prefrontal brain areas. Longitudinal studies are needed to determine if manic episodes set off progressive cortical changes, or if the association is better explained by premorbid brain conditions that increase risk for mania. We followed patients with bipolar disorder type 1 for 6 years. Structural brain magnetic resonance imaging scans were performed at baseline and follow-up. We compared patients who had at least one manic episode between baseline and follow-up (Mania group, n = 13) with those who had no manic episodes (No-Mania group, n = 18). We used measures of cortical volume, thickness, and area to assess grey matter changes between baseline and follow-up. We found significantly decreased frontal cortical volume (dorsolateral prefrontal and inferior frontal cortex) in the Mania group, but no volume changes in the No-Mania group. Our results indicate that volume decrease in frontal brain regions can be attributed to the incidence of manic episodes.
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4.
  • Ekman, Carl Johan, et al. (author)
  • A History of Psychosis in Bipolar Disorder is Associated With Gray Matter Volume Reduction.
  • 2017
  • In: Schizophrenia bulletin. - : Oxford University Press (OUP). - 1745-1701 .- 0586-7614. ; 43:1, s. 99-107
  • Journal article (peer-reviewed)abstract
    • Psychotic symptoms are prevalent in schizophrenia, bipolar disorder, and other psychiatric and neurological disorders, yet the neurobiological underpinnings of psychosis remain obscure. In the last decade, a large number of magnetic resonance imaging studies have shown differences in local gray matter volume between patients with different psychiatric syndromes and healthy controls. Few studies have focused on the symptoms, which these syndromes are constituted of. Here, we test the association between psychosis and gray matter volume by using a sample of 167 subjects with bipolar disorder, with and without a history of psychosis, and 102 healthy controls. Magnetic resonance images were analyzed on group level using a voxel-wise mass univariate analysis (Voxel-Based Morphometry). We found that patients with a history of psychosis had smaller gray matter volume in left fusiform gyrus, the right rostral dorsolateral prefrontal cortex, and the left inferior frontal gyrus compared with patients without psychosis and with healthy controls. There was no volume difference in these areas between the no-psychosis group and healthy controls. These areas have previously been structurally and functionally coupled to delusions and hallucinations. Our finding adds further evidence to the probability of these regions as key areas in the development of psychotic symptoms.
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5.
  • Isgren, Anniella, et al. (author)
  • Increased cerebrospinal fluid interleukin-8 in bipolar disorder patients associated with lithium and antipsychotic treatment.
  • 2015
  • In: Brain, behavior, and immunity. - : Elsevier BV. - 1090-2139 .- 0889-1591. ; 43, s. 198-204
  • Journal article (peer-reviewed)abstract
    • Inflammation has been linked to the pathophysiology of bipolar disorder based on studies of inflammation markers, such as cytokine concentrations, in plasma and serum samples from cases and controls. However, peripheral measurements of cytokines do not readily translate to immunological activity in the brain. The aim of the present study was to study brain immune and inflammatory activity. To this end, we analyzed cytokines in cerebrospinal fluid from 121 euthymic bipolar disorder patients and 71 age and sex matched control subjects. Concentrations of 11 different cytokines were determined using immunoassays. Cerebrospinal fluid IL-8 concentrations were significantly higher in patients as compared to controls. The other cytokines measured were only detectable in part of the sample. IL-8 concentrations were positively associated to lithium- and antipsychotic treatment. The findings might reflect immune aberrations in bipolar disorder, or be due to the effects of medication.
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6.
  • Isgren, Anniella, et al. (author)
  • Markers of neuroinflammation and neuronal injury in bipolar disorder: Relation to prospective clinical outcomes.
  • 2017
  • In: Brain, behavior, and immunity. - : Elsevier BV. - 1090-2139 .- 0889-1591. ; 65, s. 195-201
  • Journal article (peer-reviewed)abstract
    • Neuroimmune mechanisms have been linked to the pathophysiology of bipolar disorder based on studies of biomarkers in plasma, cerebrospinal fluid (CSF), and postmortem brain tissue. There are, however, no longitudinal studies investigating if CSF markers of neuroinflammation and neuronal injury predict clinical outcomes in patients with bipolar disorder. We have in previous studies found higher CSF concentrations of interleukin-8 (IL-8), monocyte chemoattractant protein 1 (MCP-1/CCL-2), chitinase-3-like protein 1 (CHI3L1/YKL-40), and neurofilament light chain (NF-L) in euthymic patients with bipolar disorder compared with controls. Here, we investigated the relationship of these CSF markers of neuroinflammation and neuronal injury with clinical outcomes in a prospective study. 77 patients with CSF analyzed at baseline were followed for 6-7years. Associations of baseline biomarkers with clinical outcomes (manic/hypomanic and depressive episodes, suicide attempts, psychotic symptoms, inpatient care, GAF score change) were investigated. Baseline MCP-1 concentrations were positively associated with manic/hypomanic episodes and inpatient care during follow-up. YKL-40 concentrations were negatively associated with manic/hypomanic episodes and with occurrence of psychotic symptoms. The prospective negative association between YKL-40 and manic/hypomanic episodes survived multiple testing correction. Concentrations of IL-8 and NF-L were not associated with clinical outcomes. High concentrations of these selected CSF markers of neuroinflammation and neuronal injury at baseline were not consistently associated with poor clinical outcomes in this prospective study. The assessed proteins may be involved in adaptive immune processes or reflect a state of vulnerability for bipolar disorder rather than being of predictive value for disease progression.
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7.
  • Jakobsson, Joel, et al. (author)
  • Decreased cerebrospinal fluid secretogranin II concentrations in severe forms of bipolar disorder.
  • 2013
  • In: Journal of psychiatry & neuroscience : JPN. - : CMA Joule Inc.. - 1488-2434 .- 1180-4882. ; 38:4
  • Journal article (peer-reviewed)abstract
    • 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.
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8.
  • Jakobsson, Joel, et al. (author)
  • Elevated Concentrations of Neurofilament Light Chain in The Cerebrospinal Fluid of Bipolar Disorder Patients.
  • 2014
  • In: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 1740-634X. ; 39, s. 2349-2356
  • Journal article (peer-reviewed)abstract
    • Bipolar disorder (BD) is characterized by mood swings between manic and depressive states. The etiology and pathogenesis of BD is unclear, but many of the affected cognitive domains, as well as neuroanatomical abnormalities, resemble symptoms and signs of small vessel disease. In small vessel disease, cerebrospinal fluid (CSF) markers reflecting damages in different cell types and subcellular structures of the brain have been established. Hence, we hypothesized that CSF markers related to small vessel disease may also be applicable as biomarkers for bipolar disorder. To investigate this hypothesis, we sampled CSF from 133 patients with bipolar disorder and 86 healthy controls. The concentrations of neurofilament light chain (NF-L), myelin basic protein (MBP), S100B, and heart-fatty acid binding protein (H-FABP) were measured in CSF and analyzed in relation to diagnosis, clinical characteristics, and ongoing medications. Hereby we found an elevation of the marker of subcortical axonal damage, NF-L, in bipolar subjects. We also identified positive associations between NF-L and treatment with atypical antipsychotics, MBP and lamotrigine, and H-FABP and lithium. These findings indicate axonal damage as an underlying neuropathological component of bipolar disorder, though the clinical value of elevated NF-L remains to be validated in follow-up studies. The associations between current medications and CSF brain injury markers might aid in the understanding of both therapeutic and adverse effects of these drugs.Neuropsychopharmacology accepted article peview online, 03 April 2014; doi:10.1038/npp.2014.81.
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9.
  • Jakobsson, Joel, et al. (author)
  • Monocyte and microglial activation in patients with mood-stabilized bipolar disorder.
  • 2015
  • In: Journal of psychiatry & neuroscience : JPN. - : CMA Joule Inc.. - 1488-2434 .- 1180-4882. ; 40:2
  • Journal article (peer-reviewed)abstract
    • 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.
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10.
  • Rolstad, Sindre, 1976, et al. (author)
  • CSF neuroinflammatory biomarkers in bipolar disorder are associated with cognitive impairment.
  • 2015
  • In: European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. - : Elsevier BV. - 1873-7862. ; 25:8, s. 1091-1098
  • Journal article (peer-reviewed)abstract
    • Persistent cognitive impairment in the euthymic state of bipolar disorder is increasingly recognized. Mounting evidence also suggests an association between neuroinflammation and cognitive dysfunction. The purpose of this study was to test if cerebrospinal fluid (CSF) markers of neuroinflammation could account for cognitive impairment in bipolar disorder. Hierarchical linear regression models were applied to account for performance in five cognitive domains using CSF neuroinflammatory biomarkers as predictors in patients with bipolar disorder type I and II (N=78). The associations between these biomarkers and cognition were further tested in healthy age- and sex-matched controls (N=86). In patients with bipolar disorder, the CSF biomarkers accounted for a significant proportion of the variance in executive functions (42.8%, p=<.0005) independently of age, medication, disease status, and bipolar subtype. The microglial marker YKL-40 had a high impact (beta=-.99), and was the only biomarker that contributed individually. CSF biomarkers were not associated with cognitive performance in healthy controls. The CSF neuroinflammation biomarker YKL-40 is associated with executive performance in euthymic bipolar disorder, but not in healthy controls.
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11.
  • Rolstad, Sindre, 1976, et al. (author)
  • Polymorphisms of BDNF and CACNA1C are not associated with cognitive functioning in bipolar disorder or healthy controls.
  • 2016
  • In: Cognitive neuropsychiatry. - : Informa UK Limited. - 1464-0619 .- 1354-6805. ; 21:3, s. 271-8
  • Journal article (peer-reviewed)abstract
    • The cause of cognitive dysfunction in bipolar disorder (BD) is not well understood. BDNF and CACNA1C are two susceptibility genes for the disorder that have also been reported to be associated with cognitive deficits in the disorder, but the studies have been small and with conflicting results. We therefore attempted to replicate an association between cognitive dysfunction with the most commonly studied single nucleotide polymorphisms rs6265 and rs1006737.
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12.
  • Rolstad, Sindre, 1976, et al. (author)
  • Polymorphisms of dopamine pathway genes NRG1 and LMX1A are associated with cognitive performance in bipolar disorder
  • 2015
  • In: Bipolar disorders. - : Wiley. - 1399-5618 .- 1398-5647. ; 17:8, s. 859-868
  • Journal article (peer-reviewed)abstract
    • LIM homeobox transcription factor 1, alpha (LMX1A) and neuregulin 1 (NRG1) are susceptibility genes for schizophrenia that have been implicated in the dopaminergic pathway and have been associated with altered cognitive functioning. We hypothesized that single nucleotide polymorphisms (SNPs) in LMX1A and NRG1 would be associated with cognitive functioning in bipolar disorder.
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13.
  • Sparding, Timea, et al. (author)
  • Classification of cognitive performance in bipolar disorder.
  • 2017
  • In: Cognitive neuropsychiatry. - : Informa UK Limited. - 1464-0619 .- 1354-6805. ; 22:5, s. 407-421
  • Journal article (peer-reviewed)abstract
    • To understand the etiology of cognitive impairment associated with bipolar disorder, we need to clarify potential heterogeneity in cognitive functioning. To this end, we used multivariate techniques to study if the correlation structure of cognitive abilities differs between persons with bipolar disorder and controls.Clinically stable patients with bipolar disorder (type I: n=64; type II: n=44) and healthy controls (n=86) were assessed with a wide range of cognitive tests measuring executive function, speed, memory, and verbal skills. Data were analysed with multivariate techniques.A distinct subgroup (∼30%) could be identified that performed significantly poorer on tests concerning memory function. This cognitive phenotype subgroup did not differ from the majority of bipolar disorder patients with respect to other demographic or clinical characteristics.Whereas the majority of patients performed similar to controls, a subgroup of patients with bipolar disorder differed substantially from healthy controls in the correlation pattern of low-level cognitive abilities. This suggests that cognitive impairment is not a general trait in bipolar disorder but characteristic of a cognitive subgroup. This has important clinical implications for cognitive rehabilitation and remediation.
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14.
  • Alnaes, Dag, et al. (author)
  • Brain Heterogeneity in Schizophrenia and Its Association With Polygenic Risk
  • 2019
  • In: JAMA psychiatry. - : AMER MEDICAL ASSOC. - 2168-6238 .- 2168-622X. ; 76:7, s. 739-748
  • Journal article (peer-reviewed)abstract
    • ImportanceBetween-individual variability in brain structure is determined by gene-environment interactions, possibly reflecting differential sensitivity to environmental and genetic perturbations. Magnetic resonance imaging (MRI) studies have revealed thinner cortices and smaller subcortical volumes in patients with schizophrenia. However, group-level comparisons may mask considerable within-group heterogeneity, which has largely remained unnoticed in the literature. ObjectivesTo compare brain structural variability between individuals with schizophrenia and healthy controls and to test whether respective variability reflects the polygenic risk score (PRS) for schizophrenia in an independent sample of healthy controls. Design, Setting, and ParticipantsThis case-control and polygenic risk analysis compared MRI-derived cortical thickness and subcortical volumes between healthy controls and patients with schizophrenia across 16 cohorts and tested for associations between PRS and MRI features in a control cohort from the UK Biobank. Data were collected from October 27, 2004, through April 12, 2018, and analyzed from December 3, 2017, through August 1, 2018. Main Outcomes and MeasuresMean and dispersion parameters were estimated using double generalized linear models. Vertex-wise analysis was used to assess cortical thickness, and regions-of-interest analyses were used to assess total cortical volume, total surface area, and white matter, subcortical, and hippocampal subfield volumes. Follow-up analyses included within-sample analysis, test of robustness of the PRS threshold, population covariates, outlier removal, and control for image quality. ResultsA comparison of 1151 patients with schizophrenia (mean [SD] age,33.8[10.6] years; 68.6% male [n=790] and 31.4% female [n=361]) with 2010 healthy controls (mean [SD] age,32.6[10.4] years; 56.0% male [n=1126] and 44.0% female [n=884]) revealed higher heterogeneity in schizophrenia for cortical thickness and area (t = 3.34), cortical (t=3.24) and ventricle (t range, 3.15-5.78) volumes, and hippocampal subfields (t range, 2.32-3.55). In the UK Biobank sample of 12 490 participants (mean [SD] age,55.9 [7.5] years; 48.2% male [n=6025] and 51.8% female [n=6465]), higher PRS was associated with thinner frontal and temporal cortices and smaller left CA2/3 (t=-3.00) but was not significantly associated with dispersion. Conclusions and RelevanceThis study suggests that schizophrenia is associated with substantial brain structural heterogeneity beyond the mean differences. These findings may reflect higher sensitivity to environmental and genetic perturbations in patients, supporting the heterogeneous nature of schizophrenia. A higher PRS was associated with thinner frontotemporal cortices and smaller hippocampal subfield volume, but not heterogeneity. This finding suggests that brain variability in schizophrenia results from interactions between environmental and genetic factors that are not captured by the PRS. Factors contributing to heterogeneity in frontotemporal cortices and hippocampus are key to furthering our understanding of how genetic and environmental factors shape brain biology in schizophrenia.
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15.
  • Becklén, Meneca, et al. (author)
  • Plasma bilirubin levels are reduced in first-episode psychosis patients and associates to working memory and duration of untreated psychosis.
  • 2021
  • In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
  • Journal article (peer-reviewed)abstract
    • Schizophrenia is a severe mental disorder and one of its characteristics is cognitive impairments. Findings regarding levels of the heme metabolite and plasma antioxidant bilirubin in schizophrenia are inconclusive. However, a recently published study indicate that low levels of bilirubin may be implicated in the memory impairments seen in the disorder. The aim of this cross-sectional study was to investigate the levels of bilirubin in individuals with a first-episode psychosis (FEP) and to examine if bilirubin levels were associated to cognitive impairments, symptoms and duration of untreated psychosis (DUP). Bilirubin levels were reduced in 39 individuals with FEP compared with 20 HC (median [IQR]: 11.0 [9.0-13.0] µM vs. 15.0 [11.5-18.5] µM). In individuals with FEP, bilirubin levels were also positively correlated to two working memory tests (r = 0.40 and r = 0.32) and inversely correlated to DUP (r = - 0.36). Findings were not influenced by confounding factors. The results confirm the antioxidant deficit previously seen in schizophrenia, but also indicate that these changes may be related to DUP. The study also confirms that bilirubin may be implicated in the cognitive deficits that accompanies the disorder, here for the first time presented in individuals with FEP.
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16.
  • Berne, Olivier, et al. (author)
  • PDRs4All : A JWST Early Release Science Program on Radiative Feedback from Massive Stars
  • 2022
  • In: Publications of the Astronomical Society of the Pacific. - : IOP Publishing. - 0004-6280 .- 1538-3873. ; 134:1035
  • Journal article (peer-reviewed)abstract
    • Massive stars disrupt their natal molecular cloud material through radiative and mechanical feedback processes. These processes have profound effects on the evolution of interstellar matter in our Galaxy and throughout the universe, from the era of vigorous star formation at redshifts of 1-3 to the present day. The dominant feedback processes can be probed by observations of the Photo-Dissociation Regions (PDRs) where the far-ultraviolet photons of massive stars create warm regions of gas and dust in the neutral atomic and molecular gas. PDR emission provides a unique tool to study in detail the physical and chemical processes that are relevant for most of the mass in inter- and circumstellar media including diffuse clouds, proto-planetary disks, and molecular cloud surfaces, globules, planetary nebulae, and star-forming regions. PDR emission dominates the infrared (IR) spectra of star-forming galaxies. Most of the Galactic and extragalactic observations obtained with the James Webb Space Telescope (JWST) will therefore arise in PDR emission. In this paper we present an Early Release Science program using the MIRI, NIRSpec, and NIRCam instruments dedicated to the observations of an emblematic and nearby PDR: the Orion Bar. These early JWST observations will provide template data sets designed to identify key PDR characteristics in JWST observations. These data will serve to benchmark PDR models and extend them into the JWST era. We also present the Science-Enabling products that we will provide to the community. These template data sets and Science-Enabling products will guide the preparation of future proposals on star-forming regions in our Galaxy and beyond and will facilitate data analysis and interpretation of forthcoming JWST observations.
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17.
  • Eren, Feride, et al. (author)
  • Immunological protein profiling of first-episode psychosis patients identifies CSF and blood biomarkers correlating with disease severity
  • 2023
  • In: Brain, behavior, and immunity. - : Elsevier. - 0889-1591 .- 1090-2139. ; 111, s. 376-385
  • Journal article (peer-reviewed)abstract
    • Background and HypothesisImmune activation is suggested to play an important role in psychosis. In this study, a large number of immune-related proteins were analyzed to obtain a more comprehensive picture of immune aberrations in schizophrenia.Study DesignNinety-two immune markers were analyzed by the Olink Protein Extension Assay (Inflammatory Panel) in plasma and cerebrospinal fluid (CSF) from 77 first-episode psychosis (FEP) patients (of which 43 later received the diagnosis of schizophrenia) and 56 healthy controls, all recruited from the Karolinska Schizophrenia Project (KaSP), Stockholm, Sweden.Study ResultsDifferential analysis showed that 12 of 92 inflammatory proteins were significantly higher in the plasma of FEP patients (n = 77) than in controls, and several proteins were positively correlated with disease severity. Patients from the same cohort diagnosed with schizophrenia (n = 43), showed significantly higher levels of 15 plasma proteins compared to controls whereas those not receiving this diagnosis showed no significant differences. The presently used OLINK inflammatory panel allowed the detection of only 47 CSF proteins of which only CD5 differed between patients and controls.ConclusionsThe levels of several peripheral immune markers, particularly those interfering with WNT/β-catenin signaling, were significantly higher in patients with FEP than in healthy controls and associated with illness severity.
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18.
  • Gutman, Boris A, et al. (author)
  • A meta-analysis of deep brain structural shape and asymmetry abnormalities in 2,833 individuals with schizophrenia compared with 3,929 healthy volunteers via the ENIGMA Consortium
  • 2022
  • In: Human Brain Mapping. - : John Wiley & Sons. - 1065-9471 .- 1097-0193. ; 43:1, s. 352-372
  • Journal article (peer-reviewed)abstract
    • Schizophrenia is associated with widespread alterations in subcortical brain structure. While analytic methods have enabled more detailed morphometric characterization, findings are often equivocal. In this meta-analysis, we employed the harmonized ENIGMA shape analysis protocols to collaboratively investigate subcortical brain structure shape differences between individuals with schizophrenia and healthy control participants. The study analyzed data from 2,833 individuals with schizophrenia and 3,929 healthy control participants contributed by 21 worldwide research groups participating in the ENIGMA Schizophrenia Working Group. Harmonized shape analysis protocols were applied to each site's data independently for bilateral hippocampus, amygdala, caudate, accumbens, putamen, pallidum, and thalamus obtained from T1-weighted structural MRI scans. Mass univariate meta-analyses revealed more-concave-than-convex shape differences in the hippocampus, amygdala, accumbens, and thalamus in individuals with schizophrenia compared with control participants, more-convex-than-concave shape differences in the putamen and pallidum, and both concave and convex shape differences in the caudate. Patterns of exaggerated asymmetry were observed across the hippocampus, amygdala, and thalamus in individuals with schizophrenia compared to control participants, while diminished asymmetry encompassed ventral striatum and ventral and dorsal thalamus. Our analyses also revealed that higher chlorpromazine dose equivalents and increased positive symptom levels were associated with patterns of contiguous convex shape differences across multiple subcortical structures. Findings from our shape meta-analysis suggest that common neurobiological mechanisms may contribute to gray matter reduction across multiple subcortical regions, thus enhancing our understanding of the nature of network disorganization in schizophrenia.
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19.
  • Haroon, Humza, et al. (author)
  • Cerebrospinal fluid proteomic signatures are associated with symptom severity of first-episode psychosis
  • 2024
  • In: Journal of Psychiatric Research. - : Elsevier. - 0022-3956 .- 1879-1379. ; 171, s. 306-315
  • Journal article (peer-reviewed)abstract
    • Apart from their diagnostic, monitoring, or prognostic utility in clinical settings, molecular biomarkers may be instrumental in understanding the pathophysiology of psychiatric disorders, including schizophrenia. Using untargeted metabolomics, we recently identified eight cerebrospinal fluid (CSF) metabolites unique to first-episode psychosis (FEP) subjects compared to healthy controls (HC). In this study, we sought to investigate the CSF proteomic signatures associated with FEP. We employed 16-plex tandem mass tag (TMT) mass spectrometry (MS) to examine the relative protein abundance in CSF samples of 15 individuals diagnosed with FEP and 15 age-and-sex-matched healthy controls (HC). Multiple linear regression model (MLRM) identified 16 differentially abundant CSF proteins between FEP and HC at p < 0.01. Among them, the two most significant CSF proteins were collagen alpha-2 (IV) chain (COL4A2: standard mean difference [SMD] = -1.12, p = 1.64 × 10-4) and neuron-derived neurotrophic factor (NDNF: SMD = -1.03, p = 4.52 × 10-4) both of which were down-regulated in FEP subjects compared to HC. We also identified several potential CSF proteins associated with the pathophysiology and the symptom profile and severity in FEP subjects, including COL4A2, NDNF, hornerin (HRNR), contactin-6 (CNTN6), voltage-dependent calcium channel subunit alpha-2/delta-3 (CACNA2D3), tropomyosin alpha-3 chain (TPM3 and TPM4). Moreover, several protein signatures were associated with cognitive performance. Although the results need replication, our exploratory study suggests that CSF protein signatures can be used to increase the understanding of the pathophysiology of psychosis.
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20.
  • Hörbeck, Elin, 1984, et al. (author)
  • Dissecting the impact of complement component 4A in bipolar disorder.
  • 2023
  • In: Brain, behavior, and immunity. - 1090-2139. ; 116, s. 150-159
  • Journal article (peer-reviewed)abstract
    • The genetic overlap between schizophrenia (SZ) and bipolar disorder (BD) is substantial. Polygenic risk scores have been shown to dissect different symptom dimensions within and across these two disorders. Here, we focused on the most strongly associated SZ risk locus located in the extended MHC region, which is largely explained by copy numbers of the gene coding for complement component 4A (C4A). First, we utilized existing brain tissue collections (N=1,202 samples) and observed no altered C4A expression in BD samples. The generated C4A seeded co-expression networks displayed no genetic enrichment for BD. To study if genetically predicted C4A expression discriminates between subphenotypes of BD, we applied C4A expression scores to symptom dimensions in a total of 4,739 BD cases with deep phenotypic data. We identified a significant association between C4A expression and psychotic mood episodes in BD type 1 (BDI). No significant association was observed between C4A expression and the occurrence of non-affective psychotic episodes in BDI, the psychosis dimensions in the total BD sample, or any other subphenotype of BD. Overall, these results points to a distinct role of C4A in BD that is restricted to vulnerability for developing psychotic symptoms during mood episodes in BDI.
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21.
  • Jakobsson, Joel, et al. (author)
  • CACNA1C polymorphism and altered phosphorylation of tau in bipolar disorder.
  • 2016
  • In: The British journal of psychiatry : the journal of mental science. - : Royal College of Psychiatrists. - 1472-1465. ; 208:2, s. 195-196
  • Journal article (peer-reviewed)abstract
    • Several genome-wide association studies and case-control studies have associated the single nucleotide polymorphism (SNP) rs1006737, situated in CACNA1C encoding the alpha 1C subunit of the L-type voltage-gated calcium channel, with bipolar disorder and other psychiatric disorders. However, the causal pathway linking genetic variants in CACNA1C with increased risk for developing brain disorders remains unclear. Here, we explored the association between the rs1006737 SNP and cerebrospinal fluid (CSF) markers. We found a significant association between the risk allele in rs1006737 and a decreased CSF hyperphosphorylated tau/total tau ratio in patients with bipolar disorder, thus linking variation in the CACNA1C gene to a neurochemical marker of neuroaxonal plasticity in those with this disorder.
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22.
  • Jonsson, Bo H, et al. (author)
  • Serum concentration of zinc is elevated in clinically stable bipolar disorder patients.
  • 2022
  • In: Brain and behavior. - : Wiley. - 2162-3279. ; 12:1
  • Journal article (peer-reviewed)abstract
    • Bipolar disorder (BD) is a chronic psychiatric disorder characterized by recurrent mood episodes interspersed with euthymic periods. A growing number of studies have indicated that zinc plays an important role in coordinating immune responses, as well as being involved in synaptic transmission. In the current study, we set out to measure serum levels of zinc in a meticulously phenotyped cohort of 121 euthymic BD subjects and 30 matched controls.Serum levels of zinc were measured by photometry. To assess the interplay between zinc levels and immune activation in BD, we measured serum levels of high-sensitive C-reactive protein (hsCRP) levels by immunoturbidimetric assay, and serum levels of monocyte chemoattractant protein-1 (MCP-1), chitinase 3-like protein 1 (YKL-40), and soluble cluster of differentiation 14 (sCD14) by electrochemiluminescence enzyme-linked immunosorbent assays. The baseline clinical diagnostic instrument for BD was the Affective Disorder Evaluation, and executive functioning was assessed by using the Delis-Kaplan Executive Function System.Controlling for potential confounding factors, BD patients displayed increased serum levels of zinc unrelated to hsCRP, MCP-1, YKL-40, and sCD14 levels. Serum levels of zinc did not associate with executive functioning or measurements of disease severity.This study suggests that the zinc homeostasis is disturbed in BD and that this dyshomeostasis is not related to ongoing mood symptoms or immune activation. Of note, serum levels were increased and hence do not support continuous zinc supplementation in BD.
  •  
23.
  • Kegel, Magdalena E., et al. (author)
  • Imbalanced Kynurenine Pathway in Schizophrenia
  • 2014
  • In: International Journal of Tryptophan Research. - : Libertas Academica. - 1178-6469. ; 7, s. 15-22
  • Journal article (peer-reviewed)abstract
    • Several studies suggest a role for kynurenic acid (KYNA) in the pathophysiology of schizophrenia. It has been proposed that increased brain KYNA levels in schizophrenia result from a pathological shift in the kynurenine pathway toward enhanced KYNA formation, away from the other branch of the pathway leading to quinolinic acid (QUIN). Here we investigate the levels of QUIN in cerebrospinal fluid (CSF) of patients with schizophrenia and healthy controls, and relate those to CSF levels of KYNA and other kynurenine metabolites from the same individuals. CSF QUIN levels from stable outpatients treated with olanzapine (n = 22) and those of controls (n = 26) were analyzed using liquid chromatography-mass spectrometry. No difference in CSF QUIN levels between patients and controls was observed (20.6 ± 1.5 nM vs. 18.2 ± 1.1 nM, P = 0.36). CSF QUIN was positively correlated to CSF kynurenine and CSF KYNA in patients but not in controls. The CSF QUIN/KYNA ratio was lower in patients than in controls (P = 0.027). In summary, the present study offers support for an over-activated and imbalanced kynurenine pathway, favoring the production of KYNA over QUIN in patients with schizophrenia.
  •  
24.
  • Klahn, Luisa, et al. (author)
  • Functional connectivity alterations of the somatomotor network in euthymic bipolar disorder
  • 2023
  • In: Neuroscience Applied. ; 2
  • Journal article (peer-reviewed)abstract
    • While individuals with bipolar disorder are assumed to recover between mood episodes, some nevertheless experience lingering subsyndromal symptoms and suffer from cognitive and functional impairments. Here, we propose that these enduring impairments may be linked to aberrations in brain networks. To test this, we conducted a resting-state functional magnetic resonance imaging (fMRI) study and used network-based statistic to compare functional connectivity between euthymic individuals with bipolar disorder (N=96) and healthy control individuals (N=61) both within and between resting-state networks. We also investigated the association of functional connectivity with lingering psychomotor symptoms and illness severity in bipolar disorder. We found stronger functional connectivity between the somatomotor network and the frontoparietal network in individuals with bipolar disorder compared with healthy controls, but weaker functional connectivity within the somatomotor network as well as between the somatomotor and the visual network. Results remained after adjusting for antipsychotic medication. No significant association with psychomotor performance and illness severity was found. We conclude that stronger functional connectivity between the somatomotor and frontoparietal network might be associated with lingering symptoms in bipolar euthymia. Dysconnectivity within the somatomotor network might relate to psychomotor symptoms beyond the impact of medication. Our findings contribute to the sparse field of somatomotor network aberrancies in bipolar disorder and may present a potential target for brain stimulation treatment.
  •  
25.
  • Koskuvi, Marja, et al. (author)
  • Lower complement C1q levels in first-episode psychosis and in schizophrenia
  • 2024
  • In: Brain, Behavior, and Immunity. - : Elsevier. - 0889-1591 .- 1090-2139. ; 117, s. 313-319
  • Journal article (peer-reviewed)abstract
    • 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.
  •  
26.
  • Larsson, Cornelia, et al. (author)
  • Facial affect recognition in first-episode psychosis is impaired but not associated with psychotic symptoms.
  • 2022
  • In: Heliyon. - : Elsevier. - 2405-8440. ; 8:9
  • Journal article (peer-reviewed)abstract
    • Introduction: Social dysfunction is a key feature of psychotic disorders such as schizophrenia linked to disability. Less is known about social functioning in the early stages of the disorder and if there is an association to psychotic symptoms.Aims: Investigate if antipsychotic drug-naïve or briefly medicated individuals with first-episode psychosis (FEP), have impaired facial affect recognition (FAR) compared to control participants and if psychotic symptoms are associated with the FAR ability.Method: Individuals with FEP (n = 67) and control participants (n = 51) performed a computer-aided FAR task on basic emotions. Psychotic symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). Group performances were compared using age and gender as covariates. The associations between FAR and performance on the subscales of PANSS were analyzed.Results: Compared to control participants, individuals with FEP were impaired in general FAR (Beta = -2.04 [95 % conf: -3.75/-1.62], p < 0.001) and FAR of negative emotions (Beta = -1.74 [95 % conf: -3.08/-1.22], p < 0.001), driven by difficulties in recognition of anger and disgust. In both groups, there was a pattern of mistaking negative emotions for other negative emotions. There were no significant group differences in FAR of happiness. No significant associations between FAR and psychotic symptoms were observed.Discussion: The results indicate that FAR, an underlying mechanism of social functioning is impaired early in the course of psychotic disorders. Current findings do not support the hypothesis that misinterpretation of facial expressions in individuals with FEP underlies or contributes to symptoms of psychosis.
  •  
27.
  • Lee, Maria, et al. (author)
  • Cognitive Function and Variability in Antipsychotic Drug-Naive Patients With First-Episode Psychosis : A Systematic Review and Meta-Analysis.
  • 2024
  • In: JAMA psychiatry. - 2168-6238.
  • Journal article (peer-reviewed)abstract
    • IMPORTANCE: Cognitive impairment contributes significantly to clinical outcome and level of function in individuals with psychotic disorders. These impairments are present already at psychosis onset at a group level; however, the question of heterogeneity in cognitive function among patients has not been systematically investigated.OBJECTIVE: To provide an updated quantification of cognitive impairment at psychosis onset before patients receive potentially confounding antipsychotic treatment, and to investigate variability in cognitive function compared with healthy controls.DATA SOURCES: In this systematic review and meta-analysis, PubMed articles were searched up to September 15, 2022.STUDY SELECTION: Original studies reporting data on cognitive function in antipsychotic drug-naive patients with first-episode psychosis (FEP) were included.DATA EXTRACTION AND SYNTHESIS: Data were independently extracted by 2 researchers. Cognitive tasks were clustered according to 6 domains of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery and the domain of executive function. Random-effects model meta-analyses of mean differences and coefficient of variation ratios (CVRs) were performed, as well as meta-regressions, assessment of study quality, and publication bias.MAIN OUTCOMES AND MEASURES: The main outcome measure was Hedges g for mean differences in cognition and CVR for within-group variability.RESULTS: Fifty studies were included in the analysis with a total of 2625 individuals with FEP (mean [SD] age, 25.2 [3.6] years, 60% male; 40% female) and 2917 healthy controls (mean [SD] age, 26.0 [4.6]; 55% male; 45% female). In all cognitive domains, the FEP group displayed significant impairment compared with controls (speed of processing: Hedges g = -1.16; 95% CI, -1.35 to -0.98; verbal learning: Hedges g = -1.08; 95% CI, -1.28 to -0.88; visual learning: Hedges g = -1.05; 95% CI, -1.27 to -0.82; working memory: Hedges g = -1.04; 95% CI, -1.35 to -0.73; attention: Hedges g = -1.03; 95% CI, -1.24 to -0.82; reasoning/problem solving: Hedges g = -0.90; 95% CI, -1.12 to -0.68; executive function: Hedges g = -0.88; 95% CI, -1.07 to -0.69). Individuals with FEP also exhibited a larger variability across all domains (CVR range, 1.34-1.92).CONCLUSIONS AND RELEVANCE: Results of this systematic review and meta-analysis identified cognitive impairment in FEP before the initiation of antipsychotic treatment, with large effect sizes. The high variability within the FEP group suggests the need to identify those individuals with more severe cognitive problems who risk worse outcomes and could benefit the most from cognitive remediation.
  •  
28.
  • Lee, Maria, et al. (author)
  • No association between cortical dopamine D2 receptor availability and cognition in antipsychotic-naive first-episode psychosis
  • 2021
  • In: NPJ SCHIZOPHRENIA. - : Springer Nature. - 2334-265X. ; 7:1
  • Journal article (peer-reviewed)abstract
    • Cognitive impairment is an important predictor of disability in schizophrenia. Dopamine neurotransmission in cortical brain regions has been suggested to be of importance for higher-order cognitive processes. The aim of this study was to examine the relationship between extrastriatal dopamine D2-R availability and cognitive function, using positron emission tomography and the high-affinity D2-R radioligand [C-11]FLB 457, in an antipsychotic-naive sample of 18 first-episode psychosis patients and 16 control subjects. We observed no significant associations between D2-R binding in the dorsolateral prefrontal cortex or hippocampus (beta = 0.013-0.074, partial r= -0.037-0.273, p = 0.131-0.841). Instead, using Bayesian statistics, we found moderate support for the null hypothesis of no relationship (BFH0:H1 = 3.3-8.2). Theoretically, our findings may suggest a lack of detrimental effects of D2-R antagonist drugs on cognition in schizophrenia patients, in line with clinical observations.
  •  
29.
  • Mätlik, Kärt, et al. (author)
  • Elevated endogenous GDNF induces altered dopamine signalling in mice and correlates with clinical severity in schizophrenia.
  • 2022
  • In: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578.
  • Journal article (peer-reviewed)abstract
    • Presynaptic increase in striatal dopamine is the primary dopaminergic abnormality in schizophrenia, but the underlying mechanisms are not understood. Here, we hypothesized that increased expression of endogenous GDNF could induce dopaminergic abnormalities that resemble those seen in schizophrenia. To test the impact of GDNF elevation, without inducing adverse effects caused by ectopic overexpression, we developed a novel in vivo approach to conditionally increase endogenous GDNF expression. We found that a 2-3-fold increase in endogenous GDNF in the brain was sufficient to induce molecular, cellular, and functional changes in dopamine signalling in the striatum and prefrontal cortex, including increased striatal presynaptic dopamine levels and reduction of dopamine in prefrontal cortex. Mechanistically, we identified adenosine A2a receptor (A2AR), a G-protein coupled receptor that modulates dopaminergic signalling, as a possible mediator of GDNF-driven dopaminergic abnormalities. We further showed that pharmacological inhibition of A2AR with istradefylline partially normalised striatal GDNF and striatal and cortical dopamine levels in mice. Lastly, we found that GDNF levels are increased in the cerebrospinal fluid of first episode psychosis patients, and in post-mortem striatum of schizophrenia patients. Our results reveal a possible contributor for increased striatal dopamine signalling in a subgroup of schizophrenia patients and suggest that GDNF-A2AR crosstalk may regulate dopamine function in a therapeutically targetable manner.
  •  
30.
  • Olsson, Sara K, et al. (author)
  • Cerebrospinal fluid kynurenic acid is associated with manic and psychotic features in patients with bipolar I disorder.
  • 2012
  • In: Bipolar disorders. - : Wiley. - 1399-5618 .- 1398-5647. ; 14:7, s. 719-26
  • Journal article (peer-reviewed)abstract
    • Olsson SK, Sellgren C, Engberg G, Landén M, Erhardt S. Cerebrospinal fluid kynurenic acid is associated with manic and psychotic features in patients with bipolar I disorder. Bipolar Disord 2012: 14: 719-726. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objectives: Kynurenic acid (KYNA), an end metabolite of tryptophan degradation, antagonizes glutamatergic and cholinergic receptors in the brain. Recently, we reported elevated levels of cerebrospinal fluid (CSF) KYNA in male patients with bipolar disorder. Here, we investigate the relationship between symptomatology and the concentration of CSF KYNA in patients with bipolar I disorder. Methods: CSF KYNA levels from euthymic male {n=21; mean age: 41years [standard deviation (SD)=14]} and female [n=34; mean age: 37years (SD=14)] patients diagnosed with bipolar I disorder were analyzed using high-performance liquid chromatography (HPLC). Results: Euthymic bipolar I disorder patients with a lifetime occurrence of psychotic features had higher CSF levels of KYNA {2.0nm [standard error of the mean (SEM)=0.2]; n=43} compared to patients without any history of psychotic features [1.3nm (SEM=0.2); n=12] (p=0.01). Logistic regression, with age as covariate, similarly showed an association between a history of psychotic features and CSF KYNA levels [n=55; odds ratio (OR)=4.9, p=0.03]. Further, having had a recent manic episode (within the previous year) was also associated with CSF KYNA adjusted for age (n=34; OR=4.4, p=0.03), and the association remained significant when adjusting for a lifetime history of psychotic features (OR=4.1, p=0.05). Conclusions: Although the causality needs to be determined, the ability of KYNA to influence dopamine transmission and behavior, along with previous reports showing increased brain levels of the compound in patients with schizophrenia and bipolar disorder, may indicate a possible pathophysiological role of KYNA in the development of manic or psychotic symptoms.
  •  
31.
  • Orhan, Funda, et al. (author)
  • CSF dopamine is elevated in first-episode psychosis and associates to symptom severity and cognitive performance.
  • 2023
  • In: Schizophrenia Research. - 0920-9964 .- 1573-2509. ; 257, s. 34-40
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: The hypothesis of dopamine dysfunction in psychosis has evolved since the mid-twentieth century. However, clinical support from biochemical analysis of the transmitter in patients is still missing. The present study assessed dopamine and related metabolites in the cerebrospinal fluid (CSF) of first-episode psychosis (FEP) subjects.METHODS: Forty first-episode psychosis subjects and twenty healthy age-matched volunteers were recruited via the Karolinska Schizophrenia Project, a multidisciplinary research consortium that investigates the pathophysiology of schizophrenia. Psychopathology, disease severity, and cognitive performance were rated as well as cerebrospinal fluid concentrations of dopamine and related metabolites were measured using a sensitive high-pressure liquid chromatography assay.RESULTS: CSF dopamine was reliably detected in 50 % of healthy controls and in 65 % of first-episode psychosis subjects and significantly higher in first-episode psychosis subjects compared to age-matched healthy controls. No difference in CSF dopamine levels was observed between drug-naive subjects and subjects with short exposure to antipsychotics. The dopamine concentrations were positively associated with illness severity and deficits in executive functioning.CONCLUSIONS: Dopamine dysfunction has long been considered a cornerstone of the pathophysiology of schizophrenia, although biochemical support for elevated brain dopamine levels has been lacking. The results of the present study, showing that FEP subjects have increased CSF dopamine levels that correlate to disease symptoms, should fill the knowledge gap in this regard.
  •  
32.
  •  
33.
  • Pils, Marlene, et al. (author)
  • Disrupted-in-schizophrenia 1 (DISC1) protein aggregates in cerebrospinal fluid are elevated in first-episode psychosis patients.
  • 2023
  • In: Psychiatry and Clinical Neurosciences. - 1323-1316 .- 1440-1819.
  • Journal article (peer-reviewed)abstract
    • AIM: The Disrupted-in-schizophrenia 1 (DISC1) protein is a key regulator at the intersection of major signaling pathways relevant for adaptive behavior. It is prone to posttranslational changes such as misassembly and aggregation but the significance of such transformations for human mental illness has remained unclear. We aimed to demonstrate the occurrence of DISC1 protein aggregates in patients with first episode psychosis (FEP).METHOD: Cerebrospinal fluid (CSF) samples of patients with FEP (n = 50) and matched healthy controls (HC; n = 47) were measured by the highly sensitive surface-based fluorescence intensity distribution analysis (sFIDA) technology that enables single aggregate detection.RESULTS: Here we demonstrate that DISC1 protein aggregates are increased in CSF samples of FEP vs. HC. The concentration was in the low femtomolar range. No correlations were found to specific symptom levels, but the difference was particularly significant in the subset of patients receiving the diagnoses "schizophrenia, unspecified" (DSM IV 295.9) or schizoaffective disorder (DSM IV 295.70) at 18-month follow-up. DISC1 protein aggregate levels did not significantly change within the 18 months observation interval, and were in average higher for individuals carrying the major DISC1 rs821577 allele before correction.CONCLUSION: The occurrence of protein aggregates in vivo in patients with psychotic disorders has not been previously reported. It underscores the significance of posttranslational modifications of proteins both as pathogenetic mechanisms and as potential diagnostic markers in these disorders. This article is protected by copyright. All rights reserved.
  •  
34.
  • Plavén-Sigray, Pontus, et al. (author)
  • Thalamic dopamine D2-receptor availability in schizophrenia : a study on antipsychotic-naive patients with first-episode psychosis and a meta-analysis.
  • 2022
  • In: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 27:2, s. 1233-1240
  • Journal article (peer-reviewed)abstract
    • Pharmacological and genetic evidence support a role for an involvement of the dopamine D2-receptor (D2-R) in the pathophysiology of schizophrenia. Previous molecular imaging studies have suggested lower levels of D2-R in thalamus, but results are inconclusive. The objective of the present study was to use improved methodology to compare D2-R density in whole thalamus and thalamic subregions between first-episode psychosis patients and healthy controls. Differences in thalamocortical connectivity was explored based on the D2-R results. 19 antipsychotic-naive first-episode psychosis patients and 19 age- and sex-matched healthy controls were examined using high-resolution Positron Emission Tomography (PET) and the high-affinity D2-R radioligand [11C]FLB457. The main outcome was D2-R binding potential (BPND) in thalamus, and it was predicted that patients would have lower binding. Diffusion tensor imaging (DTI) was performed in a subgroup of 11 patients and 15 controls. D2-R binding in whole thalamus was lower in patients compared with controls (Cohen's dz = -0.479, p = 0.026, Bayes Factor (BF) > 4). Among subregions, lower BPND was observed in the ROI representing thalamic connectivity to the frontal cortex (Cohen's dz = -0.527, p = 0.017, BF > 6). A meta-analysis, including the sample of this study, confirmed significantly lower thalamic D2-R availability in patients. Exploratory analyses suggested that patients had lower fractional anisotropy values compared with controls (Cohen's d = -0.692, p = 0.036) in the inferior thalamic radiation. The findings support the hypothesis of a dysregulation of thalamic dopaminergic neurotransmission in schizophrenia, and it is hypothesized that this could underlie a disturbance of thalamocortical connectivity.
  •  
35.
  • Pålsson, Erik, 1975, et al. (author)
  • Altered brain dopamine metabolism is a trait marker for bipolar disorder
  • 2023
  • In: Biomarkers in Neuropsychiatry. - 2666-1446. ; 9
  • Journal article (peer-reviewed)abstract
    • Pharmacological treatment, imaging, and neurochemistry studies identify altered dopamine signaling in bipolar disorder. Our previous work has shown higher concentration of homovanillic acid (HVA), the end metabolite of dopamine, in cerebrospinal fluid (CSF) from individuals with bipolar disorder compared to healthy controls. Here, we analyzed HVA concentrations from a follow-up visit in 103 adults with bipolar disorder and 57 controls from our first cohort. Further, we analyzed CSF monoamine metabolite concentrations in a second cohort of 152 adults with bipolar disorder and 55 controls. At the follow-up visit for the first cohort, HVA was higher in individuals with bipolar disorder (278 ± 102 nmol/L, p = 0.003) compared with controls (232 ± 83 nmol/L). In the second cohort, individuals with bipolar disorder had higher HVA (272 ± 97 nmol/L, p = 0.001) and lower 3-methoxy-4-hydroxyphenylglycol (MHPG, 40 ± 9 nmol/L, p = 0.002) concentrations than controls (HVA, 231 ± 71 nmol/L and MHPG, 45 ± 9 nmol/L). Baseline and follow-up measures of monoamine metabolites showed medium to high correlation to each other but did not predict course of illness. We failed to replicate the association of HVA concentration and psychotic symptoms but confirmed lower 5-hydroxyindoleacetic acid (5-HIAA) concentration in individuals treated with antidepressants. In conclusion, we confirmed high HVA concentration in CSF in patients with bipolar disorder compared to a control group. Previous work suggest that this is a feature shared with ADHD but distinct from schizophrenia and major depressive disorder. The role of increased HVA concentration in the course of illness in bipolar disorder remains unclear.
  •  
36.
  • Pålsson, Erik, 1975, et al. (author)
  • Cerebrospinal fluid monoamine metabolite profiles in bipolar disorder, ADHD, and controls.
  • 2017
  • In: Journal of neural transmission (Vienna, Austria : 1996). - : Springer Science and Business Media LLC. - 1435-1463 .- 0300-9564. ; 124:9
  • Journal article (peer-reviewed)abstract
    • Alterations in monoaminergic signaling are suggested as key aspects of the pathophysiology in bipolar disorder and ADHD, but it is not known if the monoamine metabolic profile differs between these disorders. One method to study monoaminergic systems in humans is to measure monoamine end-point metabolite concentrations in cerebrospinal fluid (CSF). Here, we analyzed CSF monoamine metabolite concentrations in 103 adults with bipolar disorder, 72 adults with ADHD, and 113 controls. Individuals with bipolar disorder had significantly higher homovanillic acid (HVA, 264±112nmol/L, p<0.001) and 5-hydroxyindoleacetic acid (5-HIAA, 116±42nmol/L, p=0.001) concentration, but lower 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG, 38±8nmol/L, p<0.001) concentrations than controls (HVA, 206±70nmol/L; 5-HIAA, 98±31nmol/L; and MHPG, 42±7nmol/L). Higher HVA concentrations were associated with a history of psychosis in the bipolar disorder sample. Subjects with ADHD had higher HVA (240±94nmol/L, p<0.001) concentrations compared with controls. In addition, SSRI treatment was associated with lower 5-HIAA concentrations in both patient groups. A power analysis indicated that for within-group comparisons, only large effects would be reliably detectable. Thus, there may be moderate-to-small effects caused by medication that were not detected due to the limited size of the sub-groups in these analyses. In conclusion, the present study suggests disorder-specific alterations of CSF monoamine metabolite concentrations in patients with bipolar disorder and ADHD compared with controls; these differences were independent of acute symptoms and medication effects.
  •  
37.
  • Schijven, Dick, et al. (author)
  • Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium
  • 2023
  • In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 0027-8424 .- 1091-6490. ; 120:14
  • Journal article (peer-reviewed)abstract
    • Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.
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38.
  • Schwieler, Lilly, et al. (author)
  • Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia - significance for activation of the kynurenine pathway.
  • 2015
  • In: Journal of Psychiatry & Neuroscience. - : CMA-CANADIAN MEDICAL ASSOC. - 1180-4882 .- 1488-2434. ; 40:2, s. 126-13
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Accumulating evidence indicates that schizophrenia is associated with brain immune activation. While a number of reports suggest increased cytokine levels in patients with schizophrenia, many of these studies have been limited by their focus on peripheral cytokines or confounded by various antipsychotic treatments. Here, well-characterized patients with schizophrenia, all receiving olanzapine treatment, and healthy volunteers were analyzed with regard to cerebrospinal fluid (CSF) levels of cytokines. We correlated the CSF cytokine levels to previously analyzed metabolites of the kynurenine (KYN) pathway.METHODS: We analyzed the CSF from patients and controls using electrochemiluminescence detection with regard to cytokines. Cell culture media from human cortical astrocytes were analyzed for KYN and kynurenic acid (KYNA) using high-pressure liquid chromatography or liquid chromatography/mass spectrometry.RESULTS: We included 23 patients and 37 controls in our study. Patients with schizophrenia had increased CSF levels of interleukin (IL)-6 compared with healthy volunteers. In patients, we also observed a positive correlation between IL-6 and the tryptophan:KYNA ratio, indicating that IL-6 activates the KYN pathway. In line with this, application of IL-6 to cultured human astrocytes increased cell medium concentration of KYNA.LIMITATIONS: The CSF samples had been frozen and thawed twice before analysis of cytokines. Median age differed between patients and controls. When appropriate, all present analyses were adjusted for age.CONCLUSION: We have shown that IL-6, KYN and KYNA are elevated in patients with chronic schizophrenia, strengthening the idea of brain immune activation in patients with this disease. Our concurrent cell culture and clinical findings suggest that IL-6 induces the KYN pathway, leading to increased production of the N-methyl-D-aspartate receptor antagonist KYNA in patients with schizophrenia.
  •  
39.
  •  
40.
  • Sellgren, Carl (author)
  • On neuroinflammation in psychotic disorders
  • 2014
  • Doctoral thesis (other academic/artistic)abstract
    • Neuroinflammation has been implicated in several psychiatric conditions. Based on experimental studies, the glia-derived tryptophan metabolite kynurenic acid (KYNA) may be especially relevant for positive psychotic symptoms and impaired executive functioning. The first two studies (I and II) of this thesis translate these experimental findings to bipolar disorder patients. Rooted in a genome-wide association study against cerebrospinal fluid (CSF) concentrations of KYNA, we used a multi-pronged approach and linked the identified genetic risk marker not only with other CSF biomarkers in bipolar patients, but also with specific symptoms such as delusions, hallucinations, and impaired executive functioning. We conducted cell studies, postmortem analyses, and clinical association studies that together suggested a sorting nexin 7 driven activation of caspase-8/IL-1ß as a mechanism underlying increased CSF concentration of KYNA in psychotic bipolar patients. Caspase-1 is activated by the purinergic ionotropic receptor P2X7R. This receptor is suggested to be internalized by a G-protein coupled receptor kinase 3 (GRK-3)-dependent mechanism. Decreased protein levels of GRK-3 have been observed in postmortem studies of schizophrenia and psychotic bipolar patients. In study III, we used a mouse with a targeted deletion for GRK3. These mice displayed impaired P2X7R internalization, increased brain levels of IL-1ß, increased immunoreactivity for the astrocytic marker glial fibrillary acidic protein (GFAP), a more pronounced accumulation of hippocampal KYNA, as well as an accentuated dopaminergic response to amphetamine. In behavior models, these animals displayed disrupted pre-pulse inhibition, as well as impaired contextual fear conditioning with spared cue-specific fear conditioning. Taken together, these findings suggest that the GRK3-/-mouse is a novel genetic animal model of schizophrenia that may prove useful in exploring the actions of the emerging immunomodulatory drugs in psychotic disorders. Study IV was a validation study aiming at defining an algorithm that identifies bipolar disorder patients in Swedish national registries as accurate as possible, a pre-requisite for study V. In the last study V of this thesis, we studied the association between psychotic disorders and rheumatoid arthritis (RA). We found that the previously reported inverse association is likely to have been confounded by underreporting and/or underdiagnosis of RA. However, an inverse association between schizophrenia and seronegative RA may be real, tentatively due to shared genetic underpinnings involving glia functioning. In conclusion, this thesis suggests an important role of glial mechanisms in the pathophysiology of the two main psychiatric disorders, schizophrenia and bipolar disorder. Our results add to growing evidence that cytokine and kynurenine metabolite signaling is tied to psychotic and cognitive symptoms. These findings open up for novel drug targets and imply that contemporary glia research can provide a rewarding foundation for investigations into pathology of psychiatric disorders.
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41.
  • Shang, Pei, et al. (author)
  • Identification of cerebrospinal fluid and serum metabolomic biomarkers in first episode psychosis patients
  • 2022
  • In: Translational Psychiatry. - : Springer Nature. - 2158-3188. ; 12:1
  • Journal article (peer-reviewed)abstract
    • Psychotic disorders are currently diagnosed by examining the patient's mental state and medical history. Identifying reliable diagnostic, monitoring, predictive, or prognostic biomarkers would be useful in clinical settings and help to understand the pathophysiology of schizophrenia. Here, we performed an untargeted metabolomics analysis using ultra-high pressure liquid chromatography coupled with time-of-flight mass spectroscopy on cerebrospinal fluid (CSF) and serum samples of 25 patients at their first-episode psychosis (FEP) manifestation (baseline) and after 18 months (follow-up). CSF and serum samples of 21 healthy control (HC) subjects were also analyzed. By comparing FEP and HC groups at baseline, we found eight CSF and 32 serum psychosis-associated metabolites with non-redundant identifications. Most remarkable was the finding of increased CSF serotonin (5-HT) levels. Most metabolites identified at baseline did not differ between groups at 18-month follow-up with significant improvement of positive symptoms and cognitive functions. Comparing FEP patients at baseline and 18-month follow-up, we identified 20 CSF metabolites and 90 serum metabolites that changed at follow-up. We further utilized Ingenuity Pathway Analysis (IPA) and identified candidate signaling pathways involved in psychosis pathogenesis and progression. In an extended cohort, we validated that CSF 5-HT levels were higher in FEP patients than in HC at baseline by reversed-phase high-pressure liquid chromatography. To conclude, these findings provide insights into the pathophysiology of psychosis and identify potential psychosis-associated biomarkers.
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42.
  • Smedler, Erik, et al. (author)
  • Reporting trigger factors for (hypo)manic episodes in bipolar disorder: association with personality and prognosis.
  • 2020
  • In: Acta psychiatrica Scandinavica. - : Wiley. - 1600-0447 .- 0001-690X. ; 141:6, s. 534-540
  • Journal article (peer-reviewed)abstract
    • To investigate external factors that trigger manic and hypomanic relapses and how this is associated with personality and clinical outcome measured as number of affective episodes over a seven-year period.This is a prospective cohort study of 204 meticulously characterized Swedish bipolar disorder patients. Personality was evaluated at baseline using the Swedish universities Scales of Personality in 170 patients, and 90 patients were followed up after approximately seven years in order to evaluate clinical outcomes.We found that 44% of the patients reported trigger factors, including sleep disturbance, work or family related issues, medication, and illicit drug use. There were no significant differences in any of the personality traits when comparing the 74 patients that reported triggers with the 90 patients that did not. At seven-year follow-up, there was no difference between the groups in number of affective episodes (depressive, hypomanic, manic or mixed), involuntary commitments, suicide attempts, or self-harm incidents since baseline.Around 40% of the patients reported external triggers for manic and hypomanic episodes. However, this was neither associated with personality traits nor number of affective episodes at seven-year follow-up.Around 40% of all bipolar disorder patients reported trigger factors for manic or hypomanic episodes. Reporting trigger factors was not associated with personality Reporting trigger factors was not associated with outcomes over a seven-year period. Limitations Patients had on average long duration of illness and may be less sensitive to external stressors than persons with recent onset. Trigger factors were identified retrospectively, and may thus be prone to recall bias. The number of affective episodes might be a too crude outcome measure as most subjects had not suffered any affective episodes at follow-up.
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43.
  • Theorell, Jakob, et al. (author)
  • Screening for pathogenic neuronal autoantibodies in serum and CSF of patients with first-episode psychosis
  • 2021
  • In: Translational Psychiatry. - : Springer Nature. - 2158-3188. ; 11:1
  • Journal article (peer-reviewed)abstract
    • Patients with autoimmune encephalitides, especially those with antibodies to the N-methyl-D-aspartate receptor (NMDAR), often present with prominent psychosis and respond well to immunotherapies. Although most patients progress to develop various neurological symptoms, it has been hypothesised that a subgroup of patients with first-episode psychosis (FEP) suffer from a forme fruste of autoimmune encephalitis. Without accurate identification, this immunotherapy-responsive subgroup may be denied disease-modifying treatments. Thirty studies addressing aspects of this hypothesis were identified in a systematic review. Amongst other shortcomings, 15/30 reported no control group and only 6/30 determined cerebrospinal fluid (CSF) autoantibodies. To ourselves address these-and other-limitations, we investigated a prospectively ascertained clinically well-characterised cohort of 71 FEP patients without traditional neurological features, and 48 healthy controls. Serum and CSF were tested for autoantibodies against seven neuronal surface autoantigens using live cell-based assays. These identified 3/71 (4%) patient sera with weak binding to either contactin-associated protein-like 2, the NMDAR or glycine receptor versus no binding from 48 control samples (p = 0.28, Fisher's test). The three seropositive individuals showed no CSF autoantibodies and no differences from the autoantibody-negative patients in their clinical phenotypes, or across multiple parameters of peripheral and central inflammation. All individuals were negative for CSF NMDAR antibodies. In conclusion, formes frustes of autoimmune encephalitis are not prevalent among FEP patients admitted to psychiatric care. Our findings do not support screening for neuronal surface autoantibodies in unselected psychotic patients.
  •  
44.
  • Trepci, Ada, et al. (author)
  • Central levels of tryptophan metabolites in subjects with bipolar disorder.
  • 2021
  • In: European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. - : Elsevier BV. - 1873-7862. ; 43, s. 52-62
  • Journal article (peer-reviewed)abstract
    • The kynurenine pathway of tryptophan degradation produces several neuroactive metabolites such as kynurenic acid (KYNA), quinolinic acid (QUIN), and picolinic acid (PIC) thought to be involved in the pathophysiology of psychosis, major depression, and suicidal behavior. Here, we analyzed cerebrospinal fluid (CSF) concentrations of tryptophan, kynurenine, KYNA, QUIN, and PIC utilizing ultra-performance liquid chromatography - tandem mass spectrometry system (UPLC-MS/MS) in persons with bipolar disorder (n=101) and healthy controls (n=80) to investigate if the metabolites correlated with depressive symptoms or to the history of suicidal behavior. Furthermore, we analyzed if genetic variants of the enzyme amino-β-carboxymuconate-semialdehyde-decarboxylase (ACMSD) were associated with the CSF concentrations of PIC and QUIN. We found that CSF KYNA and PIC concentrations, as well as the kynurenine/tryptophan ratio were increased in bipolar disorder compared with controls. CSF PIC concentrations were lower in subjects with a history of suicidal behavior than those without, supporting the hypothesis that low CSF PIC is a marker of vulnerability for suicidality. Bipolar subjects taking antidepressants had higher CSF concentrations of kynurenine and KYNA than subjects not given these medications. A negative association was found between a genetic variant of ACMSD and the ratio of PIC/QUIN, indicating that a polymorphism in ACMSD is associated with excess of QUIN formation at the expense of PIC. The present results confirm that the kynurenine pathway is activated in bipolar disorder, and suggest that shifting the activity of the kynurenine pathway away from QUIN production towards a production of KYNA and PIC might be a beneficial therapeutic strategy.
  •  
45.
  • Xu, Chengai, et al. (author)
  • CSF levels of synaptosomal-associated protein 25 and synaptotagmin-1 in first-episode psychosis subjects.
  • 2020
  • In: IBRO reports. - : Elsevier BV. - 2451-8301. ; 8, s. 136-142
  • Journal article (peer-reviewed)abstract
    • Post-mortem studies consistently show evidence of reduced synaptic protein levels in patients with schizophrenia. Clinically high-risk subjects show a steeper decrease in grey matter thickness and in vitro modeling using patient-derived cells implicate excessive synaptic pruning during neurodevelopment as a part of the schizophrenia pathophysiology. However, it is unclear to what extent synapse elimination is present during various stages of the disease, which is of clinical importance as in a real-world setting most subjects received their first-episode psychosis (FEP) diagnosis not until their mid-twenties. In the present study, we measured cerebrospinal fluid (CSF) concentrations of the two pre-synaptic proteins synaptosomal-associated protein 25 (SNAP-25) and synaptotagmin-1 (SYT-1), both of which are increased in conditions of ongoing synaptic degeneration, in 44 FEP subjects (mean age 29.9 years) and 21 healthy controls (25.9 years) using immunoprecipitation mass spectrometry. Neither protein was found to differ between healthy controls and patients, and they showed no correlation with symptom ratings, cognitive performance or antipsychotic medication. Additional studies in high-risk subjects in the early prodromal phase will be needed to address if excessive synapse destruction occurs before the development of overt psychotic symptoms.
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46.
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