Publications by authors named "Ulf Schminke"

70 Publications

Associations of carotid intima media thickness with gene expression in whole blood and genetically predicted gene expression across 48 tissues.

Hum Mol Genet 2021 Nov 12. Epub 2021 Nov 12.

LIFE Research Center of Civilization Diseases, University of Leipzig, Leipzig, Germany.

Carotid intima media thickness (cIMT) is a biomarker of subclinical atherosclerosis and a predictor of future cardiovascular events. Identifying associations between gene expression levels and cIMT may provide insight to atherosclerosis etiology. Here, we use two approaches to identify associations between mRNA levels and cIMT: differential gene expression analysis in whole blood and S-PrediXcan. We used microarrays to measure genome-wide whole blood mRNA levels of 5647 European individuals from four studies. We examined the association of mRNA levels with cIMT adjusted for various potential confounders. Significant associations were tested for replication in three studies totaling 3943 participants. Next, we applied S-PrediXcan to summary statistics from a cIMT genome-wide association study of 71 128 individuals to estimate the association between genetically determined mRNA levels and cIMT and replicated these analyses using S-PrediXcan on an independent genome-wide association study on cIMT that included 22 179 individuals from the UK Biobank. mRNA levels of TNFAIP3, CEBPD, and METRNL were inversely associated with cIMT, but these associations were not significant in the replication analysis. S-PrediXcan identified associations between cIMT and genetically determined mRNA levels for 36 genes, of which six were significant in the replication analysis, including TLN2, which had not been previously reported for cIMT. There was weak correlation between our results using differential gene expression analysis and S-PrediXcan. Differential expression analysis and S-PrediXcan represent complementary approaches for the discovery of associations between phenotypes and gene expression. Using these approaches, we prioritize TNFAIP3, CEBPD, METRNL, and TLN2 as new candidate genes whose differential expression might modulate cIMT.
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http://dx.doi.org/10.1093/hmg/ddab236DOI Listing
November 2021

Association between hepatic fat and subclinical vascular disease burden in the general population.

BMJ Open Gastroenterol 2021 09;8(1)

Institute of Epidemiology, Helmholtz Center Munich German Research Center for Environmental Health, Neuherberg, Germany

Objective: It is still controversial if increased hepatic fat independently contributes to cardiovascular risk. We aimed to assess the association between hepatic fat quantified by MRI and various subclinical vascular disease parameters.

Design: We included two cross-sectional investigations embedded in two independent population-based studies (Study of Health in Pomerania (SHIP): n=1341; Cooperative Health Research in the Region of Augsburg (KORA): n=386). The participants underwent a whole-body MRI examination. Hepatic fat content was quantified by proton-density fat fraction (PDFF). Aortic diameters in both studies and carotid plaque-related parameters in KORA were measured with MRI. In SHIP, carotid intima-media thickness (cIMT) and plaque were assessed by ultrasound. We used (ordered) logistic or linear regression to assess associations between hepatic fat and subclinical vascular disease.

Results: The prevalence of fatty liver disease (FLD) (PDFF >5.6%) was 35% in SHIP and 43% in KORA. In SHIP, hepatic fat was positively associated with ascending (β, 95% CI 0.06 (0.04 to 0.08)), descending (0.05 (0.04 to 0.07)) and infrarenal (0.02 (0.01 to 0.03)) aortic diameters, as well as with higher odds of plaque presence (OR, 95% CI 1.22 (1.05 to 1.42)) and greater cIMT (β, 95% CI 0.01 (0.004 to 0.02)) in the age-adjusted and sex-adjusted model. However, further adjustment for additional cardiometabolic risk factors, particularly body mass index, attenuated these associations. In KORA, no significant associations were found.

Conclusions: The relation between hepatic fat and subclinical vascular disease was not independent of overall adiposity. Given the close relation of FLD with cardiometabolic risk factors, people with FLD should still be prioritised for cardiovascular disease screening.
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http://dx.doi.org/10.1136/bmjgast-2021-000709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487174PMC
September 2021

Higher Trimethylamine--Oxide Plasma Levels with Increasing Age Are Mediated by Diet and Trimethylamine-Forming Bacteria.

mSystems 2021 Oct 14;6(5):e0094521. Epub 2021 Sep 14.

Microbial Interactions and Processes Research Group, Helmholtz Centre for Infection Researchgrid.7490.a, Braunschweig, Germany.

The gut microbiota-dependent metabolite trimethylamine--oxide (TMAO) is linked to an increased risk for cardiovascular diseases. Trimethylamine (TMA), which is subsequently oxidized to TMAO in the liver, is formed by intestinal bacteria via distinct biochemical routes from dietary precursors that are enriched in animal product-based foods. To get a full picture of the entire process of the diet > gut microbiota > TMAO axis, we quantified potential TMA-forming gut bacteria and plasma metabolites using gene-targeted assays and targeted metabolomics on a subsample ( = 425) of a German population-based cohort study. We specifically compared persons reporting daily meat intake with those that rarely or never consume meat. While meat intake did not predict TMAO plasma levels in our study, two major bacterial TMA-forming pathways were linked to the metabolite's concentration. Furthermore, advancing age was strongly associated with TMAO. Construction of a structural equation model allowed us to disentangle the different routes that promote higher TMAO levels with increasing age, demonstrating, for the first time, a functional role of gut microbiota in the process, where specific food items augmented abundances of TMA-forming bacteria that were associated with higher TMAO plasma concentrations. Analyses stratified by age showed an association between carotid intima-media thickness and TMAO only in individuals >65 of age, indicating that this group is particularly affected by the metabolite. Many cohort studies have investigated the link between diet and plasma TMAO levels, reporting incongruent results, while gut microbiota were only recently included into analyses. In these studies, taxonomic data were recorded that are not a good proxy for TMA formation, as specific members of various taxa exhibit genes catalyzing this reaction, demanding function-based technologies for accurate quantification of TMA-synthesizing bacteria. Using this approach, we demonstrated that abundances of the main components leading to TMAO formation, i.e., TMA precursors and TMA-forming bacteria, are uncoupled and not governed by the same (dietary) factors. Results emphasize that all levels leading to TMA(O) formation should be considered for accurate risk assessment, rejecting the simple view that diets rich in TMA precursors directly lead to increased plasma levels of this hazardous compound. The results can assist in developing strategies to reduce TMAO levels, specifically in the elderly, who are prone to TMAO-associated diseases.
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http://dx.doi.org/10.1128/mSystems.00945-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547441PMC
October 2021

Association of Thyroid Dysfunction With Cognitive Function: An Individual Participant Data Analysis.

JAMA Intern Med 2021 Nov;181(11):1440-1450

Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, South Korea.

Importance: In clinical guidelines, overt and subclinical thyroid dysfunction are mentioned as causal and treatable factors for cognitive decline. However, the scientific literature on these associations shows inconsistent findings.

Objective: To assess cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia.

Design, Setting, And Participants: This multicohort individual participant data analysis assessed 114 267 person-years (median, 1.7-11.3 years) of follow-up for cognitive function and 525 222 person-years (median, 3.8-15.3 years) for dementia between 1989 and 2017. Analyses on cognitive function included 21 cohorts comprising 38 144 participants. Analyses on dementia included eight cohorts with a total of 2033 cases with dementia and 44 573 controls. Data analysis was performed from December 2016 to January 2021.

Exposures: Thyroid function was classified as overt hyperthyroidism, subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism based on uniform thyrotropin cutoff values and study-specific free thyroxine values.

Main Outcomes And Measures: The primary outcome was global cognitive function, mostly measured using the Mini-Mental State Examination. Executive function, memory, and dementia were secondary outcomes. Analyses were first performed at study level using multivariable linear regression and multivariable Cox regression, respectively. The studies were combined with restricted maximum likelihood meta-analysis. To overcome the use of different scales, results were transformed to standardized mean differences. For incident dementia, hazard ratios were calculated.

Results: Among 74 565 total participants, 66 567 (89.3%) participants had normal thyroid function, 577 (0.8%) had overt hyperthyroidism, 2557 (3.4%) had subclinical hyperthyroidism, 4167 (5.6%) had subclinical hypothyroidism, and 697 (0.9%) had overt hypothyroidism. The study-specific median age at baseline varied from 57 to 93 years; 42 847 (57.5%) participants were women. Thyroid dysfunction was not associated with global cognitive function; the largest differences were observed between overt hypothyroidism and euthyroidism-cross-sectionally (-0.06 standardized mean difference in score; 95% CI, -0.20 to 0.08; P = .40) and longitudinally (0.11 standardized mean difference higher decline per year; 95% CI, -0.01 to 0.23; P = .09). No consistent associations were observed between thyroid dysfunction and executive function, memory, or risk of dementia.

Conclusions And Relevance: In this individual participant data analysis of more than 74 000 adults, subclinical hypothyroidism and hyperthyroidism were not associated with cognitive function, cognitive decline, or incident dementia. No rigorous conclusions can be drawn regarding the role of overt thyroid dysfunction in risk of dementia. These findings do not support the practice of screening for subclinical thyroid dysfunction in the context of cognitive decline in older adults as recommended in current guidelines.
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http://dx.doi.org/10.1001/jamainternmed.2021.5078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424529PMC
November 2021

Multiethnic Genome-Wide Association Study of Subclinical Atherosclerosis in Individuals With Type 2 Diabetes.

Circ Genom Precis Med 2021 08 9;14(4):e003258. Epub 2021 Jul 9.

Department of Epidemiology (N.F., G.H.), University of North Carolina, Chapel Hill.

Background: Coronary artery calcification (CAC) and carotid artery intima-media thickness (cIMT) are measures of subclinical atherosclerosis in asymptomatic individuals and strong risk factors for cardiovascular disease. Type 2 diabetes (T2D) is an independent cardiovascular disease risk factor that accelerates atherosclerosis.

Methods: We performed meta-analyses of genome-wide association studies in up to 2500 T2D individuals of European ancestry (EA) and 1590 T2D individuals of African ancestry with or without exclusion of prevalent cardiovascular disease, for CAC measured by cardiac computed tomography, and 3608 individuals of EA and 838 individuals of African ancestry with T2D for cIMT measured by ultrasonography within the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium.

Results: We replicated 2 loci (rs9369640 and rs9349379 near and rs10757278 near ) for CAC and one locus for cIMT (rs7412 and rs445925 near ) that were previously reported in the general EA populations. We identified one novel CAC locus (rs8000449 near at 13q13.3) at =2.0×10 in EA. No additional loci were identified with the meta-analyses of EA and African ancestry. The expression quantitative trait loci analysis with nearby expressed genes derived from arterial wall and metabolic tissues from the Genotype-Tissue Expression project pinpoints , encoding a matricellular protein involved in bone formation and bone matrix organization, as the potential candidate gene at this locus. In addition, we found significant associations (<3.1×10) for 3 previously reported coronary artery disease loci for these subclinical atherosclerotic phenotypes (rs2891168 near and rs11170820 near for CAC, and rs7412 near for cIMT).

Conclusions: Our results provide potential biological mechanisms that could link CAC and cIMT to increased cardiovascular disease risk in individuals with T2D.
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http://dx.doi.org/10.1161/CIRCGEN.120.003258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435075PMC
August 2021

Meta-analysis of epigenome-wide association studies of carotid intima-media thickness.

Eur J Epidemiol 2021 Jun 6. Epub 2021 Jun 6.

Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = -0.0264, p value = 3.5 × 10) in the discovery panel and was replicated in replication panel (beta = -0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.
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http://dx.doi.org/10.1007/s10654-021-00759-zDOI Listing
June 2021

Childhood Maltreatment and Subclinical Atherosclerosis: Findings From the General Population.

Psychosom Med 2021 06;83(5):463-469

From the Department of Psychosomatic Medicine (Spitzer, Lübke), University Medical Center Rostock, Rostock; and Departments of Psychiatry and Psychotherapy (Klinger-König, Frenzel, Grabe) and Neurology (Schminke), and Institute for Community Medicine (Völzke), University Medicine Greifswald, Greifswald, Germany.

Objective: Evidence suggests that childhood maltreatment (CM) is cross-sectionally and prospectively associated with cardiovascular disease. However, its association with proxy markers of atherosclerosis has hardly been investigated. Thus, in this general population study, we examined the association of CM with carotid plaque and intima-media thickness.

Methods: Adults from the general population free of any cardiovascular disease (n = 1909; mean [SD] age = 50.4 (13.6) years, 53.9% women) completed the self-report Childhood Trauma Questionnaire for the assessment of emotional, physical, and sexual abuse as well as emotional and physical neglect; in addition, an ultrasound of the carotid arteries was performed in each participant.

Results: At least one type of CM was reported by 25% of the participants. Carotid plaque was significantly more frequent in those with CM compared with those without (odds ratio = 1.47, 95% confidence interval = 1.19-1.81). Accounting for age and sex rendered it nonsignificant (odds ratio = 1.07, 95% confidence interval = 0.81-1.42). Emotional abuse and physical neglect were significantly associated with both carotid intima-media thickness and plaque occurrence, but these associations were fully explained by risk factors. Neither sexual nor physical abuse was related to proxy markers of atherosclerosis.

Conclusions: Our findings suggest that the relationship between CM types and subclinical atherosclerosis as well as its clinical end points is complex and remains inconclusive, suggesting the need for further research.
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http://dx.doi.org/10.1097/PSY.0000000000000940DOI Listing
June 2021

Stroke Care during the COVID-19 Pandemic: International Expert Panel Review.

Cerebrovasc Dis 2021 23;50(3):245-261. Epub 2021 Mar 23.

Department of Diagnostic and Interventional Neuroradiology, Klinikum Bremen-Mitte, Germany.

Background: Coronavirus disease 2019 (COVID-19) has placed a tremendous strain on healthcare services. This study, prepared by a large international panel of stroke experts, assesses the rapidly growing research and personal experience with COVID-19 stroke and offers recommendations for stroke management in this challenging new setting: modifications needed for prehospital emergency rescue and hyperacute care; inpatient intensive or stroke units; posthospitalization rehabilitation; follow-up including at-risk family and community; and multispecialty departmental developments in the allied professions.

Summary: The severe acute respiratory syndrome coronavirus 2 uses spike proteins binding to tissue angiotensin-converting enzyme (ACE)-2 receptors, most often through the respiratory system by virus inhalation and thence to other susceptible organ systems, leading to COVID-19. Clinicians facing the many etiologies for stroke have been sobered by the unusual incidence of combined etiologies and presentations, prominent among them are vasculitis, cardiomyopathy, hypercoagulable state, and endothelial dysfunction. International standards of acute stroke management remain in force, but COVID-19 adds the burdens of personal protections for the patient, rescue, and hospital staff and for some even into the postdischarge phase. For pending COVID-19 determination and also for those shown to be COVID-19 affected, strict infection control is needed at all times to reduce spread of infection and to protect healthcare staff, using the wealth of well-described methods. For COVID-19 patients with stroke, thrombolysis and thrombectomy should be continued, and the usual early management of hypertension applies, save that recent work suggests continuing ACE inhibitors and ARBs. Prothrombotic states, some acute and severe, encourage prophylactic LMWH unless bleeding risk is high. COVID-19-related cardiomyopathy adds risk of cardioembolic stroke, where heparin or warfarin may be preferable, with experience accumulating with DOACs. As ever, arteritis can prove a difficult diagnosis, especially if not obvious on the acute angiogram done for clot extraction. This field is under rapid development and may generate management recommendations which are as yet unsettled, even undiscovered. Beyond the acute management phase, COVID-19-related stroke also forces rehabilitation services to use protective precautions. As with all stroke patients, health workers should be aware of symptoms of depression, anxiety, insomnia, and/or distress developing in their patients and caregivers. Postdischarge outpatient care currently includes continued secondary prevention measures. Although hoping a COVID-19 stroke patient can be considered cured of the virus, those concerned for contact safety can take comfort in the increasing use of telemedicine, which is itself a growing source of patient-physician contacts. Many online resources are available to patients and physicians. Like prior challenges, stroke care teams will also overcome this one. Key Messages: Evidence-based stroke management should continue to be provided throughout the patient care journey, while strict infection control measures are enforced.
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http://dx.doi.org/10.1159/000514155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8089455PMC
June 2021

Lack of association between proton pump inhibitor use and brain aging: a cross-sectional study.

Eur J Clin Pharmacol 2021 Jul 13;77(7):1039-1048. Epub 2021 Jan 13.

Chair of Epidemiology, Ludwig-Maximilians-Universität München, UNIKA-T Augsburg, Neusässer Str. 47, 86156, Augsburg, Germany.

Purpose: Due to conflicting scientific evidence for an increased risk of dementia by intake of proton pump inhibitors (PPIs), this study investigates associations between PPI use and brain volumes, estimated brain age, and cognitive function in the general population.

Methods: Two surveys of the population-based Study of Health in Pomerania (SHIP) conducted in Northeast Germany were used. In total, 2653 participants underwent brain magnetic resonance imaging (MRI) and were included in the primary analysis. They were divided into two groups according to their PPI intake and compared with regard to their brain volumes (gray matter, white matter, total brain, and hippocampus) and estimated brain age. Multiple regression was used to adjust for confounding factors. Cognitive function was evaluated by the Verbal Learning and Memory Test (VLMT) and the Nuremberg Age Inventory (NAI) and put in relation to PPI use.

Results: No association was found between PPI use and brain volumes or the estimated brain age. The VLMT score was 1.11 lower (95% confidence interval: - 2.06 to - 0.16) in immediate recall, and 0.72 lower (95% CI: - 1.22 to - 0.22) in delayed recall in PPI users than in non-users. PPI use was unrelated to the NAI score.

Conclusions: The present study does not support a relationship between PPI use and brain aging.
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http://dx.doi.org/10.1007/s00228-020-03068-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184524PMC
July 2021

Association of traumatic stress and posttraumatic stress disorder with carotid atherosclerosis: findings from the general population.

Eur J Psychotraumatol 2020 Oct 14;11(1):1815280. Epub 2020 Oct 14.

Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.

Cumulative evidence suggests that both traumatic stress and posttraumatic stress disorder (PTSD) are cross-sectionally and prospectively linked to cardiovascular disease (CVD). However, their association with proxy markers of atherosclerosis has hardly been investigated. : The objective of this general population study was to relate traumatic stress and PTSD to carotid plaque and intima-media thickness (cIMT). 3119 adults from the general population were assessed regarding their traditional cardiovascular risk factors, and an ultrasound of the carotid arteries was performed in each participant. Based on a PTSD interview, every participant was assigned to one of three groups: no trauma; trauma, but no PTSD; and trauma with PTSD. The sample was stratified into five age groups. Trauma exposure was reported by 54.5% of the sample and 2.0% had PTSD. Traumatized participants had increased odds of self-reported CVD events compared to those without trauma exposure, even when accounted for CVD risk factors and other covariates (odds ratio [OR] = 1.51; 95% confidence interval [CI]: 1.03-2.22). This association was driven by those aged 70 years or older. Only in those aged 40 to 49 years, there was an association between cIMT and PTSD. There were no further associations between carotid plaque or cIMT and traumatic stress or PTSD. Our findings in concert with prior research suggest that the association between traumatic stress, PTSD and atherosclerosis as well as its clinical endpoints is complex and remains inconclusive.
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http://dx.doi.org/10.1080/20008198.2020.1815280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678678PMC
October 2020

Shared Genetics of Multiple System Atrophy and Inflammatory Bowel Disease.

Mov Disord 2021 02 27;36(2):449-459. Epub 2020 Oct 27.

Rita Lila Weston Institute, University College London, London, UK.

Background: Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by intracellular accumulations of α-synuclein and nerve cell loss in striatonigral and olivopontocerebellar structures. Epidemiological and clinical studies have reported potential involvement of autoimmune mechanisms in MSA pathogenesis. However, genetic etiology of this interaction remains unknown. We aimed to investigate genetic overlap between MSA and 7 autoimmune diseases and to identify shared genetic loci.

Methods: Genome-wide association study summary statistics of MSA and 7 autoimmune diseases were combined in cross-trait conjunctional false discovery rate analysis to explore overlapping genetic background. Expression of selected candidate genes was compared in transgenic MSA mice and wild-type mice. Genetic variability of candidate genes was further investigated using independent whole-exome genotyping data from large cohorts of MSA and autoimmune disease patients and healthy controls.

Results: We observed substantial polygenic overlap between MSA and inflammatory bowel disease and identified 3 shared genetic loci with leading variants upstream of the DENND1B and RSP04 genes, and in intron of the C7 gene. Further, the C7 gene showed significantly dysregulated expression in the degenerating midbrain of transgenic MSA mice compared with wild-type mice and had elevated burden of protein-coding variants in independent MSA and inflammatory bowel disease cohorts.

Conclusion: Our study provides evidence of shared genetic etiology between MSA and inflammatory bowel disease with an important role of the C7 gene in both phenotypes, with the implication of immune and gut dysfunction in MSA pathophysiology. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28338DOI Listing
February 2021

Carotid Lumen Diameter Is Associated With All-Cause Mortality in the General Population.

J Am Heart Assoc 2020 08 4;9(16):e015630. Epub 2020 Aug 4.

Department of Internal Medicine B University Medicine Greifswald Greifswald Germany.

Background Common carotid intima-media thickness (cIMT) is a biomarker for subclinical atherosclerosis and is associated with all-cause as well as cardiovascular mortality. Higher cIMT is accompanied by a compensatory increase in lumen diameter (LD) of the common carotid arteries. Whether cIMT or LD carry more information with regard to mortality is unclear. Methods and Results A total of 2751 subjects (median age 53 years; 52% female) were included. During a median follow-up of 14.9 years (range: 12.8-16.5) a total of 506 subjects died. At baseline, cIMT and LD were assessed by carotid ultrasound scans. Multivariable Cox regression models were used to relate cIMT, LD, LD adjusted for cIMT (LD+cIMT), and LD/cIMT ratio with all-cause, cardiovascular, and noncardiovascular mortality. All models were ranked using Akaike's information criterion. Harrel's c statistic was used to compare the models' predictive power for mortality. A 1-mm increase in LD was related to a higher risk for all-cause mortality (hazard ratio [HR], 1.29; 95% CI, 1.14-1.45, <0.01). This association remained significant when cIMT was added to the model (HR, 1.26; 95% CI, 1.11-1.42; <0.01). A 1-mm higher cIMT was also related with greater mortality risk (HR, 1.73; 95% CI, 1.09-2.75). The LD/cIMT ratio was not associated with all-cause mortality. LD had the lowest Akaike's information criterion regarding all-cause mortality and improved all-cause mortality prediction compared with the null model (=0.01). CIMT weakened all-cause mortality prediction compared with the LD model. Conclusions LD provided more information for all-cause mortality compared with cIMT in a large population-based sample.
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http://dx.doi.org/10.1161/JAHA.119.015630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660798PMC
August 2020

Cardiorespiratory Fitness and Gray Matter Volume in the Temporal, Frontal, and Cerebellar Regions in the General Population.

Mayo Clin Proc 2020 01;95(1):44-56

German Center for Neurodegenerative Disease, Site Rostock/Greifswald, Germany; Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Germany.

Objective: To analyze the association between cardiorespiratory fitness (CRF) and global and local brain volumes.

Participants And Methods: We studied 2103 adults (21-84 years old) from 2 independent population-based cohorts (Study of Health in Pomerania, examinations from June 25, 2008, through September 30, 2012). Cardiorespiratory fitness was measured using peak oxygen uptake (VOpeak), oxygen uptake at the anaerobic threshold ([email protected]), and maximal power output from cardiopulmonary exercise testing on a bicycle ergometer. Magnetic resonance imaging brain data were analyzed by voxel-based morphometry using regression models with adjustment for age, sex, education, smoking, body weight, systolic blood pressure, glycated hemoglobin level, and intracranial volume.

Results: Volumetric analyses revealed associations of CRF with gray matter (GM) volume and total brain volume. After multivariable adjustment, a 1-standard deviation increase in VOpeak was related to a 5.31 cm³ (95% CI, 3.27 to 7.35 cm³) higher GM volume. Whole-brain voxel-based morphometry analyses revealed significant positive relations between CRF and local GM volumes. The VOpeak was strongly associated with GM volume of the left middle temporal gyrus (228 voxels), the right hippocampal gyrus (146 voxels), the left orbitofrontal cortex (348 voxels), and the bilateral cingulate cortex (68 and 43 voxels).

Conclusion: Cardiorespiratory fitness was positively associated with GM volume, total brain volume, and specific GM and white matter clusters in brain areas not primarily involved in movement processing. These results, from a representative population sample, suggest that CRF might contribute to improved brain health and might, therefore, decelerate pathology-specific GM decrease.
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http://dx.doi.org/10.1016/j.mayocp.2019.05.030DOI Listing
January 2020

Relation of IGF-I with subclinical cardiovascular markers including intima-media thickness, left ventricular mass index and NT-proBNP.

Eur J Endocrinol 2020 Jan;182(1):79-90

Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.

Objective: Several studies revealed relations between low or high insulin-like growth factor I (IGF-I) levels and risk of cardiovascular diseases or mortality, whereas the mechanisms behind these associations are still unknown.

Design: The study aimed to explore the relations between IGF-I and changes in surrogate markers of cardiovascular disease including carotid intima-media thickness (IMT), left ventricular mass index (LVMI) and N-terminal pro-brain natriuretic peptide (NT-proBNP).

Methods: Longitudinal data of the population-based cohort Study of Health in Pomerania (SHIP) were used. IMT was measured by ultrasonography and LVMI was determined based on echocardiography. IGF-I and IGF-binding protein-3 (IGFBP-3) levels were measured by chemiluminescent immunoassays and the IGF-I/IGFBP-3 ratio was calculated. Mixed linear regression models adjusted for known cardiovascular confounders were performed.

Results: Statistical analyses demonstrated relations between low baseline IGF-I levels (beta for ΔIMT per s.d. increase -0.044 (s.e. 0.012)) or IGF-I/IGFBP-3 ratio (beta -0.045 (0.012)) and a long-term IMT increase. No associations between IGF-I, IGFBP-3 or IGF-I/IGFBP-3 ratio and changes in LVMI were detected. With respect to NT-proBNP sex-specific associations with IGF-I were found. In women, higher baseline IGF-I levels (beta for ΔNT-proBNP per s.d. increase 5.92 (2.2)) or IGF-I/IGFBP-3 ratio (beta 4.48 (2.2)) were related to an increase in NT-proBNP levels. Among men, U-shaped relations of baseline levels of IGF-I, IGFBP-3 and the IGF-I/IGFBP-3 ratio with an increase in NT-proBNP were found.

Conclusions: The study detected significant relations between IGF-I and long-term changes in IMT and NT-proBNP but not LVMI. These findings argue for different effects of the IGF-I axis with respect to various cardiovascular entities.
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http://dx.doi.org/10.1530/EJE-19-0470DOI Listing
January 2020

Progression of conventional cardiovascular risk factors and vascular disease risk in individuals: insights from the PROG-IMT consortium.

Eur J Prev Cardiol 2020 02 16;27(3):234-243. Epub 2019 Oct 16.

Department of Internal Medicine and Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, The Netherlands.

Aims: Averaged measurements, but not the progression based on multiple assessments of carotid intima-media thickness, (cIMT) are predictive of cardiovascular disease (CVD) events in individuals. Whether this is true for conventional risk factors is unclear.

Methods And Results: An individual participant meta-analysis was used to associate the annualised progression of systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with future cardiovascular disease risk in 13 prospective cohort studies of the PROG-IMT collaboration ( = 34,072). Follow-up data included information on a combined cardiovascular disease endpoint of myocardial infarction, stroke, or vascular death. In secondary analyses, annualised progression was replaced with average. Log hazard ratios per standard deviation difference were pooled across studies by a random effects meta-analysis. In primary analysis, the annualised progression of total cholesterol was marginally related to a higher cardiovascular disease risk (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.00 to 1.07). The annualised progression of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol was not associated with future cardiovascular disease risk. In secondary analysis, average systolic blood pressure (HR 1.20 95% CI 1.11 to 1.29) and low-density lipoprotein cholesterol (HR 1.09, 95% CI 1.02 to 1.16) were related to a greater, while high-density lipoprotein cholesterol (HR 0.92, 95% CI 0.88 to 0.97) was related to a lower risk of future cardiovascular disease events.

Conclusion: Averaged measurements of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol displayed significant linear relationships with the risk of future cardiovascular disease events. However, there was no clear association between the annualised progression of these conventional risk factors in individuals with the risk of future clinical endpoints.
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http://dx.doi.org/10.1177/2047487319877078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008553PMC
February 2020

GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.

Nat Commun 2018 12 3;9(1):5141. Epub 2018 Dec 3.

Department of Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA.

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.
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http://dx.doi.org/10.1038/s41467-018-07340-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277418PMC
December 2018

White matter lesions: Spatial heterogeneity, links to risk factors, cognition, genetics, and atrophy.

Neurology 2018 09 3;91(10):e964-e975. Epub 2018 Aug 3.

From the Center for Biomedical Image Computing and Analytics (M.H., A.S., G.E., N.R.B., J.D., C.D.), Department of Neurology and Penn Memory Center (M.H., D.A.W.), and Department of Biostatistics and Epidemiology (H.S.), University of Pennsylvania, Philadelphia; Department of Psychiatry (M.H., D.J., H.J.G.), Institute for Community Medicine (M.H., H.V., W.H.), and Department of Neurology (U.S.), University of Greifswald, Germany; Department of Neurology (J.B.T.), Houston Methodist Hospital, TX; German Center for Neurodegenerative Diseases (W.H., H.J.G.), Rostock/Greifswald, Germany; and Laboratory of Behavioral Neuroscience (S.M.R.), National Institute on Aging, Baltimore, MD.

Objectives: To investigate spatial heterogeneity of white matter lesions or hyperintensities (WMH).

Methods: MRI scans of 1,836 participants (median age 52.2 ± 13.16 years) encompassing a wide age range (22-84 years) from the cross-sectional Study of Health in Pomerania (Germany) were included as discovery set identifying spatially distinct components of WMH using a structural covariance approach. Scans of 307 participants (median age 73.8 ± 10.2 years, with 747 observations) from the Baltimore Longitudinal Study of Aging (United States) were included to examine differences in longitudinal progression of these components. The associations of these components with vascular risk factors, cortical atrophy, Alzheimer disease (AD) genetics, and cognition were then investigated using linear regression.

Results: WMH were found to occur nonuniformly, with higher frequency within spatially heterogeneous patterns encoded by 4 components, which were consistent with common categorizations of deep and periventricular WMH, while further dividing the latter into posterior, frontal, and dorsal components. Temporal trends of the components differed both cross-sectionally and longitudinally. Frontal periventricular WMH were most distinctive as they appeared in the fifth decade of life, whereas the other components appeared later in life during the sixth decade. Furthermore, frontal WMH were associated with systolic blood pressure and with pronounced atrophy including AD-related regions. AD polygenic risk score was associated with the dorsal periventricular component in the elderly. Cognitive decline was associated with the dorsal component.

Conclusions: These results support the hypothesis that the appearance of WMH follows age and disease-dependent regional distribution patterns, potentially influenced by differential underlying pathophysiologic mechanisms, and possibly with a differential link to vascular and neurodegenerative changes.
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http://dx.doi.org/10.1212/WNL.0000000000006116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6139818PMC
September 2018

DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis.

Nat Commun 2018 06 19;9(1):2397. Epub 2018 Jun 19.

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.

The human leukocyte antigen (HLA) haplotype DRB1*15:01 is the major risk factor for multiple sclerosis (MS). Here, we find that DRB1*15:01 is hypomethylated and predominantly expressed in monocytes among carriers of DRB1*15:01. A differentially methylated region (DMR) encompassing HLA-DRB1 exon 2 is particularly affected and displays methylation-sensitive regulatory properties in vitro. Causal inference and Mendelian randomization provide evidence that HLA variants mediate risk for MS via changes in the HLA-DRB1 DMR that modify HLA-DRB1 expression. Meta-analysis of 14,259 cases and 171,347 controls confirms that these variants confer risk from DRB1*15:01 and also identifies a protective variant (rs9267649, p < 3.32 × 10, odds ratio = 0.86) after conditioning for all MS-associated variants in the region. rs9267649 is associated with increased DNA methylation at the HLA-DRB1 DMR and reduced expression of HLA-DRB1, suggesting a modulation of the DRB1*15:01 effect. Our integrative approach provides insights into the molecular mechanisms of MS susceptibility and suggests putative therapeutic strategies targeting a methylation-mediated regulation of the major risk gene.
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http://dx.doi.org/10.1038/s41467-018-04732-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008330PMC
June 2018

Association of Circulating Chemerin With Subclinical Parameters of Atherosclerosis: Results of a Population-Based Study.

Arterioscler Thromb Vasc Biol 2018 07 31;38(7):1656-1664. Epub 2018 May 31.

From the Institute of Clinical Chemistry and Laboratory Medicine (S.Z., M.N., N.F.).

Objective: Chemerin has been shown to be associated with inflammation and metabolic syndrome, which are in turn leading risk factors for atherosclerosis. A few clinical studies have concentrated on the role of chemerin in atherosclerosis but revealed divergent findings. Therefore, we aimed to investigate the association of plasma chemerin levels with different subclinical measurements of atherosclerosis in a population-based sample.

Approach And Results: Linear and logistic regression models with different atherosclerotic parameters as subclinical outcomes were applied to analyze data from 4003 subjects of the SHIP (Study of Health in Pomerania). After adjustment for metabolic and inflammatory parameters, these models revealed no association of chemerin with carotid intima-media thickness, carotid plaque, or carotid stenosis but a significant inverse association between chemerin and ankle-brachial index. In detail, logistic regression analysis showed that a 25-ng/mL increase in chemerin was associated with a 30% higher odd (95% confidence interval, 1.20-1.41) of having an ankle-brachial index value below the 25th age- and sex-specific quartile.

Conclusions: Our analyses revealed a modest inverse association between chemerin and ankle-brachial index that remained consistent after adjustment for metabolic and inflammatory parameters. The association of chemerin with carotid intima-media thickness, carotid plaque, or carotid stenosis was not significant after adjustment for the same confounder set. The investigated subclinical atherosclerotic parameters are representative for the atherosclerotic burden of different arterial regions and different disease stages. Thus, our results might suggest that the value of chemerin as a marker of higher atherosclerotic risk differs depending on the affected arterial region and disease stage.
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http://dx.doi.org/10.1161/ATVBAHA.118.311219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039419PMC
July 2018

Predictive value for cardiovascular events of common carotid intima media thickness and its rate of change in individuals at high cardiovascular risk - Results from the PROG-IMT collaboration.

PLoS One 2018 12;13(4):e0191172. Epub 2018 Apr 12.

Radiology Department, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain.

Aims: Carotid intima media thickness (CIMT) predicts cardiovascular (CVD) events, but the predictive value of CIMT change is debated. We assessed the relation between CIMT change and events in individuals at high cardiovascular risk.

Methods And Results: From 31 cohorts with two CIMT scans (total n = 89070) on average 3.6 years apart and clinical follow-up, subcohorts were drawn: (A) individuals with at least 3 cardiovascular risk factors without previous CVD events, (B) individuals with carotid plaques without previous CVD events, and (C) individuals with previous CVD events. Cox regression models were fit to estimate the hazard ratio (HR) of the combined endpoint (myocardial infarction, stroke or vascular death) per standard deviation (SD) of CIMT change, adjusted for CVD risk factors. These HRs were pooled across studies. In groups A, B and C we observed 3483, 2845 and 1165 endpoint events, respectively. Average common CIMT was 0.79mm (SD 0.16mm), and annual common CIMT change was 0.01mm (SD 0.07mm), both in group A. The pooled HR per SD of annual common CIMT change (0.02 to 0.43mm) was 0.99 (95% confidence interval: 0.95-1.02) in group A, 0.98 (0.93-1.04) in group B, and 0.95 (0.89-1.04) in group C. The HR per SD of common CIMT (average of the first and the second CIMT scan, 0.09 to 0.75mm) was 1.15 (1.07-1.23) in group A, 1.13 (1.05-1.22) in group B, and 1.12 (1.05-1.20) in group C.

Conclusions: We confirm that common CIMT is associated with future CVD events in individuals at high risk. CIMT change does not relate to future event risk in high-risk individuals.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191172PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896895PMC
July 2018

Regional tract-specific white matter hyperintensities are associated with patterns to aging-related brain atrophy via vascular risk factors, but also independently.

Alzheimers Dement (Amst) 2018 5;10:278-284. Epub 2018 Mar 5.

Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia, PA, USA.

Introduction: We sought to investigate associations of regional white matter hyperintensities (WMHs) within white matter (WM) tracts with cardiovascular risk and brain aging-related atrophy throughout adulthood in the general population, leveraging state of the art pattern analysis methods.

Methods: We analyzed a large sample (n = 2367) from the Study of Health in Pomerania, Germany (range 20-90 years). WMHs were automatically segmented on T1-weighted and fluid-attenuated inversion recovery magnetic resonance images, and WMH volumes were calculated in WM regions defined using the John Hopkins University WM tractography atlas. Regions with the highest average WMH volume were selected. We calculated a subject-specific index, Spatial Pattern of Alteration for Recognition of Brain Aging, to measure age-related atrophy patterns. The Framingham cardiovascular disease risk score summarized the individual cardiovascular risk profile. We used structural equation models, independently for each region, using Spatial Pattern of Alteration for Recognition of Brain Aging as a dependent variable, age as an independent variable, and cardiovascular disease risk score and regional WMH volumes as mediators.

Results: Selected 12 WM regions included 75% of the total WMH burden in average. Structural equation models showed that the age effect on Spatial Pattern of Alteration for Recognition of Brain Aging was mediated by WMHs to a different extent in the superior frontal WM, anterior corona radiata, inferior frontal WM, superior corona radiata, superior longitudinal fasciculus, middle temporal WM, posterior corona radiata, superior parietal WM, splenium of corpus callosum, posterior thalamic radiation, and middle occipital WM (variance explained between 2.8% and 10.3%,  < .0001 Bonferroni corrected), but not in precentral WM.

Conclusions: Our results indicate that WMHs, in most WM tracts, might accelerate the brain aging process throughout adulthood in the general population as a result of vascular risk factors, but also independent of them. Preventive strategies against WMHs (such as controlling vascular risk factors or microglia depletion) could delay brain aging.
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http://dx.doi.org/10.1016/j.dadm.2018.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889709PMC
March 2018

Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.

Nat Genet 2018 04 12;50(4):524-537. Epub 2018 Mar 12.

Institute of Cardiovascular Research, Royal Holloway University of London, London, UK, and Ashford and St Peters Hospital, Surrey, UK.

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.
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http://dx.doi.org/10.1038/s41588-018-0058-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968830PMC
April 2018

Domains of physical activity and brain volumes: A population-based study.

Neuroimage 2017 08 11;156:101-108. Epub 2017 May 11.

German Center for Neurodegenerative Disease (DZNE), Site Rostock/Greifswald, Germany; Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Germany. Electronic address:

Observational studies and intervention trials suggest that physical activity (PA) is beneficial for human brain morphology, especially in older individuals. Few population-based studies examined whether domain-specific PA is associated with brain volumes. Accordingly, we studied putative associations of PA during leisure time, sports and work with volumes of the hippocampus, the prefrontal cortex, the temporal lobe, gray matter (GM), white matter (WM) and total brain (TBV) after 5.9 years by applying volumetric analysis and voxel-based morphometry (VBM) with SPM 8/VBM 8 to brain magnetic resonance imaging data of 834 participants (447 women) aged 25 to 83 years from the population-based Study of Health in Pomerania. The Baecke questionnaire was used to assess domain-specific PA (Leisure time, Sport, and Work Index) at baseline. After correcting for multiple testing, volumetric analyses did not show any significant association of domain-specific PA and volumes of the hippocampus, the prefrontal cortex, the temporal lobe, GM, WM and TBV. Multivariable-adjusted VBM analyses of the associations between PA domains with GM and WM volumes did not reveal any statistically significant results. Region of interest analyses revealed a statistically significant cluster of increased GM volume in the bilateral anterior cingulate cortex in association with PA during sports. In conclusion, the overall results contrast with the findings from previous studies that found significant associations between PA and brain volumes. In addition, it remains unclear whether a differential association exists between domains of PA and brain volumes. Thus, future studies with larger sample size and prospective design are needed to investigate potential domain-specific associations of PA with brain volumes.
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http://dx.doi.org/10.1016/j.neuroimage.2017.05.020DOI Listing
August 2017

Dalfampridine effects on cognition, fatigue, and dexterity.

Brain Behav 2017 01 11;7(1):e00559. Epub 2016 Nov 11.

Department of Neurology University Medicine Greifswald Greifswald Germany; Department of Neurology Carl-Thiem-Klinikum Cottbus Cottbus Germany.

Objectives: Dalfampridine exerts beneficial effects on walking ability in a subgroup of patients with multiple sclerosis (MS). These patients are termed "responders". Here, we investigated whether the responder status with respect to mobility measures would determine whether dalfampridine treatment exerts a beneficial effect on other MS symptoms. We therefore assessed walking ability, upper limb function, cognition, fatigue, visual evoked potentials (VEPs), depression, and quality of life in patients before and after dalfampridine treatment.

Methods: Patients with MS and impaired mobility were recruited. Maximal walking distance, timed 25 Foot Walk, nine hole peg test, paced auditory serial addition test (PASAT), fatigue severity scale (FSS), VEPs, Beck Depression Inventory (BDI), EuroQol five dimensional questionnaire, and quality of life visual analogue scale were determined before and after 12-14 days of dalfampridine treatment. Repeated measures analysis of variance was applied to determine the effect of dalfampridine treatment.

Results: Of the 34 patients who completed the study, 22 patients were responders and 12 patients nonresponders, according to their performance in mobility measures. Treatment effects for the entire patient cohort were observed for PASAT (= .029) and BDI (= .032). Belonging to the responder cohort did not predict the response to treatment in these tests. For the FSS, response to dalfampridine treatment was dependent on the responder status (= .001) while no effects in the total patient cohort were observed (= .680). Other neurological functions remained unaltered. For VEP latencies, no significant improvements were detected.

Conclusion: In this study, we observed beneficial effects of dalfampridine on cognition, depression, and fatigue. These effects were not limited to patients who responded to dalfampridine with improved mobility measures. These findings underscore the need to assess the beneficial effects of dalfampridine on neurological deficits in MS patients in additional randomized clinical trials.
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http://dx.doi.org/10.1002/brb3.559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5256171PMC
January 2017

Posterior versus Anterior Circulation Stroke in Young Adults: A Comparative Study of Stroke Aetiologies and Risk Factors in Stroke among Young Fabry Patients (sifap1).

Cerebrovasc Dis 2017 14;43(3-4):152-160. Epub 2017 Jan 14.

Department of Neurology, University Medicine, Ernst Moritz Arndt University, Greifswald, Germany.

Background: Although 20-30% of all strokes occur in the posterior circulation, few studies have explored the characteristics of patients with strokes in the posterior compared to the anterior circulation so far. Especially data on young patients is missing.

Methods: In this secondary analysis of data of the prospective multi-centre European sifap1 study that investigated stroke and transient ischemic attack (TIA) patients aged 18-55 years, we compared vascular risk factors, stroke aetiology, presence of white matter hyperintensities (WMH) and cerebral microbleeds (CMB) between patients with ischaemic posterior circulation stroke (PCS) and those having suffered from anterior circulation stroke (ACS) based on cerebral MRI.

Results: We diagnosed PCS in 612 patients (29.1%, 407 men, 205 women) and ACS in 1,489 patients (70.9%). Their age (median 46 vs. 47 years, p = 0.205) and stroke severity (modified Rankin Scale: both 2, p = 0.375, Barthel Index 90 vs. 85, p = 0.412) were similar. PCS was found to be more frequent among the male gender (66.5 vs. 60.1% with ACS, p = 0.003). Vertebral artery (VA) dissection was more often the cause of PCS (16.8%) than was carotid artery dissection of ACS (7.9%, p < 0.001). Likewise, small vessel disease (Trial of Org 10172 in Acute Stroke Treatment [TOAST] = 3, PCS: 14.7%, ACS: 11.8%) and stroke of other determined aetiology (TOAST = 4, PCS: 24.5%, ACS: 16.0%) were more frequent in those with PCS. Furthermore, patent foramen ovale (PFO; PCS: 31.1%, ACS: 25.4%, p = 0.029) was more often detected in patients with PCS. In contrast, large-artery atherosclerosis (TOAST = 1, PCS: 15.4%, ACS: 22.2%) and cardio-embolic stroke (TOAST = 2, PCS: 15.6%, ACS: 18.0%) were less frequent in those with PCS (p < 0.001) as were preceding cerebrovascular events (10.1 vs. 14.1%, p = 0.014), TIA (4.8 vs. 7.7%, p = 0.016) and smoking (53.2 vs. 61.0%, p = 0.001). The presence, extent, and location of WMH and CMB did not differ between the 2 groups.

Conclusions: Our data suggested a different pattern of aetiology and risk factors in young patients with PCS compared to those with ACS. These findings especially call for a higher awareness of VA dissection and potentially for more weight of a PFO as a risk factor in young patients with PCS. Clinical trial registration-URL: http://www.clinicaltrials.gov; NCT00414583.
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http://dx.doi.org/10.1159/000454840DOI Listing
December 2017

Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis.

Circ Cardiovasc Genet 2016 Dec 21;9(6):511-520. Epub 2016 Nov 21.

Background: The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease. We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent coronary heart disease.

Methods And Results: We studied a total of 25 109 European ancestry and African ancestry participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52 869 participants with common carotid intima-media thickness measured by ultrasonography within the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology). Participants were genotyped for 247 870 DNA sequence variants (231 539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and carotid intima-media thickness. APOB p.Arg3527Gln was associated with 4-fold excess CAC (P=3×10). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P=1×10) and 1.4% reduced carotid intima-media thickness (P=4×10) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for coronary heart disease (odds ratio 0.77; P=1×10).

Conclusions: Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical coronary heart disease.
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http://dx.doi.org/10.1161/CIRCGENETICS.116.001572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418659PMC
December 2016

The relationship between the metabolic syndrome and arterial wall thickness: A mosaic still to be interpreted.

Atherosclerosis 2016 12 15;255:11-16. Epub 2016 Oct 15.

Department of Public Health - and Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan.

Background And Aims: We aimed to identify clusters of metabolic syndrome (MetS) components, risky for extremely high intima-media thickness.

Methods: We studied 41,513 volunteers (men and women) from eleven cohorts worldwide, participating in the MARE (Metabolic syndrome and Artery REsearch) Consortium.

Results: Specific clusters of MetS components - high triglycerides-high blood pressure-abdominal obesity (TBW), low HDL cholesterol-high blood pressure-abdominal obesity (HBW), high glucose-high blood pressure-abdominal obesity (GBW) - were accompanied by a 50-90% significantly greater likelihood of presenting extremely high intima-media thickness (via ultrasound of carotid artery, CCA IMT), after controlling for age, sex, smoking, non-HDL cholesterol, and presence of diabetes mellitus. This likelihood is comparable to the effect of being 7-8 years older or of being a cigarette smoker or of having non-HDL cholesterol 50 mg/dl higher.

Conclusions: The consistent association of specific clusters of MetS components with extremely thick (older) large artery cross-culturally suggests that identification of those clusters in clinical practice will facilitate a personalized health care and a better - i.e. more healthy and cost-effective - prevention of major cardiovascular (CV) events.
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http://dx.doi.org/10.1016/j.atherosclerosis.2016.10.032DOI Listing
December 2016

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.

Sci Adv 2016 06 17;2(6):e1501678. Epub 2016 Jun 17.

Clinical Neuroimmunology Group, Department of Neurology, Philipps-University of Marburg, 35043 Marburg, Germany.

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.
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http://dx.doi.org/10.1126/sciadv.1501678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4928990PMC
June 2016
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