Publications by authors named "Bernhard T Baune"

401 Publications

Autoantibody profiles associated with clinical features in psychotic disorders.

Transl Psychiatry 2021 Sep 13;11(1):474. Epub 2021 Sep 13.

Discipline of Psychiatry, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.

Autoimmune processes are suspected to play a role in the pathophysiology of psychotic disorders. Better understanding of the associations between auto-immunoglobulin G (IgG) repertoires and clinical features of mental illness could yield novel models of the pathophysiology of psychosis, and markers for biological patient stratification. We undertook cross-sectional detection and quantification of auto-IgGs in peripheral blood plasma of 461 people (39% females) with established psychotic disorder diagnoses. Broad screening of 24 individuals was carried out on group level in eight clinically defined groups using planar protein microarrays containing 42,100 human antigens representing 18,914 proteins. Autoantibodies indicated by broad screening and in the previous literature were measured using a 380-plex bead-based array for autoantibody profiling of all 461 individuals. Associations between autoantibody profiles and dichotomized clinical characteristics were assessed using a stepwise selection procedure. Broad screening and follow-up targeted analyses revealed highly individual autoantibody profiles. Females, and people with family histories of obesity or of psychiatric disorders other than schizophrenia had the highest overall autoantibody counts. People who had experienced subjective thought disorder and/or were treated with clozapine (trend) had the lowest overall counts. Furthermore, six autoantibodies were associated with specific psychopathology symptoms: anti-AP3B2 (persecutory delusions), anti-TDO2 (hallucinations), anti-CRYGN (initial insomnia); anti-APMAP (poor appetite), anti-OLFM1 (above-median cognitive function), and anti-WHAMMP3 (anhedonia and dysphoria). Future studies should clarify whether there are causal biological relationships, and whether autoantibodies could be used as clinical markers to inform diagnostic patient stratification and choice of treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41398-021-01596-0DOI Listing
September 2021

HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders.

Sci Rep 2021 Sep 8;11(1):17823. Epub 2021 Sep 8.

Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan.

Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × 10; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-97140-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426488PMC
September 2021

Examining sex differences in neurodevelopmental and psychiatric genetic risk in anxiety and depression.

PLoS One 2021 2;16(9):e0248254. Epub 2021 Sep 2.

MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom.

Anxiety and depression are common mental health disorders and have a higher prevalence in females. They are modestly heritable, share genetic liability with other psychiatric disorders, and are highly heterogeneous. There is evidence that genetic liability to neurodevelopmental disorders, such as attention deficit hyperactivity disorder (ADHD) is associated with anxiety and depression, particularly in females. We investigated sex differences in family history for neurodevelopmental and psychiatric disorders and neurodevelopmental genetic risk burden (indexed by ADHD polygenic risk scores (PRS) and rare copy number variants; CNVs) in individuals with anxiety and depression, also taking into account age at onset. We used two complementary datasets: 1) participants with a self-reported diagnosis of anxiety or depression (N = 4,178, 65.5% female; mean age = 41.5 years; N = 1,315 with genetic data) from the National Centre for Mental Health (NCMH) cohort and 2) a clinical sample of 13,273 (67.6% female; mean age = 45.2 years) patients with major depressive disorder (MDD) from the Psychiatric Genomics Consortium (PGC). We tested for sex differences in family history of psychiatric problems and presence of rare CNVs (neurodevelopmental and >500kb loci) in NCMH only and for sex differences in ADHD PRS in both datasets. In the NCMH cohort, females were more likely to report family history of neurodevelopmental and psychiatric disorders, but there were no robust sex differences in ADHD PRS or presence of rare CNVs. There was weak evidence of higher ADHD PRS in females compared to males in the PGC MDD sample, particularly in those with an early onset of MDD. These results do not provide strong evidence of sex differences in neurodevelopmental genetic risk burden in adults with anxiety and depression. This indicates that sex may not be a major index of neurodevelopmental genetic heterogeneity, that is captured by ADHD PRS and rare CNV burden, in adults with anxiety and depression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248254PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8412369PMC
September 2021

Examining sex differences in neurodevelopmental and psychiatric genetic risk in anxiety and depression.

PLoS One 2021 2;16(9):e0248254. Epub 2021 Sep 2.

MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom.

Anxiety and depression are common mental health disorders and have a higher prevalence in females. They are modestly heritable, share genetic liability with other psychiatric disorders, and are highly heterogeneous. There is evidence that genetic liability to neurodevelopmental disorders, such as attention deficit hyperactivity disorder (ADHD) is associated with anxiety and depression, particularly in females. We investigated sex differences in family history for neurodevelopmental and psychiatric disorders and neurodevelopmental genetic risk burden (indexed by ADHD polygenic risk scores (PRS) and rare copy number variants; CNVs) in individuals with anxiety and depression, also taking into account age at onset. We used two complementary datasets: 1) participants with a self-reported diagnosis of anxiety or depression (N = 4,178, 65.5% female; mean age = 41.5 years; N = 1,315 with genetic data) from the National Centre for Mental Health (NCMH) cohort and 2) a clinical sample of 13,273 (67.6% female; mean age = 45.2 years) patients with major depressive disorder (MDD) from the Psychiatric Genomics Consortium (PGC). We tested for sex differences in family history of psychiatric problems and presence of rare CNVs (neurodevelopmental and >500kb loci) in NCMH only and for sex differences in ADHD PRS in both datasets. In the NCMH cohort, females were more likely to report family history of neurodevelopmental and psychiatric disorders, but there were no robust sex differences in ADHD PRS or presence of rare CNVs. There was weak evidence of higher ADHD PRS in females compared to males in the PGC MDD sample, particularly in those with an early onset of MDD. These results do not provide strong evidence of sex differences in neurodevelopmental genetic risk burden in adults with anxiety and depression. This indicates that sex may not be a major index of neurodevelopmental genetic heterogeneity, that is captured by ADHD PRS and rare CNV burden, in adults with anxiety and depression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248254PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8412369PMC
September 2021

No evidence for clinical efficacy of adjunctive celecoxib with vortioxetine in the treatment of depression: A 6-week double-blind placebo controlled randomized trial.

Eur Neuropsychopharmacol 2021 Aug 7;53:34-46. Epub 2021 Aug 7.

Discipline of Psychiatry, Adelaide Medical School, University of Adelaide, Adelaide, Australia; Lysosomal Health in Ageing, Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, Australia.

Given the role of low-grade inflammation in the pathophysiology of major depressive disorder (MDD), anti-inflammatory strategies may improve treatment outcomes in some patients. However, it is controversial whether they can be used as adjunctive treatments and whether pre-treatment levels of inflammation can predict treatment outcomes. This study was conducted to measure the efficacy of anti-inflammatory augmentation of antidepressant treatment in MDD patients; and to investigate whether treatment response was dependent on baseline inflammation levels. This parallel-group randomised, double-blind, placebo-controlled trial was conducted at the University of Adelaide (Australia). Participants with MDD were randomised to receive vortioxetine with celecoxib or vortioxetine with placebo for six weeks, and baseline blood high sensitivity C reactive protein levels were measured. Primary outcome was change in depressive symptoms (Montgomery-Åsberg Depression Rating Scale) and secondary outcomes included change in cognition (THINC-integrated tool - Codebreaker task) and functioning (Functioning Assessment Short Test) over 6 weeks. There was no evidence of superior efficacy of celecoxib augmentation over placebo on depressive symptom severity, response and remission rates, cognition and psychosocial functioning. There was also no evidence that pre-treatment inflammation levels modified the effect of celecoxib augmentation versus placebo. This observed lack of efficacy of celecoxib add-on does not support the use of celecoxib augmentation of antidepressants in the treatment of MDD in a cohort that mostly comprises treatment-resistant individuals. Additionally, C-reactive protein may not be suitable to predict treatment selection and response in MDD. The study was registered on the Australian New Zealand Clinical Trials Registry: ACTRN12617000527369 (www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12617000527369p).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.euroneuro.2021.07.092DOI Listing
August 2021

Combination of Tranylcypromine and Mirtazapine in Difficult-to-Treat Depression.

J Clin Psychopharmacol 2021 Sep-Oct 01;41(5):585-588

From the Department of Psychiatry, University Hospital Münster, University of Münster, Münster, Germany.

Background: About one third of depression patients do not respond to the first antidepressant trial. Difficult-to-treat depression was suggested to characterize the often chronic and severe course of disease. Previous data indicate that tranylcypromine is effective in case of treatment-refractory depression. Many antidepressants are contraindicated in combination with tranylcypromine and other monoamine-oxidase inhibitors because of the risk of serotonin syndrome. The combination of tranylcypromine and amitriptyline was reported to be efficacious and safe in patients with electroconvulsive therapy-resistant major depression.

Methods: In this retrospective chart review, we report a series of 3 cases, in which patients with electroconvulsive therapy-resistant depression were treated with the combination of tranylcypromine and mirtazapine. There are no published clinical data on this combination yet. Disease severity and treatment response were retrospectively assessed with the Clinical Global Impression-Severity and Improvement Scales.

Results: All 3 patients had severe difficult-to-treat depression with chronic course of disease and several times of inpatient treatment without achieving remission. The combination treatment was tolerated well, although the patients had somatic comorbidities. One patient developed mild and self-limiting neuroleptic malignant syndrome in the long-term course after dose increase of concomitant aripiprazole. All 3 patients showed either much or very much improvement.

Conclusions: Under tight clinical controls in inpatient setting and after exhausting of alternatives, the combination of tranylcypromine and mirtazapine could be considered in patients, who do not achieve adequate improvement through common treatment options recommended in the guidelines. The combination has to be ceased, if symptoms of possible serotonin syndrome occur.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JCP.0000000000001452DOI Listing
August 2021

Brain microstructural changes in mice persist in adulthood and are modulated by the palmitoyl acyltransferase ZDHHC7.

Eur J Neurosci 2021 Aug 6. Epub 2021 Aug 6.

Department of Mental Health, University of Münster, Münster, Germany.

For a long time, mice have been classified as adults with completely mature brains at 8 weeks of age, but recent research suggests that developmental brain changes occur for up to 6 months. In particular, adolescence coincides with dramatic changes of neuronal structure and function in the brain that influence the connectivity between areas like hippocampus and medial prefrontal cortex (mPFC). Neuronal development and plasticity are regulated in part by the palmitoyl acyltransferase ZDHHC7, which modulates structural connectivity between hippocampus and mPFC. The aim of the current study was to investigate whether developmental changes take place in hippocampus and mPFC microstructure even after 8 weeks of age and whether deficiency of ZDHHC7 impacts such age-dependent alterations. Altogether, 46 mice at 11, 14 or 17 weeks of age with a genetic Zdhhc7 knockout (KO) or wild type (WT) were analysed with neuroimaging and diffusion tensor-based fibre tractography. The hippocampus and mPFC regions were compared regarding fibre metrics, supplemented by volumetric and immunohistological analyses of the hippocampus. In WT animals, we identified age-dependent changes in hippocampal fibre lengths that followed a U-shaped pattern, whereas in mPFC, changes were linear. In Zdhhc7-deficient animals, the fibre statistics were reduced in both regions, whereas the hippocampus volume and the intensities of myelin and neurofilament were higher in 11-week-old KO mice compared to WTs. Our results confirmed ongoing changes of microstructure in mice up to 17 weeks old and demonstrate that deleting the Zdhhc7 gene impairs fibre development, suggesting that palmitoylation is important in this process.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ejn.15415DOI Listing
August 2021

A genome-wide association study of the longitudinal course of executive functions.

Transl Psychiatry 2021 07 10;11(1):386. Epub 2021 Jul 10.

AMEOS Clinical Center Hildesheim, Hildesheim, 31135, Germany.

Executive functions are metacognitive capabilities that control and coordinate mental processes. In the transdiagnostic PsyCourse Study, comprising patients of the affective-to-psychotic spectrum and controls, we investigated the genetic basis of the time course of two core executive subfunctions: set-shifting (Trail Making Test, part B (TMT-B)) and updating (Verbal Digit Span backwards) in 1338 genotyped individuals. Time course was assessed with four measurement points, each 6 months apart. Compared to the initial assessment, executive performance improved across diagnostic groups. We performed a genome-wide association study to identify single nucleotide polymorphisms (SNPs) associated with performance change over time by testing for SNP-by-time interactions using linear mixed models. We identified nine genome-wide significant SNPs for TMT-B in strong linkage disequilibrium with each other on chromosome 5. These were associated with decreased performance on the continuous TMT-B score across time. Variant rs150547358 had the lowest P value = 7.2 × 10 with effect estimate beta = 1.16 (95% c.i.: 1.11, 1.22). Implementing data of the FOR2107 consortium (1795 individuals), we replicated these findings for the SNP rs150547358 (P value = 0.015), analyzing the difference of the two available measurement points two years apart. In the replication study, rs150547358 exhibited a similar effect estimate beta = 0.85 (95% c.i.: 0.74, 0.97). Our study demonstrates that longitudinally measured phenotypes have the potential to unmask novel associations, adding time as a dimension to the effects of genomics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41398-021-01510-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272719PMC
July 2021

Elevated body weight modulates subcortical volume change and associated clinical response following electroconvulsive therapy.

J Psychiatry Neurosci 2021 07 5;46(4):E418-E426. Epub 2021 Jul 5.

From the Institute for Translational Psychiatry, University of Münster, Münster, Germany (Opel, Repple, Dannlowski, Redlich); Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany (Kavakbasi, Baune); the Departments of Neurology, Psychiatry, and Biobehavioral Sciences, University of California, Los Angeles, CA (Narr); the Department of Psychiatry, University of New Mexico School of Medicine, Albuquerque, NM (Abbott); the Institute of Behavioral Science, Feintein Institutes for Medical Research, Manhasset, NY (Argyelan); the Department of Psychiatry, The Zucker Hillside Hospital, Glen Oaks, NY (Argyelan); the Department of Psychiatry, University of California, Los Angeles (Espinoza); the Department of Geriatric Psychiatry, University Psychiatric Center KU Leuven, KU Leuven, Leuven, Belgium (Emsell, Vandenbulcke); the KU Leuven, Leuven Brain Institute, Department of Neurosciences, Neuropsychiatry & Geriatric Psychiatry, University Psychiatric Center KU Leuven, Belgium (Bouckaert); the Academic Center for ECT and Neurostimulation (AcCENT), University Psychiatric Center (UPC)-KU Leuven, Kortenberg, Belgium (Sienaert); the Center for Social and Affective Neuroscience, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden (Nordanskog); the Psychiatric Center Copenhagen (Rigshospitalet), Mental Health Services of the Capital Region of Denmark, Copenhagen, Denmark (Jorgensen); the Neurobiology Research Unit, Rigshospitalet and University of Copenhagen, Denmark (Paulson); the Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Denmark (Hanson); the Center for Magnetic Resonance, Department of Health Technology, Technical University of Denmark, Kgs, Lyngby, Denmark (Hanson); the GGZ in Geest Specialized Mental Health Care, Amsterdam, the Netherlands (Dols, Van Exel, Oudega); the Amsterdam UMC, Vrije Universiteit Amsterdam, Psychiatry, Amsterdam Neuroscience, Amsterdam, the Netherlands (Dols, van Exel, Oudega); the Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan (Takamiya, Kishimoto); the Department of Radiology, Haukeland University Hospital, Bergen, Norway (Ousdal); the Department of Biomedicine, University of Bergen, Bergen, Norway (Haavik); the Division of Psychiatry, Haukeland University Hospital, Bergen, Norway (Haavik, Hammar); the Department of Biological and Medical Psychology, University of Bergen, Norway (Hammar); the NORMENT, Department of Psychiatry, Haukeland University Hospital, Bergen, Norway (Oedegaard, Kessler); the Department of Clinical Medicine, University of Bergen, Bergen, Norway (Oedegaard, Kessler, Oltedal); the Department of Radiology, University of California, San Diego, La Jolla, California (Bartsch); the Mohn Medical Imaging and Visualization Centre, Department of Radiology, Haukeland University Hospital, Bergen, Norway (Bartsch, Oltedal); the Departments of Radiology, Neurosciences, and Psychiatry, University of California, San Diego (Dale); the Center for Multimodal Imaging and Genetics, University of California, San Diego, La Jolla, California (Dale); the Department of Psychiatry, University of Melbourne, Melbourne, Australia (Baune); the The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia (Baune); and the Department of Psychology, University of Halle, Halle, Germany (Redlich).

Background: Obesity is a frequent somatic comorbidity of major depression, and it has been associated with worse clinical outcomes and brain structural abnormalities. Converging evidence suggests that electroconvulsive therapy (ECT) induces both clinical improvements and increased subcortical grey matter volume in patients with depression. However, it remains unknown whether increased body weight modulates the clinical response and structural neuroplasticity that occur with ECT.

Methods: To address this question, we conducted a longitudinal investigation of structural MRI data from the Global ECT-MRI Research Collaboration (GEMRIC) in 223 patients who were experiencing a major depressive episode (10 scanning sites). Structural MRI data were acquired before and after ECT, and we assessed change in subcortical grey matter volume using FreeSurfer and Quarc.

Results: Higher body mass index (BMI) was associated with a significantly lower increase in subcortical grey matter volume following ECT. We observed significant negative associations between BMI and change in subcortical grey matter volume, with pronounced effects in the thalamus and putamen, where obese participants showed increases in grey matter volume that were 43.3% and 49.6%, respectively, of the increases found in participants with normal weight. As well, BMI significantly moderated the association between subcortical grey matter volume change and clinical response to ECT. We observed no significant association between BMI and clinical response to ECT.

Limitations: Because only baseline BMI values were available, we were unable to study BMI changes during ECT and their potential association with clinical and grey matter volume change.

Conclusion: Future studies should take into account the relevance of body weight as a modulator of structural neuroplasticity during ECT treatment and aim to further explore the functional relevance of this novel finding.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1503/jpn.200176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410473PMC
July 2021

Acute effect of vagus nerve stimulation (VNS) on brain function.

J Psychiatr Res 2021 09 24;141:136-139. Epub 2021 Jun 24.

Department of Psychiatry, University Hospital Münster, University of Münster, Münster, Germany; Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Melbourne, Australia; The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia.

Introduction: VNS is a non-pharmalogical neuromodulatory treatment option for difficult-to-treat depression. A pulse generator implanted in the left chest area is connected to an electrode that is wrapped around the left vagal nerve. It is presumed, that the vagal afferent network modulates neuronal activity in key monoaminergic structures.

Methods: We performed MEG recording during active stimulation of the left vagal nerve. Our patient was a 60 years old female treated with VNS since December 2019 due to unipolar major depression.

Results: MEG recording and analysis were possible despite stimulation signals and the metal stimulation systems. We saw a reproducible reduction of the 10-Hz-alpha amplitude after the end of the 30 s stimulation period in wide-spread areas including parieto-occipital cortex where alpha oscillations are prominently generated. During stimulation, however, alpha oscillations remained unaffected. These findings could be reproduced in a second measurement.

Conclusion: Increased alpha power was linked to depressive states and alterations of cortical activity. A reduction may indicate cortical activation by stimulation of the vagal nerve as a possible mechanism of action of VNS in depression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpsychires.2021.06.042DOI Listing
September 2021

Acute effect of vagus nerve stimulation (VNS) on brain function.

J Psychiatr Res 2021 09 24;141:136-139. Epub 2021 Jun 24.

Department of Psychiatry, University Hospital Münster, University of Münster, Münster, Germany; Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Melbourne, Australia; The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia.

Introduction: VNS is a non-pharmalogical neuromodulatory treatment option for difficult-to-treat depression. A pulse generator implanted in the left chest area is connected to an electrode that is wrapped around the left vagal nerve. It is presumed, that the vagal afferent network modulates neuronal activity in key monoaminergic structures.

Methods: We performed MEG recording during active stimulation of the left vagal nerve. Our patient was a 60 years old female treated with VNS since December 2019 due to unipolar major depression.

Results: MEG recording and analysis were possible despite stimulation signals and the metal stimulation systems. We saw a reproducible reduction of the 10-Hz-alpha amplitude after the end of the 30 s stimulation period in wide-spread areas including parieto-occipital cortex where alpha oscillations are prominently generated. During stimulation, however, alpha oscillations remained unaffected. These findings could be reproduced in a second measurement.

Conclusion: Increased alpha power was linked to depressive states and alterations of cortical activity. A reduction may indicate cortical activation by stimulation of the vagal nerve as a possible mechanism of action of VNS in depression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpsychires.2021.06.042DOI Listing
September 2021

Monocyte mitochondrial dysfunction, inflammaging, and inflammatory pyroptosis in major depression.

Prog Neuropsychopharmacol Biol Psychiatry 2021 Dec 23;111:110391. Epub 2021 Jun 23.

Department of Immunology, Erasmus Medical Center, Rotterdam 3015 GD, Netherlands.

Background: The macrophage theory of depression states that macrophages play an important role in Major Depressive Disorder (MDD).

Methods: MDD patients (N = 140) and healthy controls (N = 120) participated in a cross-sectional study investigating the expression of apoptosis/growth and lipid/cholesterol pathway genes (BAX, BCL10, EGR1, EGR2, HB-EGF, NR1H3, ABCA1, ABCG1, MVK, CD163, HMOX1) in monocytes (macrophage/microglia precursors). Gene expressions were correlated to a set of previously determined and reported inflammation-regulating genes and analyzed with respect to various clinical parameters.

Results: MDD monocytes showed an overexpression of the apoptosis/growth/cholesterol and the TNF genes forming an inter-correlating gene cluster (cluster 3) separate from the previously described inflammation-related gene clusters (containing IL1 and IL6). While upregulation of monocyte gene cluster 3 was a hallmark of monocytes of all MDD patients, upregulation of the inflammation-related clusters was confirmed to be found only in the monocytes of patients with childhood adversity. The latter group also showed a downregulation of the cholesterol metabolism gene MVK, which is known to play an important role in trained immunity and proneness to inflammation.

Conclusions: The upregulation of cluster 3 genes in monocytes of all MDD patients suggests a premature aging of the cells, i.e. mitochondrial apoptotic dysfunction and TNF "inflammaging", as a general feature of MDD. The overexpression of the IL-1/IL-6 containing inflammation clusters and the downregulation of MVK in monocytes of patients with childhood adversity indicates a shift in this condition to a more severe inflammation form (pyroptosis) of the cells, additional to the signs of premature aging and inflammaging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pnpbp.2021.110391DOI Listing
December 2021

Design and Implementation of an Informatics Infrastructure for Standardized Data Acquisition, Transfer, Storage, and Export in Psychiatric Clinical Routine: Feasibility Study.

JMIR Ment Health 2021 Jun 9;8(6):e26681. Epub 2021 Jun 9.

Department of Psychiatry, University of Münster, Münster, Germany.

Background: Empirically driven personalized diagnostic applications and treatment stratification is widely perceived as a major hallmark in psychiatry. However, databased personalized decision making requires standardized data acquisition and data access, which are currently absent in psychiatric clinical routine.

Objective: Here, we describe the informatics infrastructure implemented at the psychiatric Münster University Hospital, which allows standardized acquisition, transfer, storage, and export of clinical data for future real-time predictive modelling in psychiatric routine.

Methods: We designed and implemented a technical architecture that includes an extension of the electronic health record (EHR) via scalable standardized data collection and data transfer between EHRs and research databases, thus allowing the pooling of EHRs and research data in a unified database and technical solutions for the visual presentation of collected data and analyses results in the EHR. The Single-source Metadata ARchitecture Transformation (SMA:T) was used as the software architecture. SMA:T is an extension of the EHR system and uses module-driven engineering to generate standardized applications and interfaces. The operational data model was used as the standard. Standardized data were entered on iPads via the Mobile Patient Survey (MoPat) and the web application [email protected], and the standardized transmission, processing, display, and export of data were realized via SMA:T.

Results: The technical feasibility of the informatics infrastructure was demonstrated in the course of this study. We created 19 standardized documentation forms with 241 items. For 317 patients, 6451 instances were automatically transferred to the EHR system without errors. Moreover, 96,323 instances were automatically transferred from the EHR system to the research database for further analyses.

Conclusions: In this study, we present the successful implementation of the informatics infrastructure enabling standardized data acquisition and data access for future real-time predictive modelling in clinical routine in psychiatry. The technical solution presented here might guide similar initiatives at other sites and thus help to pave the way toward future application of predictive models in psychiatric clinical routine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2196/26681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262601PMC
June 2021

Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders.

Biol Psychiatry 2021 Mar 23. Epub 2021 Mar 23.

Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois; Department of Psychiatry and Behavioral Sciences, North Shore University Health System, Evanston, Illinois.

Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.

Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH.

Results: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10; rs73033497, p = 8.8 × 10; rs7914279, p = 6.4 × 10), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05).

Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopsych.2021.02.972DOI Listing
March 2021

Investigation of genetic loci shared between bipolar disorder and risk-taking propensity: potential implications for pharmacological interventions.

Neuropsychopharmacology 2021 08 25;46(9):1680-1692. Epub 2021 May 25.

Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy.

Patients with bipolar disorder (BD) often show increased risk-taking propensity, which may contribute to poor clinical outcome. While these two phenotypes are genetically correlated, there is scarce knowledge on the shared genetic determinants. Using GWAS datasets on BD (41,917 BD cases and 371,549 controls) and risk-taking (n = 466,571), we dissected shared genetic determinants using conjunctional false discovery rate (conjFDR) and local genetic covariance analysis. We investigated specificity of identified targets using GWAS datasets on schizophrenia (SCZ) and attention-deficit hyperactivity disorder (ADHD). The putative functional role of identified targets was evaluated using different tools and GTEx v. 8. Target druggability was evaluated using DGIdb and enrichment for drug targets with genome for REPositioning drugs (GREP). Among 102 loci shared between BD and risk-taking, 87% showed the same direction of effect. Sixty-two were specifically shared between risk-taking propensity and BD, while the others were also shared between risk-taking propensity and either SCZ or ADHD. By leveraging pleiotropic enrichment, we reported 15 novel and specific loci associated with BD and 22 with risk-taking. Among cross-disorder genes, CACNA1C (a known target of calcium channel blockers) was significantly associated with risk-taking propensity and both BD and SCZ using conjFDR (p = 0.001 for both) as well as local genetic covariance analysis, and predicted to be differentially expressed in the cerebellar hemisphere in an eQTL-informed gene-based analysis (BD, Z = 7.48, p = 3.8E-14; risk-taking: Z = 4.66, p = 1.6E-06). We reported for the first time shared genetic determinants between BD and risk-taking propensity. Further investigation into calcium channel blockers or development of innovative ligands of calcium channels might form the basis for innovative pharmacotherapy in patients with BD with increased risk-taking propensity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41386-021-01045-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280111PMC
August 2021

Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology.

Nat Genet 2021 06 17;53(6):817-829. Epub 2021 May 17.

Department of Neuroscience, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-021-00857-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192451PMC
June 2021

From multivariate methods to an AI ecosystem.

Mol Psychiatry 2021 May 12. Epub 2021 May 12.

Department of Psychiatry, University of Muenster, Münster, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41380-021-01116-yDOI Listing
May 2021

Systematic misestimation of machine learning performance in neuroimaging studies of depression.

Neuropsychopharmacology 2021 07 6;46(8):1510-1517. Epub 2021 May 6.

Department of Psychiatry, University of Münster, Münster, Germany.

We currently observe a disconcerting phenomenon in machine learning studies in psychiatry: While we would expect larger samples to yield better results due to the availability of more data, larger machine learning studies consistently show much weaker performance than the numerous small-scale studies. Here, we systematically investigated this effect focusing on one of the most heavily studied questions in the field, namely the classification of patients suffering from Major Depressive Disorder (MDD) and healthy controls based on neuroimaging data. Drawing upon structural MRI data from a balanced sample of N = 1868 MDD patients and healthy controls from our recent international Predictive Analytics Competition (PAC), we first trained and tested a classification model on the full dataset which yielded an accuracy of 61%. Next, we mimicked the process by which researchers would draw samples of various sizes (N = 4 to N = 150) from the population and showed a strong risk of misestimation. Specifically, for small sample sizes (N = 20), we observe accuracies of up to 95%. For medium sample sizes (N = 100) accuracies up to 75% were found. Importantly, further investigation showed that sufficiently large test sets effectively protect against performance misestimation whereas larger datasets per se do not. While these results question the validity of a substantial part of the current literature, we outline the relatively low-cost remedy of larger test sets, which is readily available in most cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41386-021-01020-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209109PMC
July 2021

Dendritic Cells: Neglected Modulators of Peripheral Immune Responses and Neuroinflammation in Mood Disorders?

Cells 2021 04 19;10(4). Epub 2021 Apr 19.

Department of Mental Health, University of Münster, 48149 Münster, Germany.

Affective disorders (AD) including major depressive disorder (MDD) and bipolar disorder (BD) are common mood disorders associated with increased disability and poor health outcomes. Altered immune responses characterized by increased serum levels of pro-inflammatory cytokines and neuroinflammation are common findings in patients with AD and in corresponding animal models. Dendritic cells (DCs) represent a heterogeneous population of myeloid cells that orchestrate innate and adaptive immune responses and self-tolerance. Upon sensing exogenous and endogenous danger signals, mature DCs secrete proinflammatory factors, acquire migratory and antigen presenting capacities and thus contribute to neuroinflammation in trauma, autoimmunity, and neurodegenerative diseases. However, little is known about the involvement of DCs in the pathogenesis of AD. In this review, we summarize the current knowledge on DCs in peripheral immune responses and neuroinflammation in MDD and BD. In addition, we consider the impact of DCs on neuroinflammation and behavior in animal models of AD. Finally, we will discuss therapeutic perspectives targeting DCs and their effector molecules in mood disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells10040941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072712PMC
April 2021

Acute stress reveals different impacts in male and female Zdhhc7-deficient mice.

Brain Struct Funct 2021 Jun 20;226(5):1613-1626. Epub 2021 Apr 20.

Department of Mental Health, University of Münster, Münster, Germany.

Numerous processes of neuronal development and synaptic plasticity in the brain rely on the palmitoyl acyltransferase ZDHHC7, as it palmitoylates various synaptic and extrasynaptic proteins such as neural cell adhesion molecule (NCAM) or gamma-aminobutyric acid (GABA) receptors. In addition, ZDHHC7 palmitoylates sex steroid hormone receptors and is, therefore, indirectly linked to mental disorders that often occur because of or in conjunction with stress. In this work, we investigated how ZDHHC7 affects stress responses in mice. For this purpose, genetically modified mice with a knockout of the Zdhhc7 gene (KO) and wild-type (WT) littermates of both sexes were exposed to acute stressors or control conditions and examined with regard to their behavior, brain microstructure, gene expression, and synaptic plasticity. While no behavioral effects of acute stress were found, we did find that acute stress caused reduced mRNA levels of Esr1 and Esr2 coding for estrogen receptor α and β in the medial prefrontal cortex of male WT and KO mice. Strikingly, after acute stress only male KO mice showed reduced mean fiber lengths of the medioventral hippocampus. Furthermore, Zdhhc7-deficiency impaired synaptic plasticity in mice of both sexes, while acute stress improved it in females, but not in male mice. Taken together, our findings suggest that ZDHHC7 plays a modulatory role in the brain that leads to sex-specific stress responses, possibly due to estrogen receptor-mediated signaling pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00429-021-02275-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096773PMC
June 2021

Psychological training to improve psychosocial function in patients with major depressive disorder: A randomised clinical trial.

Psychiatry Res 2021 Jun 3;300:113906. Epub 2021 Apr 3.

Department of Psychiatry and Psychotherapy, University Hospital Münster, University of Münster, Münster, Germany; Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Melbourne, Australia; The Florey Institute of Neuroscience and Mental Health, The Universit y of Melbourne, Parkville, VIC, Australia. Electronic address:

Cognitive and emotional remediation training for depression (CERT-D): a randomised controlled trial to improve cognitive, emotional and functional outcomes in depression The aim of the current study was to evaluate an experimental treatment designed to improve psychosocial function in patients with Major Depressive Disorder (MDD) by reinforcing cognitive, emotional, and social-cognitive abilities. Participants (N = 112) with current or lifetime MDD were recruited to participate in a randomised, blinded, controlled trial. Exclusion criteria included diagnosis of a substance abuse disorder, bipolar disorder organic, eating disorders, or illness which affect cognitive function. The treatment involved repeated cognitive training designed to improve cognitive, emotional, and social-cognitive abilities. In training sessions, the principles of cognitive training were applied across cognitive, emotional, and social domains, with participants completing repeated mental exercises. Exercises included critically analysing interpretations of social interactions (e.g., body language), exploring emotional reactions to stimuli, and completing game-like cognitive training tasks. Training sessions placed great emphasis on the application of trained cognitive, emotional, and social cognitive skills to psychosocial outcomes. Outcomes demonstrated significant improvement in psychosocial function, symptom severity, self-reported cognition, and social-cognition. Our findings demonstrate the efficacy of multi-domain cognitive training to improve psychosocial functioning in individuals with MDD. We suggest that the present treatment could be deployed at a lower cost and with minimal training in comparison to established psychological therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.psychres.2021.113906DOI Listing
June 2021

Brain morphology is differentially impacted by peripheral cytokines in schizophrenia-spectrum disorder.

Brain Behav Immun 2021 07 8;95:299-309. Epub 2021 Apr 8.

Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Australia; Department of Psychiatry, The University of Melbourne, Australia; Centre for Mental Health, Faculty of Health, Arts and Design, School of Health Sciences, Swinburne University, Melbourne, Australia.

Deficits in brain morphology are one of the most widely replicated neuropathological features in schizophrenia-spectrum disorder (SSD), although their biological underpinnings remain unclear. Despite the existence of hypotheses by which peripheral inflammation may impact brain structure, few studies have examined this relationship in SSD. This study aimed to establish the relationship between peripheral markers of inflammation and brain morphology and determine whether such relationships differed across healthy controls and individuals with first episode psychosis (FEP) and chronic schizophrenia. A panel of 13 pro- and anti-inflammatory cytokines were quantified from serum in 175 participants [n = 84 Healthy Controls (HC), n = 40 FEP, n = 51 Chronic SCZ]. We first performed a series of permutation tests to identify the cytokines most consistently associated with brain structural regions. Using moderation analysis, we then determined the extent to which individual variation in select cytokines, and their interaction with diagnostic status, predicted variation in brain structure. We found significant interactions between cytokine level and diagnosis on brain structure. Diagnostic status significantly moderated the relationship of IFNγ, IL4, IL5 and IL13 with frontal thickness, and of IFNγ and IL5 and total cortical volume. Specifically, frontal thickness was positively associated with IFNγ, IL4, IL5 and IL13 cytokine levels in the healthy control group, whereas pro-inflammatory cytokines IFNγ and IL5 were associated with lower total cortical volume in the FEP group. Our findings suggest that while there were no relationships detected in chronic schizophrenia, the relationship between peripheral inflammatory markers and select brain regions are differentially impacted in FEP and healthy controls. Longitudinal investigations are required to determine whether the relationship between brain structure and peripheral inflammation changes over time.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbi.2021.04.002DOI Listing
July 2021

TNF signaling via TNF receptors does not mediate the effects of short-term exercise on cognition, anxiety and depressive-like behaviors in middle-aged mice.

Behav Brain Res 2021 06 31;408:113269. Epub 2021 Mar 31.

Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia; Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Melbourne, VIC, Australia; Department of Psychiatry, The University of Münster, Münster, Germany. Electronic address:

Background: We recently reported that tumor necrosis factor (TNF) signaling via the TNFR1 and TNFR2 receptors mediates the effects of long-term exercise on locomotion, cognition and anxiety, but not depressive-like behavior. We now investigated whether the TNF signaling via its receptors also mediates the effects of short-term exercise on cognition, anxiety and depressive-like behaviors.

Methods: Thirteen-month-old C57BL/6 (WT), TNF, TNFR1, and TNFR2 mice were provided with 4 weeks of voluntary wheel running followed by behavioral testing using an established behavioral battery. Each genotype had a respective non-exercise control.

Results: There was no interaction between genotype and exercise in any of the tests but the main effect of genotype, and not exercise, were found to be significant in the open field (OF), forced-swim test (FST) and Barnes maze (BM). In the OF, the control and exercise TNFR2 mice spent significantly less time in the inner zone than mice in the control and exercise WT and TNF cohorts. In the FST, control and exercise WT mice showed significantly higher immobility time than their control and exercise TNF, TNFR1 and TNFR2 cohorts. In the BM, the latency to escape over 4 days of training was significantly higher in all KO groups compared to WT, irrespective of exercise. Also, the latency to escape to the original location during the probe trial was higher for control and exercise WT compared to corresponding TNFR1 mice. In contrast, the latency to escape to the new location was lower for control and exercise WT compared to control and exercise TNFR1 and TNFR2 mice. The latency to escape to the new location in exercise groups was longer compared to control within all genotypes.

Conclusion: While TNF signaling via the TNF receptors mediates cognition, anxiety and depressive-like behaviors independently, it does not mediate the effects of short-term exercise on these behaviors in middle-aged mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbr.2021.113269DOI Listing
June 2021

The association between genetically determined ABO blood types and major depressive disorder.

Psychiatry Res 2021 05 24;299:113837. Epub 2021 Feb 24.

Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany; German Centre for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, Germany.

ABO blood types and their corresponding antigens have long been assumed to be related to different human diseases. So far, smaller studies on the relationship between mental disorders and blood types yielded contradicting results. In this study we analyzed the association between ABO blood types and lifetime major depressive disorder (MDD). We performed a pooled analysis with data from 26 cohorts that are part of the MDD working group of the Psychiatric Genomics Consortium (PGC). The dataset included 37,208 individuals of largely European ancestry of which 41.6% were diagnosed with lifetime MDD. ABO blood types were identified using three single nucleotide polymorphisms in the ABO gene: rs505922, rs8176746 and rs8176747. Regression analyses were performed to assess associations between the individual ABO blood types and MDD diagnosis as well as putative interaction effects with sex. The models were adjusted for sex, cohort and the first ten genetic principal components. The percentage of blood type A was slightly lower in cases than controls while blood type O was more prominent in cases. However, these differences were not statistically significant. Our analyses found no evidence of an association between ABO blood types and major depressive disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.psychres.2021.113837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071927PMC
May 2021

Association Between Genetic Risk for Type 2 Diabetes and Structural Brain Connectivity in Major Depressive Disorder.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 Mar 5. Epub 2021 Mar 5.

Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany.

Background: Major depressive disorder (MDD) and type 2 diabetes mellitus (T2D) are known to share clinical comorbidity and to have genetic overlap. Besides their shared genetics, both diseases seem to be associated with alterations in brain structural connectivity and impaired cognitive performance, but little is known about the mechanisms by which genetic risk of T2D might affect brain structure and function and if they do, how these effects could contribute to the disease course of MDD.

Methods: This study explores the association of polygenic risk for T2D with structural brain connectome topology and cognitive performance in 434 nondiabetic patients with MDD and 539 healthy control subjects.

Results: Polygenic risk score for T2D across MDD patients and healthy control subjects was found to be associated with reduced global fractional anisotropy, a marker of white matter microstructure, an effect found to be predominantly present in MDD-related fronto-temporo-parietal connections. A mediation analysis further suggests that this fractional anisotropy variation may mediate the association between polygenic risk score and cognitive performance.

Conclusions: Our findings provide preliminary evidence of a polygenic risk for T2D to be linked to brain structural connectivity and cognition in patients with MDD and healthy control subjects, even in the absence of a direct T2D diagnosis. This suggests an effect of T2D genetic risk on white matter integrity, which may mediate an association of genetic risk for diabetes and cognitive impairments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bpsc.2021.02.010DOI Listing
March 2021

Apolipoprotein E homozygous ε4 allele status: Effects on cortical structure and white matter integrity in a young to mid-age sample.

Eur Neuropsychopharmacol 2021 May 27;46:93-104. Epub 2021 Feb 27.

Department of Psychiatry, University of Münster, Münster, Germany. Electronic address:

Apolipoprotein E (APOE) genotype is the strongest single gene predictor of Alzheimer's disease (AD) and has been frequently associated with AD-related brain structural alterations before the onset of dementia. While previous research has primarily focused on hippocampal morphometry in relation to APOE, sporadic recent findings have questioned the specificity of the hippocampus and instead suggested more global effects on the brain. With the present study we aimed to investigate associations between homozygous APOE ε4 status and cortical gray matter structure as well as white matter microstructure. In our study, we contrasted n = 31 homozygous APOE ε4 carriers (age=34.47 years, including a subsample of n = 12 subjects with depression) with a demographically matched sample without an ε4 allele (resulting total sample: N = 62). Morphometry analyses included a) Freesurfer based cortical segmentations of thickness and surface area measures and b) tract based spatial statistics of DTI measures. We found pronounced and widespread reductions in cortical surface area of ε4 homozygotes in 57 out of 68 cortical brain regions. In contrast, no differences in cortical thickness were observed. Furthermore, APOE ε4 homozygous carriers showed significantly lower fractional anisotropy in the corpus callosum, the right internal and external capsule, the left corona radiata and the right fornix. The present findings support a global rather than regionally specific effect of homozygous APOE ε4 allele status on cortical surface area and white matter microstructure. Future studies should aim to delineate the clinical implications of these findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.euroneuro.2021.02.006DOI Listing
May 2021

The Effect of High-Intensity Power Training on Habitual, Intervention and Total Physical Activity Levels in Older Adults with Type 2 Diabetes: Secondary Outcomes of the GREAT2DO Randomized Controlled Trial.

Geriatrics (Basel) 2021 Feb 8;6(1). Epub 2021 Feb 8.

Faculty of Medicine and Health, University of Sydney, Camperdown 2050, Australia.

Background: We examined the effect of power training on habitual, intervention and total physical activity (PA) levels in older adults with type 2 diabetes and their relationship to metabolic control.

Materials And Methods: 103 adults with type 2 diabetes were randomized to receive supervised power training or sham exercise three times/week for 12 months. Habitual, intervention, and total PA, as well as insulin resistance (HOMA2-IR) and glycosylated hemoglobin (HbA1c), were measured.

Results: Participants were aged 67.9 ± 5.5 yrs, with well-controlled diabetes (HbA1c = 7.1%) and higher than average habitual PA levels compared to healthy peers. Habitual PA did not change significantly over 12 months ( = 0.74), and there was no effect of group assignment on change over time in habitual PA over 0-6 ( = 0.16) or 0-6-12 months ( = 0.51). By contrast, intervention PA, leg press tonnage and total PA increased over both 6- and 12-month timepoints ( = 0.0001), and these changes were significantly greater in the power training compared to the sham exercise group across timepoints ( = 0.0001). However, there were no associations between changes in any PA measures over time and changes in metabolic profile.

Conclusion: Structured high-intensity power training may be an effective strategy to enhance overall PA in this high-risk cohort.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/geriatrics6010015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930974PMC
February 2021

Genome-wide association study of circulating interleukin 6 levels identifies novel loci.

Hum Mol Genet 2021 04;30(5):393-409

Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK.

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098112PMC
April 2021

Novelty seeking is associated with increased body weight and orbitofrontal grey matter volume reduction.

Psychoneuroendocrinology 2021 04 19;126:105148. Epub 2021 Jan 19.

Department of Psychiatry, University of Münster, Germany. Electronic address:

Novelty seeking (NS) has previously been identified as a personality trait that is associated with elevated body mass index (BMI) and obesity. Of note, both obesity and reduced impulse control - a core feature of NS - have previously been associated with grey matter volume (GMV) reductions in the orbitofrontal cortex (OFC). Yet, it remains unknown, if body weight-related grey matter decline in the OFC might be explained by higher levels of NS. To address this question, we studied associations between NS, BMI and brain structure in 355 healthy subjects. Brain images were pre-processed using voxel-based morphometry (VBM). BMI was calculated from self-reported height and weight. The Tridimensional Personality Questionnaire (TPQ) was used to assess NS. NS and BMI were associated positively (r = .137, p = .01) with NS being a significant predictor of BMI (B = 0.172; SE B = 0.05; ß = 0.184; p = 0.001). Significant associations between BMI and GMV specifically in the OFC (x = -44, y = 56, z = -2, t(350) = 4.34, k = 5, p = 0.011) did not uphold when correcting for NS in the model. In turn, a significant negative association between NS and OFC GMV was found independent of BMI (x = -2, y = 48, z = -10, t(349) = 4.42, k = 88, p = 0.008). Body mass-related grey matter decrease outside the OFC could not be attributed to NS. Our results suggest that body-weight-related orbitofrontal grey matter reduction can at least partly be linked to higher levels of NS. Given the pivotal role of the OFC in overweight as well as cognitive domains such as impulse inhibition, executive control and reward processing, its association with NS seems to provide a tenable neurobiological correlate for future research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.psyneuen.2021.105148DOI Listing
April 2021
-->