M Arfan Ikram

Erasmus University Rotterdam, Rotterdam, South Holland, Netherlands

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Publications (351)2913.36 Total impact

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    Barbara Franke · Jason L Stein · Stephan Ripke · Verneri Anttila · Derrek P Hibar · Kimm J E van Hulzen · Alejandro Arias-Vasquez · Jordan W Smoller · Thomas E Nichols · Michael C Neale · [...] · Paul Nyquist · Louis N Vinke · Cornelia M van Duijn · Xue Luting · Bernard Mazoyer · Joshua C Bis · Vilmundur Gudnason · Sudha Seshadri · M Arfan Ikram · Gunter Schumann ·

    Full-text · Article · Feb 2016 · Nature Neuroscience
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    ABSTRACT: Background: Higher education is associated with a lower risk of dementia, possibly because of a higher tolerance to subclinical neurodegenerative pathology. Whether higher education also protects against dementia after clinical stroke or transient ischemic attack (TIA) remains unknown. Methods: Within the population-based Rotterdam Study, 12,561 participants free of stroke, TIA and dementia were followed for occurrence of stroke, TIA and dementia. Across the levels of education, associations of incident stroke or TIA with subsequent development of dementia and differences in cognitive decline following stroke or TIA were investigated. Results: During 124,862 person-years, 1,463 persons suffered a stroke or TIA, 1,158 persons developed dementia, of whom 186 developed dementia after stroke or TIA. Risk of dementia after a stroke or TIA, compared to no stroke or TIA, was highest in the low education category (hazards ratio [HR] 1.46, 95% CI 1.18-1.81) followed by intermediate education category (HR 1.36, 95% CI 1.03-1.81). No significant association was observed in the high education category (HR 0.62, 95% CI 0.25-1.54). In gender stratified analyses, decrease in risk of dementia with increasing education was significant only in men. Conclusion: Higher education is associated with a lower risk of dementia after stroke or TIA, particularly in men, which might be explained by a higher cognitive reserve.
    Full-text · Article · Jan 2016 · Neuroepidemiology
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    Cristian Pattaro · Alexander Teumer · Mathias Gorski · Audrey Y. Chu · Man Li · Vladan Mijatovic · Maija Garnaas · Adrienne Tin · Rossella Sorice · Yong Li · [...] · Katalin Susztak · Pavel Hamet · Johanne Tremblay · Ian H. de Boer · Carsten A. Böger · Wolfram Goessling · Daniel I. Chasman · Anna Köttgen · W. H. Linda Kao · Caroline S. Fox ·

    Full-text · Article · Jan 2016 · Nature Communications
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    Full-text · Article · Jan 2016 · Science translational medicine
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    ABSTRACT: Background: Serum total cholesterol and its fractions are inversely associated with intracerebral hemorrhages (ICH) and their potential subclinical precursor, cerebral microbleeds. To ascertain whether there is a genetic basis for this inverse association, we studied established genetic loci for serum total, LDL, and HDL cholesterol, and triglycerides in their association with ICH and microbleeds. Methods: Data on 161 genetic variants for serum lipids was collected in 9011 stroke-free participants (mean age 65.8, SD 10.2; 57.9% women) of the population-based Rotterdam Study. Participants were followed from baseline (1997-2005) up to 2013 for the occurrence of ICH. A subset of 4179 participants underwent brain MRI for microbleed assessment between 2005 and 2011. We computed genetic risk scores (GRS) for the joint effect of lipid variants. Cox proportional hazards and logistic regression models were used to investigate the association of GRS of lipid fractions with ICH and microbleeds. Results: After a mean follow-up of 8.7 (SD 4.1) years, 67 (0.7%) participants suffered an ICH. Microbleed prevalence was 19.6%. Higher genetic load for high serum total and LDL cholesterol was associated with an increased risk of ICH. Higher genetic load for high serum LDL cholesterol was borderline associated with a higher prevalence of multiple lobar microbleeds. Conclusions: Genetic susceptibility for high serum total and LDL cholesterol is positively associated with incident ICH and borderline associated with multiple lobar microbleeds. We did not find a genetic basis for the previously reported inverse association between serum lipid levels and ICH.
    No preview · Article · Jan 2016 · Atherosclerosis
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    ABSTRACT: Background: The clinical use of carotid intima media thickness (cIMT) requires normal values, which may be subject to variation of geographical factors, ethnicity or measurement details. The influence of these factors has rarely been studied. The aim of this study was to determine whether normative cIMT values and their association with event risk are generalizable across populations. Design: Meta-analysis of individual participant data. Method: From 22 general population cohorts from Europe, North America and Asia we selected subjects free of cardiovascular disease. Percentiles of cIMT and cIMT progression were assessed separately for every cohort. Cox proportional hazards models for vascular events were used to estimate hazard ratios for cIMT in each cohort. The estimates were pooled across Europe, North America and Asia, with random effects meta-analysis. The influence of geography, ethnicity and ultrasound protocols on cIMT values and on the hazard ratios was examined by meta-regression. Results: Geographical factors, ethnicity and the ultrasound protocol had influence neither on the percentiles of cIMT and its progression, nor on the hazard ratios of cIMT for vascular events. Heterogeneity for percentiles of cIMT and cIMT progression was too large to create meaningful normative values. Conclusions: The distribution of cIMT values is too heterogeneous to define universal or regional population reference values. CIMT values vary widely between different studies regardless of ethnicity, geographic location and ultrasound protocol. Prediction of vascular events with cIMT values was more consistent across all cohorts, ethnicities and regions.
    Full-text · Article · Jan 2016 · European Journal of Preventive Cardiology
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    ABSTRACT: Background and purpose: Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset <60 years. Methods: The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5×10(-6) and performed in silico association analyses in an independent sample of ≤1003 cases and 7745 controls. Results: One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10(-9)). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2. Conclusions: HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.
    No preview · Article · Jan 2016 · Stroke
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    ABSTRACT: Polyneuropathy is a disabling condition of the peripheral nerves, characterized by symmetrical distal numbness and paresthesia, often accompanied with pain and weakness. Although the disease is often encountered in neurological clinics and is well known by physicians, incidence and prevalence rates are not well known. We searched EMBASE, Medline, Web-of-science, Cochrane, PubMed Publisher, and Google Scholar, for population-based studies investigating the prevalence of polyneuropathy and its risk factors. Out of 5119 papers, we identified 29 eligible studies, consisting of 11 door-to-door survey studies, 7 case-control studies and 11 cohort/database studies. Prevalence of polyneuropathy across these studies varies substantially. This can partly be explained by differences in assessment protocols and study populations. The overall prevalence of polyneuropathy in the general population seems around 1 % and rises to up to 7 % in the elderly. Polyneuropathy seemed more common in Western countries than in developing countries and there are indications that females are more often affected than males. Risk factor profiles differ across countries. In developing countries communicable diseases, like leprosy, are more common causes of neuropathy, whereas in Western countries especially diabetes, alcohol overconsumption, cytostatic drugs and cardiovascular disease are more commonly associated with polyneuropathy. In all studies a substantial proportion of polyneuropathy cases (20-30 %) remains idiopathic. Most of these studies have been performed over 15 years ago. More recent evidence suggests that the prevalence of polyneuropathy in the general population has increased over the years. Future research is necessary to confirm this increase in prevalence and to identify new and potentially modifiable risk factors.
    No preview · Article · Dec 2015 · European Journal of Epidemiology
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    Full-text · Article · Dec 2015 · The Lancet Neurology
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    ABSTRACT: Background and purpose: Serotonin-specific antidepressants may increase the risk of adverse bleeding events. In a previous cross-sectional study, we did not observe an association between antidepressant use and presence of subclinical cerebral bleedings. In this study, we investigated longitudinally whether antidepressant use is associated with an increased risk of new subclinical cerebral microbleeds. Methods: In total, 2559 participants aged ≥45 years of the population-based Rotterdam Study, all without microbleeds at baseline, underwent baseline and repeat brain magnetic resonance imaging between 2005 and 2013 (mean time interval, 3.9 years; SD, 0.5) to determine the incidence of microbleeds. Antidepressant use (yes versus no) was assessed between baseline and follow-up scan. In additional analyses, antidepressants were classified as low, intermediate, or high affinity for the serotonin transporter, and alternatively as selective serotonin reuptake inhibitors or non-selective serotonin reuptake inhibitors. We used multivariable logistic regression models to investigate the association of antidepressants with incident microbleeds. Results: Antidepressant use was associated with a higher cerebral microbleed incidence (odds ratio, 2.22; 95% confidence interval, 1.31-3.76) than nonuse. When stratified by affinity for the serotonin transporter, intermediate serotonin affinity antidepressant use was associated with an increased risk of developing microbleeds (odds ratio, 3.07; 95% confidence interval, 1.53-6.17). Finally, selective serotonin reuptake inhibitor and non-selective serotonin reuptake inhibitor use were both associated with increased microbleed incidence. Conclusions: Antidepressant use was associated with an increased risk of developing microbleeds. Our results may support findings from previous clinical studies about increased intracranial and extracranial bleeding risk in antidepressant users.
    No preview · Article · Dec 2015 · Stroke
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    ABSTRACT: Imaging plays an essential role in research on neurological diseases in the elderly. The Rotterdam Scan Study was initiated as part of the ongoing Rotterdam Study with the aim to elucidate the causes of neurological disease by performing imaging of the brain in a prospective population-based setting. Initially, in 1995 and 1999, random subsamples of participants from the Rotterdam Study underwent neuroimaging, whereas from 2005 onwards MRI has been implemented into the core protocol of the Rotterdam Study. In this paper, we discuss the background and rationale of the Rotterdam Scan Study. Moreover, we describe the imaging protocol, image post-processing techniques, and the main findings to date. Finally, we provide recommendations for future research, which will also be topics of investigation in the Rotterdam Scan Study.
    Full-text · Article · Dec 2015 · European Journal of Epidemiology
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    ABSTRACT: Introduction: H.Z. and E.E. contributed equally to this work. A.M.J.M.v.d.M. and D.R.N. jointly directed this work.It is unclear whether patients diagnosed according to International Classification of Headache Disorders criteria for migraine with aura (MA) and migraine without aura (MO) experience distinct disorders or whether their migraine subtypes are genetically related. Aim: Using a novel gene-based (statistical) approach, we aimed to identify individual genes and pathways associated both with MA and MO. Methods: Gene-based tests were performed using genome-wide association summary statistic results from the most recent International Headache Genetics Consortium study comparing 4505 MA cases with 34,813 controls and 4038 MO cases with 40,294 controls. After accounting for non-independence of gene-based test results, we examined the significance of the proportion of shared genes associated with MA and MO. Results: We found a significant overlap in genes associated with MA and MO. Of the total 1514 genes with a nominally significant gene-based p value (pgene-based ≤ 0.05) in the MA subgroup, 107 also produced pgene-based ≤ 0.05 in the MO subgroup. The proportion of overlapping genes is almost double the empirically derived null expectation, producing significant evidence of gene-based overlap (pleiotropy) (pbinomial-test = 1.5 × 10(-4)). Combining results across MA and MO, six genes produced genome-wide significant gene-based p values. Four of these genes (TRPM8, UFL1, FHL5 and LRP1) were located in close proximity to previously reported genome-wide significant SNPs for migraine, while two genes, TARBP2 and NPFF separated by just 259 bp on chromosome 12q13.13, represent a novel risk locus. The genes overlapping in both migraine types were enriched for functions related to inflammation, the cardiovascular system and connective tissue. Conclusions: Our results provide novel insight into the likely genes and biological mechanisms that underlie both MA and MO, and when combined with previous data, highlight the neuropeptide FF-amide peptide encoding gene (NPFF) as a novel candidate risk gene for both types of migraine.
    No preview · Article · Dec 2015 · Cephalalgia
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    Full-text · Dataset · Dec 2015
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    ABSTRACT: Background Cardiovascular factors and low education are important risk factors of dementia. We provide contemporary estimates of the proportion of dementia cases that could be prevented if modifiable risk factors were eliminated, i.e., population attributable risk (PAR). Furthermore, we studied whether the PAR has changed across the last two decades. Methods We included 7,003 participants of the original cohort (starting in 1990) and 2,953 participants of the extended cohort (starting in 2000) of the Rotterdam Study. Both cohorts were followed for dementia until ten years after baseline. We calculated the PAR of overweight, hypertension, diabetes mellitus, cholesterol, smoking, and education. Additionally, we assessed the PAR of stroke, coronary heart disease, heart failure, and atrial fibrillation. We calculated the PAR for each risk factor separately and the combined PAR taking into account the interaction of risk factors. Results During 57,996 person-years, 624 participants of the original cohort developed dementia, and during 26,177 person-years, 145 participants of the extended cohort developed dementia. The combined PAR in the original cohort was 0.23 (95 % CI, 0.05–0.62). The PAR in the extended cohort was slightly higher at 0.30 (95 % CI, 0.06–0.76). The combined PAR including cardiovascular diseases was 0.25 (95 % CI, 0.07–0.62) in the original cohort and 0.33 (95 % CI, 0.07–0.77) in the extended cohort. Conclusions A substantial part of dementia cases could be prevented if modifiable risk factors would be eliminated. Although prevention and treatment options of cardiovascular risk factors and diseases have improved, the preventive potential for dementia has not declined over the last two decades.
    Full-text · Article · Dec 2015 · BMC Medicine
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    ABSTRACT: Background: Atherosclerosis is a major contributor to global morbidity and mortality. Although atherosclerosis is a systemic disease, its burden varies considerably across vessel beds, which may translate into differences in mortality risk. Methods and results: From 2003 to 2006, a sample of 2408 elderly participants (mean age, 69.6±6.7 years; 52.4% female) from the population-based Rotterdam Study underwent computed tomography to quantify atherosclerotic calcification in the coronary arteries, aortic arch, extracranial, and intracranial internal carotid arteries. Mortality follow-up was complete until January 1, 2012. We investigated associations of calcification in each vessel bed with mortality using Cox regression, adjusting for age, sex, and cardiovascular risk factors. Next, all vessel beds were included into 1 model to investigate independency of associations. Finally, we investigated the predictive value of calcification beyond the predictors included in the Pooled Cohort equations. During 15 775 person-years of follow-up, 283 participants died. Larger calcification volumes in all vessels were related to higher risks of all-cause mortality, cardiovascular, and noncardiovascular mortality, independent of cardiovascular risk factors. Most prominent associations were found for aortic arch calcification and cardiovascular mortality (age- and sex-adjusted hazard ratio per 1-SD increase 2.72 [95% confidence interval, 1.85-4.02]), independent of calcification elsewhere (hazard ratio, 1.75 (95% confidence interval, 1.13-2.72]). Calcification in any vessel improved prediction for all 3 outcomes. Conclusions: Atherosclerotic load in major vessel beds is associated with an increased risk of death. In particular, aortic arch calcification volume yields unique information with regard to mortality in addition to atherosclerosis in other vessel beds.
    No preview · Article · Dec 2015 · Circulation Cardiovascular Imaging
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    ABSTRACT: White matter microstructural integrity has been related to cognition. Yet, the potential role of specific white matter tracts on top of a global white matter effect remains unclear, especially when considering specific cognitive domains. Therefore, we determined the tract-specific effect of white matter microstructure on global cognition and specific cognitive domains. In 4400 nondemented and stroke-free participants (mean age 63.7 years, 55.5% women), we obtained diffusion magnetic resonance imaging parameters (fractional anisotropy and mean diffusivity) in 14 white matter tracts using probabilistic tractography and assessed cognitive performance with a cognitive test battery. Tract-specific white matter microstructure in all supratentorial tracts was associated with poorer global cognition. Lower fractional anisotropy in association tracts, primarily the inferior fronto-occipital fasciculus, and higher mean diffusivity in projection tracts, in particular the posterior thalamic radiation, most strongly related to poorer cognition. Altered white matter microstructure related to poorer information processing speed, executive functioning, and motor speed, but not to memory. Tract-specific microstructural changes may aid in better understanding the mechanism of cognitive impairment and neurodegenerative diseases.
    No preview · Article · Dec 2015
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    ABSTRACT: MicroRNAs (miRNAs) are small non-coding RNAs that serve as key regulators of gene expression. They have been shown to be involved in a wide-range of biological processes including neurodegenerative diseases. Genetic variants in miRNAs or miRNA binding sites on their target genes could affect miRNA function and contribute to disease risk. Here, we investigated the association of miRNA-related genetic variants with PD using data from the largest GWAS on PD. Of 243 miRNA-variants, we identified rs897984:T>C in miR-4519 (p-value = 1.3×10(-5) and OR = 0.93) and rs11651671:A>G in miR-548at-5p (p-value = 1.1×10(-6) and OR = 1.09) to be associated with PD. We showed that the variant's mutant alleles change the secondary structure and decrease expression level of their related miRNAs. Subsequently, we highlighted target genes that might mediate the effects of miR-4519 and miR-548at-5p on PD. Among them, we experimentally showed that NSF is a direct target of miR-4519. Furthermore, among 48,844 miRNA binding site-variants, we found 32 variants (within 13 genes) that are associated with PD. Four of the host genes, CTSB, STX1B, IGSF9B and HSD3B7, had not previously been reported to be associated with PD. We provide evidence supporting the potential impact of the identified miRNA binding site-variants on miRNA-mediated regulation of their host genes. This article is protected by copyright. All rights reserved.
    No preview · Article · Dec 2015 · Human Mutation
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    ABSTRACT: Retinal vascular diameters are associated with (sub)clinical cardiovascular disease and short-term cardiovascular mortality, but their association with long-term mortality is uncertain. We studied the association of retinal vascular diameters with cause-specific mortality in the general adult Dutch population during 25 years of follow-up. From 1990 to 1993, arteriolar and venular diameters were measured semiautomatically on digitized images in 5674 persons (mean age 68.0 years, 59% women) from the population-based Rotterdam study. Follow-up for mortality was complete till March 2015. Associations between vascular diameters and mortality were examined using Cox proportional hazards models, adjusting for age, sex, cardiovascular risk factors, and the fellow vessel diameter. During 85 770 person-years (mean±SD: 15.1±6.67), 3794 (66.8%) persons died, of whom 1034 due to cardiovascular causes. We found that narrower arterioles and wider venules were associated with higher risk of mortality (adjusted hazard ratio [95% confidence interval] per SD decrease 1.04 [1.00-1.08] and increase 1.07 [1.03-1.12], respectively). For arterioles, these associations were strongest for cardiovascular mortality, whereas venules showed consistent associations for cardiovascular and noncardiovascular mortality. Importantly, these associations remained unchanged after excluding the first 10 years of follow-up as immortal person-time. We found evidence for effect modification with stronger associations in persons <70 years (venules only) and smokers (P value for interaction<0.01). We replicated our findings in another independent cohort from the Rotterdam Study of 3106 persons with 19 880 person-years of follow-up and 144 deaths (hazard ratio for venules 1.22 [1.00-1.49]). Markers of retinal microvasculature are associated with long-term mortality in the general adult Dutch population.
    No preview · Article · Nov 2015 · Hypertension
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    Full-text · Dataset · Nov 2015
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    ABSTRACT: Background and purpose: Mortality after stroke remains high for years, mostly because of cardiovascular causes. Given that cardiovascular pathology plays an important role in causing the initial stroke, such prestroke pathology might also influence the prognosis after stroke. Within the population-based Rotterdam Study, we examined the proportion of deaths after stroke that are attributable to pre-existent cardiovascular risk factors before stroke (the population attributable risk). Methods: We examined 1237 patients with first-ever stroke and 4928 stroke-free participants (between 1990 and 2012), matched on age, sex, examination round, and stroke date (index date). Cardiovascular risk factors measured on ≈4 years before index date were used as determinants. Participants were continuously followed up for mortality (≈6 years) after the index date. We calculated separate and combined population attributable risk of hypertension, total cholesterol, high-density lipoprotein-cholesterol, body mass index, diabetes mellitus, smoking, transient ischemic attack, and atrial fibrillation. Results: Nine hundred and nineteen patients with stroke and 2654 stroke-free participants died. The combined population attributable risk in patients with stroke was 27% (95% confidence interval, 14%-45%) and in stroke-free participants was 19% (95% confidence interval, 12%-29%). Population attributable risks of diabetes mellitus, smoking, and atrial fibrillation were higher in patients with stroke than in the reference group because of a higher prevalence of risk factors. In addition, people with atrial fibrillation and stroke had a higher hazard ratio for death than those with only atrial fibrillation. Conclusions: One quarter of deaths after stroke could theoretically be prevented with rigorous cardiovascular prevention and treatment, but this should preferably start before stroke occurrence. In addition, research into factors explaining the remaining deaths needs to be encouraged.
    No preview · Article · Nov 2015 · Stroke

Publication Stats

8k Citations
2,913.36 Total Impact Points

Institutions

  • 2006-2016
    • Erasmus University Rotterdam
      Rotterdam, South Holland, Netherlands
  • 2015
    • VU University Medical Center
      Amsterdamo, North Holland, Netherlands
  • 2006-2015
    • Erasmus MC
      • • Department of Neurology
      • • Department of Epidemiology
      Rotterdam, South Holland, Netherlands
  • 2014
    • Medical University of Graz
      • Institute of Molecular Biology and Biochemistry
      Gratz, Styria, Austria
  • 2012
    • University of California, Davis
      Davis, California, United States
    • Leiden University Medical Centre
      Leyden, South Holland, Netherlands
    • St George's, University of London
      • Stroke and Dementia Research Centre
      Londinium, England, United Kingdom
  • 2010
    • University of Massachusetts Boston
      Boston, Massachusetts, United States