| 1. |
- Joas, Erik, et al.
(author)
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Effect of CYP2C19 polymorphisms on antidepressant prescription patterns and treatment emergent mania in bipolar disorder.
- 2023
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In: The pharmacogenomics journal. - : Springer Science and Business Media LLC. - 1473-1150 .- 1470-269X. ; 23:1, s. 28-35
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Journal article (peer-reviewed)abstract
- Antidepressant medication is used extensively to treat bipolar depression despite uncertain efficacy. The cytochrome P450 (CYP) 2C19 enzyme metabolize several antidepressants, and polymorphisms in the corresponding gene CYP2C19 influence plasma concentration and hence treatment outcomes in major depressive disorder. Here, we investigate if CYP2C19 polymorphisms are associated with antidepressant treatment patterns and the risk of mania when antidepressants are used in bipolar disorder. Two single nucleotide polymorphisms (rs4244285 and rs12248560) were used to classify 5019 bipolar disorder patients into CYP2C19 metabolic phenotypes ranging from poor to ultra-rapid metabolizers. We used Swedish national registry data 2005-2017 on dispensed medications and inpatient care to estimate risks for early-treatment persistence, treatment discontinuation, switching to a new antidepressant medication, and mania within 3 months of treatment initiation in patients treated with citalopram, escitalopram, sertraline, amitriptyline, and clomipramine. Metabolic phenotypes of CYP2C19 were not robustly associated with the investigated treatment outcomes based on dispense patterns. Slower metabolism was associated with an increased risk of treatment emergent mania for sertraline (hazard ratio [HR]=1.3, 95% CI=1.04-1.62, p=0.02) and the tricyclic antidepressants amitriptyline and clomipramine (HR=1.46, 95% CI=1.05-2.02, p=0.024). In a large study of the impact of CYP2C19 metabolic phenotypes on antidepressant treatment of bipolar depression, we found an association between slower CYP2C19 metabolism and higher risk of treatment emergent mania, which is a step towards personalized risk assessments. There were, however, no clear associations with early treatment persistence, treatment discontinuation, and switching to a new antidepressant.
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| 2. |
- Göteson, Andreas, 1991, et al.
(author)
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Cerebrospinal fluid proteomics targeted for central nervous system processes in bipolar disorder
- 2021
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In: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 26, s. 7446-53
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Journal article (peer-reviewed)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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| 3. |
- Isgren, Anniella, et al.
(author)
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Cerebrospinal fluid proteomic study of two bipolar disorder cohorts
- 2022
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In: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 27:11, s. 4568-4574
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Journal article (peer-reviewed)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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| 4. |
- Jonsson, Lina, 1982, et al.
(author)
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Association of Occupational Dysfunction and Hospital Admissions With Different Polygenic Profiles in Bipolar Disorder.
- 2024
-
In: The American journal of psychiatry. - 1535-7228. ; 181:7, s. 620-629
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Journal article (peer-reviewed)abstract
- Many but not all persons with bipolar disorder require hospital care because of severe mood episodes. Likewise, some but not all patients experience long-term occupational dysfunction that extends beyond acute mood episodes. It is not known whether these dissimilar outcomes of bipolar disorder are driven by different polygenic profiles. Here, polygenic scores (PGSs) for major psychiatric disorders and educational attainment were assessed for associations with occupational functioning and psychiatric hospital admissions in bipolar disorder.A total of 4,782 patients with bipolar disorder and 2,963 control subjects were genotyped and linked to Swedish national registers. Longitudinal measures from at least 10 years of registry data were used to derive percentage of years without employment, percentage of years with long-term sick leave, and mean number of psychiatric hospital admissions per year. Ordinal regression was used to test associations between outcomes and PGSs for bipolar disorder, schizophrenia, major depressive disorder, attention deficit hyperactivity disorder (ADHD), and educational attainment. Replication analyses of hospital admissions were conducted with data from the Bipolar Disorder Research Network cohort (N=4,219).Long-term sick leave and unemployment in bipolar disorder were significantly associated with PGSs for schizophrenia, ADHD, major depressive disorder, and educational attainment, but not with the PGS for bipolar disorder. By contrast, the number of hospital admissions per year was associated with higher PGSs for bipolar disorder and schizophrenia, but not with the other PGSs.Bipolar disorder severity (indexed by hospital admissions) was associated with a different polygenic profile than long-term occupational dysfunction. These findings have clinical implications, suggesting that mitigating occupational dysfunction requires interventions other than those deployed to prevent mood episodes.
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| 5. |
- Smedler, Erik, et al.
(author)
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Association of CACNA1C polymorphisms with serum BDNF levels in bipolar disorder.
- 2021
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In: The British journal of psychiatry : the journal of mental science. - : Royal College of Psychiatrists. - 1472-1465. ; 218:2, s. 77-79
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Journal article (peer-reviewed)abstract
- Variation in the CACNA1C gene has been associated with bipolar disorder in several genome-wide association studies. This gene encodes the alpha 1C subunit of L-type voltage-gated calcium channels, which play an essential role in neurons. We analysed 39 biomarkers in either cerebrospinal fluid or serum in relation to six different CACNA1C variants in 282 patients with bipolar disorder and 90 controls. We report associations of CACNA1C risk alleles with serum levels of BDNF as well as tissue plasminogen activator, which converts pro-BDNF to mature BDNF. This sheds light on links between CACNA1C genetic variants and pathophysiological mechanisms in bipolar disorder.Declaration of interestNone.
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| 6. |
- Smedler, Erik, et al.
(author)
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CACNA1C polymorphism and brain cortical structure in bipolar disorder
- 2019
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In: Journal of psychiatry & neuroscience : JPN. - : CMA Joule Inc.. - 1488-2434 .- 1180-4882. ; 45:1
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Journal article (peer-reviewed)abstract
- The CACNA1C gene encodes the 1C subunit of L-type voltage-gated calcium channels and has been associated with several psychiatric syndromes — including bipolar disorder — in several genome-wide association studies. Experimental and clinical studies have reported changes with respect to behaviour and biomarkers in risk allele carriers, corroborating the essential role of the CACNA1C gene in neurons, during development and in the mature brain. However, the association of this gene with regional cortical thickness has not been evaluated in patients with bipolar disorder.Using magnetic resonance imaging, we measured the average cortical thickness of 68 brain regions in 87 patients genotyped for the single-nucleotide polymorphism rs1006737 in CACNA1C.We found associations with the mean thickness of several cortical areas: the left lateral orbitofrontal and rostral anterior cingulate cortices, as well as other parts of the frontal and parietal cortices.This cross-sectional cohort study could not fully differentiate correlation from causation.The CACNA1C polymorphism rs1006737 is associated with the mean thickness of cortical brain areas that have been shown to be altered in bipolar disorder.
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| 7. |
- Smedler, Erik, et al.
(author)
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Metabolomics analysis of cerebrospinal fluid suggests citric acid cycle aberrations in bipolar disorder
- 2022
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In: Neuroscience Applied. - : Elsevier BV. - 2772-4085. ; 1
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Journal article (peer-reviewed)abstract
- Mounting evidence indicates mitochondrial dysfunction in bipolar disorder pathophysiology. Here, we employed Proton Nuclear Magnetic Resonance Spectroscopy (1H NMR) of cerebrospinal fluid (CSF) samples from well-characterized bipolar disorder patients (n = 67) and healthy controls (n = 55) in order to measure absolute concentrations of multiple metabolites. Focusing on four citric acid cycle metabolites — citrate, glucose, lactate, and pyruvate — we found higher concentrations of both citrate and glucose in patients compared with controls after correcting for age, sex and body mass index, but only the difference in CSF citrate survived correction for multiple comparisons. Within the patient group, CSF citrate concentrations were higher among lithium users than non-users. In conclusion, this report adds further evidence for a mitochondrial dysfunction in bipolar disorder.
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| 8. |
- Acke, Filip, 1968, et al.
(author)
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Influence of the platinum-support interaction on the direct reduction of NOx under lean conditions
- 1998
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In: Studies in Surface Science and Catalysis. - 0167-2991. ; 116, s. 285-294
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Journal article (peer-reviewed)abstract
- Catalysts containing Pt supported on SiC, Al2O3 and ZSM-5 were prepared and studied for NOx reduction by C3H6 in Oz excess under transient (temperature ramps) and steady-state conditions. The maximum NOx reduction activity in the heating ramp experiments was similar for Pt/SiC and Pt/ZSM-5, while Pt/Al2O3 showed higher maximum activity. Both N-2 and N2O formation was observed for all catalysts, although the respective amounts varied with the investigated system. Highest Nz selectivity was observed for Pt/Al2O3. When the NOx reduction activity was studied under steady-state conditions the activity of Pt/Al2O3 decreased substantially (mainly due to a loss in N-2 production). Pt/ZSM-5 became somewhat more selective towards Na production whereas the activity and selectivity of Pt/SiC remained at about the same values as far the heating ramp experiments. Adsorbed species on the surface of the different catalysts were investigated using in-situ FTIR in order to obtain information about the reaction mechanisms. The adsorption of species on Pt/SiC was negligible, while a number of absorption bands were observed for Pt/Al2O3 (N and C containing species, and -NCO) and Pt/ZSM-5 (HC).
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| 9. |
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| 10. |
- Engström, Per, et al.
(author)
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Sulphur dioxide interaction with NOx storage catalysts
- 1999
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In: Applied Catalysis B: Environmental. - 0926-3373 .- 1873-3883. ; 22:4, s. L241-L248
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Journal article (peer-reviewed)abstract
- The effect of SO2 on the NOx storage capacity and oxidation and reduction activities of a model Pt/Rh/BaO/Al2O3 NOx storage catalyst was investigated. Addition of 2.5, 7.5 or 25 vol. ppm SO2 to a synthetic lean exhaust gas caused deactivation of the NOx storage function, the oxidation activity and the reduction activity of the catalyst. The degree of deactivation of the NOx storage capacity was found to be proportional to the total SO2 dose that the catalyst had been exposed to. SO2 was found to be accumulated in the catalyst as sulphate.
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| 11. |
- Forsberg, David, et al.
(author)
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CO2-evoked release of PGE2 modulates sighs and inspiration as demonstrated in brainstem organotypic culture.
- 2016
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In: eLife. - 2050-084X. ; 5
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Journal article (peer-reviewed)abstract
- Inflammation-induced release of prostaglandin E2 (PGE2) changes breathing patterns and the response to CO2 levels. This may have fatal consequences in newborn babies and result in sudden infant death. To elucidate the underlying mechanisms, we present a novel breathing brainstem organotypic culture that generates rhythmic neural network and motor activity for 3 weeks. We show that increased CO2 elicits a gap junction-dependent release of PGE2. This alters neural network activity in the preBötzinger rhythm-generating complex and in the chemosensitive brainstem respiratory regions, thereby increasing sigh frequency and the depth of inspiration. We used mice lacking eicosanoid prostanoid 3 receptors (EP3R), breathing brainstem organotypic slices and optogenetic inhibition of EP3R(+/+) cells to demonstrate that the EP3R is important for the ventilatory response to hypercapnia. Our study identifies a novel pathway linking the inflammatory and respiratory systems, with implications for inspiration and sighs throughout life, and the ability to autoresuscitate when breathing fails.
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| 12. |
- Fridell, Erik, 1963, et al.
(author)
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Investigation of NOx storage catalysts
- 1997
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In: 4th International Congress on Catalysis and Automotive Pollution Control (CAPoC4) in Brussels, Belgium, April 9-11, 1997.
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Conference paper (peer-reviewed)
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| 13. |
- Fridell, Erik, 1963, et al.
(author)
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Investigations of NOx storage catalysts
- 1998
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In: Studies in Surface Science and Catalysis. - 0167-2991. ; 116, s. 537-547
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Journal article (peer-reviewed)abstract
- NOx storage catalysts are used to reduce nitrogen oxides from lean-burn vehicles. The nitrogen oxides are stored in the catalyst during lean conditions and subsequently released and reduced during short periods of rich conditions. In the present study, we systematically investigate the sequence of elementary steps in the NOx reduction cycle, and the extent to which these steps influence the maximum NOx, reduction potential of the catalyst. As a model system, we use barium oxide as the NOx, storing compound in a Pt/Rh/Al2O3 system. Kinetics of NO oxidation, NO and NO2 adsorption, NO and NO2 release and reduction are studied under controlled conditions with systematic variations of temperature, gas composition, and storing/release times. The transient experiments comprise a storing phase using a lean NO/C3H6/O2/N2 gas mixture, and a regenerating phase where the O2 now is turned off. Experimentally, a significant amount of NOx is found to be stored in the Ba-containing material. A maximum in NOx storage is observed around 380 degrees C. For most of the experiments, there are clear NO and NO2 desorption peaks upon switching from the storing to the regeneration phase. TPD studies of NO and NO2 reveal a significant difference between prereduced and pre-oxidised samples where the former produce predominantly N2 and N2O at around 200 degrees C while NO and O2 desorb from the latter around 500 degrees C. In situ FTIR spectra show nitrate peaks in the region 1300-1400 cm(-1) when NOx is stored under lean conditions.
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| 14. |
- Fridell, Erik, 1963, et al.
(author)
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NOx storage in barium-containing catalysts
- 1999
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In: Journal of Catalysis. - : Elsevier BV. - 0021-9517 .- 1090-2694. ; 183:2, s. 196-209
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Journal article (peer-reviewed)abstract
- The effect of key parameters on the characteristics of barium oxide-based NOx storage catalysts was systematically investigated. Model Pt/BaO/Al2O3, BaO/Al2O3, Pt–Rh/Al2O3, and Pt–Rh/BaO/Al2O3 catalysts were prepared and evaluated with respect to NOx storage capacity using transient flow reactor studies, temperature-programmed desorption studies (TPD), and in situ Fourier transform infrared (FTIR) absorption spectroscopy. The influence of temperature, storage and regeneration times, NOx source (NO or NO2), oxygen concentration, reducing agent (C3H6, C3H8, CO, or H2), and carbon dioxide concentration onNOx storage capacity was studied. Significant amounts of NOx were found to be stored in the catalysts containing both barium oxide and noble metals. For these catalysts the following observations were made: (1) maximum NOx storage was observed at about 380C;(2) around this temperature no significant differences between NO and NO2 on NOx storage capacity could be observed;(3) a slow increase in stored NOx could be observed with increasing oxygen concentration during the lean phase;(4) significant NOx desorption peaks, mainly of NO, were observed immediately after the switch from lean to rich conditions; and (5) at about 380±C the in situ FTIR spectra show characteristic nitrate peaks in the region 1300–1400 cm¡1 when NOx was stored under lean conditions and isocyanate peaks around 2230 cm-1 when the catalysts were regenerated under rich conditions in the presence of hydrocarbons. The step leading to stored NOx is believed to involve NO2 and the presence of atomic oxygen. During the rich period, the noble metal surfaces are probably reduced, leading to breakthrough peaks when NO desorbs.
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| 15. |
- Kitambi, Satish Srinivas, et al.
(author)
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Small molecule screening platform for assessment of cardiovascular toxicity on adult zebrafish heart.
- 2012
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In: BMC physiology. - : Springer Science and Business Media LLC. - 1472-6793. ; 12
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Journal article (peer-reviewed)abstract
- Cardiovascular toxicity is a major limiting factor in drug development and requires multiple cost-effective models to perform toxicological evaluation. Zebrafish is an excellent model for many developmental, toxicological and regenerative studies. Using approaches like morpholino knockdown and electrocardiogram, researchers have demonstrated physiological and functional similarities between zebrafish heart and human heart. The close resemblance of the genetic cascade governing heart development in zebrafish to that of humans has propelled the zebrafish system as a cost-effective model to conduct various genetic and pharmacological screens on developing embryos and larvae. The current report describes a methodology for rapid isolation of adult zebrafish heart, maintenance ex vivo, and a setup to perform quick small molecule throughput screening, including an in-house implemented analysis script.Adult zebrafish were anesthetized and after rapid decapitation the hearts were isolated. The short time required for isolation of hearts allows dissection of multiple fishes, thereby obtaining a large sample size. The simple protocol for ex vivo culture allowed maintaining the beating heart for several days. The in-house developed script and spectral analyses allowed the readouts to be presented either in time domain or in frequency domain. Taken together, the current report offers an efficient platform for performing cardiac drug testing and pharmacological screens.The new methodology presents a fast, cost-effective, sensitive and reliable method for performing small molecule screening. The variety of readouts that can be obtained along with the in-house developed analyses script offers a powerful setup for performing cardiac toxicity evaluation by researchers from both academics and industry.
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| 16. |
- Li, S. J., et al.
(author)
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The 1p36 Tumor Suppressor KIF 1B beta Is Required for Calcineurin Activation, Controlling Mitochondrial Fission and Apoptosis
- 2016
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In: Developmental Cell. - : Elsevier BV. - 1534-5807 .- 1878-1551. ; 36:2, s. 164-178
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Journal article (peer-reviewed)abstract
- KIF1B beta is a candidate 1p36 tumor suppressor that regulates apoptosis in the developing sympathetic nervous system. We found that KIF1B beta activates the Ca2+-dependent phosphatase calcineurin (CN) by stabilizing the CN-calmodulin complex, relieving enzymatic autoinhibition and enabling CN substrate recognition. CN is the key mediator of cellular responses to Ca2+ signals and its deregulation is implicated in cancer, cardiac, neurodegenerative, and immune disease. We show that KIF1B beta affects mitochondria! dynamics through CN-dependent dephosphorylation of Dynamin-related protein 1 (DRP1), causing mitochondria! fission and apoptosis. Furthermore, KIF1B beta actuates recognition of all known CN substrates, implying a general mechanism for KIF1B beta in Ca2+ signaling and how Ca2+-dependent signaling is executed by CN. Pathogenic KIF1B beta mutations previously identified in neuroblastomas and pheochromocytomas all fail to activate CN or stimulate DRP1 dephosphorylation. Importantly, KIF1B beta and DRP1 are silenced in 1p36 hemizygous-deleted neuroblastomas, indicating that deregulation of calcineurin and mitochondria! dynamics contributes to high-risk and poor-prognosis neuroblastoma.
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| 17. |
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| 18. |
- Smedler, Erik, et al.
(author)
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Association of premorbid intelligence with level of functioning and illness severity in bipolar disorder.
- 2023
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In: Journal of affective disorders. - : Elsevier BV. - 1573-2517 .- 0165-0327. ; 324, s. 449-454
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Journal article (peer-reviewed)abstract
- Bipolar disorder is a severe psychiatric syndrome defined by periodic mood shifts. Patients with bipolar disorder show cognitive impairments relative to healthy controls. The risk of developing schizophrenia, and partially also bipolar disorder, has previously been shown to increase with lower premorbid intelligence. It is not known if premorbid intelligence is associated with level of functioning and illness severity of people having developed bipolar disorder.We used multiple linear and ordinal regression to analyze how premorbid intelligence, as measured at conscription, associate with functional outcome and illness severity in Swedish male bipolar disorder patients (n=788).We found that lower premorbid intelligence is associated with lower percentage of time in work, after adjusting for age and bipolar subtype, and correcting for multiple comparisons. We also found a strong negative association with the total number of inpatient episodes and psychiatric comorbidity, but not with interepisodic remission, treatment with psychotherapy or lithium or the presence of any complicating socioeconomical factors. Adjusting for confounding genetic factors using polygenic risk scores for bipolar disorder and schizophrenia had no effect on the associations.This study lacks females and controls and may thus have lower generalizability.In conclusion, premorbid intelligence is associated with both level of functioning and illness severity as well as comorbidity in bipolar disorder patients. Further research is needed to develop targeted interventions for this subgroup of bipolar disorder patients.
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| 19. |
- Smedler, Erik
(author)
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Calcium signaling and network activity : mathematical modeling and molecular mechanisms
- 2017
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Doctoral thesis (other academic/artistic)abstract
- The calcium (Ca2+) ion is a versatile second messenger present in all cells. It is involved in such diverse processes as cell division, differentiation, vesicle transport and muscle contraction. Its widespread applicability is partially explained by its wide temporal and spatial dynamics. By varying in time, oscillations arise and enable frequency modulation. Likewise, by varying in space, waves are formed and enable cross talk in-between cells in networks. In here, I present novel data on the mechanism behind Ca2+ signaling both in the form of oscillations and in the form of intercellular networks. The investigation are performed both from a theoretical point of view using mathematical modeling simulated in silico and from a molecular point of view in wet-lab experiments in vitro and in vivo. To be more specific, in Paper I, I present a method with software to identify functional networks in groups of cells and ways of analyzing them. In Paper II, this method is used to identify so-called small-world networks with scale-free properties in spontaneously active neural progenitor cells. These network formations are dependent on gap junctions and critically regulate proliferation both in neural progenitors derived from embryonic stem cells and in embryonic mouse brains. In Paper III, I present a model for the generation of spontaneous Ca2+ oscillations in neural progenitors. The essence of this model is that the spontaneous Ca2+ and electrical activity is driven by functional pacemaker cells expressing slightly more voltage-gated Ca2+ channels than the cells connected to them with gap junctions. Interestingly, one type of channel involved in this pacemaker activity is encoded by the mental disorder susceptibility gene Cacna1c. Transgenic mice lacking Cacna1c expression in the forebrain exhibit signs of increased anxiety as well as changes in brain anatomy. Finally in Paper IV, I describe a method of finding genes dependent on the frequency of Ca2+ oscillations. Cells stably expressing the light-sensitive protein melanopsin are exposed to light, after which the cellular content is collected and analyzed with RT-qPCR, RNA sequencing and phosphoproteomics. Hereby, a large network of genes and proteins dependent on frequency is identified. In conclusion, the research described below deepens our understanding on Ca2+ oscillations and network activity, using both mathematical modeling and wet-lab molecular biology experiments.
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| 20. |
- Smedler, Erik, et al.
(author)
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Cerebrospinal fluid and serum protein markers in autism: A co-twin study.
- 2021
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In: Journal of neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 158:3, s. 798-806
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Journal article (peer-reviewed)abstract
- No robust biomarkers have yet been identified for autism spectrum disorder (ASD) or autistic traits. Familial factors likely influence biomarkers such as protein concentrations. Comparing twins with ASD or high autistic traits to the less affected co-twin allows estimating the impact of familial confounding. We measured 203 proteins in cerebrospinal fluid (n=86) and serum (n=127) in twins (mean age 14.2years, 44.9% females) enriched for ASD and other neurodevelopmental conditions. Autistic traits were assessed by using the parent-report version of the Social Responsiveness Scale-2. In cerebrospinal fluid, autistic traits correlated negatively with three proteins and positively with one. In serum, autistic traits correlated positively with 15 and negatively with one. Also in serum, six were positively-and one negatively-associated with ASD. A pathway analysis of these proteins revealed immune system enrichment. In within twin pair analyses, autistic traits were associated with serum B-cell activating factor (BAFF) only, whereas Cystatin B (CSTB) remained significantly associated with ASD. These associations did not remain significant when only considering monozygotic twins. For the remainder, the within-pair analysis indicated familial confounding, including shared environment and genes, influencing both autism and protein levels. Our findings indicate proteins involved in immunity as putative biomarkers of autistic traits and ASD with partial genetic confounding. Although some results are in line with previous studies in general, further studies are needed for replication.
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| 21. |
- Smedler, Erik, et al.
(author)
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Disrupted Cacna1c gene expression perturbs spontaneous Ca2+ activity causing abnormal brain development and increased anxiety.
- 2022
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 119:7
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Journal article (peer-reviewed)abstract
- The L-type voltage-gated Ca2+ channel gene CACNA1C is a risk gene for various psychiatric conditions, including schizophrenia and bipolar disorder. However, the cellular mechanism by which CACNA1C contributes to psychiatric disorders has not been elucidated. Here, we report that the embryonic deletion of Cacna1c in neurons destined for the cerebral cortex using an Emx1-Cre strategy disturbs spontaneous Ca2+ activity and causes abnormal brain development and anxiety. By combining computational modeling with electrophysiological membrane potential manipulation, we found that neural network activity was driven by intrinsic spontaneous Ca2+ activity in distinct progenitor cells expressing marginally increased levels of voltage-gated Ca2+ channels. MRI examination of the Cacna1c knockout mouse brains revealed volumetric differences in the neocortex, hippocampus, and periaqueductal gray. These results suggest that Cacna1c acts as a molecular switch and that its disruption during embryogenesis can perturb Ca2+ handling and neural development, which may increase susceptibility to psychiatric disease.
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| 22. |
- Smedler, Erik, et al.
(author)
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Genes, biomarkers, and clinical features associated with the course of bipolar disorder.
- 2019
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In: European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. - : Elsevier BV. - 1873-7862. ; 29:10, s. 1152-1160
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Journal article (peer-reviewed)abstract
- There is considerable variability in the severity of bipolar disorder, e.g., in terms of the frequency of inpatient episodes. The long-term progression also differs, where some patients are sensitised with progressively shorter healthy intervals. Little is known about the proportion of patients being sensitised, their clinical characteristics, and biological underpinnings. We analysed long-term progression of bipolar disorder in relation to clinical characteristics (N=3074), serum biomarkers (N=745), and genetic variants (N=1401) in a cohort of Swedish bipolar disorder patients. We took advantage of the National Patient Register, providing reliable data on 35,973 psychiatric inpatient care episodes in Sweden since 1973. First, one third of the cohort cluster together with a maximum of one inpatient episode per year, while the remaining two thirds had >1 episode per year. These groups did not differ with respect to clinical features or biomarkers. Second, among patients with at least five inpatient episodes (defined as severely ill), we find one group with progressively shorter cycle-lengths (one fifth of the total cohort, N=550). Compared with those with a stable or recuperant trajectory, these patients featured lower functioning, more antidepressant treatment, as well as reduced levels of inflammatory markers in serum. Third, sensitisation was associated with a common genetic variant near the calcium channel gene CACNA2D3 at genome-wide significance. These results suggest the potential for translational research aimed at preventive actions.
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| 23. |
- Smedler, Erik, et al.
(author)
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Reporting trigger factors for (hypo)manic episodes in bipolar disorder: association with personality and prognosis.
- 2020
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In: Acta psychiatrica Scandinavica. - : Wiley. - 1600-0447 .- 0001-690X. ; 141:6, s. 534-540
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Journal article (peer-reviewed)abstract
- To investigate external factors that trigger manic and hypomanic relapses and how this is associated with personality and clinical outcome measured as number of affective episodes over a seven-year period.This is a prospective cohort study of 204 meticulously characterized Swedish bipolar disorder patients. Personality was evaluated at baseline using the Swedish universities Scales of Personality in 170 patients, and 90 patients were followed up after approximately seven years in order to evaluate clinical outcomes.We found that 44% of the patients reported trigger factors, including sleep disturbance, work or family related issues, medication, and illicit drug use. There were no significant differences in any of the personality traits when comparing the 74 patients that reported triggers with the 90 patients that did not. At seven-year follow-up, there was no difference between the groups in number of affective episodes (depressive, hypomanic, manic or mixed), involuntary commitments, suicide attempts, or self-harm incidents since baseline.Around 40% of the patients reported external triggers for manic and hypomanic episodes. However, this was neither associated with personality traits nor number of affective episodes at seven-year follow-up.Around 40% of all bipolar disorder patients reported trigger factors for manic or hypomanic episodes. Reporting trigger factors was not associated with personality Reporting trigger factors was not associated with outcomes over a seven-year period. Limitations Patients had on average long duration of illness and may be less sensitive to external stressors than persons with recent onset. Trigger factors were identified retrospectively, and may thus be prone to recall bias. The number of affective episodes might be a too crude outcome measure as most subjects had not suffered any affective episodes at follow-up.
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| 24. |
- Song, Jie, et al.
(author)
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Key subphenotypes of bipolar disorder are differentially associated with polygenic liabilities for bipolar disorder, schizophrenia, and major depressive disorder
- 2024
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In: MOLECULAR PSYCHIATRY. - 1359-4184 .- 1476-5578.
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Journal article (peer-reviewed)abstract
- Bipolar disorder (BD) features heterogenous clinical presentation and course of illness. It remains unclear how subphenotypes associate with genetic loadings of BD and related psychiatric disorders. We investigated associations between the subphenotypes and polygenic risk scores (PRS) for BD, schizophrenia, and major depressive disorder (MDD) in two BD cohorts from Sweden (N = 5180) and the UK (N = 2577). Participants were assessed through interviews and medical records for inter-episode remission, psychotic features during mood episodes, global assessment of functioning (GAF, function and symptom burden dimensions), and comorbid anxiety disorders. Meta-analyses based on both cohorts showed that inter-episode remission and GAF-function were positively correlated with BD-PRS but negatively correlated with schizophrenia-PRS (SCZ-PRS) and MDD-PRS. Moreover, BD-PRS was negatively, and MDD-PRS positively, associated with the risk of comorbid anxiety disorders. Finally, SCZ-PRS was positively associated with psychotic symptoms during mood episodes. Assuming a higher PRS of certain psychiatric disorders in cases with a positive family history, we further tested the associations between subphenotypes in index BD people and occurrence of BD, schizophrenia, or MDD in their relatives using Swedish national registries. BD patients with a relative diagnosed with BD had: (1) higher GAF and lower risk of comorbid anxiety than those with a relative diagnosed with schizophrenia or MDD, (2) lower risk of psychotic symptoms than those with a relative diagnosed with schizophrenia. Our findings shed light on the genetic underpinnings of the heterogeneity in clinical manifestations and course of illness in BD, which ultimately provide insights for developing personalized approaches to the diagnosis and treatment.
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| 25. |
- Uhlen, Per, et al.
(author)
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Calcium Signaling in Neocortical Development
- 2015
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In: Developmental Neurobiology. - : Wiley. - 1932-8451 .- 1932-846X. ; 75:4, s. 360-368
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Journal article (peer-reviewed)abstract
- The calcium ion (Ca2+) is an essential second messenger that plays a pivotal role in neurogenesis. In the ventricular zone (VZ) of the neocortex, neural stem cells linger to produce progenitor cells and subsequently neurons and glial cells, which together build up the entire adult brain. The radial glial cells, with their characteristic radial fibers that stretch from the inner ventricular wall to the outer cortex, are known to be the neural stem cells of the neocortex. Migrating neurons use these radial fibers to climb from the proliferative VZ in the inner part of the brain to the outer layers of the cortex, where differentiation processes continue. To establish the complex structures that constitute the adult cerebral cortex, proliferation, migration, and differentiation must be tightly controlled by various signaling events, including cytosolic Ca2+ signaling. During development, cells regularly exhibit spontaneous Ca2+ activity that stimulates downstream effectors, which can elicit these fundamental cell processes. Spontaneous Ca2+ activity during early neocortical development depends heavily on gap junctions and voltage dependent Ca2+ channels, whereas later in development neurotransmitters and synapses exert an influence. Here, we provide an overview of the literature on Ca2+ signaling and its impact on cell proliferation, migration, and differentiation in the neocortex. We point out important historical studies and review recent progress in determining the role of Ca2+ signaling in neocortical development. (c) 2015 Wiley Periodicals, Inc. Develop Neurobiol 75: 360-368, 2015
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