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1005 Publications visible to you, out of a total of 1005
Resting-state functional magnetic resonance imaging of the subthalamic microlesion and stimulation effects in Parkinson's disease: Indications of a principal role of the brainstem.
LIFE Adult

Abstract (Expand)

During implantation of deep-brain stimulation (DBS) electrodes in the target structure, neurosurgeons and neurologists commonly observe a "microlesion effect" (MLE), which occurs well before … initiating subthalamic DBS. This phenomenon typically leads to a transitory improvement of motor symptoms of patients suffering from Parkinson's disease (PD). Mechanisms behind MLE remain poorly understood. In this work, we exploited the notion of ranking to assess spontaneous brain activity in PD patients examined by resting-state functional magnetic resonance imaging in response to penetration of DBS electrodes in the subthalamic nucleus. In particular, we employed a hypothesis-free method, eigenvector centrality (EC), to reveal motor-communication-hubs of the highest rank and their reorganization following the surgery; providing a unique opportunity to evaluate the direct impact of disrupting the PD motor circuitry in vivo without prior assumptions. Penetration of electrodes was associated with increased EC of functional connectivity in the brainstem. Changes in connectivity were quantitatively related to motor improvement, which further emphasizes the clinical importance of the functional integrity of the brainstem. Surprisingly, MLE and DBS were associated with anatomically different EC maps despite their similar clinical benefit on motor functions. The DBS solely caused an increase in connectivity of the left premotor region suggesting separate pathophysiological mechanisms of both interventions. While the DBS acts at the cortical level suggesting compensatory activation of less affected motor regions, the MLE affects more fundamental circuitry as the dysfunctional brainstem predominates in the beginning of PD. These findings invigorate the overlooked brainstem perspective in the understanding of PD and support the current trend towards its early diagnosis.

Authors: S. Holiga, K. Mueller, H. E. Moller, D. Urgosik, E. Ruzicka, M. L. Schroeter, R. Jech

Date Published: 29th Oct 2015

Publication Type: Not specified

Human Diseases: Parkinson's disease

Brain Arousal Regulation in Carriers of Bipolar Disorder Risk Alleles.
LIFE Adult

Abstract (Expand)

OBJECTIVES: Recent genome-wide association studies identified a number of chromosomal risk loci for bipolar disorder (BD, 'manic-depressive illness'). According to the vigilance regulation … model, the regulation of brain arousal (referred to as 'vigilance') when assessed via EEG is an emerging biomarker linked to the pathogenesis of manic and depressive episodes. On this basis, the present study aimed to assess whether carriers of BD risk alleles differ in brain arousal regulation. METHODS: Healthy participants of the population-based Leipzig Health Care Study (LIFE) underwent a 20-min eyes-closed resting EEG paradigm. Brain arousal was assessed applying the computer-based Vigilance Algorithm Leipzig (VIGALL). The primary sample (n = 540) was genotyped for ten of the most reliable BD risk variants, of which two qualified for replication (n = 509). RESULTS: Primary sample analyses revealed Bonferroni-adjusted significance for rs1006737 in CACNA1C (encoding a calcium channel subunit), with risk allele carriers exhibiting relatively steep brain arousal declines. Further, carriers of two risk alleles of rs472913 at 1p32.1 showed generally lower brain arousal levels for the duration of the resting paradigm. However, both associations failed replication. CONCLUSION: Although our initial findings are in line with the vigilance regulation model and convincing in view of the previously reported notable role of ion channelopathies in BD, our results do not provide consistent evidence for a link between BD risk variants and brain arousal regulation. Several between-sample differences may account for this inconsistency. The molecular genetics of brain arousal regulation remain to be clarified.

Authors: P. Jawinski, C. Sander, N. Mauche, J. Spada, J. Huang, A. Schmidt, M. Hantzsch, R. Burkhardt, M. Scholz, U. Hegerl, T. Hensch

Date Published: 29th Oct 2015

Publication Type: Not specified

Human Diseases: bipolar disorder

First evidence for glial pathology in late life minor depression: S100B is increased in males with minor depression.
LIFE Adult

Abstract (Expand)

Minor depression is diagnosed when a patient suffers from 2 to 4 depressive symptoms for at least 2 weeks. Though minor depression is a widespread phenomenon, its pathophysiology has hardly been studied. … To get a first insight into the pathophysiological mechanisms underlying this disorder we assessed serum levels of biomarkers for plasticity, glial and neuronal function: brain-derived neurotrophic factor (BDNF), S100B and neuron specific enolase (NSE). 27 subjects with minor depressive episode and 82 healthy subjects over 60 years of age were selected from the database of the Leipzig population-based study of civilization diseases (LIFE). Serum levels of BDNF, S100B and NSE were compared between groups, and correlated with age, body-mass index (BMI), and degree of white matter hyperintensities (score on Fazekas scale). S100B was significantly increased in males with minor depression in comparison to healthy males, whereas other biomarkers did not differ between groups (p = 0.10-0.66). NSE correlated with Fazekas score in patients with minor depression (rs = 0.436, p = 0.048) and in the whole sample (rs = 0.252, p = 0.019). S100B correlated with BMI (rs = 0.246, p = 0.031) and with age in healthy subjects (rs = 0.345, p = 0.002). Increased S100B in males with minor depression, without alterations in BDNF and NSE, supports the glial hypothesis of depression. Correlation between white matter hyperintensities and NSE underscores the vascular hypothesis of late life depression.

Authors: M. Polyakova, C. Sander, K. Arelin, L. Lampe, T. Luck, M. Luppa, J. Kratzsch, K. T. Hoffmann, S. Riedel-Heller, A. Villringer, P. Schoenknecht, M. L. Schroeter

Date Published: 27th Oct 2015

Publication Type: Not specified

Human Diseases: mental depression

Epigenetic Heterogeneity of B-Cell Lymphoma: Chromatin Modifiers.
MMML-MYC-SYS

Abstract (Expand)

We systematically studied the expression of more than fifty histone and DNA (de)methylating enzymes in lymphoma and healthy controls. As a main result, we found that the expression levels of nearly all … enzymes become markedly disturbed in lymphoma, suggesting deregulation of large parts of the epigenetic machinery. We discuss the effect of DNA promoter methylation and of transcriptional activity in the context of mutated epigenetic modifiers such as EZH2 and MLL2. As another mechanism, we studied the coupling between the energy metabolism and epigenetics via metabolites that act as cofactors of JmjC-type demethylases. Our study results suggest that Burkitt's lymphoma and diffuse large B-cell Lymphoma differ by an imbalance of repressive and poised promoters, which is governed predominantly by the activity of methyltransferases and the underrepresentation of demethylases in this regulation. The data further suggest that coupling of epigenetics with the energy metabolism can also be an important factor in lymphomagenesis in the absence of direct mutations of genes in metabolic pathways. Understanding of epigenetic deregulation in lymphoma and possibly in cancers in general must go beyond simple schemes using only a few modes of regulation.

Authors: L. Hopp, L. Nersisyan, H. Loffler-Wirth, A. Arakelyan, H. Binder

Date Published: 21st Oct 2015

Publication Type: Not specified

Human Diseases: non-Hodgkin lymphoma

oposSOM: R-package for high-dimensional portraying of genome-wide expression landscapes on bioconductor.
HNPCC-Sys - Genomic and transcriptomic heterogeneity of colorectal tumours arising in Lynch syndrome

Abstract (Expand)

MOTIVATION: Comprehensive analysis of genome-wide molecular data challenges bioinformatics methodology in terms of intuitive visualization with single-sample resolution, biomarker selection, functional … information mining and highly granular stratification of sample classes. oposSOM combines those functionalities making use of a comprehensive analysis and visualization strategy based on self-organizing maps (SOM) machine learning which we call 'high-dimensional data portraying'. The method was successfully applied in a series of studies using mostly transcriptome data but also data of other OMICs realms. AVAILABILITY AND IMPLEMENTATION: oposSOM is now publicly available as Bioconductor R package. CONTACT: wirth@izbi.uni-leipzig.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Authors: H. Loffler-Wirth, M. Kalcher, H. Binder

Date Published: 1st Oct 2015

Publication Type: Not specified

Working-memory endophenotype and dyslexia-associated genetic variant predict dyslexia phenotype
Genetical Statistics and Systems Biology

Abstract (Expand)

Developmental dyslexia, a severe impairment of literacy acquisition, is known to have a neurological basis and a strong genetic background. However, effects of individual genetic variations on … dyslexia-associated deficits are only moderate and call for the assessment of the genotype’s impact on mediating neuro-endophenotypes by the imaging genetics approach. Using voxel-based morphometry (VBM) in German participants with and without dyslexia, we investigated gray matter changes and their association with impaired phonological processing, such as reduced verbal working memory. These endophenotypical alterations were, together with dyslexia-associated genetic variations, examined on their suitability as potential predictors of dyslexia. We identified two gray matter clusters in the left posterior temporal cortex related to verbal working memory capacity. Regional cluster differences correlated with genetic risk variants in TNFRSF1B. High-genetic-risk participants exhibit a structural predominance of auditory-association areas relative to auditory-sensory areas, which may partly compensate for deficient early auditory-sensory processing stages of verbal working memory. The reverse regional predominance observed in low-genetic-risk participants may in turn reflect reliance on these early auditory-sensory processing stages. Logistic regression analysis further supported that regional gray matter differences and genetic risk interact in the prediction of individuals’ diagnostic status: With increasing genetic risk, the working-memory related structural predominance of auditory-association areas relative to auditory-sensory areas classifies participants with dyslexia versus control participants. Focusing on phonological deficits in dyslexia, our findings suggest endophenotypical changes in the left posterior temporal cortex could comprise novel pathomechanisms for verbal working memory-related processes translating TNFRSF1B genotype into the dyslexia phenotype. Developmental dyslexia, a severe impairment of literacy acquisition, is known to have a neurological basis and a strong genetic background. However, effects of individual genetic variations on dyslexia-associated deficits are only moderate and call for the assessment of the genotype’s impact on mediating neuro-endophenotypes by the imaging genetics approach. Using voxel-based morphometry (VBM) in German participants with and without dyslexia, we investigated gray matter changes and their association with impaired phonological processing, such as reduced verbal working memory. These endophenotypical alterations were, together with dyslexia-associated genetic variations, examined on their suitability as potential predictors of dyslexia. We identified two gray matter clusters in the left posterior temporal cortex related to verbal working memory capacity. Regional cluster differences correlated with genetic risk variants in TNFRSF1B. High-genetic-risk participants exhibit a structural predominance of auditory-association areas relative to auditory-sensory areas, which may partly compensate for deficient early auditory-sensory processing stages of verbal working memory. The reverse regional predominance observed in low-genetic-risk participants may in turn reflect reliance on these early auditory-sensory processing stages. Logistic regression analysis further supported that regional gray matter differences and genetic risk interact in the prediction of individuals’ diagnostic status: With increasing genetic risk, the working-memory related structural predominance of auditory-association areas relative to auditory-sensory areas classifies participants with dyslexia versus control participants. Focusing on phonological deficits in dyslexia, our findings suggest endophenotypical changes in the left posterior temporal cortex could comprise novel pathomechanisms for verbal working memory-related processes translating TNFRSF1B genotype into the dyslexia phenotype.

Authors: Claudia Männel, Lars Meyer, Arndt Wilcke, Johannes Boltze, Holger Kirsten, Angela D. Friederici

Date Published: 1st Oct 2015

Publication Type: Journal article

A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease
Genetical Statistics and Systems Biology

Abstract (Expand)

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes … from the 1000 Genomes Project, we report a GWAS meta-analysis of \sim185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) \textgreater 0.05) and 2.7 million low-frequency (0.005 \textless MAF \textless 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.   Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of \sim185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) \textgreater 0.05) and 2.7 million low-frequency (0.005 \textless MAF \textless 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.   Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of \sim185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) \textgreater 0.05) and 2.7 million low-frequency (0.005 \textless MAF \textless 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.   Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of \sim185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) \textgreater 0.05) and 2.7 million low-frequency (0.005 \textless MAF \textless 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size. //  Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of \sim185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) \textgreater 0.05) and 2.7 million low-frequency (0.005 \textless MAF \textless 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.

Author: CARDIoGRAMplusC4D Consortium

Date Published: 1st Oct 2015

Publication Type: Journal article

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