http://repub.eur.nl/res/aut/8959/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/24480/ 2009-04-01T00:00:00Z Thyroid dysfunction is associated with cognitive impairment and dementia, including Alzheimer's disease (AD). It remains unclear whether thyroid dysfunction results from, or contributes to, Alzheimer pathology. We determined whether thyroid function is associated with dementia, specifically AD, and Alzheimer-type neuropathology in a prospective population-based cohort of Japanese-American men. Thyrotropin, total and free thyroxine were available in 665 men aged 71-93 years and dementia-free at baseline (1991), including 143 men who participated in an autopsy sub-study. During a mean follow-up of 4.7 (S.D.: 1.8) years, 106 men developed dementia of whom 74 had AD. Higher total and free thyroxine levels were associated with an increased risk of dementia and AD (age and sex adjusted hazard ratio (95% confidence interval) per S.D. increase in free thyroxine: 1.21 (1.04; 1.40) and 1.31 (1.14; 1.51), respectively). In the autopsied sub-sample, higher total thyroxine was associated with higher number of neocortical neuritic plaques and neurofibrillary tangles. No associations were found for thyrotropin. Our findings suggest that higher thyroxine levels are present with Alzheimer clinical disease and neuropathology. http://repub.eur.nl/res/pub/15918/ 2008-09-01T00:00:00Z Sulfation is an important pathway in the metabolism of thyroid hormone and estrogens. Sulfation of estrogens is reversible by estrogen sulfatase, but sulfation of thyroid hormone accelerates its degradation by the type 1 deiodinase in liver. Organic anion transporters (OATPs) are capable of transporting iodothyronine sulfates such as T4 sulfate (T 4S), T3S, and rT3S or estrogen sulfates like estrone sulfate (E1S), but the major hepatic transporter for these conjugates has not been identified. A possible candidate is OATP1B1 because model substrates for this transporter include the bilirubin mimic bromosulfophthalein (BSP) and E1S, and it is highly and specifically expressed in liver. Therefore, OATP1B1-transfected COS1 cells were studied by analysis of BSP, E1S, and iodothyronine sulfate uptake and metabolism. Two Caucasian populations (155 blood donors and 1012 participants of the Rotterdam Scan Study) were genotyped for the OATP1B1-Val174Ala polymorphism and associated with bilirubin, E1S, and T4S levels. OATP1B1-transfected cells strongly induced uptake of BSP, E1S, T4S, T3S, and rT3S compared with mocktransfected cells. Metabolism of iodothyronine sulfates by cotransfected type 1 deiodinase was greatly augmented in the presence of OATP1B1. OATP1B1-Val174 showed a 40% higher induction of transport and metabolism of these substrates than OATP1B1-Ala174. Carriers of the OATP1B1-Ala174 allele had higher serum bilirubin, E1S, and T 4S levels. In conclusion, OATP1B1 is an important factor in hepatic transport and metabolism of bilirubin, E1S, and iodothyronine sulfates. OATP1B1-Ala174 displays decreased transport activity and thereby gives rise to higher bilirubin, E1S, and T4S levels in carriers of this polymorphism. http://repub.eur.nl/res/pub/22438/ 2008-05-01T00:00:00Z BACKGROUND AND PURPOSE: Men, but not women, with unrecognized myocardial infarction (MI) have an increased risk of cardiac events and stroke compared with those without MI or with recognized MI. We investigated whether unrecognized MI is also a risk factor for dementia and cerebral small vessel disease (white matter lesions and brain infarction) in 2 population-based cohort studies. METHODS: In the Rotterdam Study, 6347 participants were classified at baseline (1990 to 1993) into those with recognized MI (subdivided into Q-wave and non-Q-wave MI), with unrecognized MI, and without MI based on electrocardiography and interview and were followed for incident dementia (n=613) until January 1, 2005. In the Rotterdam Scan Study, 436 nondemented persons were similarly classified based on electrocardiography and interview and underwent brain MRI for the assessment of white matter lesions and brain infarction. RESULTS: In men, unrecognized MI was associated with an increased risk of dementia (compared with men without MI hazard ratio, 2.14; 95% CI, 1.37 to 3.35) and with more white matter lesions and more often brain infarction on MRI. In women, no associations were found with unrecognized MI. Recognized MI was not associated with the risk of dementia in either sex. Men, but not women, with recognized MI had more often any brain infarction or asymptomatic brain infarction, especially if they had Q-wave MI. No consistent associations were found between recognized Q-wave or non-Q-wave MI and severity of white matter lesions. Additional adjustment for cardiovascular risk factors did not change the results. CONCLUSIONS: Men with unrecognized MI have an increased risk of dementia and more cerebral small vessel disease. http://repub.eur.nl/res/pub/29284/ 2008-05-01T00:00:00Z Objective: Elevated glucocorticoid levels are associated with dementia. A glucocorticoid receptor gene variant (ER22/23EK) is related to relative glucocorticoid resistance. We investigated whether the ER22/23EK allele is associated with dementia and structural brain abnormalities. Methods: This study was performed in two prospective population-based cohort studies among elderly. The first study included 6034 participants who were screened for dementia (mean follow-up 5.8 years). The second study included 1011 elderly subjects with an MRI at baseline and follow-up. The ER22/23EK allele was assessed for association with dementia, cognitive function and white matter lesions. Results: The ER22/23EK allele was associated with a decreased risk of dementia. Among non-demented participants, ER22/23EK-carriers had a better performance on psychomotor speed tests than non-carriers. No differences were found in memory function between genotypes. In addition, both presence and progression of white matter lesions was lower in ER22/23EK-carriers. No association was found with brain atrophy on MRI. Conclusions: Our findings suggest a protective effect of the ER22/23EK allele on the risk of dementia and white matter lesions. http://repub.eur.nl/res/pub/29317/ 2008-05-01T00:00:00Z Objective: Retinal vessel diameters, in particular larger venular diameters, have been associated with cerebrovascular disease. Larger retinal venular diameters may reflect cerebral ischemia. The authors investigated whether arteriolar oxygen saturation (SaO2) and total cerebral blood flow (CBF), indicators of cerebral oxygen supply, are associated with retinal arteriolar or venular diameters. Design: Cross-sectional study performed within the population-based Rotterdam Study. Participants: Randomly selected participants aged 55 years or older (n = 696), who underwent both an eye examination and brain magnetic resonance imaging (MRI). Methods: Arteriolar oxygen saturation was determined by pulse oximetry on the right index finger. Cerebral blood flow was assessed using a phase-contrast MRI sequence that measured the flow in the basilar and both internal carotid arteries. Brain volume was measured to express CBF per 100 ml brain volume. Retinal arteriolar and venular diameters were measured on digitized fundus color transparencies on 1 eye of each participant. Regression models were used to investigate the association of SaO2and CBF with retinal vessel diameters. Main Outcome Measures: Mean retinal arteriolar and venular diameters (in micrometers). Results: Lower SaO2was associated with larger venular diameters. Persons with SaO2less than 96% (n = 113) had on average 5 μm larger venular diameters compared with those with SaO2of 96% or more (n = 583; age- and gender-adjusted mean difference, 5.6 μm; 95% confidence interval, 1.2-10.0). Cerebral blood flow was not related to venular diameters when analyzed separately. Additional analyses showed that the association between SaO2and venular widening was confined to participants within the lowest tertile of CBF. No associations were found between SaO2or CBF and arteriolar diameters. Additional adjustment for established cardiovascular risk factors did not change the results. Conclusions: An association of lower SaO2with larger retinal venular diameters was observed, in particular in the presence of lower CBF. These findings suggest that venular widening may reflect a lower oxygen supply, especially to the brain. http://repub.eur.nl/res/pub/37138/ 2007-12-01T00:00:00Z Female patients with classical galactosemia (galactose-1-phosphate uridyltransferase [GALT] deficiency) frequently suffer from premature ovarian failure, despite treatment with a galactose-restricted diet. Earlier research has suggested an association between heterozygosity for GALT mutations and early menopause. This study evaluates the effect of carriership for classical galactosemia on ovarian reserve and menopausal age. Proven female carriers of classical galactosemia were recruited via the Dutch Galactosemia Society. All 58 participants underwent a structured interview regarding fertility, smoking status, and menopause. To determine ovarian reserve, 42 premenopausal GALT carriers underwent ovarian antral follicle count (AFC) by transvaginal ultrasound and early follicular phase blood sampling for hormonal measurement of follicle-stimulating hormone (FSH), inhibin B, and anti-Müllerian hormone (AMH). These ovarian reserve parameters were compared with a cohort of proven fertile women (n = 166). The mean age at menopause in GALT carriers was 49.7 years, which is not different from the mean age at menopause in the general population in the Netherlands. There was no difference in FSH, inhibin B, and AMH levels or in the AFC (when corrected for age and smoking status) between 42 premenopausal GALT carriers and controls. The authors conclude that there is no evidence that GALT mutation carriership affects ovarian reserve or menopausal age. http://repub.eur.nl/res/pub/35745/ 2007-09-01T00:00:00Z Objective: Inflammation plays a role in the pathogenesis of dementia and Alzheimer's disease (AD). Studies examining serum levels of C-reactive protein in relation to dementia yielded conflicting results. Since serum levels of C-reactive protein are partly determined by genetic factors, we examined the association between genetic variation in the C-reactive protein gene with dementia and AD. Methods: This study was performed in the Rotterdam Study, a population-based prospective cohort study among elderly. Polymorphisms in the C-reactive protein gene (1184C > T, 2042C > T and 2911C > G) tagging the common haplotypes were genotyped and haplotypes were constructed. During follow-up (mean 9.2 years) 607 dementia cases were identified. We estimated the association between polymorphisms and haplotypes with dementia and AD with Cox' proportional hazard models. Results: The T allele of the C-reactive protein 2042C > T polymorphism, related to lower serum levels of C-reactive protein, was associated with a lower risk of dementia and AD. This association was strongest in APOE ε4 allele carriers. Conclusion: These findings suggest that C-reactive protein plays a role in development of dementia. http://repub.eur.nl/res/pub/35781/ 2007-07-01T00:00:00Z PURPOSE. Retinal venular dilatation is associated with systemic inflammation. The hypothesis for the current study was that larger retinal venular diameters are related to the His allele of the Tyr402His polymorphism in the complement factor H (CFH) gene, a major inhibitor of the complement pathway. Possible effect modification by smoking and inflammatory markers was examined. METHODS. This cross-sectional study was performed within the Rotterdam Study, a population-based study among elderly persons aged 55 years and older. The Tyr402His polymorphism of the CFH gene was genotyped in 5066 participants and retinal arteriolar and venular diameters were graded on digitized fundus transparencies. RESULTS. Genotype frequencies were 41% in TyrTyr, 45% in TyrHis, and 14% in HisHis carriers. The His402allele was associated with smaller rather than larger venular diameters (age-and sex-adjusted means and standard errors [in micrometers] were 222.5 ± 0.45 for TyrTyr, 221.9 ± 0.43 for TyrHis, and 220.6 ± 0.78 for HisHis carriers; P-trend = 0.03). This association was apparent only in never-smokers and was not modified by the inflammatory markers erythrocyte sedimentation rate, leukocyte count, C-reactive protein, or fibrinogen. Adjustment for cardiovascular risk factors did not change results. No associations were found with arteriolar diameters. CONCLUSIONS. The findings do not support the hypothesis that the His402allele is related to larger retinal venular diameters. The association with smaller retinal venular diameters most likely is a chance finding, because it was present only among never-smokers and was not modified by inflammatory mediators of complement. These results suggest that the Tyr402His variant is not related to retinal venular diameters. Copyright http://repub.eur.nl/res/pub/13953/ 2007-05-23T00:00:00Z First described 100 years ago by Alois Alzheimer, the clinico-pathological entity that we now call Alzheimer disease was initially presented as a clinically unusual type of dementia. 1 Nowadays, Alzheimer disease is recognized as the main cause of dementia and one of the most disabling and burdensome health conditions worldwide.2,3 The number of people affected by dementia is estimated to double every 20 years to over 80 million by 2040.3 This will not only affect patients and their caregivers, but will also put an enormous demand on health care and welfare resources. http://repub.eur.nl/res/pub/36103/ 2007-05-01T00:00:00Z Retinal vessels may provide a way to study the cerebral microcirculation. In particular, larger retinal venular diameters have been associated with cerebrovascular disease. An inflammatory response may underlie this association. In a population-based cohort study among 5,279 participants aged 55 years or older with graded retinal vessel diameters, we observed that greater serum levels of C-reactive protein and fibrinogen and greater lipoprotein-associated phospholipase A2activity were strongly associated with larger venular diameters. Weaker associations were found with arteriolar diameters. Out findings support the hypothesis that larger retinal venular diameters reflect systemic inflammation and suggest that inflammation is involved in cerebrovascular disease. http://repub.eur.nl/res/pub/36094/ 2007-05-01T00:00:00Z Objective: Atherosclerosis has been implicated in the development of dementia and its major subtypes, Alzheimer's disease and vascular dementia. However, support for this association mainly comes from cross-sectional studies. We investigated the association of atherosclerosis with dementia and subtypes of dementia during long follow-up, with various noninvasive measures of atherosclerosis. Methods: This study was based on 6,647 participants in the Rotterdam Study, a population-based prospective cohort study among 7,983 elderly subjects. At baseline (1990-1993) and at the third survey (1997-1999), common carotid intima media thickness, carotid plaques, and peripheral arterial disease (measured as ankle-brachial index) were measured. During follow-up (mean, 9.0 years), 678 subjects developed dementia. We estimated the associations of different measures of atherosclerosis with risk for dementia and subtypes of dementia by means of Cox proportional hazard models. Analyses were repeated and stratified on duration of follow-up. To evaluate competing risk for mortality, we examined the association between measures of atherosclerosis and risk for dementia or mortality by combining the two in a single outcome measure. Results: We found that atherosclerosis, predominantly carotid atherosclerosis, was associated with an increased risk for dementia during short follow-up. This association attenuated with longer follow-up, likely because of the strong association between atherosclerosis and mortality. The associations did not differ across apolipoprotein E genotypes. Interpretation: Our findings suggest that atherosclerosis is associated with an increased risk for dementia. Stronger associations between atherosclerosis and mortality may attenuate the association between atherosclerosis and dementia in prospective cohort studies with long follow-up periods. http://repub.eur.nl/res/pub/37030/ 2007-04-01T00:00:00Z Background: Subjective memory complaints are common in the elderly. Although memory complaints are associated with an increased risk of Alzheimer's disease in persons with cognitive impairment as well as in persons with normal cognition, they are commonly considered of less importance than objective cognitive measures. We hypothesized that the clinical relevance of subjective memory complaints might vary with educational background. Methods: The study was performed within the Rotterdam Study, a prospective population-based cohort study among 7983 persons 55 years and older. Subjective memory complaints and level of education were assessed in the baseline interview (1990 to 1993). During a mean follow-up of 9.0 years we identified 568 incident Alzheimer's disease patients. We estimated the association between subjective memory complaints and risk of dementia by means of Cox proportional hazard models. Results: The association between subjective memory complaints and risk of Alzheimer's disease varied across levels of education. The risk of Alzheimer's disease associated with subjective memory complaints was higher in highly educated persons (age- and sex-adjusted hazard ratio, 2.33; 95% confidence interval [CI], 1.00-5.49) than in persons with a low education (age- and sex-adjusted hazard ratio, 1.53; 95% CI, 1.15-2.05) (P value for interaction, .02). In highly educated persons without objective cognitive impairment (Mini-Mental State Examination score, 29 or 30) the risk of Alzheimer's disease was highest (age- and sex-adjusted hazard ratio, 2.98; 95% CI, 1.76-5.02). Conclusions: Especially in persons with a high level of education who still perform well on formal cognitive tests, subjective memory complaints might be an important first sign of imminent Alzheimer's disease. http://repub.eur.nl/res/pub/35585/ 2007-02-01T00:00:00Z Context: Thyroid function has been related to Alzheimer disease (AD) and neuroimaging markers thereof. Whether thyroid dysfunction contributes to or results from developing AD remains unclear. Variations in the deiodinase type 1 (DIO1) and type 2 (DIO2) genes that potentially alter thyroid hormone bioactivity may help in elucidating the role of thyroid function in AD. Objective: We investigated the association of recently identified polymorphisms in the DIO1 (D1a-C/T, D1b-A/G) and DIO2 (D2-ORFa-Gly3Asp, D2-Thr92Ala) genes with circulating thyroid parameters and early neuroimaging markers of AD. Design and Participants: The Rotterdam Scan Study is a population-based cohort study among 1,077 elderly individuals aged 60-90 yr. Main Outcome Measures: DIO1 and DIO2 polymorphisms and serum TSH, free T4, T3, and reverse T3(rT3) levels were determined in 995 nondemented elderly, including 473 persons with assessments of hippocampal and amygdalar volume on brain magnetic resonance imaging. Results: Carriers of the D1a-T allele had higher serum free T4and rT3, lower T3, and lower T3/rT3. The D1b-G allele was associated with higher serum T3and T3/rT3. The DIO2 variants were not associated with serum thyroid parameters. No associations were found with hippocampal or amygdalar volume. Conclusion: This is the first study to report an association of D1a-C/T and D1b-A/G polymorphisms with iodothyronine levels in the elderly. Polymorphisms in the DIO1 and DIO2 genes are not associated with early magnetic resonance imaging markers of AD. This suggests that the previously reported association between iodothyronine levels and brain atrophy reflects comorbidity or nonthyroidal illness rather than thyroid hormones being involved in developing AD. Copyright http://repub.eur.nl/res/pub/14102/ 2007-01-01T00:00:00Z CONTEXT: Recently, it was proposed that a combination of the 83,557insA polymorphism in the 11beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) gene and the R453Q polymorphism in the hexose-6-phosphate dehydrogenase (H6PD) gene interacts to cause cortisone reductase deficiency (CRD) when at least three alleles are affected. OBJECTIVE: The aim was to study the separate and combined effects of these polymorphisms on body composition, adrenal androgen production, blood pressure, glucose metabolism, and the incidence of dementia in the healthy elderly population. DESIGN/SETTING/PARTICIPANTS: The Rotterdam study (n = 6105) and the Frail Old Men study (n = 347) are population-based cohort studies in the elderly. MAIN OUTCOME MEASURES: Genotype distributions and influences of (combined) genotypes on body mass index, adrenal androgen production, waist to hip ratio, systolic and diastolic blood pressure, fasting glucose levels, glucose tolerance test, and incidence of dementia were measured. RESULTS: No influence of the HSD11B1 83,557insA (allele frequencies 22.0 and 21.5%) and H6PD R453Q (allele frequencies 22.9 and 20.2%) variants was found for the different outcome measures that were investigated, either separately or when at least three alleles were affected. CONCLUSIONS: Two population-based studies among Caucasian elderly showed no evidence for (combined) effects of two polymorphisms in the HSD11B1 and H6PD genes on body composition, adrenal androgen production, blood pressure, glucose metabolism, and incidence of dementia. Moreover, the high frequencies observed for these two polymorphisms do not correspond to the low incidence of CRD observed in the general population. Altogether, it is unlikely that these polymorphisms cause CRD. http://repub.eur.nl/res/pub/10352/ 2004-01-01T00:00:00Z PURPOSE: A lower retinal arteriolar-to-venular ratio (AVR) has been suggested to reflect generalized arteriolar narrowing and to predict the risk of cardiovascular diseases. The contribution of the separate arteriolar and venular diameters to this AVR is unknown. Thus, associations between retinal arteriolar and venular diameters, and the AVR on the one hand and blood pressure, atherosclerosis, inflammation markers, and cholesterol levels on the other were examined in the Rotterdam Study. METHODS: In this cross-sectional population-based study, for one eye of each subject (> or =55 years; n = 5674), retinal arteriolar and venular diameters (in micrometers) of the blood columns were summed on digitized images. At baseline blood pressures, cholesterol levels, and markers of atherosclerosis and inflammation were also measured. RESULTS: With increasing blood and pulse pressures, retinal arteriolar and venular diameters and the AVR decreased significantly and linearly. Lower arteriolar diameters were associated with increased carotid intima-media thickness. Larger venular diameters were associated with higher carotid plaque score, more aortic calcifications, lower ankle-arm index, higher leukocyte count, higher erythrocyte sedimentation rate, higher total serum cholesterol, lower HDL, higher waist-to-hip ratio, and smoking. A lower AVR was related to increased carotid intima-media thickness, higher carotid plaque score, higher leukocyte count, lower HDL, higher body mass index, higher waist-to-hip ratio, and smoking. CONCLUSIONS: Because larger venular diameters are associated with atherosclerosis, inflammation, and cholesterol levels, the AVR does not depend only on generalized arteriolar narrowing due to the association between smaller arteriolar diameters and higher blood pressures. These data indicate that retinal venular diameters are variable and may play their own independent role in predicting cardiovascular disorders.