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142 Publications visible to you, out of a total of 142
Genomic and transcriptomic heterogeneity of colorectal tumours arising in Lynch syndrome.
LIFE - Leipzig Research Center for Civilization Diseases

Abstract (Expand)

Colorectal cancer (CRC) arising in Lynch syndrome (LS) comprises tumours with constitutional mutations in DNA mismatch repair genes. There is still a lack of whole-genome and transcriptome studies of … LS-CRC to address questions about similarities and differences in mutation and gene expression characteristics between LS-CRC and sporadic CRC, about the molecular heterogeneity of LS-CRC, and about specific mechanisms of LS-CRC genesis linked to dysfunctional mismatch repair in LS colonic mucosa and the possible role of immune editing. Here, we provide a first molecular characterization of LS tumours and of matched tumour-distant reference colonic mucosa based on whole-genome DNA-sequencing and RNA-sequencing analyses. Our data support two subgroups of LS-CRCs, G1 and G2, whereby G1 tumours show a higher number of somatic mutations, a higher amount of microsatellite slippage, and a different mutation spectrum. The gene expression phenotypes support this difference. Reference mucosa of G1 shows a strong immune response associated with the expression of HLA and immune checkpoint genes and the invasion of CD4+ T cells. Such an immune response is not observed in LS tumours, G2 reference and normal (non-Lynch) mucosa, and sporadic CRC. We hypothesize that G1 tumours are edited for escape from a highly immunogenic microenvironment via loss of HLA presentation and T-cell exhaustion. In contrast, G2 tumours seem to develop in a less immunogenic microenvironment where tumour-promoting inflammation parallels tumourigenesis. Larger studies on non-neoplastic mucosa tissue of mutation carriers are required to better understand the early phases of emerging tumours. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Authors: H. Binder, L. Hopp, M. R. Schweiger, S. Hoffmann, F. Juhling, M. Kerick, B. Timmermann, S. Siebert, C. Grimm, L. Nersisyan, A. Arakelyan, M. Herberg, P. Buske, H. Loeffler-Wirth, M. Rosolowski, C. Engel, J. Przybilla, M. Peifer, N. Friedrichs, G. Moeslein, M. Odenthal, M. Hussong, S. Peters, S. Holzapfel, J. Nattermann, R. Hueneburg, W. Schmiegel, B. Royer-Pokora, S. Aretz, M. Kloth, M. Kloor, R. Buettner, J. Galle, M. Loeffler

Date Published: 21st Jul 2017

Publication Type: Not specified

Human Diseases: Lynch syndrome, colorectal cancer

White matter hyperintensities associated with small vessel disease impair social cognition beside attention and memory.
LIFE Adult

Abstract (Expand)

Age-related white matter hyperintensities (WMH) are a manifestation of white matter damage seen on magnetic resonance imaging (MRI). They are related to vascular risk factors and cognitive impairment. … This study investigated the cognitive profile at different stages of WMH in a large community-dwelling sample; 849 subjects aged 21 to 79 years were classified on the 4-stage Fazekas scale according to hyperintense lesions seen on individual T2-weighted fluid-attenuated inversion recovery MRI scans. The evaluation of cognitive functioning included seven domains of cognitive performance and five domains of subjective impairment, as proposed by the DSM-5. For the first time, the impact of age-related WMH on Theory of Mind was investigated. Differences between Fazekas groups were analyzed non-parametrically and effect sizes were computed. Effect sizes revealed a slight overall cognitive decline in Fazekas groups 1 and 2 relative to healthy subjects. Fazekas group 3 presented substantial decline in social cognition, attention and memory, although characterized by a high inter-individual variability. WMH groups reported subjective cognitive decline. We demonstrate that extensive WMH are associated with specific impairment in attention, memory, social cognition, and subjective cognitive performance. The detailed neuropsychological characterization of WMH offers new therapeutic possibilities for those affected by vascular cognitive decline.

Authors: J. Kynast, L. Lampe, T. Luck, S. Frisch, K. Arelin, K. T. Hoffmann, M. Loeffler, S. G. Riedel-Heller, A. Villringer, M. L. Schroeter

Date Published: 8th Jul 2017

Publication Type: Journal article

Human Diseases: COL4A1-related familial vascular leukoencephalopathy

Could High Mental Demands at Work Offset the Adverse Association Between Social Isolation and Cognitive Functioning? Results of the Population-Based LIFE-Adult-Study.
LIFE Adult

Abstract (Expand)

OBJECTIVES: The study investigated whether high mental demands at work, which have shown to promote a good cognitive functioning in old age, could offset the adverse association between social isolation … and cognitive functioning. METHODS: Based on data from the population-based LIFE-Adult-Study, the association between cognitive functioning (Verbal Fluency Test, Trail Making Test B) and social isolation (Lubben Social Network Scale) as well as mental demands at work (O*NET database) was analyzed via linear regression analyses adjusted for age, sex, education, and sampling weights. RESULTS: Cognitive functioning was significantly lower in socially isolated individuals and in individuals working in low mental demands jobs-even in old age after retirement and even after taking into account the educational level. An interaction effect suggested stronger effects of mental demands at work in socially isolated than nonisolated individuals. CONCLUSIONS: The findings suggest that working in high mental-demand jobs could offset the adverse association between social isolation and cognitive functioning. Further research should evaluate how interventions that target social isolation and enhance mentally demanding activities promote a good cognitive functioning in old age.

Authors: F. S. Rodriguez, M. L. Schroeter, A. V. Witte, C. Engel, M. Loffler, J. Thiery, A. Villringer, T. Luck, S. G. Riedel-Heller

Date Published: 4th Jul 2017

Publication Type: Journal article

ASSOCIATION OF HIPPOCAMPAL VOLUMES WITH COGNITIVE TASKS IN A LARGE POPULATION-BASED COHORT
LIFE - Leipzig Research Center for Civilization Diseases

Abstract (Expand)

Background: Hippocampal volume, assessed via high-resolution MRI, is associated with memory and visuospatial performance in humans (Squire, 2004) and specifically prone to develop atrophy with age … (Apostolova,2015). This process has been linked to neurodegenerative diseases, such as Alzheimer’s disease (Apostolova,2015) and a decline of cognitive functions (Bruno,2016). However, due to differences in study-design and characteristics certain heterogeneity in results remains, in particular considering subfieldspecific effects (deFlores,2015). Therefore, we aim to determine the association of volumes of the whole hippocampus and its subfields on cognition in a large population-based cohort. Methods: Subjects: 1956 healthy participants from the Leipzig Research-Center-for-Civilization-Disease, aged 19-82years with MRI and neuropsychological tests (mean-age=57.61,±15.08SD). Exclusion: stroke, major-brain-pathologies, central-nervous-medication. Independent Variables: Volume of hippocampus and its subfields (CornuAmmonis1, 2-3, 4-DentateGyrus,(Pre-)subiculum). Dependent Variables: Verbal word-list learning, verbal-fluency, TrailMakingTask-(TMT)-A&B. Covariates: sex, age, years-of-education, total grey-mattervolume Image Analysis on high-resolution T1-images assessed at 3T. Hippocampal volumes were estimated using automatic segmentation analysis implemented in FreeSurfer (www.freesurfer.net). Statistical Analysis: Independent and dependent variables were first entered into Pearson Correlations. Variables with a correlation coefficient of r>0.1 were entered into multiple linear-regressions and adjusted for potential confounding(forward inclusion-model). Results: According to bivariate correlations, better performance in verbal-learning, verbal-fluency and TMT-A&B correlated moderately with larger whole-hippocampal volume and the volumes of all subfields(all |r|>0.102, all p0.046, all p0.5). Conclusions: Using a large cross-sectional cohort of healthy adults we found that volumes of the whole-hippocampus and subfields covering the CA4/dentate-gyrus region were weakly, yet specifically associated with verbal-learning and spatial processing-speed. Our preliminary results are in line with previous studies presuming a differential involvement of the hippocampus in tasks of verbal-learning and spatial processing (Oosterman,2010). Upcoming analyses implementing parcellation along the anteriorposterior- axis and random-effect-models might help to further disentangle these effects.

Authors: S. Huhn, R. Zhang, Frauke Beyer, L. Lampe, T. Luck, S. G. Riedel-Heller, M. L. Schroeter, Markus Löffler, M. Stumvoll, A. Villringer, A. V. Witte

Date Published: 1st Jul 2017

Publication Type: Not specified

Human Diseases: cognitive disorder, dementia

Recorded and Reported Sleepiness: The Association Between Brain Arousal in Resting State and Subjective Daytime Sleepiness.
LIFE Adult

Abstract (Expand)

Objectives: Daytime sleepiness is a significant public health concern. Early evidence points toward the computerized VIGALL (Vigilance Algorithm Leipzig) as time-efficient tool to assess sleepiness … objectively. In the present study, we investigated the association between VIGALL variables of EEG vigilance (indicating brain arousal in resting state) and subjective daytime sleepiness in the LIFE cohort study. Additionally, we validated VIGALL against the self-rated likelihood of having fallen asleep during the conducted resting EEG and against heart periods. Methods: Participants of the primary sample LIFE 60+ (N = 1927, 60-79 years) and replication sample LIFE 40+ (N = 293, 40-56 years) completed the Epworth Sleepiness Scale (ESS). After an average interval of 3 weeks (LIFE 60+) and 65 weeks (LIFE 40+), respectively, participants underwent a single 20-minute resting EEG, analyzed using VIGALL 2.1. Results: Analyses revealed significant associations between ESS and EEG vigilance in LIFE 60+ (rho = -0.17, p = 1E-14) and LIFE 40+ (rho = -0.24, p = 2E-5). Correlations between EEG vigilance and self-rated sleep likelihood reached rho = -0.43 (p = 2E-91) in LIFE 60+ and rho = -0.50 (p = 5E-20) in LIFE 40+. Overall, strongest correlations were obtained for EEG vigilance variable "slope index." Furthermore, lower EEG vigilance was consistently associated with longer heart periods. Conclusions: The present study contributes to the validation of VIGALL. Despite the considerable interval between ESS and EEG assessment dates, the strength of ESS-VIGALL association approximates prior ESS-Multiple Sleep Latency Test results. In this light, VIGALL might constitute an economical choice for the objective assessment of daytime sleepiness in large cohort studies. The discriminative power to identify disorders of hypersomnolence, however, remains to be addressed.

Authors: P. Jawinski, J. Kittel, C. Sander, J. Huang, J. Spada, C. Ulke, K. Wirkner, T. Hensch, U. Hegerl

Date Published: 1st Jul 2017

Publication Type: Journal article

Disentangling the neural correlates of corticobasal syndrome and corticobasal degeneration with systematic and quantitative ALE meta-analyses.
LIFE Adult

Abstract (Expand)

Corticobasal degeneration is a scarce neurodegenerative disease, which can only be confirmed by histopathological examination. Reported to be associated with various clinical syndromes, its classical … clinical phenotype is corticobasal syndrome. Due to the rareness of corticobasal syndrome/corticobasal degeneration and low numbers of patients included in single studies, meta-analyses are particularly suited to disentangle features of the clinical syndrome and histopathology. Using PubMed, we identified 11 magnetic resonance imaging studies measuring atrophy in 22 independent cohorts with 200 patients contrasted to 318 healthy controls. The anatomic likelihood estimation method was applied to reveal affected brain regions across studies. Corticobasal syndrome was related to gray matter loss in the basal ganglia/thalamus, frontal, parietal, and temporal lobes. In corticobasal degeneration patients, atrophy in the thalamus, frontal, temporal, and occipital lobes were found. Finally, in a conjunction analysis, the bilateral thalamus, the bilateral posterior frontomedian cortex, posterior midcingulate cortex and premotor area/supplementary motor area, and the left posterior superior and middle frontal gyrus/precentral gyrus were identified as areas associated with both, corticobasal syndrome and corticobasal degeneration. Remarkably, atrophy in the premotor area/supplementary motor area and posterior midcingulate/frontomedian cortex seems to be specific for corticobasal syndrome/corticobasal degeneration, whereas atrophy in the thalamus and the left posterior superior and middle frontal gyrus/precentral gyrus are also associated with other neurodegenerative diseases according to anatomic likelihood estimation method meta-analyses. Our study creates a new conceptual framework to understand, and distinguish between clinical features (corticobasal syndrome) and histopathological findings (corticobasal degeneration) by powerful data-driven meta-analytic approaches. Furthermore, it proposes regional-specific atrophy as an imaging biomarker for diagnosis of corticobasal syndrome/corticobasal degeneration ante-mortem.

Authors: F. Albrecht, S. Bisenius, R. Morales Schaack, J. Neumann, M. L. Schroeter

Date Published: 27th Jun 2017

Publication Type: Journal article

Human Diseases: neurodegenerative disease

Stability of BDNF in Human Samples Stored Up to 6 Months and Correlations of Serum and EDTA-Plasma Concentrations.
LIFE Adult

Abstract (Expand)

Brain-derived neurotrophic factor (BDNF), an important neural growth factor, has gained growing interest in neuroscience, but many influencing physiological and analytical aspects still remain unclear. … In this study we assessed the impact of storage time at room temperature, repeated freeze/thaw cycles, and storage at -80 degrees C up to 6 months on serum and ethylenediaminetetraacetic acid (EDTA)-plasma BDNF. Furthermore, we assessed correlations of serum and plasma BDNF concentrations in two independent sets of samples. Coefficients of variations (CVs) for serum BDNF concentrations were significantly lower than CVs of plasma concentrations (n = 245, p = 0.006). Mean serum and plasma concentrations at all analyzed time points remained within the acceptable change limit of the inter-assay precision as declared by the manufacturer. Serum and plasma BDNF concentrations correlated positively in both sets of samples and at all analyzed time points of the stability assessment (r = 0.455 to rs = 0.596; p < 0.004). In summary, when considering the acceptable change limit, BDNF was stable in serum and in EDTA-plasma up to 6 months. Due to a higher reliability, we suggest favoring serum over EDTA-plasma for future experiments assessing peripheral BDNF concentrations.

Authors: M. Polyakova, H. Schlogl, J. Sacher, M. Schmidt-Kassow, J. Kaiser, M. Stumvoll, J. Kratzsch, M. L. Schroeter

Date Published: 3rd Jun 2017

Publication Type: Journal article

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