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1.	Beaumont, Robin N, et al. (författare) Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth. 2023 Ingår i: Nature genetics. - 1546-1718 .- 1061-4036. ; 55:11, s. 1807-19 Tidskriftsartikel (refereegranskat)abstract A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n=65,405), maternal (n=61,228) and paternal (n=52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth.
2.	Brandt, Christine Lycke, et al. (författare) Cognitive effort and schizophrenia modulate large-scale functional brain connectivity 2015 Ingår i: Schizophrenia Bulletin. - 0586-7614 .- 1745-1701. ; 41:6, s. 1360-1369 Tidskriftsartikel (refereegranskat)abstract Schizophrenia (SZ) is characterized by cognitive dysfunction and disorganized thought, in addition to hallucinations and delusions, and is regarded a disorder of brain connectivity. Recent efforts have been made to characterize the underlying brain network organization and interactions. However, to which degree connectivity alterations in SZ vary across different levels of cognitive effort is unknown. Utilizing independent component analysis (ICA) and methods for delineating functional connectivity measures from functional magnetic resonance imaging (fMRI) data, we investigated the effects of cognitive effort, SZ and their interactions on between-network functional connectivity during 2 levels of cognitive load in a large and well-characterized sample of SZ patients (n = 99) and healthy individuals (n = 143). Cognitive load influenced a majority of the functional connections, including but not limited to fronto-parietal and default-mode networks, reflecting both decreases and increases in between-network synchronization. Reduced connectivity in SZ was identified in 2 large-scale functional connections across load conditions, with a particular involvement of an insular network. The results document an important role of interactions between insular, default-mode, and visual networks in SZ pathophysiology. The interplay between brain networks was robustly modulated by cognitive effort, but the reduced functional connectivity in SZ, primarily related to an insular network, was independent of cognitive load, indicating a relatively general brain network-level dysfunction.
3.	Docherty, Anna R, et al. (författare) GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors. 2023 Ingår i: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 180:10, s. 723-738 Tidskriftsartikel (refereegranskat)abstract Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses.Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors.This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.
4.	Lycke Brandt, Christine, et al. (författare) Working memory networks and activation patterns in schizophrenia and bipolar disorder : comparison with healthy controls 2014 Ingår i: British Journal of Psychiatry. - 0007-1250 .- 1472-1465. ; 204:4, s. 290-298 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Schizophrenia and bipolar disorder are severe mental disorders with overlapping genetic and clinical characteristics, including cognitive impairments. An important question is whether these disorders also have overlapping neuronal deficits.AIMS: To determine whether large-scale brain networks associated with working memory, as measured with functional magnetic resonance imaging (fMRI), are the same in both schizophrenia and bipolar disorder, and how they differ from those in healthy individuals.METHOD: Patients with schizophrenia (n = 100) and bipolar disorder (n = 100) and a healthy control group (n = 100) performed a 2-back working memory task while fMRI data were acquired. The imaging data were analysed using independent component analysis to extract large-scale networks of task-related activations.RESULTS: Similar working memory networks were activated in all groups. However, in three out of nine networks related to the experimental task there was a graded response difference in fMRI signal amplitudes, where patients with schizophrenia showed greater activation than those with bipolar disorder, who in turn showed more activation than healthy controls. Secondary analysis of the patient groups showed that these activation patterns were associated with history of psychosis and current elevated mood in bipolar disorder.CONCLUSIONS: The same brain networks were related to working memory in schizophrenia, bipolar disorder and controls. However, some key networks showed a graded hyperactivation in the two patient groups, in line with a continuum of neuronal abnormalities across psychotic disorders.
5.	Mullins, Niamh, et al. (författare) Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors 2022 Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 91:3, s. 313-327 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
6.	Mullins, Niamh, et al. (författare) GWAS of Suicide Attempt in Psychiatric Disorders and Association With Major Depression Polygenic Risk Scores 2019 Ingår i: American Journal of Psychiatry. - : American Psychiatric Association Publishing. - 0002-953X .- 1535-7228. ; 176:8, s. 651-660 Tidskriftsartikel (refereegranskat)abstract Objective: More than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium.Methods: The samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders.Results: Three genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%).Conclusions: This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.
7.	Oddsson, Asmundur, et al. (författare) Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality 2023 Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1 Tidskriftsartikel (refereegranskat)abstract Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.
8.	Solé Navais, Pol, et al. (författare) Genetic effects on the timing of parturition and links to fetal birth weight. 2023 Ingår i: Nature genetics. - 1546-1718. ; 55:4, s. 559-567 Tidskriftsartikel (refereegranskat)abstract The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration (n=195,555), identifying 22 associated loci (24 independent variants) and an enrichment in genes differentially expressed during labor. A meta-analysis of preterm delivery (18,797 cases, 260,246 controls) revealed six associated loci and large genetic similarities with gestational duration. Analysis of the parental transmitted and nontransmitted alleles (n=136,833) shows that 15 of the gestational duration genetic variants act through the maternal genome, whereas 7 act both through the maternal and fetal genomes and 2 act only via the fetal genome. Finally, the maternal effects on gestational duration show signs of antagonistic pleiotropy with the fetal effects on birth weight: maternal alleles that increase gestational duration have negative fetal effects on birth weight. The present study provides insights into the genetic effects on the timing of parturition and the complex maternal-fetal relationship between gestational duration and birth weight.
9.	Stefansson, Hreinn, et al. (författare) Homozygosity for R47H in TREM2 and the Risk of Alzheimer's Disease 2024 Ingår i: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 390:23, s. 2217-2219 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
10.	Van Schijndel, Jessica E., et al. (författare) Dual association of a TRKA polymorphism with schizophrenia 2011 Ingår i: Psychiatric Genetics. - : Lippincott Williams & Wilkins. - 0955-8829 .- 1473-5873. ; 21:3, s. 125-131 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE: An interaction between predisposing genes and environmental stressors is thought to underlie the neurodevelopmental disorder schizophrenia. In a targeted gene screening, we previously found that the minor allele of the single nucleotide polymorphism (SNP) rs6336 in the neurotrophic tyrosine kinase receptor 1 (NTRK1/TRKA) gene is associated with schizophrenia as a risk factor.METHODS: We genotyped the TRKA SNP in a total of eight independent Caucasian schizophrenia case-control groups.RESULT: Remarkably, although in five of the groups a higher frequency of the risk allele was indeed found in the patients compared with the controls, in the three other groups the SNP acted as a protective factor.CONCLUSION: An intriguing possibility is that this dual character of the TRKA SNP is caused by its interaction with endophenotypic and/or epistatic factors.
11.	Welander-Vatn, Audun, et al. (författare) The neural correlates of cognitive control in bipolar I disorder : an fMRI study of medial frontal cortex activation during a Go/No-go task 2013 Ingår i: Neuroscience Letters. - 0304-3940 .- 1872-7972. ; 549, s. 51-56 Tidskriftsartikel (refereegranskat)abstract In addition to dysregulation of mood, bipolar I disorder (BD I) is characterized by abnormalities in the execution of cognitive control. Hypoactivation of a specific sub-region in the cognitive control network, located in the medial frontal cortex, has been described among BD I patients. The aim of this study was to investigate whether patients with BD I showed decreased activation in this brain region as compared to healthy controls when performing a cognitive control task. Twenty-four BD I patients and 24 healthy controls performed a Go/No-go task during a functional magnetic resonance imaging (fMRI) session. Performance and response times were recorded. The BD I subjects had significantly slower response times and more patients made errors of omission compared to the healthy controls during the task. Both BD I subjects and healthy controls demonstrated activations in the brain region of interest during the task, but analyses revealed no statistically significant differences between groups. Although the patients display some deviances in behavioural measures, this study reveals no significant differences between BD I subjects and healthy controls in recruitment of the medial frontal cortex during a Go/No-go task.
12.	Abé, Christoph, et al. (författare) Longitudinal Structural Brain Changes in Bipolar Disorder: A Multicenter Neuroimaging Study of 1232 Individuals by the ENIGMA Bipolar Disorder Working Group. 2022 Ingår i: Biological psychiatry. - : Elsevier BV. - 1873-2402 .- 0006-3223. ; 91:6, s. 582-592 Tidskriftsartikel (refereegranskat)abstract Bipolar disorder (BD) is associated with cortical and subcortical structural brain abnormalities. It is unclear whether such alterations progressively change over time, and how this is related to the number of mood episodes. To address this question, we analyzed a large and diverse international sample with longitudinal magnetic resonance imaging (MRI) and clinical data to examine structural brain changes over time in BD.Longitudinal structural MRI and clinical data from the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) BD Working Group, including 307 patients with BD and 925 healthy control subjects, were collected from 14 sites worldwide. Male and female participants, aged 40 ± 17 years, underwent MRI at 2 time points. Cortical thickness, surface area, and subcortical volumes were estimated using FreeSurfer. Annualized change rates for each imaging phenotype were compared between patients with BD and healthy control subjects. Within patients, we related brain change rates to the number of mood episodes between time points and tested for effects of demographic and clinical variables.Compared with healthy control subjects, patients with BD showed faster enlargement of ventricular volumes and slower thinning of the fusiform and parahippocampal cortex (0.18
13.	Alnaes, Dag, et al. (författare) Brain Heterogeneity in Schizophrenia and Its Association With Polygenic Risk 2019 Ingår i: JAMA psychiatry. - : AMER MEDICAL ASSOC. - 2168-6238 .- 2168-622X. ; 76:7, s. 739-748 Tidskriftsartikel (refereegranskat)abstract ImportanceBetween-individual variability in brain structure is determined by gene-environment interactions, possibly reflecting differential sensitivity to environmental and genetic perturbations. Magnetic resonance imaging (MRI) studies have revealed thinner cortices and smaller subcortical volumes in patients with schizophrenia. However, group-level comparisons may mask considerable within-group heterogeneity, which has largely remained unnoticed in the literature. ObjectivesTo compare brain structural variability between individuals with schizophrenia and healthy controls and to test whether respective variability reflects the polygenic risk score (PRS) for schizophrenia in an independent sample of healthy controls. Design, Setting, and ParticipantsThis case-control and polygenic risk analysis compared MRI-derived cortical thickness and subcortical volumes between healthy controls and patients with schizophrenia across 16 cohorts and tested for associations between PRS and MRI features in a control cohort from the UK Biobank. Data were collected from October 27, 2004, through April 12, 2018, and analyzed from December 3, 2017, through August 1, 2018. Main Outcomes and MeasuresMean and dispersion parameters were estimated using double generalized linear models. Vertex-wise analysis was used to assess cortical thickness, and regions-of-interest analyses were used to assess total cortical volume, total surface area, and white matter, subcortical, and hippocampal subfield volumes. Follow-up analyses included within-sample analysis, test of robustness of the PRS threshold, population covariates, outlier removal, and control for image quality. ResultsA comparison of 1151 patients with schizophrenia (mean [SD] age,33.8[10.6] years; 68.6% male [n=790] and 31.4% female [n=361]) with 2010 healthy controls (mean [SD] age,32.6[10.4] years; 56.0% male [n=1126] and 44.0% female [n=884]) revealed higher heterogeneity in schizophrenia for cortical thickness and area (t = 3.34), cortical (t=3.24) and ventricle (t range, 3.15-5.78) volumes, and hippocampal subfields (t range, 2.32-3.55). In the UK Biobank sample of 12 490 participants (mean [SD] age,55.9 [7.5] years; 48.2% male [n=6025] and 51.8% female [n=6465]), higher PRS was associated with thinner frontal and temporal cortices and smaller left CA2/3 (t=-3.00) but was not significantly associated with dispersion. Conclusions and RelevanceThis study suggests that schizophrenia is associated with substantial brain structural heterogeneity beyond the mean differences. These findings may reflect higher sensitivity to environmental and genetic perturbations in patients, supporting the heterogeneous nature of schizophrenia. A higher PRS was associated with thinner frontotemporal cortices and smaller hippocampal subfield volume, but not heterogeneity. This finding suggests that brain variability in schizophrenia results from interactions between environmental and genetic factors that are not captured by the PRS. Factors contributing to heterogeneity in frontotemporal cortices and hippocampus are key to furthering our understanding of how genetic and environmental factors shape brain biology in schizophrenia.
14.	Aminoff, Sofie Ragnhild, et al. (författare) An association between affective lability and executive functioning in bipolar disorder. 2012 Ingår i: Psychiatry Research. - 0165-1781 .- 1872-7123. ; 198:1, s. 58-61 Tidskriftsartikel (refereegranskat)abstract Studies suggest altered affect regulation manifested by affective lability in manic/mixed and euthymic states in patients with bipolar disorder (BD). Altered affect regulation may arise from disturbances in interactions between the cognitive and the emotional brain networks. However, the relationship between affective lability and executive function has not previously been studied. Our aim was to investigate affective lability, as measured with the Affective Lability Scale (ALS) in patients with BD (N=32) compared to healthy controls (HC) (N=60), and its relationship to executive functioning. We found significantly higher ALS scores in the BD than in the HC group, indicating a higher degree of affective lability in patients with BD. Sub-sample analysis revealed a significant positive relationship between affective lability and semantic set shifting abilities in BD only. These findings suggest that higher levels of affective lability compared with controls are a trait as well as state dependent in BD, and that disturbed affective lability may arise from an aberrant interaction between cognitive and emotional brain networks.
15.	Aminoff, Sofie R, et al. (författare) Decreased self-reported arousal in schizophrenia during aversive picture viewing compared to bipolar disorder and healthy controls. 2011 Ingår i: Psychiatry Research. - 0165-1781 .- 1872-7123. ; 185:3, s. 309-314 Tidskriftsartikel (refereegranskat)abstract Both schizophrenia (SCZ) and bipolar disorder (BD) are associated with disturbances in emotion processing. Previous studies suggest that patients with SCZ assess unpleasant pictures as less arousing than healthy controls (HC), while patients with BD assess neutral pictures as more arousing than HC. No previous studies have investigated whether there is a difference in emotional response across all three groups. Our aim was to explore whether there was a difference in the evaluation of valence and in arousal between SCZ, BD and HC for aversive and neutral pictures. We showed 72 pictures (neutral, non-socially aversive and socially aversive) from the International Affective Picture System (IAPS) to 347 subjects. There was a clear interaction effect between the diagnostic group and increasing picture aversiveness for both valence and arousal. There were no significant differences in valence ratings between the different groups or in arousal ratings on any type of stimuli between BD patients and HC. However, SCZ patients reported significantly lower arousal for aversive stimuli, particularly with a social content, when compared to BD patients and HC. This was more pronounced in females. The presence of lifetime psychotic symptoms did not influence emotional responses.
16.	Andreou, Dimitrios, et al. (författare) d-amino acid oxidase activator gene (DAOA) variation affects cerebrospinal fluid homovanillic acid concentrations in healthy Caucasians 2012 Ingår i: European Archives of Psychiatry and Clinical Neuroscience. - : Springer Science and Business Media LLC. - 0940-1334 .- 1433-8491. ; 262:7, s. 549-556 Tidskriftsartikel (refereegranskat)abstract The d-amino acid oxidase activator (DAOA) protein regulates the function of d-amino oxidase (DAO), an enzyme that catalyzes the oxidative deamination of d-3,4-dihydroxyphenylalanine (D-DOPA) and d-serine. D-DOPA is converted to l-3,4-DOPA, a precursor of dopamine, whereas d-serine participates in glutamatergic transmission. We hypothesized that DAOA polymorphisms are associated with dopamine, serotonin and noradrenaline turnover in the human brain. Four single-nucleotide polymorphisms, previously reported to be associated with schizophrenia, were genotyped. Cerebrospinal fluid (CSF) samples were drawn by lumbar puncture, and the concentrations of the major dopamine metabolite homovanillic acid (HVA), the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) and the major noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured. Two of the investigated polymorphisms, rs3918342 and rs1421292, were significantly associated with CSF HVA concentrations. Rs3918342 was found to be nominally associated with CSF 5-HIAA concentrations. None of the polymorphisms were significantly associated with MHPG concentrations. Our results indicate that DAOA gene variation affects dopamine turnover in healthy individuals, suggesting that disturbed dopamine turnover is a possible mechanism behind the observed associations between genetic variation in DAOA and behavioral phenotypes in humans.
17.	Andreou, Dimitrios, et al. (författare) Dystrobrevin-binding protein 1 gene (DTNBP1) variants associated with cerebrospinal fluid homovanillic acid and 5-hydroxyindoleacetic acid concentrations in healthy volunteers 2011 Ingår i: European Neuropsychopharmacology. - : Elsevier BV. - 0924-977X .- 1873-7862. ; 21:9, s. 700-704 Tidskriftsartikel (refereegranskat)abstract The dystrobrevin binding protein-1 (DTNBP1) gene encodes dysbindin-1, a protein involved in neurodevelopmental and neurochemical processes related mainly to the monoamine dopamine. We investigated possible associations between eleven DTNBP1 polymorphisms and cerebrospinal fluid (CSF) concentrations of the major dopamine metabolite homovanillic acid (HVA), the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), and the major noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy human subjects (n=132). Two polymorphisms, rs2619538 and rs760666, were nominally associated with CSF HVA and 5-HIAA concentrations, whereas a third polymorphism, rs909706, showed association only with HVA. After correction for multiple testing only the associations between rs2619538 and HVA and 5-HIAA concentrations remained significant. No significant association was found between any of the investigated DTNBP1 polymorphisms and CSF MHPG concentrations. The results suggest that genetic variation in DTNBP1 gene affects the regulation of dopamine and serotonin turnover in the central nervous system of healthy volunteers.
18.	Andreou, Dimitrios, et al. (författare) Tryptophan hydroxylase gene 1 (TPH1) variants associated with cerebrospinal fluid 5-hydroxyindole acetic acid and homovanillic acid concentrations in healthy volunteers 2010 Ingår i: Psychiatry Research. - : Elsevier BV. - 0165-1781 .- 1872-7123. ; 180:2-3, s. 63-67 Tidskriftsartikel (refereegranskat)abstract Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in serotonin synthesis. We investigated possible relationships between five TPH1 gene polymorphisms and cerebrospinal fluid (CSF) concentrations of the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the major dopamine metabolite homovanillic acid (HVA), and the major norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy volunteers (n = 132). The G-allele of the TPH1 rs4537731 (A-6526G) polymorphism was associated with 5-HIM and HVA, but not MHPG concentrations. None of the other four TPH1 polymorphisms (rs211105, rs1800532, rs1799913 and rs7933505) were significantly associated with any of the monoamine metabolite concentrations. Two (rs4537731G/rs211105T/rs1800532C/rs1799913C/rs7933505G and rs4537731A/rs211105T/rs1800532C/rs1799913C/rs7933505G) of five common TPH1 five-allele haplotypes were associated with 5-HIAA and HVA concentrations in opposite directions. None of the common haplotypes was associated with MHPG concentrations in the CSF. The results suggest that TPH1 gene variation participates in the regulation of serotonin and dopamine turnover rates in the central nervous system of healthy human subjects.
19.	Andreou, Dimitrios, et al. (författare) Tyrosine hydroxylase Val81Met polymorphism : lack of association with schizophrenia 2009 Ingår i: Psychiatric Genetics. - 0955-8829 .- 1473-5873. ; 19:5, s. 273-274 Tidskriftsartikel (refereegranskat)
20.	Arango, Celso, et al. (författare) Risk and protective factors for mental disorders beyond genetics: an evidence-based atlas 2021 Ingår i: World Psychiatry. - : John Wiley & Sons. - 1723-8617 .- 2051-5545. ; 20:3, s. 417-436 Tidskriftsartikel (refereegranskat)abstract Decades of research have revealed numerous risk factors for mental disorders beyond genetics, but their consistency and magnitude remain uncer-tain. We conducted a "meta-umbrella" systematic synthesis of umbrella reviews, which are systematic reviews of meta-analyses of individual studies, by searching international databases from inception to January 1, 2021. We included umbrella reviews on non-purely genetic risk or protective factors for any ICD/DSM mental disorders, applying an established classification of the credibility of the evidence: class I (convincing), class II (highly suggestive), class III (suggestive), class IV (weak). Sensitivity analyses were conducted on prospective studies to test for temporality (reverse causation), TRANSD criteria were applied to test transdiagnosticity of factors, and A Measurement Tool to Assess Systematic Reviews (AMSTAR) was employed to address the quality of meta-analyses. Fourteen eligible umbrella reviews were retrieved, summarizing 390 meta-analyses and 1,180 associations between putative risk or protective factors and mental disorders. We included 176 class I to III evidence associations, relating to 142 risk/protective factors. The most robust risk factors (class I or II, from prospective designs) were 21. For dementia, they included type 2 diabetes mellitus (risk ratio, RR from 1.54 to 2.28), depression (RR from 1.65 to 1.99) and low frequency of social contacts (RR=1.57). For opioid use disorders, the most robust risk factor was tobacco smoking (odds ratio, OR=3.07). For non-organic psychotic disorders, the most robust risk factors were clinical high risk state for psychosis (OR=9.32), cannabis use (OR=3.90), and childhood adversities (OR=2.80). For depressive disorders, they were widowhood (RR=5.59), sexual dysfunction (OR=2.71), three (OR=1.99) or four-five (OR=2.06) metabolic factors, childhood physical (OR=1.98) and sexual (OR=2.42) abuse, job strain (OR=1.77), obesity (OR=1.35), and sleep disturbances (RR=1.92). For autism spectrum disorder, the most robust risk factor was maternal overweight pre/during pregnancy (RR=1.28). For attention-deficit/hyperactivity disorder (ADHD), they were maternal pre-pregnancy obesity (OR=1.63), maternal smoking during pregnancy (OR=1.60), and maternal overweight pre/during pregnancy (OR=1.28). Only one robust protective factor was detected: high physical activity (hazard ratio, HR=0.62) for Alzheimers disease. In all, 32.9% of the associations were of high quality, 48.9% of medium quality, and 18.2% of low quality. Transdiagnostic class I-III risk/protective factors were mostly involved in the early neurodevelopmental period. The evidence-based atlas of key risk and protective factors identified in this study represents a benchmark for advancing clinical characterization and research, and for expanding early intervention and preventive strategies for mental disorders.
21.	Barth, Claudia, et al. (författare) In vivo white matter microstructure in adolescents with early-onset psychosis : a multi-site mega-analysis 2023 Ingår i: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 28, s. 1159-1169 Tidskriftsartikel (refereegranskat)abstract Emerging evidence suggests brain white matter alterations in adolescents with early-onset psychosis (EOP; age of onset <18 years). However, as neuroimaging methods vary and sample sizes are modest, results remain inconclusive. Using harmonized data processing protocols and a mega-analytic approach, we compared white matter microstructure in EOP and healthy controls using diffusion tensor imaging (DTI). Our sample included 321 adolescents with EOP (median age=16.6 years, interquartile range (IQR)=2.14, 46.4% females) and 265 adolescent healthy controls (median age=16.2 years, IQR=2.43, 57.7% females) pooled from nine sites. All sites extracted mean fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) for 25 white matter regions of interest per participant. ComBat harmonization was performed for all DTI measures to adjust for scanner differences. Multiple linear regression models were fitted to investigate case-control differences and associations with clinical variables in regional DTI measures. We found widespread lower FA in EOP compared to healthy controls, with the largest effect sizes in the superior longitudinal fasciculus (Cohen's d=0.37), posterior corona radiata (d=0.32), and superior fronto-occipital fasciculus (d=0.31). We also found widespread higher RD and more localized higher MD and AD. We detected significant effects of diagnostic subgroup, sex, and duration of illness, but not medication status. Using the largest EOP DTI sample to date, our findings suggest a profile of widespread white matter microstructure alterations in adolescents with EOP, most prominently in male individuals with early-onset schizophrenia and individuals with a shorter duration of illness.
22.	Bauer, Michael, et al. (författare) Association between solar insolation and a history of suicide attempts in bipolar I disorder. 2019 Ingår i: Journal of psychiatric research. - : Elsevier BV. - 1879-1379 .- 0022-3956. ; 113, s. 1-9 Tidskriftsartikel (refereegranskat)abstract In many international studies, rates of completed suicide and suicide attempts have a seasonal pattern that peaks in spring or summer. This exploratory study investigated the association between solar insolation and a history of suicide attempt in patients with bipolar I disorder. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area on Earth. Data were collected previously from 5536 patients with bipolar I disorder at 50 collection sites in 32 countries at a wide range of latitudes in both hemispheres. Suicide related data were available for 3365 patients from 310 onset locations in 51 countries. 1047 (31.1%) had a history of suicide attempt. There was a significant inverse association between a history of suicide attempt and the ratio of mean winter solar insolation/mean summer solar insolation. This ratio is smallest near the poles where the winter insolation is very small compared to the summer insolation. This ratio is largest near the equator where there is relatively little variation in the insolation over the year. Other variables in the model that were positively associated with suicide attempt were being female, a history of alcohol or substance abuse, and being in a younger birth cohort. Living in a country with a state-sponsored religion decreased the association. (All estimated coefficients p<0.01). In summary, living in locations with large changes in solar insolation between winter and summer may be associated with increased suicide attempts in patients with bipolar disorder. Further investigation of the impacts of solar insolation on the course of bipolar disorder is needed.
23.	Beck, Dani, et al. (författare) Adipose tissue distribution from body MRI is associated with cross-sectional and longitudinal brain age in adults 2022 Ingår i: NeuroImage. - : Elsevier Science Ltd. - 2213-1582. ; 33 Tidskriftsartikel (refereegranskat)abstract There is an intimate body-brain connection in ageing, and obesity is a key risk factor for poor cardiometabolic health and neurodegenerative conditions. Although research has demonstrated deleterious effects of obesity on brain structure and function, the majority of studies have used conventional measures such as waist-to-hip ratio, waist circumference, and body mass index. While sensitive to gross features of body composition, such global anthropometric features fail to describe regional differences in body fat distribution and composition. The sample consisted of baseline brain magnetic resonance imaging (MRI) acquired from 790 healthy participants aged 18-94 years (mean +/- standard deviation (SD) at baseline: 46.8 +/- 16.3), and follow-up brain MRI collected from 272 of those individuals (two time-points with 19.7 months interval, on average (min = 9.8, max = 35.6). Of the 790 included participants, cross-sectional body MRI data was available from a subgroup of 286 participants, with age range 19-86 (mean = 57.6, SD = 15.6). Adopting a mixed cross-sectional and longitudinal design, we investigated cross-sectional body magnetic resonance imaging measures of adipose tissue distribution in relation to longitudinal brain structure using MRI-based morphometry (T1) and diffusion tensor imaging (DTI). We estimated tissue-specific brain age at two time points and performed Bayesian multilevel modelling to investigate the associations between adipose measures at follow-up and brain age gap (BAG) - the difference between actual age and the prediction of the brains biological age - at baseline and follow-up. We also tested for interactions between BAG and both time and age on each adipose measure. The results showed credible associations between T1-based BAG and liver fat, muscle fat infiltration (MFI), and weight-to-muscle ratio (WMR), indicating older-appearing brains in people with higher measures of adipose tissue. Longitudinal evidence supported interaction effects between time and MFI and WMR on T1-based BAG, indicating accelerated ageing over the course of the study period in people with higher measures of adipose tissue. The results show that specific measures of fat distribution are associated with brain ageing and that different compartments of adipose tissue may be differentially linked with increased brain ageing, with potential to identify key processes involved in age-related transdiagnostic disease processes.
24.	Beck, Dani, et al. (författare) Dissecting unique and common variance across body and brain health indicators using age prediction 2024 Ingår i: Human Brain Mapping. - : WILEY. - 1065-9471 .- 1097-0193. ; 45:6 Tidskriftsartikel (refereegranskat)abstract Ageing is a heterogeneous multisystem process involving different rates of decline in physiological integrity across biological systems. The current study dissects the unique and common variance across body and brain health indicators and parses inter-individual heterogeneity in the multisystem ageing process. Using machine-learning regression models on the UK Biobank data set (N = 32,593, age range 44.6-82.3, mean age 64.1 years), we first estimated tissue-specific brain age for white and gray matter based on diffusion and T1-weighted magnetic resonance imaging (MRI) data, respectively. Next, bodily health traits, including cardiometabolic, anthropometric, and body composition measures of adipose and muscle tissue from bioimpedance and body MRI, were combined to predict 'body age'. The results showed that the body age model demonstrated comparable age prediction accuracy to models trained solely on brain MRI data. The correlation between body age and brain age predictions was 0.62 for the T1 and 0.64 for the diffusion-based model, indicating a degree of unique variance in brain and bodily ageing processes. Bayesian multilevel modelling carried out to quantify the associations between health traits and predicted age discrepancies showed that higher systolic blood pressure and higher muscle-fat infiltration were related to older-appearing body age compared to brain age. Conversely, higher hand-grip strength and muscle volume were related to a younger-appearing body age. Our findings corroborate the common notion of a close connection between somatic and brain health. However, they also suggest that health traits may differentially influence age predictions beyond what is captured by the brain imaging data, potentially contributing to heterogeneous ageing rates across biological systems and individuals. A 'body age' model trained on health traits demonstrated comparable age prediction accuracy to models trained solely on brain MRI data. Health traits may differentially influence age predictions beyond what is captured by the brain imaging data, revealing a degree of unique variance in brain and bodily ageing processes. image
25.	Belloy, Michael E., et al. (författare) Challenges at the APOE locus : a robust quality control approach for accurate APOE genotyping 2022 Ingår i: Alzheimer's Research & Therapy. - : Springer Nature. - 1758-9193. ; 14:1 Tidskriftsartikel (refereegranskat)abstract Background: Genetic variants within the APOE locus may modulate Alzheimer's disease (AD) risk independently or in conjunction with APOE2/3/4 genotypes. Identifying such variants and mechanisms would importantly advance our understanding of APOE pathophysiology and provide critical guidance for AD therapies aimed at APOE. The APOE locus however remains relatively poorly understood in AD, owing to multiple challenges that include its complex linkage structure and uncertainty in APOE2/3/4 genotype quality. Here, we present a novel APOE2/3/4 filtering approach and showcase its relevance on AD risk association analyses for the rs439401 variant, which is located 1801 base pairs downstream of APOE and has been associated with a potential regulatory effect on APOE.Methods: We used thirty-two AD-related cohorts, with genetic data from various high-density single-nucleotide polymorphism microarrays, whole-genome sequencing, and whole-exome sequencing. Study participants were filtered to be ages 60 and older, non-Hispanic, of European ancestry, and diagnosed as cognitively normal or AD (n = 65,701). Primary analyses investigated AD risk in APOE4/4 carriers. Additional supporting analyses were performed in APOE3/4 and 3/3 strata. Outcomes were compared under two different APOE2/3/4 filtering approaches.Results: Using more conventional APOE2/3/4 filtering criteria (approach 1), we showed that, when in-phase with APOE4, rs439401 was variably associated with protective effects on AD case-control status. However, when applying a novel filter that increases the certainty of the APOE2/3/4 genotypes by applying more stringent criteria for concordance between the provided APOE genotype and imputed APOE genotype (approach 2), we observed that all significant effects were lost. Conclusions: We showed that careful consideration of APOE genotype and appropriate sample filtering were crucial to robustly interrogate the role of the APOE locus on AD risk. Our study presents a novel APOE filtering approach and provides important guidelines for research into the APOE locus, as well as for elucidating genetic interaction effects with APOE2/3/4.
26.	Boen, Rune, et al. (författare) Beyond the global brain differences : intraindividual variability differences in 1q21.1 distal and 15q11.2 bp1-bp2 deletion carriers 2024 Ingår i: Biological Psychiatry. - 0006-3223 .- 1873-2402. ; 95:2, s. 147-160 Tidskriftsartikel (refereegranskat)abstract Background: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure.Methods: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual's regional difference and global difference, were used to test for regional differences that diverge from the global difference.Results: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness.Conclusions: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment.
27.	Bolstad, Ingeborg, et al. (författare) Aversive event anticipation affects connectivity between the ventral striatum and the orbitofrontal cortex in an fMRI avoidance task 2013 Ingår i: PLOS ONE. - 1932-6203. ; 8:6, s. e68494- Tidskriftsartikel (refereegranskat)abstract Ability to anticipate aversive events is important for avoiding dangerous or unpleasant situations. The motivation to avoid an event is influenced by the incentive salience of an event-predicting cue. In an avoidance fMRI task we used tone intensities to manipulate salience in order to study the involvement of the orbitofrontal cortex in processing of incentive salience. In the task, cues predicting either aversive or neutral avoidable tones were presented. Ventral striatum, amygdala and anterior insula activations were significantly stronger during presentation of cues for aversive than neutral tones. A psychophysiological interaction analysis showed stronger connectivity between the ventral striatum and the orbitofrontal cortex during aversive than neutral conditions. The present study shows an interaction between the ventral striatum, a structure previously linked to negative incentive salience, and the orbitofrontal cortex supporting a role for this region in processing salience. In addition, this study replicates previous findings suggesting that the task is robust.
28.	Bolstad, Ingeborg, et al. (författare) Aversive event anticipation affects connectivity between the ventral striatum and the orbitofrontal cortex in an fMRI avoidance task 2013 Ingår i: PLoS ONE. - : Public Library of Science. - 1932-6203. ; 8:6 Tidskriftsartikel (refereegranskat)abstract Ability to anticipate aversive events is important for avoiding dangerous or unpleasant situations. The motivation to avoid an event is influenced by the incentive salience of an event-predicting cue. In an avoidance fMRI task we used tone intensities to manipulate salience in order to study the involvement of the orbitofrontal cortex in processing of incentive salience. In the task, cues predicting either aversive or neutral avoidable tones were presented. Ventral striatum, amygdala and anterior insula activations were significantly stronger during presentation of cues for aversive than neutral tones. A psychophysiological interaction analysis showed stronger connectivity between the ventral striatum and the orbitofrontal cortex during aversive than neutral conditions. The present study shows an interaction between the ventral striatum, a structure previously linked to negative incentive salience, and the orbitofrontal cortex supporting a role for this region in processing salience. In addition, this study replicates previous findings suggesting that the task is robust.
29.	Bolstad, Ingeborg, et al. (författare) Effects of haloperidol and aripiprazole on the human mesolimbic motivational system : a pharmacological fMRI study 2015 Ingår i: European Neuropsychopharmacology. - 0924-977X .- 1873-7862. ; 25:12, s. 2252-2261 Tidskriftsartikel (refereegranskat)abstract The atypical antipsychotic drug aripiprazole is a partial dopamine (DA) D2 receptor agonist, which differentiates it from most other antipsychotics. This study compares the brain activation characteristic produced by aripiprazole with that of haloperidol, a typical D2 receptor antagonist. Healthy participants received an acute oral dose of haloperidol, aripiprazole or placebo, and then performed an active aversive conditioning task with aversive and neutral events presented as sounds, while blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was carried out. The fMRI task, targeting the mesolimbic motivational system that is thought to be disturbed in psychosis, was based on the conditioned avoidance response (CAR) animal model - a widely used test of therapeutic potential of antipsychotic drugs. In line with the CAR animal model, the present results show that subjects given haloperidol were not able to avoid more aversive than neutral task trials, even though the response times were shorter during aversive events. In the aripiprazole and placebo groups more aversive than neutral events were avoided. Accordingly, the task-related BOLD-fMRI response in the mesolimbic motivational system was diminished in the haloperidol group compared to the placebo group, particularly in the ventral striatum, whereas the aripiprazole group showed task-related activations intermediate of the placebo and haloperidol groups. The current results show differential effects on brain function by aripiprazole and haloperidol, probably related to altered DA transmission. This supports the use of pharmacological fMRI to study antipsychotic properties in humans.
30.	Bolstad, Ingeborg, et al. (författare) Effects of haloperidol and aripiprazole on the human mesolimbic motivational system : a pharmacological fMRI study 2015 Ingår i: European Neuropsychopharmacology. - : Elsevier. - 0924-977X .- 1873-7862. ; 25:12, s. 2252-2261 Tidskriftsartikel (refereegranskat)abstract The atypical antipsychotic drug aripiprazole is a partial dopamine (DA) D2 receptor agonist, which differentiates it from most other antipsychotics. This study compares the brain activation characteristic produced by aripiprazole with that of haloperidol, a typical D2 receptor antagonist. Healthy participants received an acute oral dose of haloperidol, aripiprazole or placebo, and then performed an active aversive conditioning task with aversive and neutral events presented as sounds, while blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was carried out. The fMRI task, targeting the mesolimbic motivational system that is thought to be disturbed in psychosis, was based on the conditioned avoidance response (CAR) animal model - a widely used test of therapeutic potential of antipsychotic drugs. In line with the CAR animal model, the present results show that subjects given haloperidol were not able to avoid more aversive than neutral task trials, even though the response times were shorter during aversive events. In the aripiprazole and placebo groups more aversive than neutral events were avoided. Accordingly, the task-related BOLD-fMRI response in the mesolimbic motivational system was diminished in the haloperidol group compared to the placebo group, particularly in the ventral striatum, whereas the aripiprazole group showed task-related activations intermediate of the placebo and haloperidol groups. The current results show differential effects on brain function by aripiprazole and haloperidol, probably related to altered DA transmission. This supports the use of pharmacological fMRI to study antipsychotic properties in humans.
31.	Bolstad, Ingeborg, et al. (författare) No difference in frontal cortical activity during an executive functioning task after acute doses of aripiprazole and haloperidol 2015 Ingår i: Frontiers in Human Neuroscience. - 1662-5161 .- 1662-5161. ; 9 Tidskriftsartikel (refereegranskat)abstract Background: Aripiprazole is an atypical antipsychotic drug that is characterized by partial dopamine D2 receptor agonism. Its pharmacodynamic profile is proposed to be beneficial in the treatment of cognitive impairment, which is prevalent in psychotic disorders. This study compared brain activation characteristics produced by aripiprazole with that of haloperidol, a typical D2 receptor antagonist, during a task targeting executive functioning.Methods: Healthy participants received an acute oral dose of haloperidol, aripiprazoleor placebo before performing an executive functioning task while blood-oxygen-level dependent (BOLD) functional magnetic resonance imaging (fMRI) was carried out.Results: There was a tendency towards reduced performance in the aripiprazole group compared to the two other groups. The image analysis yielded a strong task related BOLD-fMRI response within each group. An uncorrected between-group analysis showed that aripiprazole challenge resulted in stronger activation in the frontal and temporal gyri and the putamen compared with haloperidol challenge, but after correcting for multiple testing there was no significant group difference.Conclusion: No significant group differences between aripiprazole and haloperidol infrontal cortical activation were obtained when corrected for multiple comparisons.
32.	Bolstad, Ingeborg, et al. (författare) No difference in frontal cortical activity during an executive functioning task after acute doses of aripiprazole and haloperidol 2015 Ingår i: Frontiers in Human Neuroscience. - : Frontiers Media S.A.. - 1662-5161. ; 9 Tidskriftsartikel (refereegranskat)abstract Background: Aripiprazole is an atypical antipsychotic drug that is characterized by partial dopamine D2 receptor agonism. Its pharmacodynamic profile is proposed to be beneficial in the treatment of cognitive impairment, which is prevalent in psychotic disorders. This study compared brain activation characteristics produced by aripiprazole with that of haloperidol, a typical D2 receptor antagonist, during a task targeting executive functioning. Methods: Healthy participants received an acute oral dose of haloperidol, aripiprazoleor placebo before performing an executive functioning task while blood-oxygen-level dependent (BOLD) functional magnetic resonance imaging (fMRI) was carried out. Results: There was a tendency towards reduced performance in the aripiprazole group compared to the two other groups. The image analysis yielded a strong task related BOLD-fMRI response within each group. An uncorrected between-group analysis showed that aripiprazole challenge resulted in stronger activation in the frontaland temporal gyri and the putamen compared with haloperidol challenge, but after correcting for multiple testing there was no significant group difference. Conclusion: No significant group differences between aripiprazole and haloperidol infrontal cortical activation were obtained when corrected for multiple comparisons.
33.	Brandt, Christine Lycke, et al. (författare) Cognitive effort and schizophrenia modulate large-scale functional brain connectivity 2015 Ingår i: Schizophrenia Bulletin. - : Oxford University Press. - 0586-7614 .- 1745-1701. ; 41:6, s. 1360-1369 Tidskriftsartikel (refereegranskat)abstract Schizophrenia (SZ) is characterized by cognitive dysfunction and disorganized thought, in addition to hallucinations and delusions, and is regarded a disorder of brain connectivity. Recent efforts have been made to characterize the underlying brain network organization and interactions. However, to which degree connectivity alterations in SZ vary across different levels of cognitive effort is unknown. Utilizing independent component analysis (ICA) and methods for delineating functional connectivity measures from functional magnetic resonance imaging (fMRI) data, we investigated the effects of cognitive effort, SZ and their interactions on between-network functional connectivity during 2 levels of cognitive load in a large and well-characterized sample of SZ patients (n = 99) and healthy individuals (n = 143). Cognitive load influenced a majority of the functional connections, including but not limited to fronto-parietal and default-mode networks, reflecting both decreases and increases in between-network synchronization. Reduced connectivity in SZ was identified in 2 large-scale functional connections across load conditions, with a particular involvement of an insular network. The results document an important role of interactions between insular, default-mode, and visual networks in SZ pathophysiology. The interplay between brain networks was robustly modulated by cognitive effort, but the reduced functional connectivity in SZ, primarily related to an insular network, was independent of cognitive load, indicating a relatively general brain network-level dysfunction.
34.	Calkova, Tereza, et al. (författare) Cytomegalovirus infection associated with lower IQ in adolescent patients with schizophrenia spectrum disorders : A preliminary report 2022 Ingår i: Journal of Psychiatric Research. - : Elsevier. - 0022-3956 .- 1879-1379. ; 151, s. 571-574 Tidskriftsartikel (refereegranskat)abstract Cytomegalovirus (CMV) infection of immunocompetent hosts is usually inapparent, but typically results in a non-silent chronic latency which is considerably more active than previously considered. In adults with schizophrenia spectrum disorders, CMV latent infection has been associated with cognitive disturbance including lower intelligent quotient (IQ). We hypothesized that the same pattern will be present in adolescent patients with schizophrenia spectrum disorders (early-onset non-affective psychosis). We included 17 adolescents with schizophrenia spectrum disorders (10 patients with schizophrenia, one patient with schizoaffective disorder and six patients with psychosis not otherwise specified), mean age 16.7 years, females 71% and CMV seropositivity 35%. Current IQ was estimated with the Wechsler Abbreviated Scale of Intelligence. CMV immunoglobulin G (IgG) concentrations were measured by solid-phase immunoassays and expressed as dichotomous measures (seropositive/CMV + vs. seronegative/CMV-). CMV + patients (mean IQ 91) had significantly lower full-scale IQ than CMV- patients (mean IQ 110) (20 units difference; p < 0.001). Post-hoc analyses showed that CMV + patients had both lower performance and lower verbal IQ relative to CMV- patients (p = 0.001 and 0.049, respectively). In this preliminary report, we found that CMV IgG seropositivity, reflecting previous CMV infection and current latency, was associated with lower IQ. This may be indicative of an unfavorable impact of CMV infection on general intelligence in early-onset non-affective psychosis.
35.	Cheesman, Rosa, et al. (författare) How interactions between ADHD and schools affect educational achievement : a family-based genetically sensitive study. 2022 Ingår i: Journal of Child Psychology and Psychiatry. - : Wiley-Blackwell Publishing Inc.. - 0021-9630 .- 1469-7610. ; 63:10, s. 1174-1185 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Children with ADHD tend to achieve less than their peers in school. It is unknown whether schools moderate this association. Nonrandom selection of children into schools related to variations in their ADHD risk poses a methodological problem.METHODS: We linked data on ADHD symptoms of inattention and hyperactivity and parent-child ADHD polygenic scores (PGS) from the Norwegian Mother, Father, and Child Cohort Study (MoBa) to achievement in standardised tests and school identifiers. We estimated interactions of schools with individual differences between students in inattention, hyperactivity, and ADHD-PGS using multilevel models with random slopes for ADHD effects on achievement over schools. In our PGS analyses, we adjust for parental selection of schools by adjusting for parental ADHD-PGS (a within-family PGS design). We then tested whether five school sociodemographic measures explained any interactions.RESULTS: Analysis of up to 23,598 students attending 2,579 schools revealed interactions between school and ADHD effects on achievement. The variability between schools in the effects of inattention, hyperactivity and within-family ADHD-PGS on achievement was 0.08, 0.07 and 0.05 SDs, respectively. For example, the average effect of inattention on achievement was β = -0.23 (SE = 0.009), but in 2.5% of schools with the weakest effects, the value was -0.07 or less. ADHD has a weaker effect on achievement in higher-performing schools. Schools make more of a difference to the achievements of students with higher levels of ADHD, explaining over four times as much variance in achievement for those with high versus average inattention symptoms. School sociodemographic measures could not explain the ADHD-by-school interactions.CONCLUSIONS: Although ADHD symptoms and genetic risk tend to hinder achievement, schools where their effects are weaker do exist. Differences between schools in support for children with ADHD should be evened out.
36.	Chen, Chi-Hua, et al. (författare) Leveraging genome characteristics to improve gene discovery for putamen subcortical brain structure 2017 Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 7 Tidskriftsartikel (refereegranskat)abstract Discovering genetic variants associated with human brain structures is an on-going effort. The ENIGMA consortium conducted genome-wide association studies (GWAS) with standard multi-study analytical methodology and identified several significant single nucleotide polymorphisms (SNPs). Here we employ a novel analytical approach that incorporates functional genome annotations (e.g., exon or 5′UTR), total linkage disequilibrium (LD) scores and heterozygosity to construct enrichment scores for improved identification of relevant SNPs. The method provides increased power to detect associated SNPs by estimating stratum-specific false discovery rate (FDR), where strata are classified according to enrichment scores. Applying this approach to the GWAS summary statistics of putamen volume in the ENIGMA cohort, a total of 15 independent significant SNPs were identified (conditional FDR < 0.05). In contrast, 4 SNPs were found based on standard GWAS analysis (P < 5 × 10−8). These 11 novel loci include GATAD2B, ASCC3, DSCAML1, and HELZ, which are previously implicated in various neural related phenotypes. The current findings demonstrate the boost in power with the annotation-informed FDR method, and provide insight into the genetic architecture of the putamen.
37.	Córdova-Palomera, Aldo, et al. (författare) Genetic control of variability in subcortical and intracranial volumes 2021 Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 26:8, s. 3876-3883 Tidskriftsartikel (refereegranskat)abstract Sensitivity to external demands is essential for adaptation to dynamic environments, but comes at the cost of increased risk of adverse outcomes when facing poor environmental conditions. Here, we apply a novel methodology to perform genome-wide association analysis of mean and variance in ten key brain features (accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, intracranial volume, cortical surface area, and cortical thickness), integrating genetic and neuroanatomical data from a large lifespan sample (n = 25,575 individuals; 8-89 years, mean age 51.9 years). We identify genetic loci associated with phenotypic variability in thalamus volume and cortical thickness. The variance-controlling loci involved genes with a documented role in brain and mental health and were not associated with the mean anatomical volumes. This proof-of-principle of the hypothesis of a genetic regulation of brain volume variability contributes to establishing the genetic basis of phenotypic variance (i.e., heritability), allows identifying different degrees of brain robustness across individuals, and opens new research avenues in the search for mechanisms controlling brain and mental health.
38.	Dahl, Johan, et al. (författare) The plasma levels of various cytokines are increased during ongoing depression and are reduced to normal levels after recovery. 2014 Ingår i: Psychoneuroendocrinology. - : Elsevier BV. - 1873-3360 .- 0306-4530. ; 45:Apr 6, s. 77-86 Tidskriftsartikel (refereegranskat)abstract Cytokines are implicated in the pathophysiology of major depressive disorder (MDD). However, the pattern of alterations in cytokine levels is still unclear. The current study investigated the plasma levels of a range of cytokines in a follow-up design, with the aim of determining their involvement in depression.
39.	de Girolamo, Giovanni, et al. (författare) Medical comorbidities in bipolar disorder (BIPCOM) : clinical validation of risk factors and biomarkers to improve prevention and treatment. Study protocol. 2024 Ingår i: International journal of bipolar disorders. - : Springer. - 2194-7511. ; 12:1 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: BIPCOM aims to (1) identify medical comorbidities in people with bipolar disorder (BD); (2) examine risk factors and clinical profiles of Medical Comorbidities (MC) in this clinical group, with a special focus on Metabolic Syndrome (MetS); (3) develop a Clinical Support Tool (CST) for the personalized management of BD and medical comorbidities.METHODS: The BIPCOM project aims to investigate MC, specifically MetS, in individuals with BD using various approaches. Initially, prevalence rates, characteristics, genetic and non-genetic risk factors, and the natural progression of MetS among individuals with BD will be assessed by analysing Nordic registers, biobanks, and existing patient datasets from 11 European recruiting centres across 5 countries. Subsequently, a clinical study involving 400 participants from these sites will be conducted to examine the clinical profiles and incidence of specific MetS risk factors over 1 year. Baseline assessments, 1-year follow-ups, biomarker analyses, and physical activity measurements with wearable biosensors, and focus groups will be performed. Using this comprehensive data, a CST will be developed to enhance the prevention, early detection, and personalized treatment of MC in BD, by incorporating clinical, biological, sex and genetic information. This protocol will highlight the study's methodology.DISCUSSION: BIPCOM's data collection will pave the way for tailored treatment and prevention approaches for individuals with BD. This approach has the potential to generate significant healthcare savings by preventing complications, hospitalizations, and emergency visits related to comorbidities and cardiovascular risks in BD. BIPCOM's data collection will enhance BD patient care through personalized strategies, resulting in improved quality of life and reduced costly interventions. The findings of the study will contribute to a better understanding of the relationship between medical comorbidities and BD, enabling accurate prediction and effective management of MetS and cardiovascular diseases.TRIAL REGISTRATION: ISRCTN68010602 at https://www.isrctn.com/ISRCTN68010602 . Registration date: 18/04/2023.
40.	de Zwarte, Sonja M. C., et al. (författare) Intelligence, educational attainment, and brain structure in those at familial high-risk for schizophrenia or bipolar disorder 2022 Ingår i: Human Brain Mapping. - : John Wiley & Sons. - 1065-9471 .- 1097-0193. ; 43:1, s. 414-430 Tidskriftsartikel (refereegranskat)abstract First-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD-FDRs are inconsistent. Here, we performed a meta-analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ-FDRs, 867 BD-FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ-FDRs showed a pattern of widespread thinner cortex, while BD-FDRs had widespread larger cortical surface area. IQ was lower in SZ-FDRs (d = -0.42, p = 3 × 10-5 ), with weak evidence of IQ reductions among BD-FDRs (d = -0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group-effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ-FDRs and more pronounced effects in BD-FDRs. To conclude, SZ-FDRs and BD-FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ-FDRs and BD-FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.
41.	de Zwarte, Sonja M. C., et al. (författare) The association between familial risk and brain abnormalities is disease specific : an ENIGMA-relatives study of schizophrenia and bipolar disorder 2019 Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 86:7, s. 545-556 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects.METHODS: We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects.RESULTS: FDRs-BD had significantly larger ICV (d = +0.16, q < .05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = -0.12, q < .05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d < -0.09, q < .05 corrected); and third ventricle was larger (d = +0.15, q < .05 corrected). The findings were not explained by psychopathology in the relatives or control subjects.CONCLUSIONS: Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct.
42.	Desikan, Rahul S, et al. (författare) Heart fatty acid binding protein and Abeta-associated Alzheimer's neurodegeneration. 2013 Ingår i: Molecular neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 8:1 Tidskriftsartikel (refereegranskat)abstract Epidemiological and molecular findings suggest a relationship between Alzheimer's disease (AD) and dyslipidemia, although the nature of this association is not well understood.
43.	Desikan, Rahul S, et al. (författare) The role of clusterin in amyloid-β-associated neurodegeneration. 2014 Ingår i: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 71:2, s. 180-7 Tidskriftsartikel (refereegranskat)abstract Converging evidence indicates that clusterin, a chaperone glycoprotein, influences Alzheimer disease neurodegeneration. However, the precise role of clusterin in Alzheimer disease pathogenesis is still not well understood.
44.	Dima, Danai, et al. (författare) Subcortical volumes across the lifespan : Data from 18,605 healthy individuals aged 3-90 years. 2022 Ingår i: Human Brain Mapping. - : Wiley. - 1065-9471 .- 1097-0193. ; 43:1, s. 452-469 Tidskriftsartikel (refereegranskat)abstract Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.
45.	Ellinghaus, David, et al. (författare) Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci 2016 Ingår i: Nature Genetics. - New York, USA : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 48:5, s. 510-518 Tidskriftsartikel (refereegranskat)abstract We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European ancestry, we identified 244 independent multidisease signals, including 27 new genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multidisease signals with expression data sets from human, rat and mouse together with epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases genetically identical to those with another disease, possibly owing to diagnostic misclassification, molecular subtypes or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes.
46.	Frangou, Sophia, et al. (författare) Cortical thickness across the lifespan : Data from 17,075 healthy individuals aged 3-90 years 2022 Ingår i: Human Brain Mapping. - : John Wiley & Sons. - 1065-9471 .- 1097-0193. ; 43:1, s. 431-451 Tidskriftsartikel (refereegranskat)abstract Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.
47.	Guintivano, Jerry, et al. (författare) Meta-Analyses of Genome-Wide Association Studies for Postpartum Depression 2023 Ingår i: American Journal of Psychiatry. - : American Psychiatric Association Publishing. - 0002-953X .- 1535-7228. ; 180:12, s. 884-895 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE: Postpartum depression (PPD) is a common subtype of major depressive disorder (MDD) that is more heritable, yet is understudied in psychiatric genetics. The authors conducted meta-analyses of genome-wide association studies (GWASs) to investigate the genetic architecture of PPD.METHOD: Meta-analyses were conducted on 18 cohorts of European ancestry (17,339 PPD cases and 53,426 controls), one cohort of East Asian ancestry (975 cases and 3,780 controls), and one cohort of African ancestry (456 cases and 1,255 controls), totaling 18,770 PPD cases and 58,461 controls. Post-GWAS analyses included 1) single-nucleotide polymorphism (SNP)-based heritability ([Formula: see text]), 2) genetic correlations between PPD and other phenotypes, and 3) enrichment of the PPD GWAS findings in 27 human tissues and 265 cell types from the mouse central and peripheral nervous system.RESULTS: No SNP achieved genome-wide significance in the European or the trans-ancestry meta-analyses. The [Formula: see text] of PPD was 0.14 (SE=0.02). Significant genetic correlations were estimated for PPD with MDD, bipolar disorder, anxiety disorders, posttraumatic stress disorder, insomnia, age at menarche, and polycystic ovary syndrome. Cell-type enrichment analyses implicate inhibitory neurons in the thalamus and cholinergic neurons within septal nuclei of the hypothalamus, a pattern that differs from MDD.CONCLUSIONS: While more samples are needed to reach genome-wide levels of significance, the results presented confirm PPD as a polygenic and heritable phenotype. There is also evidence that despite a high correlation with MDD, PPD may have unique genetic components. Cell enrichment results suggest GABAergic neurons, which converge on a common mechanism with the only medication approved by the U.S. Food and Drug Administration for PPD (brexanolone).
48.	Gurholt, Tiril P., et al. (författare) Intracranial and subcortical volumes in adolescents with early‐onset psychosis : A multisite mega‐analysis from the ENIGMA consortium 2020 Ingår i: Human Brain Mapping. - Stockholm : Wiley. - 1065-9471 .- 1097-0193. ; 43:1, s. 373-384 Tidskriftsartikel (refereegranskat)abstract Early-onset psychosis disorders are serious mental disorders arising before the age of 18 years. Here, we investigate the largest neuroimaging dataset, to date, of patients with early-onset psychosis and healthy controls for differences in intracranial and subcortical brain volumes. The sample included 263 patients with early-onset psychosis (mean age: 16.4 ± 1.4 years, mean illness duration: 1.5 ± 1.4 years, 39.2% female) and 359 healthy controls (mean age: 15.9 ± 1.7 years, 45.4% female) with magnetic resonance imaging data, pooled from 11 clinical cohorts. Patients were diagnosed with early-onset schizophrenia (n = 183), affective psychosis (n = 39), or other psychotic disorders (n = 41). We used linear mixed-effects models to investigate differences in intracranial and subcortical volumes across the patient sample, diagnostic subgroup and antipsychotic medication, relative to controls. We observed significantly lower intracranial (Cohen's d = −0.39) and hippocampal (d = −0.25) volumes, and higher caudate (d = 0.25) and pallidum (d = 0.24) volumes in patients relative to controls. Intracranial volume was lower in both early-onset schizophrenia (d = −0.34) and affective psychosis (d = −0.42), and early-onset schizophrenia showed lower hippocampal (d = −0.24) and higher pallidum (d = 0.29) volumes. Patients who were currently treated with antipsychotic medication (n = 193) had significantly lower intracranial volume (d = −0.42). The findings demonstrate a similar pattern of brain alterations in early-onset psychosis as previously reported in adult psychosis, but with notably low intracranial volume. The low intracranial volume suggests disrupted neurodevelopment in adolescent early-onset psychosis.
49.	Gurholt, Tiril P., et al. (författare) Linking sarcopenia, brain structure and cognitive performance: a large-scale UK Biobank study 2024 Ingår i: Brain Communications. - : OXFORD UNIV PRESS. - 2632-1297. ; 6:2 Tidskriftsartikel (refereegranskat)abstract Sarcopenia refers to age-related loss of muscle mass and function and is related to impaired somatic and brain health, including cognitive decline and Alzheimer's disease. However, the relationships between sarcopenia, brain structure and cognition are poorly understood. Here, we investigate the associations between sarcopenic traits, brain structure and cognitive performance. We included 33 709 UK Biobank participants (54.2% female; age range 44-82 years) with structural and diffusion magnetic resonance imaging, thigh muscle fat infiltration (n = 30 561) from whole-body magnetic resonance imaging (muscle quality indicator) and general cognitive performance as indicated by the first principal component of a principal component analysis across multiple cognitive tests (n = 22 530). Of these, 1703 participants qualified for probable sarcopenia based on low handgrip strength, and we assigned the remaining 32 006 participants to the non-sarcopenia group. We used multiple linear regression to test how sarcopenic traits (probable sarcopenia versus non-sarcopenia and percentage of thigh muscle fat infiltration) relate to cognitive performance and brain structure (cortical thickness and area, white matter fractional anisotropy and deep and lower brain volumes). Next, we used structural equation modelling to test whether brain structure mediated the association between sarcopenic and cognitive traits. We adjusted all statistical analyses for confounders. We show that sarcopenic traits (probable sarcopenia versus non-sarcopenia and muscle fat infiltration) are significantly associated with lower cognitive performance and various brain magnetic resonance imaging measures. In probable sarcopenia, for the included brain regions, we observed widespread significant lower white matter fractional anisotropy (77.1% of tracts), predominantly lower regional brain volumes (61.3% of volumes) and thinner cortical thickness (37.9% of parcellations), with \|r\| effect sizes in (0.02, 0.06) and P-values in (0.0002, 4.2e(-29)). In contrast, we observed significant associations between higher muscle fat infiltration and widespread thinner cortical thickness (76.5% of parcellations), lower white matter fractional anisotropy (62.5% of tracts) and predominantly lower brain volumes (35.5% of volumes), with \|r\| effect sizes in (0.02, 0.07) and P-values in (0.0002, 1.9e(-31)). The regions showing the most significant effect sizes across the cortex, white matter and volumes were of the sensorimotor system. Structural equation modelling analysis revealed that sensorimotor brain regions mediate the link between sarcopenic and cognitive traits [probable sarcopenia: P-values in (0.0001, 1.0e-11); muscle fat infiltration: P-values in (7.7e(-05), 1.7e(-12))]. Our findings show significant associations between sarcopenic traits, brain structure and cognitive performance in a middle-aged and older adult population. Mediation analyses suggest that regional brain structure mediates the association between sarcopenic and cognitive traits, with potential implications for dementia development and prevention.
50.	Gurholt, Tiril P., et al. (författare) Population-based body-brain mapping links brain morphology with anthropometrics and body composition 2021 Ingår i: Translational Psychiatry. - : Springer Nature. - 2158-3188. ; 11:1 Tidskriftsartikel (refereegranskat)abstract Understanding complex body-brain processes and the interplay between adipose tissue and brain health is important for understanding comorbidity between psychiatric and cardiometabolic disorders. We investigated associations between brain structure and anthropometric and body composition measures using brain magnetic resonance imaging (MRI; n=24,728) and body MRI (n=4973) of generally healthy participants in the UK Biobank. We derived regional and global measures of brain morphometry using FreeSurfer and tested their association with (i) anthropometric measures, and (ii) adipose and muscle tissue measured from body MRI. We identified several significant associations with small effect sizes. Anthropometric measures showed negative, nonlinear, associations with cerebellar/cortical gray matter, and brain stem structures, and positive associations with ventricular volumes. Subcortical structures exhibited mixed effect directionality, with strongest positive association for accumbens. Adipose tissue measures, including liver fat and muscle fat infiltration, were negatively associated with cortical/cerebellum structures, while total thigh muscle volume was positively associated with brain stem and accumbens. Regional investigations of cortical area, thickness, and volume indicated widespread and largely negative associations with anthropometric and adipose tissue measures, with an opposite pattern for thigh muscle volume. Self-reported diabetes, hypertension, or hypercholesterolemia were associated with brain structure. The findings provide new insight into physiological body-brain associations suggestive of shared mechanisms between cardiometabolic risk factors and brain health. Whereas the causality needs to be determined, the observed patterns of body-brain relationships provide a foundation for understanding the underlying mechanisms linking psychiatric disorders with obesity and cardiovascular disease, with potential for the development of new prevention strategies.

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