Rijn, M.J.E. van

Incidence and Prognosis of Transient Neurological Attacks (Article)

2007-12-26T00:00:00Z

CONTEXT: Transient neurological attacks (TNAs) are attacks with temporary (<24 hours) neurological symptoms. These symptoms can be focal, nonfocal, or a mixture of both. The prognostic significance of TNAs with focal symptoms (better known as transient ischemic attacks [TIAs]) is well understood. Conversely, hardly anything is known about the prognostic significance of TNAs with nonfocal or mixed symptoms. OBJECTIVE: To study the incidence and prognosis of focal TNAs (or TIAs), nonfocal TNAs, and mixed TNAs. DESIGN, SETTING, AND PARTICIPANTS: The study population comprised 6062 community-dwelling Rotterdam Study participants who were aged 55 years or older and free from stroke, myocardial infarction, and dementia at baseline (1990-1993). They were followed up for events until January 1, 2005. We analyzed the associations between incident TNAs and subsequent adverse events with age- and sex-adjusted Cox regression models. MAIN OUTCOME MEASURES: Stroke, ischemic heart disease, or dementia. RESULTS: During 60 535 person-years, 548 participants developed TNA (282 focal, 228 nonfocal, and 38 mixed). The incidence rate per 1000 person-years was 4.7 (95% confidence interval [CI], 4.1-5.2) for focal TNA, 3.8 (95% CI, 3.3-4.3) for nonfocal TNA, and 0.6 (95% CI, 0.4-0.9) for mixed TNA. Participants with focal TNA were at higher risk of subsequent stroke than participants without TNA (n = 46 vs 540; hazard ratio [HR], 2.14; 95% confidence interval [CI]; 1.57-2.91) but had an equal risk of ischemic heart disease and dementia. Nonfocal TNA patients were at higher risk of stroke (27 vs 540; HR, 1.56; 95% CI, 1.08-2.28) and dementia (30 vs 552; HR, 1.59; 95% CI, 1.11-2.26) than participants without TNA. Mixed TNA patients were at higher risk of stroke (6 vs 540; HR, 2.48; 95% CI, 1.11-5.56), ischemic heart disease (8 vs 779; HR, 2.26; 95% CI, 1.07-4.78), vascular death (8 vs 594; HR, 2.54; 95% CI, 1.31-4.91), and dementia (7 vs 552; HR, 3.46; 95% CI, 1.72-6.98) than participants without TNA. CONCLUSION: Patients who experience nonfocal TNAs, and especially those with mixed TNAs, have a higher risk of major vascular diseases and dementia than persons without TNA.

Incidence and prognosis of transient neurological attacks (Article)

2007-12-26T00:00:00Z

Context: Transient neurological attacks (TNAs) are attacks with temporary (<24 hours) neurological symptoms. These symptoms can be focal, nonfocal, or a mixture of both. The prognostic significance of TNAs with focal symptoms (better known as transient ischemic attacks [TIAs]) is well understood. Conversely, hardly anything is known about the prognostic significance of TNAs with nonfocal or mixed symptoms. Objective: To study the incidence and prognosis of focal TNAs (or TIAs), nonfocal TNAs, and mixed TNAs. Design, Setting, and Participants: The study population comprised 6062 community-dwelling Rotterdam Study participants who were aged 55 years or older and free from stroke, myocardial infarction, and dementia at baseline (1990-1993). They were followed up for events until January 1, 2005. We analyzed the associations between incident TNAs and subsequent adverse events with age- and sex-adjusted Cox regression models. Main Outcome Measures: Stroke, ischemic heart disease, or dementia. Results: During 60 535 person-years, 548 participants developed TNA (282 focal, 228 nonfocal, and 38 mixed). The incidence rate per 1000 person-years was 4.7 (95% confidence interval [CI], 4.1-5.2) for focal TNA, 3.8 (95% CI, 3.3-4.3) for nonfocal TNA, and 0.6 (95% CI, 0.4-0.9) for mixed TNA. Participants with focal TNA were at higher risk of subsequent stroke than participants without TNA (n=46 vs 540; hazard ratio [HR], 2.14; 95% confidence interval [CI]; 1.57-2.91) but had an equal risk of ischemic heart disease and dementia. Nonfocal TNA patients were at higher risk of stroke (27 vs 540; HR, 1.56; 95% CI, 1.08-2.28) and dementia (30 vs 552; HR, 1.59; 95% CI, 1.11-2.26) than participants without TNA. Mixed TNA patients were at higher risk of stroke (6 vs 540; HR, 2.48; 95% CI, 1.11-5.56), ischemic heart disease (8 vs 779; HR, 2.26; 95% CI, 1.07-4.78), vascular death (8 vs 594; HR, 2.54; 95%CI, 1.31-4.91), and dementia (7 vs 552; HR, 3.46; 95% CI, 1.72-6.98) than participants without TNA. Conclusion: Patients who experience nonfocal TNAs, and especially those with mixed TNAs, have a higher risk of major vascular diseases and dementia than persons without TNA.

Polymorphisms of the renin-angiotensin system are associated with blood pressure, atherosclerosis and cerebral white matter pathology (Article)

2007-10-01T00:00:00Z

BACKGROUND: The renin-angiotensin system is involved in the development of hypertension, atherosclerosis and cardiovascular disease. We studied the association between the M235T polymorphism of the angiotensinogen gene (AGT) and the C573T polymorphism of the angiotensin II type 1 receptor (AT1R) and blood pressure, carotid atherosclerosis and cerebrovascular disease. METHODS: We genotyped over 6000 subjects from the Rotterdam Study and more than 1000 subjects from the Rotterdam Scan Study. We used logistic regression and univariate analyses, adjusting for age and sex with, for AGT, the MM and, for AT1R, the TT genotype as reference. RESULTS: We found that AGT-235T increased systolic (p for trend = 0.03) and diastolic blood pressure (p for trend = 0.04). The prevalence of carotid plaques was increased 1.25-fold (95% CI 1.02-1.52) in AGT-TT carriers. There was a significant increase in mean volume deep subcortical white matter lesions (WML) for AGT-TT carriers (1.78 ml vs 1.09 ml in the reference group; p = 0.008). A significant interaction was found between AGT and AT1R, further increasing the effect on periventricular and subtotal WML (p for interaction = 0.02). We found a non-significant increased risk of silent brain infarction for AGT-TT carriers and AT1R-CC carriers, but no effect on stroke. CONCLUSION: We found an association between AGT and blood pressure, atherosclerosis and WML. Also, we found synergistic effects between AGT and AT1R on the development of WML. These findings raise the question of whether the renin-angiotensin system may be a therapeutic target for the prevention of cerebral white matter pathology.

The first case of variant Creutzfeldt-Jakob disease in the Netherlands [6] (Article)

2007-07-01T00:00:00Z

Cerebrovascular risk factors do not contribute to genetic variance of cognitive function. The ERF study (Article)

2007-05-01T00:00:00Z

Impaired cognition in later life may result from Alzheimer's disease-related pathology, but also from vascular pathology. We studied to what extent vascular risk explained heritability of cognition in 780 individuals, related in one extended pedigree in a genetically isolated population, in the ERF study. Heritability was estimated using variance components modelling (SOLAR). Univariate analyses included models with and without vascular disease; bivariate analyses included both cognitive and vascular traits, such as blood pressure, serum glucose or lipids. Heritability for immediate and delayed recall, recognition, semantic fluency, Trail making B and Stroop tests was significant, with estimates from 0.16 to 0.36. Vascular factors did not affect cognitive functions, except immediate recall and the Stroop test. Heritability estimates did not change significantly when adjusted for vascular disease. We found no genetic correlation between cognition and vascular traits. Therefore, in this population vascular disease is mildly associated with cognitive dysfunction, and in those with vascular disease, the underlying genetic risk factors are not likely to account for the genetic variation in cognition at adult age.

Dissecting the Genetics of Stroke (Doctoral Thesis)

2007-04-11T00:00:00Z

Stroke is a leading cause of death and disability in the Western world. It is a complex disease resulting from environmental factors and genetic factors, as well as gene-gene and geneenvironment interactions. Many studies have attempted to unravel the genetic aetiology of stroke, but results have been inconsistent. Most have used the candidate gene approach, but genome-wide linkage analyses have also been performed. Recently, results of genome-wide association studies have been reported, however, this approach has not yet been used to study the genetics of stroke. Stroke is a heterogeneous disease, which can be subtyped into ischaemic stroke (80%) and haemorrhagic stroke (20%), with diff erent underlying pathways. In order to reduce the complexity of stroke, intermediate phenotypes have been studied, such as hypertension, carotid atherosclerosis and cerebral white matter lesions. Another approach has been to study stroke in a genetically isolated population.

Heritability of blood pressure traits and the genetic contribution to blood pressure variance explained by four blood-pressure-related genes (Article)

2007-03-01T00:00:00Z

OBJECTIVE: To study the heritability of four blood pressure traits and the proportion of variance explained by four blood-pressure-related genes. METHODS: All participants are members of an extended pedigree from a Dutch genetically isolated population. Heritability and genetic correlations of systolic blood pressure, diastolic blood pressure, mean arterial pressure and pulse pressure were assessed using a variance components approach (SOLAR). Polymorphisms of the α-adducin (ADD1), angiotensinogen (AGT), angiotensin II type 1 receptor (AT1R) and G protein β3 (GNB3) genes were typed. RESULTS: Heritability estimates were significant for all four blood pressure traits, ranging between 0.24 and 0.37. Genetic correlations between systolic blood pressure, diastolic blood pressure and mean arterial pressure were high (0.93-0.98), and those between pulse pressure and diastolic blood pressure were low (0.05). The ADD1 polymorphism explained 0.3% of the variance of pulse pressure (P = 0.07), and the polymorphism of GNB3 explained 0.4% of the variance of systolic blood pressure (P = 0.02), 0.2% of mean arterial pressure (P = 0.05) and 0.3% of pulse pressure (P = 0.06). CONCLUSION: Genetic factors contribute to a substantial proportion of blood pressure variance. In this study, the effect of polymorphisms of ADD1, AGT, AT1R and GNB3 explained a very small proportion of the heritability of blood pressure traits. As new genes associated with blood pressure are localized in the future, their effect on blood pressure variance should be calculated.

Alpha-adducin polymorphism, atherosclerosis, and cardiovascular and cerebrovascular risk (Article)

2006-12-01T00:00:00Z

BACKGROUND AND PURPOSE: Carriers of the 460Trp allele of the alpha-adducin gene (ADD1) show higher rates of sodium reabsorption compared with homozygous carriers of the Gly460 allele and were found to have an increased risk of hypertension and cardiovascular disease. We studied the association between the Gly460Trp polymorphism and atherosclerosis, cardiovascular disease, and cerebrovascular disease. METHODS: Intima-media thickness of the common carotid artery, as well as incident stroke and myocardial infarction, were studied within 6471 subjects of the Rotterdam Study. Within 1018 subjects of the Rotterdam Scan Study, prevalent silent brain infarcts and cerebral white matter lesions were studied. Subjects were grouped into 460Trp carriers (variant carriers) and homozygous carriers of the Gly460 allele (reference). RESULTS: Intima-media thickness of the common carotid artery was 0.80 mm in variant carriers compared with 0.79 mm in the reference group (P=0.04). Variant carriers had an increased risk of any stroke (hazard ratio [HR], 1.22; 95% CI, 1.02 to 1.45), ischemic stroke (HR, 1.29; 95% CI, 1.02 to 1.63), hemorrhagic stroke (HR, 1.07; 95% CI, 0.59 to 1.92), and of myocardial infarction (HR, 1.33; 95% CI, 1.05 to 1.69). For any ischemic stroke, there was a significant interaction between the Gly460Trp polymorphism and hypertension. Variant carriers more often had a silent brain infarct (odds ratio, 1.36; 95% CI, 0.98 to 1.88) and had more subcortical white matter lesions than the reference group (1.45 vs1.24 mL; P=0.22). CONCLUSIONS: The Gly460Trp polymorphism is associated with atherosclerosis, cardiovascular disease, and cerebrovascular disease, especially in hypertensive subjects.

Insulin-like growth factor I promoter polymorphism, risk of stroke, and survival after stroke: the Rotterdam study (Article)

2006-01-01T00:00:00Z

BACKGROUND AND PURPOSE: Low levels of insulin-like growth factor I (IGF-I) predispose to atherosclerosis and may therefore increase the risk of stroke. Low levels have also been found to influence the outcome of cardiovascular and cerebrovascular disease. A polymorphism in the promoter region of the IGF-I gene influences IGF-I levels. Non-carriers of the 192 bp allele have lower levels of IGF-I compared with 192 bp allele carriers. We studied the IGF-I polymorphism in relation to the risk of stroke and survival after stroke. METHODS: We studied 6808 subjects of the Rotterdam Study, who were followed for the occurrence of stroke and death after stroke. Subjects were grouped according to the 192 bp allele of IGF-I into non-carriers, heterozygotes, and homozygotes. The risk of stroke and survival after stroke was studied using Cox regression analysis, adjusting for age and sex, with homozygotes for the wildtype allele as the reference. RESULTS: Non-carriers had a relative risk of 0.8 (95% CI: 0.6 to 1.0) for the occurrence of any stroke and 0.7 (95% CI: 0.5 to 1.0) for ischaemic stroke. For non-carriers, the relative risk of death after any stroke was 1.5 (95% CI: 1.0 to 2.2). After an ischaemic stroke, this relative risk was 1.5 (95% CI: 0.9 to 2.6) and after a haemorrhagic stroke 5.2 (95% CI: 1.3 to 21.5). CONCLUSIONS: Our study suggests that IGF-I is a significant determinant of survival after stroke.