1. |
- Malmqvist, Anna, et al.
(författare)
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Increased peripheral levels of TARC/CCL17 in first episode psychosis patients
- 2019
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Ingår i: Schizophrenia Research. - : ELSEVIER. - 0920-9964 .- 1573-2509. ; 210, s. 221-227
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Tidskriftsartikel (refereegranskat)abstract
- Background: Evidence for a link between the pathophysiology of schizophrenia and the immune system is mounting. Altered levels of chemokines in plasma have previously been reported in patients with schizophrenia under antipsychotic medication. Here we aimed to study both peripheral and central chemokine levels in drugnaive or short-time medicated first episode psychosis (FEP) patients. Method: We analyzed nine chemokines in plasma and CSF from 41 FEP patients and 22 healthy controls using electrochemiluminescence assay. Results: In plasma four chemokines; TARC/CCL17, eotaxin/CCL11, MDC/CCL22, IP-10/CXCL10 and in CSF one chemokine; IP-10/CXCL10 showed reliable detection in N50% of the cases. FEP patients displayed increased levels of TARC/CCL17 in plasma compared to healthy controls, 89.6 (IQR 66.2-125.8) pg/mL compared to 48.6 (IQR 28.0-71.7) pg/mL (p = 0.001). The difference was not attributed to confounding factors. Plasma TARC/CCL17 was not associated with PANSS, CGI or GAF scores, neither with cognitive functions. The chemokines eotaxin/CCL11, MDC/CCL22, IP-10/CXCL10 in plasma and IP-10/CXCL10 in CSF did not differ between FEP patients and controls. Conclusion: In line with a previous study showing that chronic patients with schizophrenia display increased plasma TARC/CCL17 levels, we here found an elevation in FEP patients suggesting a role of TARC/CCL17 in early stages of schizophrenia. The exactmechanism of this involvement is still unknown and future longitudinal studies as well as studies of central and peripheral chemokine levels would be of great interest. (C) 2018 Elsevier B.V. All rights reserved.
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2. |
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3. |
- Shang, Pei, et al.
(författare)
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Identification of cerebrospinal fluid and serum metabolomic biomarkers in first episode psychosis patients
- 2022
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Ingår i: Translational Psychiatry. - : Springer Nature. - 2158-3188. ; 12:1
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Tidskriftsartikel (refereegranskat)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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4. |
- Trepci, Ada, et al.
(författare)
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Quantification of Plasma Kynurenine Metabolites Following One Bout of Sprint Interval Exercise
- 2020
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Ingår i: International Journal of Tryptophan Research. - : SAGE Publications. - 1178-6469. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- The kynurenine pathway of tryptophan degradation produces several neuroactive metabolites suggested to be involved in a wide variety of diseases and disorders, however, technical challenges in reliably detecting these metabolites hampers cross-comparisons. The main objective of this study was to develop an accurate, robust and precise bioanalytical method for simultaneous quantification of ten plasma kynurenine metabolites. As a secondary aim, we applied this method on blood samples taken from healthy subjects conducting 1 session of sprint interval exercise (SIE). It is well accepted that physical exercise is associated with health benefits and reduces risks of psychiatric illness, diabetes, cancer and cardiovascular disease, but also influences the peripheral and central concentrations of kynurenines. In line with this, we found that in healthy old adults (n = 10; mean age 64 years), levels of kynurenine increased 1 hour (P =.03) after SIE, while kynurenic acid (KYNA) concentrations were elevated after 24 hours (P =.02). In contrast, no significant changes after exercise were seen in young adults (n = 10; mean age 24 years). In conclusion, the described method performs well in reliably detecting all the analyzed metabolites in plasma samples. Furthermore, we also detected an age-dependent effect on the degree by which a single intense training session affects kynurenine metabolite levels.
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5. |
- Aeinehband, Shahin, et al.
(författare)
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Cerebrospinal fluid kynurenines in multiple sclerosis : relation to disease course and neurocognitive symptoms
- 2016
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Ingår i: Brain, behavior, and immunity. - : Elsevier. - 0889-1591 .- 1090-2139. ; 51, s. 47-55
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system, with a high rate of neurocognitive symptoms for which the molecular background is still uncertain. There is accumulating evidence for dysregulation of the kynurenine pathway (KP) in different psychiatric and neurodegenerative conditions. We here report the first comprehensive analysis of cerebrospinal fluid (CSF) kynurenine metabolites in MS patients of different disease stages and in relation to neurocognitive symptoms. Levels of tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QUIN) were determined with liquid chromatography mass spectrometry in cell-free CSF. At the group level MS patients (cohort 1; n = 71) did not differ in absolute levels of TRP, KYN, KYNA or QUIN as compared to non-inflammatory neurological disease controls (n = 20). Stratification of patients into different disease courses revealed that both absolute QUIN levels and the QUIN/KYN ratio were increased in relapsing-remitting MS (RRMS) patients in relapse. Interestingly, secondary progressive MS (SPMS) displayed a trend for lower TRP and KYNA, while primary progressive (PPMS) patients displayed increased levels of all metabolites, similar to a group of inflammatory neurological disease controls (n = 13). In the second cohort (n = 48), MS patients with active disease and short disease duration were prospectively evaluated for neuropsychiatric symptoms. In a supervised multivariate analysis using orthogonal projection to latent structures (OPLS-DA) depressed patients displayed higher KYNA/TRP and KYN/TRP ratios, mainly due to low TRP levels. Still, this model had low predictive value and could not completely separate the clinically depressed patients from the non-depressed MS patients. No correlation was evident for other neurocognitive measures. Taken together these results demonstrate that clinical disease activity and differences in disease courses are reflected by changes in KP metabolites. Increased QUIN levels of RRMS patients in relapse and generally decreased levels of TRP in SPMS may relate to neurotoxicity and failure of remyelination, respectively. In contrast, PPMS patients displayed a more divergent pattern more resembling inflammatory conditions such as systemic lupus erythematosus. The pattern of KP metabolites in RRMS patients could not predict neurocognitive symptoms.
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6. |
- Alnaes, Dag, et al.
(författare)
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Brain Heterogeneity in Schizophrenia and Its Association With Polygenic Risk
- 2019
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Ingår i: JAMA psychiatry. - : AMER MEDICAL ASSOC. - 2168-6238 .- 2168-622X. ; 76:7, s. 739-748
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Tidskriftsartikel (refereegranskat)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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7. |
- Balter, Leonie J. T., et al.
(författare)
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Lipopolysaccharide-induced changes in the kynurenine pathway and symptoms of sickness behavior in humans
- 2023
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Ingår i: Psychoneuroendocrinology. - 0306-4530 .- 1873-3360. ; 153
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Tidskriftsartikel (refereegranskat)abstract
- Metabolites of the kynurenine pathway are hypothesized to be implicated in inflammation-associated depression, but there is a lack of experimental studies in humans assessing the kinetics of kynurenine metabolites in relation to experimentally-induced sickness. The aim of the present study was to assess changes in the kynurenine pathway and to explore its relation to symptoms of sickness behavior during an acute experimental immune challenge.This double-blind placebo-controlled randomized cross-over study included 22 healthy human participants (n = 21 both sessions, Mage = 23.4, SD = 3.6, nine women) who received an intravenous injection of 2.0 ng/kg lipopolysaccharide (LPS) and saline (placebo) on two different occasions in a randomized order. Blood samples (0 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h, 7 h post-injection) were analyzed for kynurenine metabolites and inflammatory cytokines. The intensity of symptoms of sickness behavior was assessed using the 10-item Sickness Questionnaire at 0 h, 1.5 h, 3 h, 5 h, and 7 h post-injection.LPS induced significantly lower concentrations of plasma tryptophan (at 2 h, 4 h, 5 h, and 7 h post-injection), kynurenine (at 2 h, 3 h, 4 h, and 5 h post-injection), nicotinamide (at 4 h, 5 h, and 7 h post-injection), and higher levels for quinolinic acid at 5 h post-injection as compared to placebo. LPS did not affect kynurenic acid, 3-hydroxykynurenine, and picolinic acid. The development of the sickness symptoms was largely similar across items, with the highest levels around 1.5–3 h post-injection. Changes in plasma levels of kynurenine metabolites seem to coincide rather than precede or follow changes in subjective sickness. Exploratory analyses indicate that higher Sickness Questionnaire total scores at 1.5–5 h post-injection were correlated with lower kynurenic acid and nicotinamide levels.These results lend further support for LPS-induced changes in the kynurenine pathway, but may not, as interpreted from blood levels, causally link to LPS-induced acute symptoms of sickness behavior. Future research may consider a larger sample to further scrutinize the role of the kynurenine pathway in the sickness response.
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8. |
- Bay-Richter, Cecilie, et al.
(författare)
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A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate receptor in depression and suicidality
- 2015
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Ingår i: Brain, behavior, and immunity. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 0889-1591 .- 1090-2139. ; 43, s. 110-117
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with depression and suicidality suffer from low-grade neuroinflammation. Proinflammatory cytokines activate indoleamine 2,3-dioxygenase, an initial enzyme of the kynurenine pathway. This pathway produces neuroactive metabolites, including quinolinic- and kynurenic acid, binding to the glutamate N-methyl-D-aspartate-receptor, which is hypothesized to be part of the neural mechanisms underlying symptoms of depression. We therefore hypothesized that symptoms of depression and suicidality would fluctuate over time in patients prone to suicidal behavior, depending on the degree of inflammation and kynurenine metabolite levels in the cerebrospinal fluid (CSF). Methods: We measured cytokines and kynurenine metabolites in CSF, collected from suicide attempters at repeated occasions over 2 years (total patient samples n = 143, individuals n = 30) and healthy controls (n = 36). The association between the markers and psychiatric symptoms was assessed using the Montgomery Asberg Depression Rating Scale and the Suicide Assessment Scale. Results: Quinolinic acid was increased and kynurenic acid decreased over time in suicidal patients versus healthy controls. Furthermore, we found a significant association between low kynurenic acid and severe depressive symptoms, as well as between high interleukin-6 levels and more severe suicidal symptoms. Conclusions: We demonstrate a long-term dysregulation of the kynurenine pathway in the central nervous system of suicide attempters. An increased load of inflammatory cytokines was coupled to more severe symptoms. We therefore suggest that patients with a dysregulated kynurenine pathway are vulnerable to develop depressive symptoms upon inflammatory conditions, as a result the excess production of the NMDA-receptor agonist quinolinic acid. This study provides a neurobiological framework supporting the use of NMDA-receptor antagonists in the treatment of suicidality and depression. (C) 2014 Elsevier Inc. All rights reserved.
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9. |
- Becklén, Meneca, et al.
(författare)
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Plasma bilirubin levels are reduced in first-episode psychosis patients and associates to working memory and duration of untreated psychosis.
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)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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10. |
- Carlborg, Andreas, et al.
(författare)
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CSF kynurenic acid and suicide risk in schizophrenia spectrum psychosis
- 2013
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Ingår i: Psychiatry Research. - : Elsevier BV. - 0165-1781 .- 1872-7123. ; 205:1-2, s. 165-7
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Tidskriftsartikel (refereegranskat)abstract
- Relationships between concentrations of cerebrospinal fluid (CSF) kynurenic acid (KYNA) and suicidal behavior were evaluated in 59 patients with psychosis after 22 years of follow-up. Three patients died from suicide and nine patients had a history of attempted suicide. Patients with attempted suicide had significantly lower concentrations of CSF KYNA.
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11. |
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12. |
- Eren, Feride, et al.
(författare)
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Immunological protein profiling of first-episode psychosis patients identifies CSF and blood biomarkers correlating with disease severity
- 2023
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Ingår i: Brain, behavior, and immunity. - : Elsevier. - 0889-1591 .- 1090-2139. ; 111, s. 376-385
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Tidskriftsartikel (refereegranskat)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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13. |
- Erhardt, Sophie, et al.
(författare)
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Connecting Inflammation with Glutamate Agonism in Suicidality
- 2013
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Ingår i: Neuropsychopharmacology. - : Nature Publishing Group: Open Access Hybrid Model Option A. - 0893-133X .- 1740-634X. ; 38:5, s. 743-752
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Tidskriftsartikel (refereegranskat)abstract
- The NMDA-receptor antagonist ketamine has proven efficient in reducing symptoms of suicidality, although the mechanisms explaining this effect have not been detailed in psychiatric patients. Recent evidence points towards a low-grade inflammation in brains of suicide victims. Inflammation leads to production of quinolinic acid (QUIN) and kynurenic acid (KYNA), an agonist and antagonist of the glutamatergic N-methyl-D-aspartate (NMDA) receptor, respectively. We here measured QUIN and KYNA in the cerebrospinal fluid (CSF) of 64 medication-free suicide attempters and 36 controls, using gas chromatography mass spectrometry and high-performance liquid chromatography. We assessed the patients clinically using the Suicide Intent Scale and the Montgomery Asberg Depression Rating Scale (MADRS). We found that QUIN, but not KYNA, was significantly elevated in the CSF of suicide attempters (Pandlt;0.001). As predicted, the increase in QUIN was associated with higher levels of CSF interleukin-6. Moreover, QUIN levels correlated with the total scores on Suicide Intent Scale. There was a significant decrease of QUIN in patients who came for follow-up lumbar punctures within 6 months after the suicide attempt. In summary, we here present clinical evidence of increased QUIN in the CSF of suicide attempters. An increased QUIN/KYNA quotient speaks in favor of an overall NMDA-receptor stimulation. The correlation between QUIN and the Suicide Intent Scale indicates that changes in glutamatergic neurotransmission could be specifically linked to suicidality. Our findings have important implications for the detection and specific treatment of suicidal patients, and might explain the observed remedial effects of ketamine. Neuropsychopharmacology (2013) 38, 743-752; doi:10.1038/npp.2012.248; published online 9 January 2013
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14. |
- Erhardt, Sophie
(författare)
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Importance of endogenous kynurenic acid in brainm catecholaminergic processes and in the pathophysiology of schizophrenia
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Kynurenic acid is a metabolite of tryptophan and the only known naturally occurring NMethylD-Aspartic acid (NMDA)-receptor antagonist (at the co-agonist glycine site) in the human brain. The aim of the present work was to investigate the physiological and pharmacological significance of endogenous kynurenic acid as well as its putative pathophysiological implications. For this purpose in vivo extracellular single unit recording from rat brain catecholamine neurons were used. An inhibitor of kynurenine 3-hydroxylase (PNU 156561A) was administered i.v. (40 mg/kg; 3-9 hours before the electrophysiological experiment) to cause an elevation of endogenous kynurenic acid levels. This effect was mediated by blockade of an alternative pathway for the precursor of kynurenine, thereby promoting the synthesis of kynurenic acid. After each experiment, the brains were rapidly taken out an analysis of kynurenic acid were performed using an isocratic reversed-phase HPLC system. Pharmacologically induced elevation (3-5 fold) of endogenous kynurenic acid levels was associated with increased firing rate and burst activity and a decreased regularity of firing of midbrain dopamine (DA) neurons. These actions were reversed by treatment with D-cycloscrine (128 mg/kg iv., 5 min), an agonist at the glycine site of the NMDA receptor. The effects of PNU 156561A on the neuronal activity of midbrain DA neurons are in all probability induced by a blockade of NMDA receptors by kynurenic acid and mediated via inhibition of GABAergic afferents. The GABA A-agonist muscimol produces a paradoxical hyperactivity of substantia nigra (SN) DA neurons. Pretreatment with PNU 156561A, producing an increase in endogenous kynurenic acid, as well as systemically administered MK-801 or intracerebroventricular administration of kynurenic acid clearly antagonized this excitatory action of muscimol. However, in rats with elevated levels of endogenous kynurenic acid muscimol's excitatory action was reversed into a pure inhibitory response. Our results suggest an excitatory glutamatergic component in the actions of muscimol on SN DA neurons. Previous studies have shown that systemically administered nicotine is associated with an activation of rat midbrain DA neurons and noradrenergic (NA) neurons in the locus coeruleus (LC). Elevation of endogenous kynurenic acid by PNU 156561A was found to antagonize the nicotine-induced (25-200 µg/kg i.v.) increase in firing rate of LC NA neurons. Similarly, the increase in firing rate and burst firing activity of ventral tegmental area (VTA) DA neurons elicited by nicotine (1.5-400 µg/kg i.v.) was antagonized but also. reversed into an inhibitory response by elevated levels of kynurenic acid. These antagonistic actions induced by PNU 156561A pretreatment were prevented by administration of D-cycloserine (128 mg/kg i.v., 5 min). A novel finding in this study is that the activation of VTA DA neurons by nicotine was preceded a short-lasting inhibition in firing rate. This inhibitory action of nicotine was antagonized by pretreatment with the selective GABAbeta receptor antagonist CGP 35348 (200 mg/kg i.v., 3 min). In addition, CGP 35348 also facilitated the nicotine-induced increase in burst firing activity of VTA DA neurons. We propose that nicotine exerts both excitatory and inhibitory actions of VTA DA neurons and that these effects are related to release of glutamate in 1, re and GABA, respectively. Present experimental data support a contribution of endogenous kynurenic acid in brain glutamatergic neurotransmission. Further, our findings demonstrate that a moderate elevation in rain kynurenic acid levels produces dysregulation of neuronal firing of midbrain DA neurons, similarly to the effects of systemic administration of the NMDA receptor antagonists phencyclidine (PCP, angel dust) or ketamine. Schizophrenia is thought to be mediated, at least in part, by dysregulation of the midbrain DA pathways and interestingly, both PCP and ketamine induce schizophrenia-like positive and negative symptoms as well as cognitive dysfunction in healthy volunteers, and furthermore, aggravate psychotic symptoms in schizophrenic patients. Based upon these findings we investigated the endogenous levels of kynurenic acid in cerebrospinal fluid (CSF) in patients with schizophrenia. CSF levels of kynurenic acid from 28 schizophrenic patients (25 of whom were drug- naive) and 17 healthy volunteers were analyzed. Kynurenic acid was detected in all controls, with little inter-individual variation (0.97 ±0.07 nM). In patients suffering from schizophrenia, CSF levels of kynurenic acid levels were higher than in volunteers (1.67 ±0.27 nM; p=0.038, Mann-Whitney U-test) and the variation between individuals was larger, with a maximum value of 6.8 nM. These results indicate a contribution of kynurenic acid in the pathophysiology of schizophrenia.
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15. |
- Erhardt, Sophie, et al.
(författare)
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Kynurenic acid levels ae elevated in the cerebrospinal fluid of patients with schizophrenia
- 2001
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Ingår i: Neuroscience Letters. - 0304-3940 .- 1872-7972. ; 313:1-2, s. 96-98
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Tidskriftsartikel (refereegranskat)abstract
- Kynurenic acid is an endogenous glutamate antagonist with a preferential action at the glycine-site of the N-methyl D-aspartate-receptor. Mounting evidence indicate that the compound is significantly involved in basal neurophysiological processes in the brain. In the present investigation, cerebrospinal fluid (CSF) level of kynurenic acid was analyzed in 28 male schizophrenic patients and 17 male healthy controls by means of high pressure liquid chromatography and fluorescence detection. Schizophrenic patients showed elevated CSF levels of kynurenic acid (1.67 ▒ 0.27 nM) compared to the control group (0.97 ▒ 0.07 nM). Furthermore, CSF levels of kynurenic acid in schizophrenic patients were also found to correlate with age. The present finding is indicative of a contribution of kynurenic acid in the pathogenesis of schizophrenia. ⌐ 2001 Elsevier Science Ireland Ltd. All rights reserved.
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16. |
- Erhardt, Tobias, et al.
(författare)
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High-resolution aerosol data from the top 3.8kyr of the East Greenland Ice coring Project (EGRIP) ice core
- 2023
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Ingår i: Earth System Science Data. - 1866-3508. ; 15:11, s. 5079-5091
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Tidskriftsartikel (refereegranskat)abstract
- Here we present the high-resolution continuous flow analysis (CFA) data from the top 479m of the East Greenland Ice coring Project (EGRIP) ice core covering the past 3.8kyr. The data consist of 1mm depth-resolution profiles of calcium, sodium, ammonium, nitrate, and electrolytic conductivity as well as decadal averages of these profiles. The nominally 1mm data represent an oversampling of the record as the true resolution is limited by the analytical setup to approximately 1cm. Alongside the data we provide a description of the measurement setup, procedures, the relevant references for the specific methods as well as an assessment of the precision of the measurements, the sample-to-depth assignment, and the depth and temporal resolution of the data set. The error in absolute depth assignment of the data may be on the order of 2cm; however, relative depth offsets between the records of the individual species are only on the order of 1mm. The presented data have sub-annual resolution over the entire depth range and have already formed part of the data for an annually layer-counted timescale for the EGRIP ice core used to improve and revise the multi-core Greenland ice-core chronology (GICC05) to a new version, GICC21 . The data are available in full 1mm resolution and decadal averages on PANGAEA (10.1594/PANGAEA.945293, ).
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17. |
- Haroon, Humza, et al.
(författare)
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Cerebrospinal fluid proteomic signatures are associated with symptom severity of first-episode psychosis
- 2024
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Ingår i: Journal of Psychiatric Research. - : Elsevier. - 0022-3956 .- 1879-1379. ; 171, s. 306-315
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Tidskriftsartikel (refereegranskat)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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18. |
- Isung, Josef, et al.
(författare)
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Differential effects on blood and cerebrospinal fluid immune protein markers and kynurenine pathway metabolites from aerobic physical exercise in healthy subjects
- 2021
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Mounting evidence shows that physical exercise modulates systemic inflammation. However, its effect on cerebrospinal fluid (CSF) immune-marker profiles in man are largely unknown. We here report a study on healthy subjects (n=27, males=12, mean age 28.7, range 22-52) allocated to either an acute exercise setting over four consecutive days, or a training intervention over 4 weeks. Paired plasma and CSF samples collected at baseline, after 7 days of exercise abstention, and the day after completion of the exercise interventions, were analyzed for protein inflammation markers using a multiplex proximity extension assay and neurotransmitters and kynurenine pathway (KP) metabolites using liquid chromatography, respectively. Routine cell counts, and albumin, immunoglobulin G and neurofilament light chain concentrations in CSF remained unchanged in both paradigms, while several inflammatory proteins became upregulated after acute exercise. However, only changes in three CSF (vascular endothelial growth factor-A, interleukin-7 and matrix metalloproteinase-10) and 12 plasma proteins reached significance levels after adjustment for multiple comparisons and exclusion of less stable proteins. Similarly, KP metabolites only changed among participants after acute exercise, while neurotransmitter levels, except for increased CSF serine, remained stable. Both in plasma and CSF changes in KP metabolites and inflammatory proteins correlated, suggesting that these processes are functionally linked. These findings suggest that acute aerobic physical exercise affects immune markers and KP metabolites systemically and in the CSF.
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19. |
- Janelidze, Shorena, et al.
(författare)
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Altered chemokine levels in the cerebrospinal fluid and plasma of suicide attempters
- 2013
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Ingår i: Psychoneuroendocrinology. - : Elsevier. - 0306-4530 .- 1873-3360. ; 38:6, s. 853-862
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Tidskriftsartikel (refereegranskat)abstract
- Chemokines constitute a class of small inflammatory proteins that control the chemotaxis of leukocytes. They are also present in the central nervous system (CNS) and contribute to diverse physiological functions, such as the regulation of cell migration, axonal growth and neuronal survival. It is to date not known whether chemokines in the CNS are affected in psychiatric disorders. In this study, chemokine levels were measured in the cerebrospinal fluid (CSF) of 137 psychiatric patients in conjunction to a suicide attempt, and 43 healthy controls. A subgroup of patients (n = 42) was followed up with blood samples 12 years after the initial CSF collection, when they did not show suicidal behavior. The follow-up chemokine levels were compared to those of psychiatric patients (n = 17) who had never attempted suicide. Ultrasensitive chemokine multiplex immunoassay was used to quantify eotaxin-1 (CCL11), interferon gamma-induced protein-10 (IP-10, CXCL10), macrophage inflammatory protein-1 beta (MIP-1 beta, CCL4), monocyte chemotactic protein-1 (MCP-1, CCL2), MCP-4 (CCL13) and thymus and activation regulated chemokine (TARC, CCL17). Patients were diagnosed using DSM-III-R/DSM-IV, and assessed using the Comprehensive Psychopathological Rating Scale (CPRS), including subscales, and the Suicidal Intent Scale (SIS). CSF eotaxin-1, MIP-1 beta, MCP-1, MCP-4 and TARC were significantly lower in suicide attempters than in healthy controls. Low chemokine levels were specifically associated with psychotic symptoms and pain. In the samples collected at follow-up, TARC was significantly lower in suicide attempters compared to psychiatric patients who had never attempted suicide. We also found a positive correlation between blood TARC and brain-derived neurotrophic factor (BDNF) levels. Our study thus provides evidence of reduced chemokine levels in suicide attempters, both in the acute suicidal setting, and at long-term, compared to non-attempters. These results warrant future studies on the detailed neurobiological functions of chemokines in psychiatric patients. (C) 2012 Elsevier Ltd. All rights reserved.
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20. |
- Janelidze, Shorena, et al.
(författare)
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IL-8 is associated with anxiety in suicidal patients: genotypes and biological measures in cerebrospinal fluid and plasma
- 2015
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Ingår i: Acta Psychiatrica Scandinavica. - : Wiley. - 0001-690X .- 1600-0447. ; 131:4, s. 269-278
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Tidskriftsartikel (refereegranskat)abstract
- Objective Recent studies indicate that inflammation may play a role in the pathophysiology of suicidality. Interleukin-8 (IL-8) is a chemokine that in addition to its function in the immune system also exert neuroprotective properties. The involvement of this chemokine in neuropsychiatric conditions is incompletely known. Method We measured plasma and cerebrospinal fluid (CSF) IL-8, as well as the genotype frequency of a single nucleotide polymorphism (-251A/T, rs4073) in the promoter region of the IL8 gene, in suicide attempters (n = 206) and healthy controls (n = 578). Results Plasma and CSF levels of IL-8 were significantly lower in suicide attempters with anxiety than in healthy controls. IL-8 in both plasma and CSF correlated negatively with symptoms of anxiety. Compared with the population-based cohort, the IL-8-251T allele was more prevalent among female suicide attempters. Furthermore, suicide attempters carrying this allele showed more severe anxiety. This correlative study warrants further mechanistic studies on the effects of IL-8 in the central nervous system. Conclusion We suggest that IL-8 might be involved in the biological mechanisms mediating resilience to anxiety. Thus, our findings highlight the chemokine IL-8 as a potential target for future development of anti-anxiety treatments and suicide prevention.
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21. |
- Kaufmann, Tobias, et al.
(författare)
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Common brain disorders are associated with heritable patterns of apparent aging of the brain
- 2019
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Ingår i: Nature Neuroscience. - : Nature Publishing Group. - 1097-6256 .- 1546-1726. ; 22:10, s. 1617-
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Tidskriftsartikel (refereegranskat)abstract
- Common risk factors for psychiatric and other brain disorders are likely to converge on biological pathways influencing the development and maintenance of brain structure and function across life. Using structural MRI data from 45,615 individuals aged 3-96 years, we demonstrate distinct patterns of apparent brain aging in several brain disorders and reveal genetic pleiotropy between apparent brain aging in healthy individuals and common brain disorders.
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22. |
- Kegel, Magdalena E., et al.
(författare)
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Imbalanced Kynurenine Pathway in Schizophrenia
- 2014
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Ingår i: International Journal of Tryptophan Research. - : Libertas Academica. - 1178-6469. ; 7, s. 15-22
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Tidskriftsartikel (refereegranskat)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.
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23. |
- Kegel, Magdalena E., et al.
(författare)
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Kynurenic acid and psychotic symptoms and personality traits in twins with psychiatric morbidity
- 2017
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Ingår i: Psychiatry Research. - : Elsevier. - 0165-1781 .- 1872-7123. ; 247, s. 105-112
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Tidskriftsartikel (refereegranskat)abstract
- Increased cytokines and kynurenic acid (KYNA) levels in cerebrospinal fluid (CSF) have been reported in patients with schizophrenia and bipolar disorder. The aim of the present study was to investigate cytokines and kynurenines in the CSF of twin pairs discordant for schizophrenia or bipolar disorder and to study these CSF markers in relation to psychotic symptoms and personality traits. CSF levels of tryptophan (TRP), KYNA, quinolinic acid (QUIN), interleukin (IL)-6, IL-8 and tumor necrosis factor-alpha (TNF-α) were analyzed in 23 twins with schizophrenia or bipolar disorder, and in their not affected co-twins. Ratings of psychotic symptoms and personality traits were made using the Scales for Assessment of Negative and Positive symptoms, the Structured Clinical Interview for DSM-IV - Axis II Disorders, and the Schizotypal Personality Questionnaire - Brief. A total score for psychotic symptoms and personality traits was constructed for analysis. CSF KYNA was associated with the score for psychotic symptom and personality traits. TNF-α and IL-8 were associated, and the intra-pair differences scores of TNF-α and IL-8 were highly correlated. Intraclass correlations indicated genetic influences on CSF KYNA, TRP, IL-8 and TNF-α. The association between KYNA and psychotic symptoms further supports a role of KYNA in psychotic disorders.
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24. |
- Koskuvi, Marja, et al.
(författare)
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Lower complement C1q levels in first-episode psychosis and in schizophrenia
- 2024
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Ingår i: Brain, Behavior, and Immunity. - : Elsevier. - 0889-1591 .- 1090-2139. ; 117, s. 313-319
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Tidskriftsartikel (refereegranskat)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.
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25. |
- Krasikova, Raisa, et al.
(författare)
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Synthesis and Preclinical Evaluation of 6-[18F]Fluorine-α-methyl-l-tryptophan, a Novel PET Tracer for Measuring Tryptophan Uptake
- 2020
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Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 11:12, s. 1756-1761
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Tidskriftsartikel (refereegranskat)abstract
- The positron emission tomography (PET) radioligand α-[11C]methyl-l-tryptophan ([11C]AMT) has been used to assess tryptophan metabolism in cancer, epilepsy, migraine, and autism. Despite its extensive application, the utility of this tracer is currently hampered by the short half-life of the radionuclide used for its labeling (11C, t1/2 = 20.4 min). We herein report the design, synthesis, radiolabeling, and initial in vivo evaluation of a fluorine-18 (18F, t 1/2 = 109.7 min) labeled analogue that is fluorinated in the 6-position of the aromatic ring ([18F]6-F-AMTr). In a head-to-head comparison between [18F]6-F-AMTr and [11C]AMT in mice using PET, peak brain radioactivity, regional brain distribution, and kinetic profiles were similar between the two tracers. [18F]6-F-AMTr was however not a substrate for IDO1 or TPH as determined in in vitro enzymatic assays. The brain uptake of the tracer is thus more likely related to LAT1 transport over the blood-brain barrier than metabolism along the serotonin or kynurenine pathways.
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26. |
- Larsson, Cornelia, et al.
(författare)
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Facial affect recognition in first-episode psychosis is impaired but not associated with psychotic symptoms.
- 2022
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Ingår i: Heliyon. - : Elsevier. - 2405-8440. ; 8:9
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Tidskriftsartikel (refereegranskat)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.
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27. |
- Lee, Maria, et al.
(författare)
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Cognitive Function and Variability in Antipsychotic Drug-Naive Patients With First-Episode Psychosis : A Systematic Review and Meta-Analysis.
- 2024
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Ingår i: JAMA psychiatry. - 2168-6238.
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Tidskriftsartikel (refereegranskat)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.
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28. |
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29. |
- Lee, Maria, et al.
(författare)
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No association between cortical dopamine D2 receptor availability and cognition in antipsychotic-naive first-episode psychosis
- 2021
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Ingår i: NPJ SCHIZOPHRENIA. - : Springer Nature. - 2334-265X. ; 7:1
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Tidskriftsartikel (refereegranskat)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.
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30. |
- Linderholm, Klas R, et al.
(författare)
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Increased Levels of Kynurenine and Kynurenic Acid in the CSF of Patients With Schizophrenia
- 2012
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Ingår i: Schizophrenia Bulletin. - : Oxford University Press. - 0586-7614 .- 1745-1701. ; 38:3, s. 426-432
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Tidskriftsartikel (refereegranskat)abstract
- Background: The kynurenic acid (KYNA) hypothesis for schizophrenia is partly based on studies showing increased brain levels of KYNA in patients. KYNA is an endogenous metabolite of tryptophan (TRP) produced in astrocytes and antagonizes N-methyl-D-aspartate and alpha7* nicotinic receptors. Methods: The formation of KYNA is determined by the availability of substrate, and hence, we analyzed KYNA and its precursors, kynurenine (KYN) and TRP, in the cerebrospinal fluid (CSF) of patients with schizophrenia. CSF from male patients with schizophrenia on olanzapine treatment (n = 16) was compared with healthy male volunteers (n = 29). Results: KYN and KYNA concentrations were higher in patients with schizophrenia (60.7 +/- 4.37nM and 2.03 +/- 0.23nM, respectively) compared with healthy volunteers (28.6 +/- 1.44nM and 1.36 +/- 0.08nM, respectively), whereas TRP did not differ between the groups. In all subjects, KYN positively correlated to KYNA. Conclusion: Our results demonstrate increased levels of CSF KYN and KYNA in patients with schizophrenia and further support the hypothesis that KYNA is involved in the pathophysiology of schizophrenia.
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31. |
- Lindqvist, Daniel, et al.
(författare)
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Interleukin-6 Is Elevated in the Cerebrospinal Fluid of Suicide Attempters and Related to Symptom Severity
- 2009
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Ingår i: BIOLOGICAL PSYCHIATRY. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 66:3, s. 287-292
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Tidskriftsartikel (refereegranskat)abstract
- Background: Depressive disorders are associated with immune system alterations that can be detected in the blood. Cytokine concentrations in cerebrospinal fluid (CSF) and their relationship to aspects of suicidality have previously not been investigated. Methods: We measured interleukin-1 beta interleukin-6 (IL-6), interleukin-8, and tumor necrosis factor-a (TNF-alpha) in CSF and plasma of suicide attempters (n = 63) and healthy control subjects (n = 47). Patients were classified according to diagnosis and violent or nonviolent suicide attempt. We evaluated suicidal ideation and depressive symptoms using the Suicide Assessment Scale and the Montgomery-Asberg Depression Rating Scale (MADRS). We also analyzed the relation between cytokines and monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in CSF, as well as the integrity of the blood-brain barrier as reflected by the CSF:serum albumin ratio. Results: IL-6 in CSF was significantly higher in suicide attempters than in healthy control subjects. Patients who performed violent suicide attempts displayed the highest IL-6. Furthermore, there was a significant positive correlation between MANS scores and CSF IL-6 levels in all patients. IL-6 and TNF-a correlated significantly with 5-HIAA and HVA in CSF, but not with MHPG. Cytokine levels in plasma and CSF were not associated, and patients with increased blood-brain barrier permeability did not exhibit elevated cytokine levels. Conclusions: We propose a role for CSF IL-6 in the symptomatology of suicidal behavior, possibly through mechanisms involving alterations of dopamine and serotonin metabolism.
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32. |
- Millischer, Vincent, et al.
(författare)
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Twelve-week physical exercise does not have a long-lasting effect on kynurenines in plasma of depressed patients
- 2017
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Ingår i: Neuropsychiatric Disease and Treatment. - : Dove Medical Press. - 1176-6328 .- 1178-2021. ; 13, s. 967-972
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Tidskriftsartikel (refereegranskat)abstract
- Background: Physical exercise has well-characterized positive effects on depressive symptoms. The underlying biologic mechanisms are, however, far from established. A recently discovered mechanism has linked the enhanced conversion of kynurenine to kynurenic acid (KYNA) to an increased resilience toward stress-induced depression in mice. The aim of this study was to translate these findings to humans.Materials and methods: Kynurenine and KYNA levels were measured by high-performance liquid chromatography in plasma samples from 117 patients affected by mild-to-moderate depression before and within a week after a 12-week training period at three different intensities. The patients were part of the Regassa study.Results: No differences in plasma levels of kynurenine and KYNA or in their ratio could be detected between before and after training. No effect of the intensity group could be observed. No correlation with the improvement in cardiovascular fitness (Åstrand score) or the improvement in mood (Montgomery Åsberg Depression Rating Scale score) could be observed.Limitations: As the Regassa study is based on an intention-to-treat protocol, the exact time and the exact intensity of the physical exercise are not known. Analyses of pulse data as well as personal interviews, however, were used to control the exercise protocols. Furthermore, the observations reflect chronic changes.Conclusion: Physical exercise positively affects mood and cardiovascular fitness, but does not lead to long-lasting changes in plasma levels of kynurenine and KYNA in patients affected by mild-to-moderate depression.
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33. |
- Mätlik, Kärt, et al.
(författare)
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Elevated endogenous GDNF induces altered dopamine signalling in mice and correlates with clinical severity in schizophrenia.
- 2022
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Ingår i: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578.
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Tidskriftsartikel (refereegranskat)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.
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34. |
- Nilsson, Linda K, et al.
(författare)
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Cerebrospinal fluid kynurenic acid in male and female controls - Correlation with monoamine metabolites and influences of confounding factors
- 2007
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Ingår i: Journal of Psychiatric Research. - : Elsevier BV. - 0022-3956 .- 1879-1379. ; 41:1-2, s. 144-151
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Tidskriftsartikel (refereegranskat)abstract
- The concentrations of the tryptophan metabolite kynurenic acid (KYNA) and the monoamine metabolites homovanillic acid (HVA), 5-hydroxy-indoleacetic acid (5-HIAA) and 4-hydroxy-3-methoxyphenylglycol (HMPG) were determined in the cerebrospinal fluid (CSF) from 43 healthy volunteers (30 males and 13 females). Healthy female controls displayed higher CSF concentration of KYNA (1.91 nM ± 0.20) compared to healthy male controls (1.06 nM ± 0.07) and lower CSF levels of HMPG (39.2 nM ± 2.0 and 43.4 ± 1.2, respectively). CSF levels of HVA and 5-HIAA did not differ between females (181.3 nM ± 21.9 and 93.7 nM ± 11.4, respectively) and males (138.9 nM ± 12.6 and 74.8 nM ± 5.9, respectively). Positive intercorrelations were found between CSF KYNA, HVA and 5-HIAA while CSF content of HMPG did not correlate with KYNA or the other monoamine metabolites in CSF. A negative correlation was found between back length and CSF concentrations of KYNA, HVA and 5-HIAA and also between CSF KYNA levels and body height. The results of the present study suggest that concentrations of KYNA and the monoamine metabolites in CSF from healthy controls are dependent on gender and back length, which must be taken in consideration when analysing mixed groups of men and women. The higher KYNA concentration found in female controls compared to male might be attributed to a shorter back in women compared to men. Furthermore, these findings suggest that increased KYNA formation is associated with an increased dopamine and serotonin turnover. © 2005 Elsevier Ltd. All rights reserved.
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35. |
- Nilsson-Todd, Linda K, et al.
(författare)
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Cerebrospinal fluid kynurenic acid in male patients with schizophrenia - Correlation with monoamine metabolites
- 2007
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Ingår i: Acta Neuropsychiatrica. - : Cambridge University Press (CUP). - 0924-2708 .- 1601-5215. ; 19:1, s. 45-52
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Tidskriftsartikel (refereegranskat)abstract
- Background: The tryptophan metabolite kynurenic acid (KYNA) is an endogenous glutamate/nicotinic receptor antagonist. Previous studies have shown that the concentration of the compound is increased in cerebrospinal fluid (CSF) of patients with schizophrenia. Furthermore, it has been found that the CSF concentration of KYNA is positively correlated to CSF concentrations of the monoamine metabolites homovanillic acid (HVA) and 5-hydroxy indoleacetic acid (5-HIAA) in healthy control subjects. Objectives: To study the correlations between KYNA and the monoamine metabolites HVA, 5-HIAA and 4-hydroxy-3- methoxyphenylglycol (HMPG) in CSF of male patients (n = 53, ranging from 20 to 48 years of age) with verified schizophrenia. Methods: CSF was obtained by lumbar puncture, and KYNA analysis was performed with an isocratic reversed-phase high-performance liquid chromatography system connected to a fluorescence detector. HVA, 5-HIAA and HMPG concentrations were measured by mass fragmentography with deuterium-labelled internal standards. Results: Positive intercorrelations were found between CSF KYNA, HVA and 5-HIAA, while CSF content of HMPG did not correlate to KYNA or any of the monoamine metabolites in CSF. Conclusion: The results of this study suggest that increased KYNA formation is associated with an increased dopamine and serotonin turnover in male patients with schizophrenia. © 2007 Blackwell Munksgaard.
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36. |
- Olsson, Sara K, et al.
(författare)
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Cerebrospinal fluid kynurenic acid is associated with manic and psychotic features in patients with bipolar I disorder.
- 2012
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Ingår i: Bipolar disorders. - : Wiley. - 1399-5618 .- 1398-5647. ; 14:7, s. 719-26
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Tidskriftsartikel (refereegranskat)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.
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37. |
- Olsson, Sara K., et al.
(författare)
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Elevated levels of kynurenic acid in the cerebrospinal fluid of patients with bipolar disorder
- 2010
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Ingår i: Journal of Psychiatry & Neuroscience. - : CMA Joule Inc.. - 1180-4882 .- 1488-2434. ; 35:3, s. 195-199
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Tidskriftsartikel (refereegranskat)abstract
- 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 functiona We measured the levels of KYNA in the cerebrospinal fluid T vSyU 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] cad, va dad, nM, SEM cacln p = 0.002. The levels of KYNA were positively correlated with age among bipolar patients but not healthy volunteersa Limitations: The influence of ongoing drug treatment among patients cannot be ruled outa We conducted our study during the euthymic phase of the diseasea Conclusion: Brain KYNA levels are increased in euthymic men with bipolar disorder. In addition, KYNA levels increased with age in these patientsa 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.
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38. |
- Orhan, Funda, et al.
(författare)
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CSF dopamine is elevated in first-episode psychosis and associates to symptom severity and cognitive performance.
- 2023
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Ingår i: Schizophrenia Research. - 0920-9964 .- 1573-2509. ; 257, s. 34-40
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Tidskriftsartikel (refereegranskat)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.
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39. |
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40. |
- Paul, Elisabeth, 1991-, et al.
(författare)
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Peripheral and central kynurenine pathway abnormalities in major depression
- 2022
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Ingår i: Brain, behavior, and immunity. - : Academic Press Inc - Elsevier Science. - 0889-1591 .- 1090-2139. ; 101, s. 136-145
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Tidskriftsartikel (refereegranskat)abstract
- Considerable data relate major depressive disorder (MDD) with aberrant immune system functioning. Pro inflammatory cytokines facilitate metabolism of tryptophan along the kynurenine pathway (KP) putatively resulting in reduced neuroprotective and increased neurotoxic KP metabolites in MDD, in addition to modulating metabolic and immune function. This central nervous system hypothesis has, however, only been tested in the periphery. Here, we measured KP-metabolite levels in both plasma and cerebrospinal fluid (CSF) of depressed patients (n = 63/36 respectively) and healthy controls (n = 48/33). Further, we assessed the relation between KP abnormalities and brain-structure volumes, as well as body mass index (BMI), an index of metabolic disturbance associated with atypical depression. Plasma levels of picolinic acid (PIC), the kynurenic/quinolinic acid ratio (KYNA/QUIN), and PIC/QUIN were lower in MDD, but QUIN levels were increased. In the CSF, we found lower PIC in MDD. Confirming previous work, MDD patients had lower hippocampal, and amygdalar volumes. Hippocampal and amygdalar volumes were correlated positively with plasma KYNA/QUIN ratio in MDD patients. BMI was increased in the MDD group relative to the control group. Moreover, BMI was inversely correlated with plasma and CSF PIC and PIC/QUIN, and positively correlated with plasma QUIN levels in MDD. Our results partially confirm previous peripheral KP findings and extend them to the CSF in MDD. We present the novel finding that abnormalities in KP metabolites are related to metabolic disturbances in depression, but the relation between KP metabolites and depression-associated brain atrophy might not be as direct as previously hypothesized.
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41. |
- Pils, Marlene, et al.
(författare)
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Disrupted-in-schizophrenia 1 (DISC1) protein aggregates in cerebrospinal fluid are elevated in first-episode psychosis patients.
- 2023
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Ingår i: Psychiatry and Clinical Neurosciences. - 1323-1316 .- 1440-1819.
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Tidskriftsartikel (refereegranskat)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.
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42. |
- Plavén-Sigray, Pontus, et al.
(författare)
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Thalamic dopamine D2-receptor availability in schizophrenia : a study on antipsychotic-naive patients with first-episode psychosis and a meta-analysis.
- 2022
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Ingår i: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 27:2, s. 1233-1240
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Tidskriftsartikel (refereegranskat)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.
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43. |
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44. |
- Schalling, Martin, et al.
(författare)
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Nya rön om schizofreni kan ge ny diagnostik och behandling
- 2015
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Ingår i: Läkartidningen. - : Läkartidningen Förlag. - 0023-7205 .- 1652-7518. ; 112
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Forskningsöversikt (övrigt vetenskapligt/konstnärligt)abstract
- Remarkable progress has been made in the understanding of schizophrenia in the past few years. A driving force has been genome wide association studies that have now led to the identification of over 100 vulnerability loci, implicating functions in the immune system, calcium signaling as well as dopamine and glutamate transmission. In coupling the genetic information to functional data sets from imaging and cognitive studies there is a promise of developing radically improved understanding of schizophrenia, and in some cases new therapies based on immune modulation. As we develop more knowledge and better therapies there will likely be a reduction in stigmatization that is a very real problem for those affected and their families.
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45. |
- Schwieler, Lilly, et al.
(författare)
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A novel, robust method for quantification of multiple kynurenine pathway metabolites in the cerebrospinal fluid
- 2020
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Ingår i: Bioanalysis. - : Future Science Ltd. - 1757-6180 .- 1757-6199. ; 12:6, s. 379-392
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Kynurenine metabolites are potential modulators of psychiatric disease. We aimed to develop a highly sensitive biochemical analysis of cerebrospinal fluid (CSF) tryptophan (TRP) metabolites, to investigate the stability of metabolites and to confirm our previous findings of aberrant CSF quinolinic acid (QUIN) and picolinic acid (PIC) in suicide attempters using this method. Methodology & results: Ten CSF TRP metabolites were analyzed with ultraperformance LC-MS/MS. The method showed small intra- and interassay variation. Metabolites were stable following freeze-thaw cycles. A decreased CSF PIC/QUIN ratio was found in suicide attempters. Conclusion: The feasibility of reliably determining CSF TRP metabolites were demonstrated, including separation of the two isomers PIC and nicotinic acid (NA) and the finding of a reduced PIC/QUIN ratio replicated in suicide attempters.
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46. |
- Schwieler, Lilly, et al.
(författare)
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Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia - significance for activation of the kynurenine pathway.
- 2015
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Ingår i: Journal of Psychiatry & Neuroscience. - : CMA-CANADIAN MEDICAL ASSOC. - 1180-4882 .- 1488-2434. ; 40:2, s. 126-13
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Tidskriftsartikel (refereegranskat)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.
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47. |
- Svensson, Martina, et al.
(författare)
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A physically active lifestyle is associated with lower long-term incidence of bipolar disorder in a population-based, large-scale study
- 2022
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Ingår i: International journal of bipolar disorders. - : Springer Science and Business Media LLC. - 2194-7511. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Physical activity has been proposed to be beneficial for the symptomatic control of bipolar disorder, but the duration of the effects, sex-specific mechanisms, and impact of exercise intensity are not known. Method: With an observational study design, we followed skiers and age and sex-matched non-skiers from the general population to investigate if participation in a long-distance cross-country ski race (Vasaloppet) was associated with a lower risk of getting diagnosed with bipolar disorder. Using the Swedish population and patient registries, skiers in Vasaloppet and age and sex-matched non-skiers from the general population were analyzed for any diagnosis of bipolar disorder after participation in the race. Additionally, we used finishing time of the ski race as a proxy for intensity levels to investigate if exercise intensity impacts the risk of bipolar disorder among the physically active skiers. Results: Previous participation in a long distance ski race (n = 197,685, median age 36 years, 38% women) was associated with a lower incidence of newly diagnosed bipolar compared to an age and sex-matched general population (n = 197,684) during the up to 21 years follow-up (adjusted hazard ratio, HR = 0.48). The finishing time of the race did not significantly impact the risk of bipolar disorder in men. Among women, high performance (measured as the finishing time to complete the race, a proxy for higher exercise dose) was associated with an increased risk of bipolar disorder compared to slower skiing women (HR = 2.07). Conclusions: Our results confirm that a physically active lifestyle is associated with a lower risk of developing bipolar disorder. Yet, to elucidate the direction of causality in this relationship requires complementary study designs. And the influence of physical performance level on the risk of bipolar disorder warrants further examinations among women.
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48. |
- Svensson, Martina, et al.
(författare)
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Long distance ski racing is associated with lower long-term incidence of depression in a population based, large-scale study
- 2019
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Ingår i: Psychiatry Research. - : ELSEVIER IRELAND LTD. - 0165-1781 .- 1872-7123. ; 281
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Tidskriftsartikel (refereegranskat)abstract
- Physical activity has been proposed to be beneficial for prevention of depression, although the importance of exercise intensity, sex-specific mechanisms, and duration of the effects need to be clarified. Using an observational study design, following 395,369 individuals up to 21 years we studied whether participation in an ultralong-distance cross-country ski race was associated with lower risk of developing depression. Skiers (participants in the race) and matched non-skiers from the general population (non-participants in the race) were studied after participation (same year for non-participation) in the race using the Swedish population and patient registries. The risk of depression in skiers (n = 197,685, median age 36 years, 38% women) was significantly lower, to nearly half of that in non-skiers (adjusted hazard ratio, HR 0.53) over the follow-up period. Further, a higher fitness level (measured as the finishing time to complete the race, a proxy for higher exercise dose) was associated with lower incidence of depression in men (adjusted HR 0.65), but not in women. Our results support the recommendations of engaging in physical activity as a preventive strategy decreasing the risk for depression in both men and women. Furthermore, the exercise could reduce risk for depression in a dose-dependent matter, in particular in males.
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49. |
- Svensson, Martina, et al.
(författare)
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Physical Activity Is Associated With Lower Long-Term Incidence of Anxiety in a Population-Based, Large-Scale Study
- 2021
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Ingår i: Frontiers in Psychiatry. - : Frontiers Media S.A.. - 1664-0640. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Physical activity may prevent anxiety, but the importance of exercise intensity, sex-specific mechanisms, and duration of the effects remains largely unknown. We used an observational study design to follow 395,369 individuals for up to 21 years to investigate if participation in an ultralong-distance cross-country ski race (Vasaloppet, up to 90 km) was associated with a lower risk of developing anxiety. Skiers in the race and matched non-skiers from the general population were studied after participation in the race using the Swedish population and patient registries. Skiers (n = 197,685, median age 36 years, 38% women) had a significantly lower risk of developing anxiety during the follow-up compared to non-skiers (adjusted hazard ratio, HR 0.42). However, among women, higher physical performance (measured as the finishing time to complete the race, a proxy for higher exercise dose) was associated with an increased risk of anxiety compared to slower skiing women (HR 2.00). For men, the finishing time of the race did not significantly impact the risk of anxiety. Our results support the recommendations of engaging in physical activity to decrease the risk of anxiety in both men and women. The impact of physical performance level on the risk of anxiety requires further investigations among women.
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50. |
- Söderlund, Johan, et al.
(författare)
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Elevation of cerebrospinal fluid interleukin-1ß in bipolar disorder.
- 2010
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Ingår i: Journal of psychiatry & neuroscience : JPN. - : CMA Joule Inc.. - 1488-2434 .- 1180-4882. ; 35:6
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Tidskriftsartikel (refereegranskat)abstract
- 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 pathophysiology 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 dis order 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)-1ß 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, respect ively). Patients with 1 or more manic/hypomanic episodes during the last year showed significantly higher levels of IL-1ß (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-1ß in bipolar disorder.
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