| 11. |
- 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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| 12. |
- 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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| 13. |
- 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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| 14. |
- 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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| 15. |
- 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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| 16. |
- 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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| 17. |
- 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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| 18. |
- 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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| 19. |
- 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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| 20. |
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