http://repub.eur.nl/res/aut/24200/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/32496/ 2012-03-01T00:00:00Z Stroke is a frequent disorder in elderly people. Despite improvements in primary prevention, the burden of stroke remains high and is predicted to even increase in the near future due to aging of the population. Therefore, additional targets for primary prevention are urgently needed. Most previous epidemiological studies have not specifically studied the two main subtypes of stroke, i.e., cerebral infarction and intracerebral hemorrhage, whereas differences in etiology between these subtypes suggest that they may have different risk profiles. Therefore, primary prevention may benefit from the identification of subtype-specific determinants. The aims of this thesis were to study trends in stroke incidence rates and stroke risk factors in the past twenty years, and to identify new determinants for any stroke, cerebral infarction, and intracerebral hemorrhage. The studies described in this thesis were part of the Rotterdam Study, a large population-based cohort study among elderly people who were followed from 1990 up to the present day for the occurrence of stroke and other diseases that are frequent in the elderly. Changes in stroke incidence rates and stroke risk factors in Rotterdam in the Netherlands between 1990 and 2008 were described in chapter 2. The major finding was a 34% decrease in stroke incidence rates in men, but no change in women. The prevalence of risk factors, such as hypertension and obesity had increased, although cigarette smoking had decreased in men. Other risk factors, such as atrial fibrillation, low high-density lipoprotein cholesterol and diabetes mellitus were unchanged. However, the proportion of men and women taking preventive medication had increased enormously. The divergent trends in stroke incidence rates in men and women stress the need for adequate recognition and treatment of stroke risk factors in women. In chapter 3, I reported my findings regarding the association of the plasma protein von Willebrand factor, which plays an important role in hemostasis but also marks the presence of endothelial dysfunction, with stroke and its subtype cerebral infarction. Higher von Willebrand factor levels were associated with an increased risk of stroke and cerebral infarction (chapter 3.1). However, genetic determinants of von Willebrand factor levels were not associated with stroke risk, either individually or joint in a weighted sum score (chapter 3.2). These findings suggest that von Willebrand factor is a marker for stroke risk, but probably not an important causal factor. Chapter 4 includes three studies concerning the association between retinal characteristics and risk of any stroke, cerebral infarction and intracerebral hemorrhage. The first study showed that wider retinal venular calibers were not only associated with an increased risk of cerebral infarction, but also with an increased risk of intracerebral hemorrhage (chapter 4.1). Furthermore, these associations were stronger for lobar than deep intracerebral hemorrhages. Both narrower arteriolar calibers and wider venular calibers were strongly associated with risk of anticoagulation-related intracerebral hemorrhage. The second study showed that the presence of retinopathy signs was associated with an increased risk of any stroke, but that this association was due to an increased risk of unspecified stroke and not due to an increased risk of either cerebral infarction or intracerebral hemorrhage (chapter 4.2). The third study addressed the association between age-related macular degeneration and risk of stroke and showed that late stage age-related macular degeneration was associated with an increased risk of intracerebral hemorrhage, but not with risk of cerebral infarction (chapter 4.3). Altogether, these three studies suggest that several retinal characteristics may be used as markers for future or present cerebrovascular pathology. Chapter 5 contains three studies on metabolic determinants of stroke. In chapter 5.1 I described the association between serum lipid fractions and risk of intracerebral hemorrhage and presence of cerebral microbleeds, and showed that low triglyceride levels are associated with an increased risk of intracerebral hemorrhage, and with the presence of deep or infratentorial microbleeds, but not with lobar microbleeds. Because deep and infratentorial microbleeds are considered markers of arteriolosclerosis, whereas lobar microbleeds more likely reflect amyloid angiopathy, these findings suggest that low triglyceride levels may play a role in the development of arteriolosclerotic microangiopathy. Chapter 5.2 addressed the association between liver enzyme levels and risk of intracerebral hemorrhage, and the role of alcohol in this association. Alkaline phosphatase and lactate dehydrogenase were associated with an increased risk of intracerebral hemorrhage independently of alcohol intake. However, aspartate transaminase, alanine transaminase and gamma-glutamyltranspeptidase were associated with intracerebral hemorrhage only in people who drink excessive amounts of alcohol. In chapter 5.3, I described the associations between insulin resistance markers and risk of any stroke, cerebral infarction and intracerebral hemorrhage in nondiabetic elderly. Insulin resistance markers were not associated with risk of any stroke or its subtypes. Although diabetes mellitus is a strong risk factor for stroke, these findings suggest that below the diabetes threshold, the degree of insulin resistance is not associated with risk of any stroke, cerebral infarction or intracerebral hemorrhage. Chapter 6 is a general discussion of the main findings, methodological issues concerning the classification of stroke subtypes, potential clinical implications of the main findings and future perspectives. To conclude, in this thesis I reported on several new determinants of cerebral infarction and intracerebral hemorrhage. Future research should further unravel the pathophysiologic mechanisms and investigate the potential of these determinants as risk predictors or as targets for preventive intervention. http://repub.eur.nl/res/pub/33356/ 2011-08-01T00:00:00Z Background and Purpose-Age-related macular degeneration (AMD) and stroke are both frequent diseases in the elderly. A link between AMD and stroke has been suggested, because both disorders have many risk factors in common. The aim of this study was to investigate the association between AMD and stroke and the subtypes cerebral infarction and intracerebral hemorrhage in the general elderly population. Methods-This study was part of the population-based Rotterdam Study and included 6207 participants aged 55 years who were stroke-free at baseline (1990 to 1993). Signs of AMD were assessed on fundus photographs at baseline and at regular follow-up examinations and were categorized in 5 stages (0 to 4) representing an increasing severity. Late AMD (Stage 4) was subdivided into dry and wet AMD. Follow-up for incident stroke was complete up to January 1, 2007. Data were analyzed using time-dependent Cox regression models adjusted for age, sex, and potential confounders. Results-During a median follow-up of 13.6 years, 726 participants developed a stroke (397 cerebral infarction, 59 intracerebral hemorrhage, 270 unspecified). Late AMD was associated with an increased risk of any stroke (hazard ratio, 1.56; 95% CI, 1.08 to 2.26) due to a strong association with intracerebral hemorrhage (hazard ratio, 6.11; 95% CI, 2.34 to 15.98). In contrast, late AMD was not associated with cerebral infarction. Earlier AMD stages were not associated with risk of stroke or any of its subtypes. Conclusions-We found that late AMD is strongly associated with intracerebral hemorrhage, but not with cerebral infarction, in the general elderly population. http://repub.eur.nl/res/pub/33647/ 2011-08-01T00:00:00Z AimsSince atherosclerosis is a systemic process, risk prediction would benefit from targeting multiple components of cardiovascular disease simultaneously. To this end, it is useful to examine the predictive value of non-invasive measures of atherosclerosis in various vascular beds for both coronary heart disease (CHD) and cerebrovascular disease.Methods and resultsBetween September 2003 and February 2006, 2153 asymptomatic participants (69.6 ± 6.6 years) from the Rotterdam Study underwent a multi-detector computed tomography scan. During a median follow-up of 3.5 years, 58 CHD events (myocardial infarction and CHD death) and 52 cerebrovascular events (TIA and stroke) occurred. Participants were classified into low (<5), intermediate (510), and high (>10) 5-year risk categories based on a refitted Framingham risk model. The model was extended by coronary, aortic arch, or carotid calcium and reclassification percentages were calculated. For the outcome CHD, the C-statistic improved from 0.693 for the Framingham refitted model to 0.743, 0.740, and 0.749 by addition of coronary, aortic arch, and carotid calcium, respectively. Reclassification was most substantial in the intermediate risk group where addition of coronary calcium reclassified 56 of persons [net reclassification improvement (NRI): 15; P < 0.01)]. Adding aortic arch calcium led to a reclassification of 32 of persons (NRI: 8; P 0.01) and adding carotid calcium reclassified 51 (NRI: 9; P 0.02). In contrast, calcification in any of the three vascular beds did not improve cerebrovascular risk prediction.ConclusionCoronary, aortic arch, and carotid artery calcification significantly improved risk prediction of CHD but not of cerebrovascular events. http://repub.eur.nl/res/pub/33377/ 2011-07-01T00:00:00Z Background and Purpose- Depression after stroke is common. Like stroke, transient ischemic attack (TIA) is a manifestation of long-term atherosclerotic damage to the brain. However, the risk of depression developing after a TIA is uncertain. We studied whether TIA increases the risk of incident late-life depression. Methods- A cohort study of 5095 inhabitants of Rotterdam, the Netherlands, was performed between 1993 and 2005. Participants were aged 56 years or older and free of depression at baseline. TIA and depression were identified through regular standardized examinations and continuous monitoring of medical records. We estimated hazard ratios (HR) with time-varying Cox regression analyses, adjusting for sociodemographic and health-related factors. Results- During follow-up, 407 depressive syndromes occurred, of which 103 met criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM) for depressive disorders. TIA was significantly associated with the risk of incident depressive syndromes (HR, 1.68; 95% CI, 1.12-2.51) and DSM-defined depressive disorders (HR, 2.42; 95% CI, 1.26-4.67). The risk of depressive syndromes increased with the number of TIA a person had experienced (HR, 1.45; 95% CI, 1.17-1.81), as did the risk of depressive disorders (HR, 1.63; 95% CI, 1.18-2.24). In persons without a history of depression at baseline, we found an almost 3-fold increased risk of DSM-defined depressive disorders (HR, 2.91; 95% CI, 0.96-8.81). Conclusions- TIA was independently associated with an increased risk of incident depression. Our finding suggests that symptomatic cerebrovascular disease increases the vulnerability to late-life depression. Copyright http://repub.eur.nl/res/pub/27402/ 2010-12-01T00:00:00Z Background and Purpose- Narrower retinal arteriolar calibers and wider venular calibers are associated with cardiovascular disease, including cerebral infarction. We investigated the association between retinal vascular calibers and the long-term risk for stroke and its subtypes with particular focus on intracerebral hemorrhage. Methods- We included 5518 participants (aged ≥55 years) from the prospective population-based Rotterdam Study who were stroke-free at baseline (1990-1993) and of whom digital retinal images were available. Follow-up for incident stroke was complete up to January 1, 2007. Data were analyzed with Cox proportional hazards models adjusted for age and sex and additionally for potential confounders. Arteriolar and venular calibers were entered both separately and simultaneously in the models. Results- During an average follow-up of 11.5 years, 623 participants developed a first-ever stroke (50 hemorrhagic, 361 ischemic, 212 unspecified). Larger venular caliber was independently associated with an increased risk for stroke (hazard ratio [HR] per SD increase: 1.20; 95% confidence interval [CI]: 1.09 to 1.33), cerebral infarction (HR: 1.28; 95% CI: 1.13 to 1.46), and intracerebral hemorrhage (HR: 1.53; 95% CI: 1.09 to 2.15). Much weaker, only borderline significant associations were found between arteriolar caliber and risk for stroke (HR per SD decrease: 1.12; 95% CI: 0.99 to 1.23), cerebral infarction (HR: 1.12; 95% CI, 0.98 to 1.27), and intracerebral hemorrhage (HR: 1.25; 95% CI: 0.87 to 1.79). Retinal vascular calibers were strongly associated with lobar hemorrhages and oral anticoagulant-related hemorrhages. Conclusion- Larger retinal venular caliber is associated with an increased risk for stroke in the general population and, in particular, with an increased risk for intracerebral hemorrhage. http://repub.eur.nl/res/pub/20211/ 2010-10-01T00:00:00Z Objective: Multidetector computed tomography (MDCT), which has been mainly used to study coronary atherosclerosis, also enables non-invasive measurement of carotid and aortic atherosclerosis and might be suitable for screening in the general population. The aim of this study was to investigate the associations of carotid artery, aortic arch and coronary artery calcification as assessed by MDCT, with presence of stroke. Methods: The study was embedded in the population-based Rotterdam Study and comprises 2521 persons (mean age 69.7 ± 6.8 years, 48% males) that underwent an MDCT scan. History of stroke was reported by 96 persons. We used multivariable logistic regression to investigate the associations of calcification in the carotid arteries, aortic arch, and coronary arteries with presence of stroke. Results: We found strong and graded associations of prevalent stroke with carotid artery (OR quartile 4 versus 1 (95% CI): 5.0 (2.2-11.0)), aortic arch (3.3 (1.5-7.4)) and coronary artery calcification (3.1 (1.3-7.3)), independent of cardiovascular risk factors. Only the association of carotid artery calcification with presence of stroke was independent of calcification in the other two vessel beds. Conclusion: In this population-based study, we found a strong and graded association of prevalent stroke with carotid artery, aortic arch and coronary artery calcification, independent of cardiovascular risk factors. After additional adjustment for calcification in the other vessel beds, prevalent stroke was still significantly related to carotid calcification, but no longer to aortic arch or coronary calcification. http://repub.eur.nl/res/pub/22158/ 2010-10-01T00:00:00Z Background And Purpose-: Many studies have investigated the role of plasma von Willebrand factor level in coronary heart disease, but few have investigated its role in stroke. The aim of this study was to determine if von Willebrand factor levels are associated with the risk of stroke. Methods-: The study was part of the Rotterdam Study, a large population-based cohort study among subjects aged ≥55 years. We included 6 250 participants who were free from stroke at baseline (1997 to 2001) and for whom blood samples were available. Follow-up for incident stroke was complete up to January 1, 2005. Data were analyzed with Cox proportional hazards models adjusted for age and sex and additionally with models adjusted for other potential confounders including ABO blood group. A subgroup analysis was performed in participants without atrial fibrillation. Effect modification by sex was tested on a multiplicative and on an additive scale. Results-: During an average follow-up time of 5.0 years, 290 first-ever strokes occurred, of which 197 were classified as ischemic. The risk of stroke increased with increasing von Willebrand factor levels (age- and sex-adjusted hazard ratios per SD increase in von Willebrand factor level: 1.12 [95% CI, 1.01 to 1.25] for stroke, 1.13 [95% CI, 0.99 to 1.29] for ischemic stroke). Adjustments for additional confounders slightly attenuated the association. The association was also present in subjects without atrial fibrillation and did not differ between sexes. Conclusion-: High von Willebrand factor levels are associated with stroke risk in the general population. http://repub.eur.nl/res/pub/18671/ 2010-03-01T00:00:00Z Increased circulating amino-terminal pro-B-type natriuretic (NT-proBNP) levels are a marker of cardiac dysfunction but also associate with coronary heart disease and stroke. We aimed to investigate whether increased circulating NT-proBNP levels have additive prognostic value for first cardiovascular and cerebrovascular events beyond classic risk factors. In a community-based cohort of 5063 participants free of cardiovascular disease, aged ≥55 years, circulating NT-proBNP levels and cardiovascular risk factors were measured. Participants were followed for the occurrence of first major fatal or nonfatal cardiovascular event. A total of 420 participants developed a first cardiovascular event (108 fatal). After adjustment for classic risk factors, the hazard ratio for cardiovascular events was 2.32 (95% CI: 1.55 to 2.70) in men and 3.08 (95% CI: 1.91 to 3.74) in women for participants with NT-proBNP in the upper compared with the lowest tertile. Corresponding hazard ratios for coronary heart disease, heart failure, and ischemic stroke were 2.01 (95% CI: 1.14 to 2.59), 2.90 (95% CI: 1.33 to 4.34), and 2.06 (95% CI: 0.91 to 3.18) for men and 2.95 (95% CI: 1.30 to 4.55), 5.93 (95% CI: 2.04 to 11.2), and 2.07 (95% CI: 1.00 to 2.97) for women. Incorporation of NT-proBNP in the classic risk model significantly improved the C-statistic both in men and women and resulted in a net reclassification improvement of 9.2% (95% CI: 3.5% to 14.9%; P=0.001) in men and 13.3% (95% CI: 5.9% to 20.8%; P<0.001) in women. We conclude that, in an asymptomatic older population, NT-proBNP improves risk prediction not only of heart failure but also of cardiovascular disease in general beyond classic risk factors, resulting in a substantial reclassification of participants to a lower or higher risk category. http://repub.eur.nl/res/pub/20888/ 2010-01-01T00:00:00Z BACKGROUND AND PURPOSE We describe a left-handed patient with transient aphasia and bilateral carotid stenosis. Computed tomography (CT) arteriography showed a 90% stenosis of the right and 30% stenosis of the left internal carotid artery. Head CT and magnetic resonance imaging (MRI) of the brain showed no recent ischemic changes. As only the symptomatic side would require surgical intervention, and because hemispheric dominance for language in left-handed patients may be either left or right sided, a preoperative assessment of hemispheric dominance was required. METHODS We used functional MRI to determine hemispheric dominance for language and hence to establish the indication for carotid endarterectomy surgery. RESULTS Functional MRI demonstrated right hemispheric dominance for language and right-sided carotid endarterectomy was performed. CONCLUSIONS We propose that the clinical use of functional MRI as a noninvasive imaging technique for the assessment of hemispheric language dominance may be extended to the assessment of hemispheric language dominance prior to carotid endarterectomy.