Age-Related Macular Degeneration and the Risk of Stroke
The Rotterdam Study
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.
Age-related macular degeneration (AMD) is a chronic disorder and the major cause of permanent visual impairment among elderly people in developed countries.1 Its early signs are the presence of drusen and pigmentary abnormalities in the macula. These early abnormalities are frequent in elderly people and cause only minimal visual symptoms. Early AMD may progress to late AMD, often associated with severe and irreversible loss of vision.2
Several risk factors for stroke, including smoking, hypertension, carotid artery disease, cholesterol levels, diabetes, and obesity, have also been associated with an increased risk of AMD.3–6 Because of the overlap in risk factors, a common causal pathway has been hypothesized to underlie the development of both stroke and AMD.3 Previous studies that investigated the association between AMD and stroke reported inconsistent results.7–11 Most studies did not distinguish between early and late AMD nor did they subdivide late AMD into dry (atrophic) or wet (neovascular) AMD. Besides, except for a study based on medical reimbursement claims, no previous study presented separate associations for the subtypes cerebral infarction and intracerebral hemorrhage.8
The purpose of the present study was to investigate in a large population-based cohort of elderly people if AMD was associated with risk of stroke and its subtypes cerebral infarction and intracerebral hemorrhage. In addition, we analyzed if any of these associations also held for the various AMD stages.
This study is part of the Rotterdam Study, an ongoing prospective population-based cohort study, which started in 1990.12 All inhabitants who were age ≥55 years and living in Ommoord, a district in Rotterdam in The Netherlands, were invited to participate. Invitation to the study occurred in random order. Baseline examinations, including a standardized interview, physical examination, and blood sampling, took place between 1990 and 1993. These were followed by a first follow-up examination from 1993 to 1994, a second from 1997 to 1999, and a third from 2000 to 2004. After enrollment, participants were continuously monitored for a variety of diseases that are frequent in the elderly, including stroke.12 The study was approved by the Medical Ethics Committee of the Erasmus Medical Center in Rotterdam. Written informed consent was obtained from all participants.
Of the initial cohort of 10 725 eligible individuals, 7983 participated in the baseline interview. Because the ophthalmologic part of the study became operational after the main study had started, a smaller number of participants (n=6780) underwent the ophthalmologic examination. Gradable fundus photographs were available of 6418 participants. After exclusion of participants who had a stroke before baseline (n=182) or had refused informed consent for the collection of follow-up data from general practitioners (n=31), a total of 6207 participants was included in the present analyses.
Assessment of Stroke
Stroke was defined as rapidly developing clinical signs of focal or global disturbance of cerebral function with no apparent cause other than a vascular origin.13 History of stroke at baseline was assessed during the baseline interview and verified in medical records. After enrollment in the Rotterdam Study, participants were continuously monitored for incident stroke through automated linkage of the study database with files from general practitioners. Nursing home physicians' files and files from general practitioners of participants who moved out of the district were scrutinized as well. Additional information was obtained from hospital records. Potential strokes were reviewed by research physicians and verified by an experienced stroke neurologist (P.J.K.). Strokes were further classified as cerebral infarction or intracerebral hemorrhage based on neuroimaging reports. If neuroimaging was lacking, a stroke was classified as unspecified. Subarachnoid hemorrhages were excluded.
Participants were followed from baseline to stroke, death, last health status update when they were known to be stroke-free, or January 1, 2007, whichever came first. Follow-up was complete up to January 1, 2007, for 96.1% of potential person-years.
Definition of AMD
Fundus photographs covering a 35° field centered on the macula were taken at each visit (Topcon TRV-50VT fundus camera; Topcon Optical Co, Tokyo, Japan) after pharmacological mydriasis. Signs of AMD were graded according to the modified international classification and grading system by the same 2 trained professionals who graded AMD from baseline to the present under the supervision of senior ophthalmologists (J.R.V. and P.T.V.M.d.J.), who were masked for all other determinants.14–16 We categorized these signs into 5 mutually exclusive stages 0 to 4 that represent an increasing severity of AMD. No AMD was defined as Stage 0, no signs of AMD at all or only small, hard drusen (<63 μm); Stage 1 was defined as soft distinct drusen (≥63 μm) or only pigmentary abnormalities. Stage 2 was defined as soft indistinct drusen (≥125 μm), reticular drusen only, or soft distinct drusen (≥63 μm) with pigmentary abnormalities. Stage 3 included soft indistinct drusen (≥125 μm) or reticular drusen with pigmentary abnormalities. Late AMD (Stage 4) was subdivided into dry (atrophic) AMD and wet (neovascular) AMD. Persons were classified in Stage 0 to 4 based on the eye with the more severe stage.
Lesions that were considered to be the result of generalized disease such as diabetic retinopathy, chorioretinitis, high myopia, trauma, congenital diseases, or photocoagulation for reasons other than for choroidal neovascularization were excluded from AMD classification.
Blood pressure was calculated as the mean of 2 measurements with the random-zero sphygmomanometer at the right brachial artery at the time the subject was in a sitting position. Hypertension was defined as a diastolic blood pressure of ≥90 mm Hg and/or a systolic blood pressure of ≥140 mm Hg and/or the use of antihypertensive medication. Total serum cholesterol and high-density lipoprotein cholesterol were measured in nonfasting blood with an automated enzymatic procedure. Diabetes mellitus was defined as a nonfasting or postload serum glucose level ≥11.1 mmol/L and/or the use of glucose-lowering medication. Serum C-reactive protein levels were determined by the Rate Near Infrared Particle Immunoassay method (Immage high sensitive CRP; Beckman Coulter). Smoking behavior, medication use, and alcohol consumption were assessed as part of the interview.17 Atherosclerotic plaques were visualized with ultrasonography at 3 sites (common carotid artery, bifurcation, and internal carotid artery, both left and right).18 Participants were genotyped for the complement factor H (CFH) Y402H polymorphism in genomic DNA with an allelic discrimination assay (TaqMan; Applied Biosystems, Foster City, CA).19 Apolipoprotein E (APOE) genotype was determined on DNA samples using a polymerase chain reaction followed by enzymatic digestion.20
We calculated the hazard ratio and 95% CI of the risk of stroke in AMD cases using a Cox regression model with AMD stage as a time-dependent exposure variable. Stage 0 (no AMD) was defined as the reference category. We also determined the risk of stroke associated with dry AMD and wet AMD relative to no AMD. All analyses were adjusted for age and sex (Model 1) and for the following potential confounders: diabetes, systolic blood pressure, antihypertensive medication, current smoking, total cholesterol, high-density lipoprotein cholesterol, carotid artery plaques, body mass index, alcohol intake and C-reactive protein (Model 2), APOE (model 3), and CFH (Model 4). To examine the presence of effect modification by APOE or CFH, we performed analyses according to strata of APOE and strata of CFH and by entering interaction terms into the models. Missing values in covariates were imputed with a linear regression model based on age and sex.
During 69 152 person-years of follow-up (median, 13.6 years), 726 participants developed a stroke, which was classified in 397 as cerebral infarction, in 59 as intracerebral hemorrhage, and in 270 as unspecified. Baseline characteristics of the study population are shown in Table 1. At baseline, the median age was 67.6 years, and 59.6% of the participants were women.
Table 2 shows the associations between successive AMD stages and risk of any stroke, cerebral infarction, and intracerebral hemorrhage. There was no association between early AMD (Stage 1 to 3) and any stroke. Late AMD (Stage 4) was associated with an increased risk of any stroke independent of potential confounders. We found a strong association between Stage 4 AMD and intracerebral hemorrhage be it that the numbers were small and the 95% CI large. The association between AMD and intracerebral hemorrhage was only slightly attenuated after adjustment for known stroke risk factors (Model 2) and remained significant after adjustment for APOE (hazard ratio, 7.05; 95% CI, 2.68 to 18.57) and CFH (9.46; 95% CI, 3.56 to 26.11). In contrast, AMD was not associated with risk of cerebral infarction.
In Table 3, we present the associations between dry AMD and wet AMD and the risk of stroke and its subtypes. Both dry and wet AMD were associated with intracerebral hemorrhage. Neither dry nor wet AMD was associated with cerebral infarction.
The association between late AMD and any stroke was not modified by APOE or CFH. However, because of relatively small numbers of intracerebral hemorrhage, no reliable analyses on the presence of effect modification by APOE or CFH in this subgroup were feasible.
In this prospective population-based cohort study among elderly people, we found that persons with late AMD had a higher risk of stroke than persons without AMD. Dividing stroke into its subtypes cerebral infarction and intracerebral hemorrhage revealed that late AMD was strongly associated with intracerebral hemorrhage but not with cerebral infarction. Early AMD was not associated with the risk of stroke or any of its subtypes.
There are 2 explanations for the lack of a gradual relationship between AMD stage and intracerebral hemorrhage. First of all, there seems to be a threshold, that is, AMD seems only associated with intracerebral hemorrhage once it has progressed to an advanced stage. This suggests that there might be a shared underlying process that leads to progression of early to late AMD as well as to intracerebral hemorrhage. Second, we performed time-varying analyses in which we took into account not only prevalent AMD stage, but also incident AMD and progression of AMD over time. If we had limited the analyses to prevalent AMD, we probably would have found a more gradual relationship between AMD stage and intracerebral hemorrhage. However, using time-varying analysis, we were able to detect that, besides persons who had late AMD at baseline, only persons with early AMD at baseline who progressed to late AMD during follow-up had an increased risk of intracerebral hemorrhage.
Recently, several population-based studies have reported on the association between AMD and stroke or stroke-related mortality. The Atherosclerosis Risk in Communities Study found early AMD to be associated with stroke in middle-aged people (aged 49 to 73 years).11 In contrast, the Cardiovascular Health Study reported that neither early nor late AMD increased the risk of stroke in elderly people (aged 69 to 97 years).9 The Blue Mountains Eye Study found that early and late AMD were not associated with stroke mortality,10 whereas a study from Taiwan found that neovascular AMD increased the risk of stroke-related death.7 Only 1 study divided stroke into subtypes and found that the risks of both cerebral infarction and intracerebral hemorrhage were increased in people with either neovascular or nonneovascular AMD.8 However, a limitation of the study was that the classification of stroke and AMD were both based on medical reimbursement claims and therefore vulnerable to misclassification. Because the studies conducted so far were heterogeneous with respect to exposure categories and outcome definitions, results are not easily comparable. In addition to these earlier studies, we aimed to study the whole spectrum of AMD abnormalities in relation to stroke and particularly to distinguish intracerebral hemorrhage from cerebral infarction.
We found that late AMD was associated with an increased risk of intracerebral hemorrhage independent of stroke risk factors, APOE genotype, and CFH genotype. The mechanism underlying this association is unknown. Although we cannot exclude a causal role of AMD in the development of intracerebral hemorrhage, a common underlying causal pathway seems more likely. Several mechanisms for the association between AMD and stroke have been proposed, 1 of which is atherosclerosis.21 The Rotterdam Study previously reported that subclinical manifestations of atherosclerosis, that is, carotid artery plaques and intima-media thickness, are associated with AMD.5,6 However, our finding that AMD is associated with intracerebral hemorrhage rather than cerebral infarction indicates that atherosclerosis is probably not a major link between AMD and stroke. Also, adjustment for the presence of carotid artery plaques and other measures of atherosclerosis did not influence our findings.
Another common underlying mechanism that has been proposed is inflammation. Recent studies have shown that the complement system plays an important role in the development of AMD, emphasizing an inflammatory pathogenesis of AMD.22,23 The role of inflammation in intracerebral hemorrhage is unclear. Inflammation and complement activation contribute to the development of secondary brain injury after intracerebral hemorrhage,24 but there is no evidence for their contribution to the onset of intracerebral hemorrhage.25 In the present study, the association between AMD and intracerebral hemorrhage remained unchanged after adjustment for C-reactive protein levels or CFH, suggesting that inflammation and complement activation are less likely to explain the association. Nevertheless, we cannot rule out the possibility of other inflammatory proteins or complement components being involved in a common pathway.
Polymorphisms of the APOE gene affect both AMD and stroke and have also been suggested as a common mechanism. Carriers of the APOE ϵ2 allele are at a slightly increased risk of developing AMD, whereas the ϵ4 allele appears to be protective.26 Regarding stroke, the APOE ϵ2 allele seems to be associated with intracerebral hemorrhage and the ϵ4 allele with cerebral infarction.27 In the current study, however, late AMD was associated with intracerebral hemorrhage independently of APOE genotype.
Although the possibility of residual confounding cannot be excluded, our findings suggest that the association between AMD and intracerebral hemorrhage is largely independent of atherosclerosis, inflammation, complement activation, and APOE. Therefore, it seems most likely that the association is due to determinants that we did not measure in our study.
The strengths of this study are the prospective and population-based design, the large number of participants, and the long duration of follow-up. Thorough stroke monitoring procedures and the nearly complete follow-up (loss of potential person-years only 3.8%) allowed us to identify virtually all incident stroke events, even in participants who had not been admitted to a hospital, for example, people living in nursing homes or participants who had a fatal stroke. However, an implication of this approach was that neuroimaging was often lacking; hence, 36% of strokes could not be classified as intracerebral hemorrhage or cerebral infarction. Another advantage of this study was that we were able to use detailed data on AMD abnormalities at 4 time points (at baseline and follow-up visits), which increased the power of our study. However, because the numbers of late AMD cases and intracerebral hemorrhages in our study were limited, analyses were based on small numbers of events. Therefore, our findings require replication in other cohorts.
In conclusion, in this large prospective population-based cohort study among elderly people, we found a strong association between late AMD and risk of intracerebral hemorrhage. In contrast, AMD was not associated with the risk of cerebral infarction. The mechanism of the association is yet unknown and needs further investigation.
Sources of Funding
The Rotterdam Study is supported by the Erasmus Medical Center Rotterdam, the Erasmus University Rotterdam, The Netherlands Organization for Scientific Research (NWO), The Netherlands Organization for Health Research and Development (ZonMW), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. This study was supported by grants from the following institutions: Stichting Lijf en Leven, Krimpen aan de Lek; MD Fonds, Utrecht; Rotterdamse Vereniging Blindenbelangen, Rotterdam; Stichting Oogfonds Nederland, Utrecht; Blindenpenning, Amsterdam; Blindenhulp, The Hague; Algemene Nederlandse Vereniging ter Voorkoming van Blindheid, Doorn; Landelijke Stichting voor Blinden en Slechtzienden, Utrecht; Swart van Essen, Rotterdam; Stichting Winckel-Sweep, Utrecht; Henkes Stichting, Rotterdam; Laméris Ootech BV, Nieuwegein; Medical Workshop, de Meern; and Topcon Europe BV, Capelle aan de IJssel, all in the Netherlands. The sponsors or funding organizations had no role in the design, conduct, analysis or publication of this research.
The contributions of inhabitants, general practitioners, and pharmacists of the Ommoord district to the Rotterdam Study are gratefully acknowledged.
- Received February 4, 2011.
- Revision received February 25, 2011.
- Accepted March 8, 2011.
- © 2011 American Heart Association, Inc.
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