Ikram, M.K.

Epidemiology of dementia in Asia: Insights on prevalence, trends and novel risk factors (Article)

2012-10-15T00:00:00Z

Asia is the most populous region in the world and its rapidly growing societies are the sources of global development. However, accompanying this rapid growth is aging of the population with increasing occurrence of diseases, of which dementia is the most prominent, which provide major challenges to healthcare systems. Dementia prevalence in Asia has previously been found to be lower than Western populations, but recent studies show that age-specific prevalence rates are similar globally. Overall dementia prevalence is expected to rise dramatically across Asia due to maturing populations. Earlier Asian studies reported a lower prevalence of Alzheimer's disease (AD) and a higher prevalence of vascular dementia (VaD). Recent studies, however, show a reversal of this ratio that now parallels that of Western countries. This change may be attributed to an altered demographic profile, urbanization, environmental reactions, ethnicity and advances in the use of neuroimaging modalities. Several factors may influence the results of epidemiological studies including changes in societal perception of aging, family attitudes, validity of assessment tools due to language and literacy, and medical practitioners' expertise in recognizing dementia. Nevertheless, epidemiological studies in Asia may reveal factors contributory to inter-ethnic differences in dementia. Potentially modifiable risk factors apparent only in low and middle-income countries and gene-environment interactions may underlie these disparities and identification of such factors may lead to effective treatments.

Genome-wide meta-analysis of five asian cohorts identifies pdgfra as a susceptibility locus for corneal astigmatism (Article)

2011-12-01T00:00:00Z

Corneal astigmatism refers to refractive abnormalities and irregularities in the curvature of the cornea, and this interferes with light being accurately focused at a single point in the eye. This ametropic condition is highly prevalent, influences visual acuity, and is a highly heritable trait. There is currently a paucity of research in the genetic etiology of corneal astigmatism. Here we report the results from five genome-wide association studies of corneal astigmatism across three Asian populations, with an initial discovery set of 4,254 Chinese and Malay individuals consisting of 2,249 cases and 2,005 controls. Replication was obtained from three surveys comprising of 2,139 Indians, an additional 929 Chinese children, and an independent 397 Chinese family trios. Variants in PDGFRA on chromosome 4q12 (lead SNP: rs7677751, allelic odds ratio = 1.26 (95% CI: 1.16-1.36), Pmeta= 7.87×10-9) were identified to be significantly associated with corneal astigmatism, exhibiting consistent effect sizes across all five cohorts. This highlights the potential role of variants in PDGFRA in the genetic etiology of corneal astigmatism across diverse Asian populations.

Age-related macular degeneration and the risk of stroke: The rotterdam study (Article)

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.

Retinal vascular calibers and the risk of intracerebral hemorrhage and cerebral infarction: The rotterdam study (Article)

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.

A genome-wide association study for myopia and refractive error identifies a susceptibility locus at 15q25 (Article)

2010-10-01T00:00:00Z

Myopia and hyperopia are at opposite ends of the continuum of refraction, the measure of the eyeĝ€2s ability to focus light, which is an important cause of visual impairment (when aberrant) and is a highly heritable trait. We conducted a genome-wide association study for refractive error in 4,270 individuals from the TwinsUK cohort. We identified SNPs on 15q25 associated with refractive error (rs8027411, P = 7.91 × 10-8). We replicated this association in six adult cohorts of European ancestry with a combined 13,414 individuals (combined P = 2.07 × 10-9). This locus overlaps the transcription initiation site of RASGRF1, which is highly expressed in neurons and retina and has previously been implicated in retinal function and memory consolidation. Rasgrf1-/-mice show a heavier average crystalline lens (P = 0.001). The identification of a susceptibility locus for refractive error on 15q25 will be important in characterizing the molecular mechanism responsible for the most common cause of visual impairment.

A genome-wide association study identifies a susceptibility locus for refractive errors and myopia at 15q14 (Letter To Editor)

2010-09-01T00:00:00Z

Refractive errors are the most common ocular disorders worldwide and may lead to blindness. Although this trait is highly heritable, identification of susceptibility genes has been challenging. We conducted a genome-wide association study for refractive error in 5,328 individuals from a Dutch population-based study with replication in four independent cohorts (combined 10,280 individuals in the replication stage). We identified a significant association at chromosome 15q14 (rs634990, P = 2.21 × 10−14). The odds ratio of myopia compared to hyperopia for the minor allele (minor allele frequency = 0.47) was 1.41 (95% CI 1.16–1.70) for individuals heterozygous for the allele and 1.83 (95% CI 1.42–2.36) for individuals homozygous for the allele. The associated locus is near two genes that are expressed in the retina, GJD2 and ACTC1, and appears to harbor regulatory elements which may influence transcription of these genes. Our data suggest that common variants at 15q14 influence susceptibility for refractive errors in the general population.

A genome-wide association study identifies a susceptibility locus for refractive errors and myopia at 15q14 (Letter To Editor)

2010-09-01T00:00:00Z

A genome-wide association study of optic disc parameters (Article)

2010-06-01T00:00:00Z

The optic nerve head is involved in many ophthalmic disorders, including common diseases such as myopia and open-angle glaucoma. Two of the most important parameters are the size of the optic disc area and the vertical cup-disc ratio (VCDR). Both are highly heritable but genetically largely undetermined. We performed a meta-analysis of genome-wide association (GWA) data to identify genetic variants associated with optic disc area and VCDR. The gene discovery included 7,360 unrelated individuals from the population-based Rotterdam Study I and Rotterdam Study II cohorts. These cohorts revealed two genome-wide significant loci for optic disc area, rs1192415 on chromosome 1p22 (p =6.72*10-19) within 117 kb of the CDC7 gene and rs1900004 on chromosome 10q21.3-q22.1 (p=2.67*10-33) within 10 kb of the ATOH7 gene. They revealed two genome-wide significant loci for VCDR, rs1063192 on chromosome 9p21 (p =6.15*10-11) in the CDKN2B gene and rs10483727 on chromosome 14q22.3-q23 (p=2.93*10-10) within 40 kbp of the SIX1 gene. Findings were replicated in two independent Dutch cohorts (Rotterdam Study III and Erasmus Rucphen Family study; N=3,612), and the TwinsUK cohort (N=843). Meta-analysis with the replication cohorts confirmed the four loci and revealed a third locus at 16q12.1 associated with optic disc area, and four other loci at 11q13, 13q13, 17q23 (borderline significant), and 22q12.1 for VCDR. ATOH7 was also associated with VCDR independent of optic disc area. Three of the loci were marginally associated with open-angle glaucoma. The protein pathways in which the loci of optic disc area are involved overlap with those identified for VCDR, suggesting a common genetic origin. © 2010 Ramdas et al.

Retinal vascular calibers and risk of late-life depression: The rotterdam study (Article)

2010-05-01T00:00:00Z

Objectives: To test the "vascular depression" hypothesis, the authors investigated whether smaller retinal arteriolar or larger venular calibers, which are markers of cerebral microvascular disease, were associated with incident late-life depression. Methods: The authors included 3,605 participants (age ≥55 years) from the population-based Rotterdam Study with no depression at baseline (1993-1995) and fundus photographs gradable for retinal vascular caliber measurements. The authors identified persons with incident depressive symptoms and syndromes using psychiatric interviews during follow-up visits and continuous monitoring. The follow-up was complete until October 2005. Results: After a mean follow-up of 9.0 years, 555 participants developed incident depression, including 312 with depressive syndrome. Neither smaller arteriolar (age-and sex-adjusted hazard ratio: 1.01; 95% confidence interval: 0.93-1.10), nor larger venular calibers (hazard ratio: 1.02; 95% confidence interval: 0.94-1.12) were associated with incident depressive syndromes. Conclusions: Our data showed no evidence of an association between retinal vascular calibers and incident late-life depression.

Transient focal cerebral ischaemia and bilateral pulmonary embolism after desmopressin treatment for von Willebrand's disease (Article)

2008-09-12T00:00:00Z

Arteriolar Oxygen Saturation, Cerebral Blood Flow, and Retinal Vessel Diameters. The Rotterdam Study (Article)

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.

Retinal vessel diameters and risk of impaired fasting glucose or diabetes: the Rotterdam study (Article)

2006-01-01T00:00:00Z

The association between a smaller retinal arteriolar-to-venular ratio (AVR) and incident diabetes may be due to arteriolar narrowing, venular dilatation, or both. We investigated associations between baseline vessel diameters and incident impaired fasting glucose or diabetes in a population-based cohort (aged > or =55 years). Baseline retinal vessel diameters (1990-1993) were measured on digitized images of 2,309 subjects with a normal glucose tolerance test (postload glucose <7.8 mmol/l). At follow-up (1997-1999), impaired fasting glucose was defined as 6.1-7.0 mmol/l and diabetes as > or =7.0 mmol/l and/or antidiabetic medication use. Odds ratios (ORs) per SD increase in venular diameters were 1.13 (95% CI 1.00-1.29) for impaired fasting glucose and 1.09 (0.90-1.33) for diabetes. ORs per SD decrease in arteriolar diameters were 1.12 (0.98-1.27) and 1.08 (0.89-1.31) and per SD decrease in AVR were 1.29 (1.13-1.46) and 1.19 (0.98-1.45). After adjustment for cardiovascular risk factors, the associations were unaltered for venules and disappeared for arterioles. After stratification on age, associations between venular dilatation and impaired fasting glucose (1.23 [1.02-1.47]) or diabetes (1.18 [0.89-1.56]) were mainly present in participants aged <70 years. In conclusion, in our study, the risk of impaired fasting glucose and diabetes with AVR was explained by venular dilatation rather than arteriolar narrowing, warranting more focus on the causes of this dilatation.

Retinal Vessels and Diseases in the Elderly: the Rotterdam study (Doctoral Thesis)

2005-09-07T00:00:00Z

Retinal vessel diameters and incident open-angle glaucoma and optic disc changes: the Rotterdam study. (Article)

2005-04-01T00:00:00Z

PURPOSE: It remains unclear whether reduced retinal blood flow and smaller arterioles, reported to exist in patients with open-angle glaucoma (OAG), are a cause or a consequence of ganglion cell loss. We examined whether baseline retinal vessel diameters were related to incident (i)OAG or incident optic disc changes in a population-based sample. METHODS: In the prospective population-based Rotterdam Study, baseline diameters of retinal arterioles and venules (1990-1993) were measured in digitized images of 3469 persons (aged 55 years and older) at risk for OAG. The follow-up examinations took place from 1997 to 1999. iOAG was based on the presence of incident glaucomatous visual field loss and/or incident glaucomatous optic neuropathy. Changes in neuroretinal rim, cup area, or vertical cup-to-disc ratio were calculated with a semiautomated image analyzer in 2782 persons. RESULTS: After a mean follow-up time of 6.5 years, 74 participants had iOAG. At baseline, the mean arteriolar diameter was 147.5 +/- 14.2 microm (SD) and the venular, 222.9 +/- 20.0 microm. Neither arteriolar diameters (odds ratio [OR] per SD decrease: 0.82; 95% confidence interval [CI]: 0.66-1.03) nor venular ones (OR per SD increase: 1.20; 95% CI: 0.95-1.53) were significantly related to iOAG. Baseline retinal vessel diameters did not predict changes in the optic disc. Additional adjustment for cardiovascular risk factors did not alter these results. CONCLUSIONS: The data show that baseline retinal vessel diameters did not influence the risk of iOAG or incident optic disc changes. These data provide no evidence for a retinal vascular role in the pathogenesis of OAG.

Are retinal arteriolar or venular diameters associated with markers for cardiovascular disorders? The Rotterdam Study (Article)

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.

Blood pressure, atherosclerosis, and the incidence of age-related maculopathy: the Rotterdam Study (Article)

2003-01-01T00:00:00Z

PURPOSE: To determine whether blood pressure and subclinical atherosclerosis are associated with incident age-related maculopathy (ARM). METHODS: The study was performed within the Rotterdam Study, a population-based, prospective cohort study in Rotterdam, The Netherlands. A total of 4822 subjects who at baseline were aged 55 years more, were free of ARM, and participated in at least one of two follow-up examinations after a mean of 2 and 6.5 years, were included in the study. At baseline, blood pressure and the presence of atherosclerosis were determined. ARM was assessed according to the International Classification and Grading System and defined as large, soft drusen with pigmentary changes; indistinct drusen; or atrophic or neovascular age-related macular degeneration. RESULTS: After a mean follow-up of 5.2 years, incident ARM was diagnosed in 417 subjects. Increased systolic blood pressure or pulse pressure was associated with a higher risk of ARM. Adjusted for age, gender, smoking, total and high-density lipoprotein cholesterol, body mass index, and diabetes mellitus, odds ratios (OR) per 10-mm Hg increase were 1.08 (95% confidence interval [CI]: 1.03-1.14) and 1.11 (95% CI: 1.04-1.18), respectively. Moreover, different measures of atherosclerosis were associated with the risk of ARM. An increase in carotid wall thickness (OR per 1 SD, 1.15; 95% CI: 1.03-1.28) increased the risk of ARM. The lowest compared with the highest tertile of ankle-arm index had an OR of 1.32 (95% CI: 1.00-1.75). A weak association was found between aortic calcifications and the risk of ARM. CONCLUSIONS: Elevated systolic blood or pulse pressure or the presence of atherosclerosis may increase the risk of development of ARM.

Relationship between refraction and prevalent as well as incident age-related maculopathy: the Rotterdam Study (Article)

2003-01-01T00:00:00Z

PURPOSE: To study the relationship between baseline spherical equivalents (SphE) of refraction and prevalent as well as incident age-related maculopathy (pARM and iARM, respectively). METHODS: The study was performed as part of the Rotterdam Study, a population-based, prospective cohort study. The SphE (in diopters), measured with autorefraction and subjective optimization, was recorded in 6209 subjects aged 55 years or more. Aphakic or pseudophakic eyes at baseline were excluded. Stereoscopic transparencies of the macular region were graded according to the International Classification and Grading System. ARM was defined as large soft drusen with pigmentary changes, or indistinct drusen, or atrophic or neovascular age-related macular degeneration (AMD). For the prevalence analyses, ARM was classified into no, p(early)ARM, or pAMD, and in each subject the eye with the most advanced ARM and the corresponding refraction was selected. After a mean 5.2 years of follow-up, 4935 subjects had complete data for these incidence analyses. In each subject, the eye with iARM was selected. RESULTS: The age- and gender-adjusted odds ratio (OR) of pARM (n = 536) for every diopter of progress toward hyperopia was 1.09 (95% confidence interval [CI]1.04-1.13). For p(early)ARM (n = 440) the OR was 1.09 (1.04-1.14) and for pAMD (n = 96) the OR was 1.09 (1.00-1.19). Baseline refraction was significantly associated with increased risk of iARM (n = 497). For each diopter of progress toward hyperopia the OR was 1.05 (95% CI 1.01-1.10). Additional adjustments for smoking, atherosclerosis, and blood pressure did not alter the relationship. CONCLUSIONS: These population-based incidence data confirm results from prevalence and case-control studies that there is an association between hyperopia and ARM.