| 1. |
- Bridel, Claire, et al.
(författare)
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Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology : A Systematic Review and Meta-analysis
- 2019
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157. ; 76:9, s. 1035-1048
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Forskningsöversikt (refereegranskat)abstract
- Importance Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date.Objectives To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions.Data Sources PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC.Study Selection Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex.Data Extraction and Synthesis Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept.Main Outcome and Measure The cNfL levels adjusted for age and sex across diagnoses.Results Data were collected for 10 059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes.Conclusions and Relevance These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.
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| 2. |
- Brinkmalm-Westman, Ann, 1966, et al.
(författare)
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Targeting synaptic pathology with a novel affinity mass spectrometry approach.
- 2014
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Ingår i: Molecular & cellular proteomics : MCP. - 1535-9484. ; 13:10, s. 2584-92
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Tidskriftsartikel (refereegranskat)abstract
- We report a novel strategy for studying synaptic pathology by concurrently measuring levels of four SNARE complex proteins from individual brain tissue samples. This method combines affinity purification and mass spectrometry and can be applied directly for studies of SNARE complex proteins in multiple species or modified to target other key elements in neuronal function. We use the technique to demonstrate altered levels of presynaptic proteins in Alzheimer disease patients and prion-infected mice.
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| 3. |
- Ekroos, Johan, et al.
(författare)
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Effects of landscape composition and configuration on pollination in a native herb : a field experiment
- 2015
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Ingår i: Oecologia. - : Springer Science and Business Media LLC. - 0029-8549 .- 1432-1939. ; 179:2, s. 509-518
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Tidskriftsartikel (refereegranskat)abstract
- Bumble bee abundance in agricultural landscapes is known to decrease with increasing distance from seminatural grasslands, but whether the pollination of bumble-bee-pollinated wild plants shows a similar pattern is less well known. In addition, the relative effects of landscape composition (landscape heterogeneity) and landscape configuration (distance from seminatural grassland) on wild plant pollination, and the interaction between these landscape effects, have not been studied using landscape-level replication. We performed a field experiment to disentangle these landscape effects on the pollination of a native herb, the sticky catchfly (Lychnis viscaria), while accounting for the proportion of oilseed rape across landscapes and the local abundance of bee forage flowers. We measured pollen limitation (the degree to which seed set is pollen-limited), seed set, and seed set stability using potted plants placed in landscapes that differed in heterogeneity (composition) and distance from seminatural grassland (configuration). Pollen limitation and seed set in individual plants did not respond to landscape composition, landscape configuration, or proportion of oilseed rape. Instead, seed set increased with increasing local bee forage flower cover. However, we found within-plant variability in pollen limitation and seed set to increase with increasing distance from seminatural pasture. Our results suggest that average within-plant levels of pollen limitation and seed set respond less swiftly than the within-plant variability in pollen limitation and seed set to changes in landscape configuration. Although landscape effects on pollination were less important than predicted, we conclude that landscape configuration and local habitat characteristics play larger roles than landscape composition in the pollination of L. viscaria.
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| 4. |
- Eriksson, Hanna, et al.
(författare)
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Quantitative membrane proteomics applying narrow range peptide isoelectric focusing for studies of small cell lung cancer resistance mechanisms
- 2008
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Ingår i: Proteomics. - : Wiley. - 1615-9853 .- 1615-9861. ; 28:5C, s. 3275-3276
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Tidskriftsartikel (refereegranskat)abstract
- Drug resistance is often associated with upregulation of membrane-associated drug-efflux systems, and thus global membrane proteomics methods are valuable tools in the search for novel components of drug resistance phenotypes. Herein we have compared the microsomal proteome from the lung cancer cell line H69 and its isogenic Doxorubicin-resistant subcell line H69AR. The method used includes microsome preparation, iTRAQ labeling followed by narrow range peptide IEF in an immobilized pH-gradient (IPG-IEF) and LC-MS/MS analysis. We demonstrate that the microsomal preparation and iTRAQ labeling is reproducible regarding protein content and composition. The rationale using narrow range peptide IPG-IEF separation is demonstrated by its ability to: (i) lowering the complexity of the sample by two-thirds while keeping high proteome coverage (96%), (ii) providing high separation efficiency, and (iii) allowing for peptide validation and possibly identifications of post-transcriptional modifications. After analyzing one-fifth of the IEF fractions (effective pH range of 4.0-4.5), a total of 3704 proteins were identified, among which 527 were predicted to be membrane proteins. One of the proteins found to be differentially expressed was Serca 2, a calcium pump located in the ER membrane that potentially could result in changes of apoptotic response toward Doxorubicin.
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| 5. |
- Göteson, Andreas, 1991, et al.
(författare)
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A serum proteomic study of two case-control cohorts identifies novel biomarkers for bipolar disorder
- 2022
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- We set out to identify novel protein associations with potential as clinically viable biomarkers for bipolar disorder. To this end, we used proximity extension assay to analyze 201 unique proteins in blood serum from two independent cohorts comprising patients with bipolar disorder and healthy controls (total n = 493). We identified 32 proteins significantly associated with bipolar disorder in both case-control cohorts after adjusting for relevant covariates. Twenty-two findings are novel to bipolar disorder, but 10 proteins have previously been associated with bipolar disorder: chitinase-3-like protein 1, C-C motif chemokine 3 (CCL3), CCL4, CCL20, CCL25, interleukin 10, growth/differentiation factor-15, matrilysin (MMP-7), pro-adrenomedullin, and TNF-R1. Next, we estimated the variance in serum protein concentrations explained by psychiatric drugs and found that some case-control associations may have been driven by psychiatric drugs. The highest variance explained was observed between lithium use and MMP-7, and in post-hoc analyses and found that the serum concentration of MMP-7 was positively associated with serum lithium concentration, duration of lithium therapy, and inversely associated with estimated glomerular filtration rate in an interaction with lithium. This is noteworthy given that MMP-7 has been suggested as a mediator of renal tubulointerstitial fibrosis, which is characteristic of lithium-induced nephropathy. Finally, we used machine learning to evaluate the classification performance of the studied biomarkers but the average performance in unseen data was fair to moderate (area under the receiver operating curve = 0.72). Taken together, our serum biomarker findings provide novel insight to the etiopathology of bipolar disorder, and we present a suggestive biomarker for lithium-induced nephropathy. © 2022, The Author(s).
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| 6. |
- Göteson, Andreas, 1991, et al.
(författare)
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Cerebrospinal fluid proteomics targeted for central nervous system processes in bipolar disorder
- 2021
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 26, s. 7446-53
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Tidskriftsartikel (refereegranskat)abstract
- The etiopathology of bipolar disorder is largely unknown. We collected cerebrospinal fluid (CSF) samples from two independent case-control cohorts (total n = 351) to identify proteins associated with bipolar disorder. A panel of 92 proteins targeted towards central nervous system processes identified two proteins that replicated across the cohorts: the CSF concentrations of testican-1 were lower, and the CSF concentrations of C-type lectin domain family 1 member B (CLEC1B) were higher, in cases than controls. In a restricted subgroup analysis, we compared only bipolar type 1 with controls and identified two additional proteins that replicated in both cohorts: draxin and tumor necrosis factor receptor superfamily member 21 (TNFRSF21), both lower in cases than controls. This analysis additionally revealed several proteins significantly associated with bipolar type 1 in one cohort, falling just short of replicated statistical significance in the other (tenascin-R, disintegrin and metalloproteinase domain-containing protein 23, cell adhesion molecule 3, RGM domain family member B, plexin-B1, and brorin). Next, we conducted genome-wide association analyses of the case-control-associated proteins. In these analyses, we found associations with the voltage-gated calcium channel subunit CACNG4, and the lipid-droplet-associated gene PLIN5 with CSF concentrations of TNFRSF21 and CLEC1B, respectively. The reported proteins are involved in neuronal cell-cell and cell-matrix interactions, particularly in the developing brain, and in pathways of importance for lithium's mechanism of action. In summary, we report four novel CSF protein associations with bipolar disorder that replicated in two independent case-control cohorts, shedding new light on the central nervous system processes implicated in bipolar disorder.
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| 7. |
- Isgren, Anniella, et al.
(författare)
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Cerebrospinal fluid proteomic study of two bipolar disorder cohorts
- 2022
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 27:11, s. 4568-4574
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Tidskriftsartikel (refereegranskat)abstract
- The pathophysiology of bipolar disorder remains to be elucidated and there are no diagnostic or prognostic biomarkers for the condition. In this explorative proteomic study, we analyzed 201 proteins in cerebrospinal fluid (CSF) from mood stable bipolar disorder patients and control subjects sampled from two independent cohorts, amounting to a total of 204 patients and 144 controls. We used three Olink Multiplex panels, whereof one specifically targets immune biomarkers, to assess a broad set of CSF protein concentrations. After quality control and removal of proteins with a low detection rate, 105 proteins remained for analyses in relation to case-control status and clinical variables. Only case-control differences that replicated across cohorts were considered. Results adjusted for potential confounders showed that CSF concentrations of growth hormone were lower in bipolar disorder compared with controls in both cohorts. The effect size was larger when the analysis was restricted to bipolar disorder type 1 and controls. We found no indications of immune activation or other aberrations. Growth hormone exerts many effects in the central nervous system and our findings suggest that growth hormone might be implicated in the pathophysiology of bipolar disorder.
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| 8. |
- Isgren, Anniella, et al.
(författare)
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Increased cerebrospinal fluid interleukin-8 in bipolar disorder patients associated with lithium and antipsychotic treatment.
- 2015
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Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 1090-2139 .- 0889-1591. ; 43, s. 198-204
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation has been linked to the pathophysiology of bipolar disorder based on studies of inflammation markers, such as cytokine concentrations, in plasma and serum samples from cases and controls. However, peripheral measurements of cytokines do not readily translate to immunological activity in the brain. The aim of the present study was to study brain immune and inflammatory activity. To this end, we analyzed cytokines in cerebrospinal fluid from 121 euthymic bipolar disorder patients and 71 age and sex matched control subjects. Concentrations of 11 different cytokines were determined using immunoassays. Cerebrospinal fluid IL-8 concentrations were significantly higher in patients as compared to controls. The other cytokines measured were only detectable in part of the sample. IL-8 concentrations were positively associated to lithium- and antipsychotic treatment. The findings might reflect immune aberrations in bipolar disorder, or be due to the effects of medication.
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| 9. |
- Isgren, Anniella, et al.
(författare)
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Markers of neuroinflammation and neuronal injury in bipolar disorder: Relation to prospective clinical outcomes.
- 2017
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Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 1090-2139 .- 0889-1591. ; 65, s. 195-201
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Tidskriftsartikel (refereegranskat)abstract
- Neuroimmune mechanisms have been linked to the pathophysiology of bipolar disorder based on studies of biomarkers in plasma, cerebrospinal fluid (CSF), and postmortem brain tissue. There are, however, no longitudinal studies investigating if CSF markers of neuroinflammation and neuronal injury predict clinical outcomes in patients with bipolar disorder. We have in previous studies found higher CSF concentrations of interleukin-8 (IL-8), monocyte chemoattractant protein 1 (MCP-1/CCL-2), chitinase-3-like protein 1 (CHI3L1/YKL-40), and neurofilament light chain (NF-L) in euthymic patients with bipolar disorder compared with controls. Here, we investigated the relationship of these CSF markers of neuroinflammation and neuronal injury with clinical outcomes in a prospective study. 77 patients with CSF analyzed at baseline were followed for 6-7years. Associations of baseline biomarkers with clinical outcomes (manic/hypomanic and depressive episodes, suicide attempts, psychotic symptoms, inpatient care, GAF score change) were investigated. Baseline MCP-1 concentrations were positively associated with manic/hypomanic episodes and inpatient care during follow-up. YKL-40 concentrations were negatively associated with manic/hypomanic episodes and with occurrence of psychotic symptoms. The prospective negative association between YKL-40 and manic/hypomanic episodes survived multiple testing correction. Concentrations of IL-8 and NF-L were not associated with clinical outcomes. High concentrations of these selected CSF markers of neuroinflammation and neuronal injury at baseline were not consistently associated with poor clinical outcomes in this prospective study. The assessed proteins may be involved in adaptive immune processes or reflect a state of vulnerability for bipolar disorder rather than being of predictive value for disease progression.
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| 10. |
- Jakobsson, Joel, et al.
(författare)
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Altered Concentrations of Amyloid Precursor Protein Metabolites in the Cerebrospinal Fluid of Patients with Bipolar Disorder
- 2013
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Ingår i: Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 0893-133X .- 1740-634X. ; 38:4, s. 664-672
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Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder is a psychiatric disorder characterized by recurrent episodes of mania/hypomania and depression. Progressive cognitive dysfunction such as impairments in executive function and verbal memory is common in euthymic bipolar patients. The cerebrospinal fluid has previously been used to study neurodegenerative processes in Alzheimer’s disease, from which changes in three core biomarkers have emerged as indicative of degeneration: amyloid β, total tau, and hyperphosphorylated tau. Here, neurodegeneration in bipolar disorder was investigated by assessing the association between bipolar disorder and cerebrospinal fluid biomarkers for neurodegenerative processes. Cerebrospinal fluid was obtained from 139 bipolar disorder patients and 71 healthy controls. Concentrations of total and phosphorylated tau, amyloid β1-42, amyloid β38/β40/β42, and the soluble forms of amyloid precursor protein were measured in patients vs controls. The concentrations of the soluble forms of amyloid precursor protein were significantly lower in bipolar patients compared with controls. The amyloid β42/amyloid β38 and the amyloid β42/amyloid β40 ratios were higher in bipolar patients than controls. There were no discernible differences in the concentrations of total/phosphorylated tau, amyloid β1-42, or amyloid β38/β40/β42. The concentrations of the biomarkers within the bipolar patient group were further associated with different ongoing medical treatments and diagnostic subgroups. The findings suggest that the amyloid precursor protein metabolism is altered in bipolar disorder. The results may have implications for the understanding of the pathophysiology of bipolar disorder and for the development of treatment strategies. Importantly, there were no signs of an Alzheimer-like neurodegenerative process among bipolar patients.
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| 11. |
- Jakobsson, Joel, et al.
(författare)
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CACNA1C polymorphism and altered phosphorylation of tau in bipolar disorder.
- 2016
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Ingår i: The British journal of psychiatry : the journal of mental science. - : Royal College of Psychiatrists. - 1472-1465. ; 208:2, s. 195-196
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Tidskriftsartikel (refereegranskat)abstract
- Several genome-wide association studies and case-control studies have associated the single nucleotide polymorphism (SNP) rs1006737, situated in CACNA1C encoding the alpha 1C subunit of the L-type voltage-gated calcium channel, with bipolar disorder and other psychiatric disorders. However, the causal pathway linking genetic variants in CACNA1C with increased risk for developing brain disorders remains unclear. Here, we explored the association between the rs1006737 SNP and cerebrospinal fluid (CSF) markers. We found a significant association between the risk allele in rs1006737 and a decreased CSF hyperphosphorylated tau/total tau ratio in patients with bipolar disorder, thus linking variation in the CACNA1C gene to a neurochemical marker of neuroaxonal plasticity in those with this disorder.
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| 12. |
- Jakobsson, Joel, et al.
(författare)
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Decreased cerebrospinal fluid secretogranin II concentrations in severe forms of bipolar disorder.
- 2013
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Ingår i: Journal of psychiatry & neuroscience : JPN. - : CMA Joule Inc.. - 1488-2434 .- 1180-4882. ; 38:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Bipolar disorder is a common psychiatric mood disorder that is defined by recurrent episodes of abnormally elevated mood and depression. Progressive structural brain changes in individuals with bipolar disorder have been suggested to be associated with defects in the secretion of neurotrophic factors. We sought to assess how the regulated secretory pathway in the brain is affected in patients with bipolar disorder by measuring chromogranin B and secretogranin II, which are 2 cerebrospinal fluid (CSF) biological markers for this process. Methods: We measured the concentrations of chromogranin B (peptide 439-451) and secretogranin II (peptide 154-165) in the CSF of patients with well-defined bipolar disorder and healthy controls. The lifetime severity of bipolar disorder was rated using the Clinical Global Impression (CGI) scale. Results: We included 126 patients with bipolar disorder and 71 healthy controls in our analysis. Concentrations of secretogranin II were significantly lower in patients with bipolar disorder type I than in healthy controls. The reduction was most pronounced in patients with high CGI scores (i.e., severe disease). Limitations: The cross-sectional design of the current study limits the ability to pinpoint the causalities behind the observed associations. Conclusion: This study shows that the CSF marker secretogranin II has the potential to act as a biological marker for severe forms of bipolar disorder. Our findings indicate that patients with bipolar disorder possess defects in the regulatory secretory pathway, which may be of relevance to the progressive structural brain changes seen in those with severe forms of the disease.
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| 13. |
- Jakobsson, Joel, et al.
(författare)
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Elevated Concentrations of Neurofilament Light Chain in The Cerebrospinal Fluid of Bipolar Disorder Patients.
- 2014
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Ingår i: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 1740-634X. ; 39, s. 2349-2356
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Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder (BD) is characterized by mood swings between manic and depressive states. The etiology and pathogenesis of BD is unclear, but many of the affected cognitive domains, as well as neuroanatomical abnormalities, resemble symptoms and signs of small vessel disease. In small vessel disease, cerebrospinal fluid (CSF) markers reflecting damages in different cell types and subcellular structures of the brain have been established. Hence, we hypothesized that CSF markers related to small vessel disease may also be applicable as biomarkers for bipolar disorder. To investigate this hypothesis, we sampled CSF from 133 patients with bipolar disorder and 86 healthy controls. The concentrations of neurofilament light chain (NF-L), myelin basic protein (MBP), S100B, and heart-fatty acid binding protein (H-FABP) were measured in CSF and analyzed in relation to diagnosis, clinical characteristics, and ongoing medications. Hereby we found an elevation of the marker of subcortical axonal damage, NF-L, in bipolar subjects. We also identified positive associations between NF-L and treatment with atypical antipsychotics, MBP and lamotrigine, and H-FABP and lithium. These findings indicate axonal damage as an underlying neuropathological component of bipolar disorder, though the clinical value of elevated NF-L remains to be validated in follow-up studies. The associations between current medications and CSF brain injury markers might aid in the understanding of both therapeutic and adverse effects of these drugs.Neuropsychopharmacology accepted article peview online, 03 April 2014; doi:10.1038/npp.2014.81.
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| 14. |
- Jakobsson, Joel
(författare)
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Molecular mechanisms in synaptic vesicle recycling
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neurons communicate through specialized contacts called synapses, which consist of pre- and postsynaptic compartments separated by a narrow synaptic cleft. The stimulus- dependent rapid influx of calcium ions into the presynaptic compartment induces fusion of neurotransmitter-filled vesicles with the plasma membrane and release of their content into the synaptic cleft. The vesicle membrane then needs to be recycled to avoid disruption of synapse morphology and depletion of synaptic vesicles. Three pathways have been described in the literature: clathrin-mediated endocytosis in which vesicles already the size of synaptic vesicles are retrieved at the periactive zone, bulk endocytosis in which larger pieces of membrane are retrieved, and kiss-and-run in which the vesicle remains intact and forms only a transient fusion pore through which neurotransmitter is released. In this thesis, the molecular mechanisms of synaptic vesicle recycling were studied using acute perturbations in lamprey giant reticulospinal axons. The aim was to clarify three different aspects in the recycling machinery: first – how the clathrin coat assembly is regulated, second – how dynamin-dependent fission is regulated, and third – how the synapse copes with intense activity. Three proteins (epsin, EHD, and syndapin) were cloned in Lampetra fluviatilis using PCR-based methods. Binding partners were identified in pull-down assays and lipid-interacting properties were investigated in liposome sedimentation, tubulation, and budding assays. The cloned proteins were further used in the immunization of rabbits for the generation of domain-specific antibodies. These antibodies were used for Western blot, immunoprecipitations, immunolocalization, and presynaptic microinjections. Microinjection experiments were mainly analyzed with electron microscopy to reveal morphological phenotypes. All three proteins cloned in this thesis showed a high degree of homology in protein and lipid interacting regions with their mammalian orthologs as well as similar biochemical properties. The proteins were all localized to the pre-synaptic compartment where they were shown to accumulate at specific regions during synaptic activity: epsin – to the coat of clathrin-coated pits, EHD – to neck regions of GTP S induced endocytic structures, and syndapin – to the peri-active zone (excluding clathrin-coated pits). Perturbation of epsin, EHD, and syndapin in living synapses impaired synaptic vesicle recycling, observed as a loss of synaptic vesicles. Disruption of epsin’s N- terminal region inhibited coat assembly while perturbation of epsin’s clathrin/AP-2- binding domain resulted in abnormal coat assembly. Perturbation of EHD resulted in an accumulation of clathrin coated pits with long necks indicating an impairment of endocytic fission. The perturbation of syndapin was associated with a massive accumulation of membranous cisternae and invaginations, but not of clathrin-coated pits at the plasma membrane. The findings in this thesis suggest that epsin links membrane deformation to clathrin-coated pit formation with a potential role in regulating the size of synaptic vesicles, that EHD regulates dynamin-mediated fission in an ATP-dependent fashion, and that syndapin is required for bulk endocytosis and for stabilizing the plasma membrane during intense synaptic activity. Thus, this thesis has added new knowledge about the molecular network that mediates synaptic vesicle recycling.
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| 15. |
- Jakobsson, Joel, et al.
(författare)
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Monocyte and microglial activation in patients with mood-stabilized bipolar disorder.
- 2015
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Ingår i: Journal of psychiatry & neuroscience : JPN. - : CMA Joule Inc.. - 1488-2434 .- 1180-4882. ; 40:2
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Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder is associated with medical comorbidities that have been linked to systemic inflammatory mechanisms. There is, however, limited evidence supporting a role of neuroinflammation in bipolar disorder. Here we tested whether microglial activation and associated tissue remodelling processes are related to bipolar disorder by analyzing markers in cerebrospinal fluid (CSF) and serum from patients and healthy controls.
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| 16. |
- Jakobsson, Joel, et al.
(författare)
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Regulation of Synaptic Vesicle Budding and Dynamin Function by an EHD ATPase
- 2011
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Ingår i: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 31:39, s. 13972-13980
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Tidskriftsartikel (refereegranskat)abstract
- Eps15 homology domain-containing proteins (EHDs) are conserved ATPases implicated in membrane remodeling. Recently, EHD1 was found to be enriched at synaptic release sites, suggesting a possible involvement in the trafficking of synaptic vesicles. We have investigated the role of an EHD1/3 ortholog (1-EHD) in the lamprey giant reticulospinal synapse. 1-EHD was detected by immunogold at endocytic structures adjacent to release sites. In antibody microinjection experiments, perturbation of 1-EHD inhibited synaptic vesicle endocytosis and caused accumulation of clathrin-coated pits with atypical, elongated necks. The necks were covered with helix-like material containing dynamin. To test whether 1-EHD directly interferes with dynamin function, we used fluid-supported bilayers as in vitro assay. We found that 1-EHD strongly inhibited vesicle budding induced by dynamin in the constant presence of GTP. 1-EHD also inhibited dynamin-induced membrane tubulation in the presence of GTP gamma S, a phenomenon linked with dynamin helix assembly. Our in vivo results demonstrate the involvement of 1-EHD in clathrin/dynamin-dependent synaptic vesicle budding. Based on our in vitro observations, we suggest that 1-EHD acts to limit the formation of long, unproductive dynamin helices, thereby promoting vesicle budding.
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| 17. |
- Johansson, Viktoria, et al.
(författare)
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Cerebrospinal fluid microglia and neurodegenerative markers in twins concordant and discordant for psychotic disorders.
- 2017
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Ingår i: European Archives of Psychiatry and Clinical Neuroscience. - : Springer. - 0940-1334 .- 1433-8491. ; 267:5, s. 391-402
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia and bipolar disorder are debilitating psychiatric disorders with partially shared symptomatology including psychotic symptoms and cognitive impairment. Aberrant levels of microglia and neurodegenerative cerebrospinal fluid (CSF) markers have previously been found in schizophrenia and bipolar disorder. We aimed to analyze familial and environmental influences on these CSF markers and their relation to psychiatric symptoms and cognitive ability. CSF was collected from 17 complete twin pairs, nine monozygotic and eight dizygotic, and from one twin sibling. Two pairs were concordant for schizophrenia, and 11 pairs discordant for schizophrenia, schizoaffective disorder or bipolar disorder, and four pairs were not affected by psychotic disorders. Markers of microglia activation [monocyte chemoattractant protein-1 (MCP-1), chitinase 3-like protein 1 (YKL-40), and soluble cluster of differentiation 14 (sCD14)], markers of β-amyloid metabolism (AβX-38, AβX-40, AβX-42 and Aβ1-42), soluble amyloid precursor proteins (sAPP-α and sAPP-β), total tau (T-tau), phosphorylated tau (P-tau), and CSF/serum albumin ratio were measured in CSF using immunoassays. Heritability of the CSF markers was estimated, and associations to psychiatric and cognitive measurements were analyzed. Heritability estimates of the microglia markers were moderate, whereas several neurodegenerative markers showed high heritability. In contrast, AβX-42, Aβ1-42, P-tau and CSF/serum albumin ratio were influenced by dominant genetic variation. Higher sCD14 levels were found in twins with schizophrenia or bipolar disorder compared to their not affected co-twins, and higher sCD14-levels were associated with psychotic symptoms. The study provides support for a significant role of sCD14 in psychotic disorders and a possible role of microglia activation in psychosis.
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| 18. |
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| 19. |
- Lautner, Ronald, et al.
(författare)
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Apolipoprotein e genotype and the diagnostic accuracy of cerebrospinal fluid biomarkers for Alzheimer disease.
- 2014
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Ingår i: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 71:10, s. 1183-91
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Tidskriftsartikel (refereegranskat)abstract
- Several studies suggest that the apolipoprotein E (APOE) ε4 allele modulates cerebrospinal fluid (CSF) levels of β-amyloid 42 (Aβ42). Whether this effect is secondary to the association of the APOE ε4 allele with cortical Aβ deposition or whether APOE ε4 directly influences CSF levels of Aβ42 independently of Aβ pathology remains unknown.
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| 20. |
- Lööw, Joel, et al.
(författare)
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A CHANGING WORK ENVIRONMENT IN THE WAKE OF THE COVID-19 PANDEMIC? – OBSERVATIONS FROM MANAGERS IN A SWEDISH MINING COMPANY
- 2023
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Ingår i: Occupational Safety and Hygiene – SHO2023 Proceedings Book. - : Portuguese Society of Occupational Safety and Hygiene (SPOSHO). - 9789895486342 ; , s. 376-389, s. 376-389
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Konferensbidrag (refereegranskat)abstract
- Background: The Covid-19 pandemic has changed work life in many ways for many people; however, it is still an open question as to what changes will become permanent and what aspects of work life will return to that which was considered “normal” before the pandemic.Objective: In this study, the authors describe and analyse the effects of Covid-19 on managers in a large Swedish mining company.Method: This study is based on both quantitative and qualitative methods. Empirical material is used to explore the effects of the pandemic on the work environments of managers. Results are based on interviews in combination with a self-assessment process regarding how the managers allocated their work time during a work week.Results: The results describe the work activities of the studied managers supported with quotes from interview studies to illustrate to most central observations of how work has changed due to the Covid-19 pandemic.Conclusion: The results are summarized into six hypotheses: 1) the workday was densified due to remote meetings; 2) "double work" during meetings was the rule, rather than the exception; 3) meetings became more focused; 4) meetings became more accessible; 5) the manager became less operational; and 6) a new work culture was created.Application: This is an exploratory study of consequences and effects of Covid-19 pandemic summarized in six hypotheses that can befruitful for further and future studies.
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| 21. |
- Pålsson, Erik, 1975, et al.
(författare)
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Markers of glutamate signaling in cerebrospinal fluid and serum from patients with bipolar disorder and healthy controls
- 2015
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Ingår i: European Neuropsychopharmacology. - : Elsevier BV. - 0924-977X. ; 25:1, s. 133-140
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Tidskriftsartikel (refereegranskat)abstract
- Glutamate is the major excitatory neurotransmitter in the brain. Aberrations in glutamate signaling have been linked to the pathophysiology of mood disorders. Increased plasma levels of glutamate as well as higher glutamine+glutamate levels in the brain have been demonstrated in patients with bipolar disorder as compared to healthy controls. In this study, we explored the glutamate hypothesis of bipolar disorder by examining peripheral and central levels of amino acids related to glutamate signaling. A total of 215 patients with bipolar disorder and 112 healthy controls from the Swedish St. Goran bipolar project were included in this study. Glutamate, glutamine, glycine, L-serine and D-serine levels were determined in serum and in cerebrospinal fluid using high performance liquid chromatography with fluorescence detection. Serum levels of glutamine, glycine and D-serine were significantly higher whereas L-serine levels were lower in patients with bipolar disorder as compared to controls. No differences between the patient and control group in amino acid levels were observed in cerebrospinal fluid. The observed differences in serum amino acid levels may be interpreted as a systemic aberration in amino acid metabolism that affects several amino acids related to glutamate signaling. (C) 2014 Elsevier B.V. and ECNP. All rights reserved.
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| 22. |
- Rolstad, Sindre, 1976, et al.
(författare)
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Cognitive Performance and Cerebrospinal Fluid Biomarkers of Neurodegeneration: A Study of Patients with Bipolar Disorder and Healthy Controls
- 2015
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 10:5
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of the present study was to investigate if cerebrospinal fluid (CSF) biomarkers of neurodegeneration are associated with cognition in bipolar disorder and healthy controls, respectively. CSF concentrations of total and phosphorylated tau, amyloid beta (A beta) 1-42, ratios of A beta 42/40 and A beta 42/38, soluble amyloid precursor protein alpha and beta, and neurofilament light chain protein were analyzed in relation to neuropsychological performance in 82 euthymic bipolar disorder patients and 71 healthy controls. Linear regression models were applied to account for performance in five cognitive domains using the CSF biomarkers. In patients, the CSF biomarkers explained a significant proportion of the variance (15-36%, p =. 002 -<. 0005) in all cognitive domains independently of age, medication, disease status, and bipolar subtype I or II. However, the CSF biomarkers specifically mirroring Alzheimer-type brain changes, i.e., P-tau and A beta 1-42, did not contribute significantly. In healthy controls, CSF biomarkers did not explain the variance in cognitive performance. Selected CSF biomarkers of neurodegenerative processes accounted for cognitive performance in persons with bipolar disorder, but not for healthy controls. Specifically, the ratios of A beta 42/40 and A beta 42/38 were consistently associated with altered cognitive performance.
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| 23. |
- Rolstad, Sindre, 1976, et al.
(författare)
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CSF neuroinflammatory biomarkers in bipolar disorder are associated with cognitive impairment.
- 2015
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Ingår i: European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. - : Elsevier BV. - 1873-7862. ; 25:8, s. 1091-1098
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Tidskriftsartikel (refereegranskat)abstract
- Persistent cognitive impairment in the euthymic state of bipolar disorder is increasingly recognized. Mounting evidence also suggests an association between neuroinflammation and cognitive dysfunction. The purpose of this study was to test if cerebrospinal fluid (CSF) markers of neuroinflammation could account for cognitive impairment in bipolar disorder. Hierarchical linear regression models were applied to account for performance in five cognitive domains using CSF neuroinflammatory biomarkers as predictors in patients with bipolar disorder type I and II (N=78). The associations between these biomarkers and cognition were further tested in healthy age- and sex-matched controls (N=86). In patients with bipolar disorder, the CSF biomarkers accounted for a significant proportion of the variance in executive functions (42.8%, p=<.0005) independently of age, medication, disease status, and bipolar subtype. The microglial marker YKL-40 had a high impact (beta=-.99), and was the only biomarker that contributed individually. CSF biomarkers were not associated with cognitive performance in healthy controls. The CSF neuroinflammation biomarker YKL-40 is associated with executive performance in euthymic bipolar disorder, but not in healthy controls.
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| 24. |
- Sandberg, Johan V, et al.
(författare)
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Low neuropeptide Y in cerebrospinal fluid in bipolar patients is associated with previous and prospective suicide attempts.
- 2014
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Ingår i: European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. - : Elsevier BV. - 1873-7862. ; 24:12, s. 1907-15
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Tidskriftsartikel (refereegranskat)abstract
- The attempted and accomplished suicide rates in patients with bipolar disorder are 40-50% and 15-20%, respectively. No biological markers that help predict suicide been identified. Human and experimental animal data indicate that dysregulation of the neuropeptide Y (NPY) system plays a role in depression, anxiety, and posttraumatic stress disorder (PTSD). The aim of this study was to explore if low cerebrospinal fluid (CSF) NPY is associated with (1) past suicide attempts, (2) future suicide attempts, and (3) trait anxiety. Lumbar puncture was performed on 120 clinically stable patients with bipolar disorder enrolled in the St Göran Bipolar Project, where the number of previous suicide attempts was documented. NPY-like immunoreactivity (NPY-LI) was determined in cerebrospinal fluid (CSF). Patients were reexamined one year after the lumbar puncture and suicide attempts were recorded. NPY-LI was significantly lower in patients with a history of suicide attempt than in patients who had not attempted suicide prior to lumbar puncture. Importantly, NPY-LI was markedly lower in patients who made a suicide attempt during the follow-up period compared to patients who did not. Patients who attempted suicide during the follow-up also had markedly lower NPY-LI than those with previous suicide attempts who did not reattempt. Our results suggest that low CSF NPY-LI predicts future suicide attempts. The data are in line with the hypothesis that NPY signaling is altered in affective disorders and states of emotional dysregulation.
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| 25. |
- Sandberg, Johan V, et al.
(författare)
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Proteins associated with future suicide attempts in bipolar disorder: A large-scale biomarker discovery study
- 2022
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578.
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Tidskriftsartikel (refereegranskat)abstract
- Suicide is a major cause of death worldwide. Several biological systems have been implicated in suicidal behavior but studies of candidate biomarkers have failed to produce clinically relevant biomarkers for suicide prediction. The objective of the present study was to identify novel candidate biomarkers for suicidal behavior. We used a nested case-control study design where a large cohort of patients with bipolar disorder (N = 5 110) were followed up to 8 years after blood sampling. We included patients that attempted suicide during follow-up (N = 348) and matched bipolar disorder patients from the same cohort who did not attempt suicide during the study period (N = 348) and analyzed a total of 92 proteins with a neuro exploratory multiplex panel. Using a multivariate classification algorithm devised to minimize bias in variable selection, we identified a parsimonious set of proteins that best discriminated bipolar disorder patients with and without prospective suicide attempts. The algorithm selected 16 proteins for the minimal-optimal classification model, which outperformed 500 models with permuted outcome (p = 0.0004) but had low sensitivity (53%) and specificity (64%). The candidate proteins were then entered in separate logistic regression models to calculate protein-specific associations with prospective suicide attempts. In individual analyses, three of these proteins were significantly associated with prospective suicide attempt (SCGB1A1, ANXA10, and CETN2). Most of the candidate proteins are novel to suicide research.
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| 26. |
- Vinberg, Stig, 1954-, et al.
(författare)
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Do leadership behaviours, work environments and the health of managers in Sweden and outside Sweden differ?—a study of a large international mining company
- 2023
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Ingår i: Mineral Economics. - : Springer Nature. - 2191-2203 .- 2191-2211. ; 36:4, s. 655-666
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Tidskriftsartikel (refereegranskat)abstract
- The mining industry faces specific challenges related to the working conditions and safety of employees. Studies indicate that the leadership behaviours, working conditions and health of managers are of importance for the working conditions and health of subordinates. Therefore, the aim here is to study these factors in a large international mining company with its head office in Sweden. The specific focus is on identifying similarities and differences that may exist between managers in Sweden and managers outside Sweden. An online survey with validated questions has been distributed to all managers in the company. The main findings are that both managers in and outside of Sweden report relatively high values regarding relation-, structure- and change-oriented leadership behaviours. In addition, managers also rated HEL (healthy and effective leadership) behaviours with relatively high values. The managers in Sweden rate relation orientation with the highest value and the managers outside Sweden rate structure orientation with the highest value. These differences have been confirmed by a regression analysis that identified significant associations between the group of managers based outside Sweden and higher structure orientated leadership behaviours. Both manager groups rate relatively high values regarding job satisfaction and self-rated health. However, they rate relatively high work demand values. The main conclusions are that there are different patterns in leadership behaviours between these two manager groups that can be related to cross-culture factors. Further investigation of the reasons for these differences is important in this industrial sector.
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| 27. |
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| 28. |
- Yoshimi, N., et al.
(författare)
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Cerebrospinal fluid metabolomics identifies a key role of isocitrate dehydrogenase in bipolar disorder: evidence in support of mitochondrial dysfunction hypothesis
- 2016
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 21:11, s. 1504-1510
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Tidskriftsartikel (refereegranskat)abstract
- Although evidence for mitochondrial dysfunction in the pathogenesis of bipolar disorder (BD) has been reported, the precise biological basis remains unknown, hampering the search for novel biomarkers. In this study, we performed metabolomics of cerebrospinal fluid (CSF) from male BD patients (n = 54) and age-matched male healthy controls (n = 40). Subsequently, postmortem brain analyses, genetic analyses, metabolomics of CSF samples from rats treated with lithium or valproic acid were also performed. After multivariate logistic regression, isocitric acid (isocitrate) levels were significantly higher in the CSF from BD patients than healthy controls. Furthermore, gene expression of two subtypes (IDH3A and IDH3B) of isocitrate dehydrogenase (IDH) in the dorsolateral prefrontal cortex from BD patients was significantly lower than that of controls, although the expression of other genes including, aconitase (ACO1, ACO2), IDH1, IDH2 and IDH3G, were not altered. Moreover, protein expression of IDH3A in the cerebellum from BD patients was higher than that of controls. Genetic analyses showed that IDH genes (IDH1, IDH2, IDH3A, IDH3B) and ACO genes (ACO1, ACO2) were not associated with BD. Chronic (4 weeks) treatment with lithium or valproic acid in rats did not alter CSF levels of isocitrate, and mRNA levels of Idh3a, Idh3b, Aco1 and Aco2 genes in the rat brain. These findings suggest that abnormality in the metabolism of isocitrate by IDH3A in the mitochondria plays a key role in the pathogenesis of BD, supporting the mitochondrial dysfunction hypothesis of BD. Therefore, IDH3 in the citric acid cycle could potentially be a novel therapeutic target for BD.
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| 29. |
- Zetterberg, Henrik, 1973, et al.
(författare)
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Blood-cerebrospinal fluid barrier dysfunction in patients with bipolar disorder in relation to antipsychotic treatment
- 2014
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Ingår i: Psychiatry Research. - : Elsevier BV. - 0165-1781 .- 1872-7123. ; 217:3, s. 143-146
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Tidskriftsartikel (refereegranskat)abstract
- Blood-cerebrospinal barrier (BCB) dysfunction has previously been shown in subjects with schizophrenia and depressed patients with attempted suicide. Bipolar disorder (BPD) shares clinical features with both these disorders, but it is unknown if the integrity of the BCB is altered also in BPD. To assess if BCB function in BPD we surveyed 134 mood-stabilized BPD patients and 86 healthy controls. Serum and cerebrospinal fluid (CSF) samples were collected and analyzed for albumin concentration by immunonephelometry. CSF/serum albumin ratio, an established measure of BCB function, was significantly elevated in BPD patients as compared to controls. After stratifying patients according to diagnostic subtype, BPD I patients had the highest CSF/serum albumin ratios. Moreover, BPD patients on antipsychotic treatment had higher CSF/serum albumin ratio than BPD patients on other treatments. When excluding BPD patients on antipsychotic treatment the difference in CSF/serum albumin ratio between the BPD and control groups disappeared. In conclusion, antipsychotic treatment in BPD is associated with elevated CSF/serum albumin ratio, tentatively as a sign of impaired BCB function. Whether this elevation is caused by antipsychotic treatment or is associated with a certain subtype of BPD, requiring antipsychotic treatment, remains to be determined. (C) 2014 Elsevier Ireland 'Ltd. All rights reserved.
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| 30. |
- Zhang, R. Y., et al.
(författare)
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Genome-wide study of immune biomarkers in cerebrospinal fluid and serum from patients with bipolar disorder and controls
- 2020
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder is a common, chronic psychiatric disorder. Despite high heritability, there is a paucity of identified genetic risk factors. Immune biomarkers are under more direct genetic influence than bipolar disorder. To explore the genetic associations with immune biomarker levels in cerebrospinal fluid (CSF) and blood serum which previously showed differences in bipolar disorder, we performed a study involving 291 individuals (184 bipolar disorder patients and 107 controls). The biomarkers assayed in both CSF and serum were: chitinase-3-like protein-1 (YKL-40), monocyte chemoattractant protein-1 (MCP-1), soluble cluster of differentiation (sCD14), tissue inhibitor of metalloproteinases-1 and 2 (TIMP-1 and TIMP-2). C-reactive protein (CRP) was only quantified in serum, and interleukin 8 (IL-8) measures were only available in CSF. Genome-wide association studies were conducted using PLINK for each of three genotyping waves and incorporated covariates for population substructure, age, sex, and body mass index (BMI). Results were combined by meta-analysis. Genome-wide significant associations were detected for all biomarkers except TIMP-1 and TIMP-2 in CSF. The strongest association in CSF was found for markers within the CNTNAP5 gene with YKL-40 (rs150248456, P=2.84x10(-10)). The strongest association in serum was also for YKL-40 but localized to the FANCI gene (rs188263039, P=5.80x10(-26)). This study revealed numerous biologically plausible genetic associations with immune biomarkers in CSF and blood serum. Importantly, the genetic variants regulating immune biomarker levels in CSF and blood serum differ. These results extend our knowledge of how biomarkers showing alterations in bipolar disorder are genetically regulated.
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