Age-related Maculopathy Lesions Research Articles

CFH Y402H and ARMS2 A69S Polymorphisms and Oral Supplementation with Docosahexaenoic Acid in Neovascular Age-Related Macular Degeneration Patients: The NAT2 Study.

PurposeGenetic susceptibility could be modified by environmental factors and may also influence differential responses to treatments for age-related macular degeneration (AMD). We investigated whether genotype could influence response to docosahexaenoic acid (DHA)-supplementation in the occurrence of choroidal new vessels (CNV).MethodsThe Nutritional AMD Treatment 2 (NAT2) study was a randomized, placebo-controlled, double-blind, parallel, comparative study, including 250 patients aged 55 to 85 years with early lesions of age-related maculopathy, visual acuity better than 0.4 Logarithm of Minimum Angle of Resolution units in the study eye and neovascular AMD in the fellow eye. Patients were randomized at baseline to receive either 3 daily fish-oil capsules, each containing 280 mg DHA, 90 mg EPA and 2 mg Vitamin E, or placebo.ResultsPatients carrying the risk allele (C) for CFH Y402H had no statistically significant increased risk for developing CNV in the study eye (Hazard Ratio (HR)=0.97; 95% Confidence Interval (CI): 0.54-1.76 for heterozygous and HR=1.29; 95%CI: 0.69-2.40 for homozygous). Patients carrying the risk allele (T) for ARMS2 A69S had no statistically significant increased risk for developing CNV in the study eye (HR=1.68; 95%CI: 0.91-3.12) for heterozygous and HR=1.78; 95%CI: 0.90-3.52 for homozygous). A significant interaction was observed between CFH Y402H and DHA-supplementation (p=0.01). We showed a protective effect of DHA-supplementation among homozygous non-risk patients. Among these patients, occurrence of CNV was 38.2% in placebo group versus 16.7% in DHA group (p=0.008).ConclusionsThese results suggest that a genetic predisposition to AMD conferred by the CFH Y402H variant limits the benefit provided by DHA supplementation.Trial RegistrationISRCTN registry 98246501

Oral Docosahexaenoic Acid in the Prevention of Exudative Age-Related Macular Degeneration: The Nutritional AMD Treatment 2 Study

To evaluate the efficacy of docosahexaenoic acid (DHA)-enriched oral supplementation in preventing exudative age-related macular degeneration (AMD). The Nutritional AMD Treatment 2 study was a randomized, placebo-controlled, double-blind, parallel, comparative study. Two hundred sixty-three patients 55 years of age or older and younger than 85 years with early lesions of age-related maculopathy and visual acuity better than 0.4 logarithm of minimum angle of resolution units in the study eye and neovascular AMD in the fellow eye. Patients were assigned randomly to receive either 840 mg/day DHA and 270 mg/day eicosapentaenoic acid (EPA) from fish oil capsules or the placebo (olive oil capsules) for 3 years. The primary outcome measure was time to occurrence of choroidal neovascularization (CNV) in the study eye. Secondary outcome measures in the study eye were: incidence of CNV developing in patients, changes in visual acuity, occurrence and progression of drusen, and changes in EPA plus DHA level in red blood cell membrane (RBCM). Time to occurrence and incidence of CNV in the study eye were not significantly different between the DHA group (19.5±10.9 months and 28.4%, respectively) and the placebo group (18.7±10.6 months and 25.6%, respectively). In the DHA group, EPA plus DHA levels increased significantly in RBCM (+70%; P<0.001), suggesting that DHA easily penetrated cells, but this occurred unexpectedly also in the placebo group (+9%; P = 0.007). In the DHA-allocated group, patients steadily achieving the highest tertile of EPA plus DHA levels in RBCM had significantly lower risk (-68%; P = 0.047; hazard ratio, 0.32; 95% confidence interval, 0.10-0.99) of CNV developing over 3 years. No marked changes from baseline in best-corrected visual acuity, drusen progression, or geographic atrophy in the study eye were observed throughout the study in either group. In patients with unilateral exudative AMD, 3 years of oral DHA-enriched supplementation had the same effect on CNV incidence in the second eye as did the placebo. However, RBCM fatty acid measurements revealed that CNV incidence was significantly reduced in DHA-supplemented patients showing a steadily high EPA plus DHA index over 3 years. Proprietary or commercial disclosure may be found after the references.

Mitochondrial DNA Haplogroups and Age-Related Maculopathy

To investigate whether mitochondrial haplogroups are associated with age-related maculopathy (ARM). We assessed the association between mitochondrial haplogroups and ARM in a population-based sample of 3509 persons aged 49 years or older residing west of Sydney. Retinal photographs of both eyes were taken (1999-2001) and subsequently graded for ARM following the Wisconsin grading system. Genetic analysis for mitochondrial DNA haplogroups was performed. Associations between these genetic markers and risk factors for ARM were assessed. After adjusting for age, sex, and smoking, haplogroup H was associated with a reduced prevalence of any (early and late) ARM (odds ratio [OR], 0.75; 95% confidence interval [CI], 0.58-0.97), early ARM (OR, 0.75; 95% CI, 0.57-0.98), and large distinct and indistinct soft drusen (OR, 0.70; 95% CI, 0.56-0.89). Haplogroup J was associated with a higher prevalence of large, soft distinct drusen (OR, 1.80; 95% CI, 1.18-2.73). Haplogroup U was associated with an increased prevalence of retinal pigment abnormalities (OR, 1.45; 95% CI, 1.11-1.91). Our findings of associations between different haplogroup types and prevalent ARM or ARM lesions suggest that these haplogroups may be genetic markers indicative of an individual's susceptibility to ARM.

Circulating Inflammatory Markers and Hemostatic Factors in Age-Related Maculopathy: A Population-Based Case–Control Study

To examine the relationship between circulating inflammatory markers, hemostatic factors, and age-related maculopathy (ARM). A population-based, cross-sectional case-control study drawn from the Blue Mountains Eye Study included 159 early and 38 late ARM cases, and 433 controls matched for age, gender, and smoking. ARM lesions were assessed from retinal photographs according to the Wisconsin ARM grading system. Circulating inflammatory markers (high-sensitivity C-reactive protein [hsCRP], intercellular adhesion molecule [ICAM]-1, and interleukin [IL]-6), white cell count (WCC), and hemostatic factors (fibrinogen, homocysteine, plasminogen activator inhibitor [PAI]-1 and von Willebrand factor [vWF]) were assessed. Age, gender, current smoking, body mass index, hypertension, history of stroke, and cardiovascular events were adjusted for. Adjusted mean levels of each marker were compared between persons with early ARM, those with late ARM, and control subjects, and are presented as probabilities. Adjusted associations with ARM were examined continuously (per SD), and are presented as odds ratios (ORs) and 95% confidence intervals (CIs). Summarizing z scores for inflammation and hemostatic dysfunction were calculated. Increased PAI-1 level was associated with both early (OR 1.2, 95% CI 1.0-1.4 per SD increase) and late ARM (OR 1.3, 95% CI 0.9-1.9 per SD increase). Elevated ICAM-1 level was marginally associated with late ARM (OR 1.3, 95% CI 1.0-1.7 per SD increase). No other significant associations were found between the remaining inflammatory or hemostatic markers and either early or late ARM. Summarized z scores for inflammatory or hemostatic markers also did not suggest any associations. There was no consistent pattern of association found between ARM and circulating inflammatory markers or hemostatic factors in this population-based case-control study.

Intake of Zinc and Antioxidant Micronutrients and Early Age-Related Maculopathy Lesions

Background: Macular degeneration, the end stage of age-related maculopathy (ARM), is the leading cause of legal blindness worldwide, and few modifiable risk factors are known. The high concentration of carotenoids in the macula, plus evidence linking oxidative stress to ARM and carotenoids to antioxidation, generated the hypothesis that higher antioxidant intakes can prevent ARM. Results of observational and intervention studies have been inconsistent. Objective: To evaluate associations between intakes of zinc and antioxidant micronutrients and early ARM. Methods: Between 1993 and 1995, ARM was assessed in 398 Boston-area women aged 53–74 y using the Wisconsin Age-related Maculopathy System of grading retinal fundus photographs. The women were a subset of the Nurses' Health Study cohort. Micronutrient intake was assessed by semi-quantitative food frequency questionnaires administered four times between 1980 and the baseline eye examinations. Results: After multivariate adjustment for potential confounders, 1980 energy-adjusted intakes of alpha-carotene, beta-carotene, lycopene, total retinol, total vitamin A, and total vitamin E were significantly inversely related to the prevalence of pigmentary abnormalities (PA). Furthermore, increasing frequency of consuming foods high in alpha-or beta-carotene was associated with lower odds of PA; compared to women consuming these foods < 5 times/wk, odds ratios (95% CI) were 0.7 (0.3–1.6) for 5–6 times/wk, 0.6 (0.2–1.3) for 7–9.5 times/wk, and 0.3 (0.1–0.7)for ≥10 times/wk. Lutein/zeaxanthin intakes and more recent intakes of most carotenoids were unrelated to PA, and intakes of zinc and antioxidant micronutrients were unrelated to having large or intermediate drusen alone.

Ten-Year Incidence and Progression of Age-Related Maculopathy: The Blue Mountains Eye Study

To assess the 10-year incidence of age-related maculopathy (ARM) in an older Australian cohort. Population-based cohort study. Three thousand six hundred fifty-four Blue Mountains Eye Study participants > or =49 years old were examined during 1992 through 1994; 2335 (75% of survivors) were reexamined after 5 years (1997-1999) and 1952 (76% of survivors) after 10 years (2002-2004). The same graders performed retinal photographic grading in all examinations, using the Wisconsin Age-Related Maculopathy Grading System. Photographs of participants with ARM lesions at any of the examinations were subsequently regraded using a side-by-side comparison method. The diagnosis of incident late ARM was given if neovascular ARM or geographic atrophy was detected at either follow-up examination in persons free of these lesions at baseline. Incident early ARM was diagnosed if early ARM (soft indistinct or reticular drusen or combined soft distinct drusen and retinal pigment abnormality) was present in persons free of early and late ARM at baseline. Age-related maculopathy incidence was calculated using Kaplan-Meier methods to incorporate information from both 5- and 10-year examinations. Discrete logistic models were used to assess the risk of incident late ARM according to various baseline factors, including early ARM lesion characteristics. After excluding 72 late ARM cases present at baseline, 2395 of 3582 subjects at risk of late ARM (67%) were reexamined at either follow-up time point or both follow-up time points. Over the 10-year period, 72 of 2395 subjects (3.7%) developed late ARM and 266 of 2255 subjects (14.1%) developed early ARM. After age standardization to the Beaver Dam Eye Study population, our 10-year incidences of late and early ARM were 2.8% and 10.8%, respectively. Baseline age and early ARM lesion characteristics and severity were strong predictors of late ARM incidence. Long-term follow-up of this older population confirms that the risk of ARM progression is related strongly to the severity of early-stage lesions. The study provides evidence-based criteria for identifying persons at high risk of developing late ARM.

Cataract Surgery and the 10-Year Incidence of Age-Related Maculopathy: The Blue Mountains Eye Study

To assess the long-term (10-year) risk of late age-related maculopathy (ARM) in eyes that had previously undergone cataract surgery (before the baseline examination). Population-based cohort study. In the Blue Mountains Eye Study (BMES) cohort, 2335 of 3654 baseline participants > or =49 years old (75% of survivors) were reexamined after 5 years and 1952 (76% of survivors) were reexamined after 10 years. At the baseline examination, nonphakic (aphakic or pseudophakic) eyes were identified at slit-lamp examination and confirmed at lens photographic grading. Side-by-side grading of baseline and follow-up stereoretinal photographs was performed using the Wisconsin ARM grading system. Eye-specific data were analyzed using Kaplan-Meier estimates and generalized estimating equation models, adjusting for correlation between the 2 eyes. Incident late ARM was defined if either neovascular ARM or geographic atrophy developed in eyes without either lesion at baseline. After excluding eyes with either late ARM lesion at baseline or that had missing photographs at either examination, 4763 eyes were considered at risk of incident late ARM, including 132 eyes that had cataract surgery before the baseline examination. Late ARM developed in 10 of 132 nonphakic eyes (7.6%) compared to 96 of 4631 phakic eyes (2.1%). After adjusting for baseline age, gender, smoking, and presence of early ARM lesions, nonphakic (cataract surgical) eyes had a 3-fold risk of developing late-stage ARM (odds ratio [OR], 3.3; 95% confidence interval [CI], 1.1-9.9) or neovascular ARM (OR, 3.4; 95% CI, 1.1-10.9) compared to phakic eyes. Our findings support the hypothesis that the long-term risk of developing late ARM is higher in cataract surgical eyes, consistent with findings from the Beaver Dam Eye Study.

Cataract surgery in patients with age‐related maculopathy: preoperative diagnosis and postoperative visual acuity

To report the reliability in detecting age-related maculopathy (ARM) lesions before cataract surgery and postoperative visual acuity (VA) in cataract surgery patients with ARM. Medical records of surgical patients in a large public hospital, west of Sydney, were reviewed retrospectively. Detection of ARM lesions was compared before and after surgery to determine sensitivity and specificity of preoperative diagnoses. Postoperative VA was assessed 4 weeks after surgery. Data were available for 721/784 eyes (92.0%) of 656 patients aged 60 years or older. ARM lesions were detected in 98 eyes (13.6%) before and 92 eyes (12.8%) after surgery. Sensitivities for detecting late ARM lesions, soft drusen and retinal pigment epithelium abnormalities preoperatively were 100%, 94% and 69%, respectively. Corresponding specificities were 100%, 100% and 77%, respectively. Postoperative VA achieved or remained 6/12 or better in 81.6% of eyes. A high sensitivity and specificity in detecting late ARM lesions and soft drusen preoperatively, and a good postoperative VA outcome is achievable in patients with preoperative early ARM lesions.

Risk factors for age‐related maculopathy in a 14‐year follow‐up study: the Copenhagen City Eye Study

To examine the association between potential risk factors and the 14-year incidence of age-related maculopathy (ARM). Population-based cohort study. At baseline, 946 volunteers participated in the study during 1986--88. These subjects were between 60 and 80 years of age and lived in the Østerbro district of Copenhagen. Excluding participants who had died since baseline, 359 subjects (97.3% of survivors) were re-examined 14 years later, during 2000--2002. A total of 31.8% (301/946) of the original material was included in the risk factor analyses. Participants underwent an ophthalmological examination at Rigshospitalet, the National University Hospital of Copenhagen. Similar standardized protocols for physical examination were used at the baseline and follow-up examinations. Age-related maculopathy lesions were determined by the same grader grading colour fundus photographs from both examinations using a modification of the Wisconsin Age-related Maculopathy Grading System protocol. Of the 359 participants, 94 had incident early ARM and 52 had incident late ARM at follow-up in either eye. In logistic regression, the risk factors for early ARM or worse were as follows: cataract (odds ratio [OR] 2.8, 95% confidence interval [CI] 1.2-6.2); family history of ARM (OR 4.5, 95% CI 1.3--15.5), and alcohol consumption >250 g/week (OR 4.6, 95% CI 1.1-19.2). High levels of apolipoprotein B (>100 mg/l) decreased the risk of development of early ARM or worse (OR 0.4, 95% CI 0.2-0.8), while high levels of apolipoprotein A1 (>or= 150 mg/l) increased the risk of late ARM (OR 2.5, 95% CI 1.2-5.3). Advanced age at baseline was also associated with the incidence of late ARM (OR 2.0, 95% CI 1.4-2.9). These findings indicate a direct correlation between age, cataract, family history, alcohol consumption, the apolipoproteins A1 and B and the 14-year incidence of ARM.

Esterified and unesterified cholesterol in drusen and basal deposits of eyes with age-related maculopathy

To address the potential for an outer segment (OS) contribution to the sub-retinal pigment epithelium (RPE) lesions of age-related maculopathy (ARM), we quantified esterified and unesterified cholesterol (EC, UC) with the sterol-specific fluorescent probe filipin in cryosections of ARM eyes. Twenty six eyes from 20 donors were preserved <5 hr after death in 4% paraformaldehyde ( n=16) or 2.5% glutaraldehyde/1% paraformaldehyde ( n=10). Eyes had exudative late ARM ( n=6), geographic atrophy ( n=15), and drusen ≥125 μm ( n=11). Sections were stained with filipin for UC or were extracted and hydrolysed with cholesterol esterase before filipin staining for EC. Drusen varied in cholesterol content, with a rough correlation between EC and UC. Dome-shaped drusen contained distinctive, loosely packed UC-rich loops. In basal deposits, EC and UC were more prominent near Bruch's membrane than near the RPE. A UC-rich material was localized within the subretinal space ( n=4). Maximum filipin fluorescence due to UC was quantified in 47 lesions (19 drusen, 24 basal deposits, and 4 sub-retinal) from 12 ARM eyes and compared to OS and inner plexiform layer (IPL) of uninvolved retina in the same sections. Relative to IPL, UC fluorescence was higher in lesions (mean± s. d: 1.63±0.69) and lower in OS (0.64±0.18). If only the packing of membranes explained fluorescence intensity, then one would expect much higher intensities in membrane-rich OS than in lesions. Because the converse is true, the membranous material in lesions must be more highly enriched in cholesterol on a per unit area basis. UC in sub-RPE deposits cannot be derived directly from OS without considerable intracellular processing within RPE, additional cholesterol sources, or both.

Retina expresses microsomal triglyceride transfer protein: implications for age-related maculopathy

The principal extracellular lesions of age-related maculopathy (ARM), the leading cause of vision loss in the elderly, involve Bruch's membrane (BrM), a thin vascular intima between the retinal pigment epithelium (RPE) and its blood supply. With age, 80-100 nm solid particles containing esterified cholesterol (EC) accumulate in normal BrM, and apolipoprotein B (apoB) immunoreactivity is detectable in BrM- and ARM-associated lesions. Yet little evidence indicates that increased plasma cholesterol is a risk factor for ARM. To determine if RPE is capable of assembling its own apoB-containing lipoprotein, we examined RPE for the expression of microsomal triglyceride transfer protein (MTP), which is required for this process. Consistent with previous evidence for apoB expression, MTP is expressed in RPE, the ARPE-19 cell line, and, unexpectedly, retinal ganglion cells, which are neurons of the central nervous system. De novo synthesis and secretion of neutral lipid by ARPE-19 was supported by high levels of radiolabeled EC and triglyceride in medium after supplementation with oleate. Lipoprotein assembly and secretion is implicated as a constitutive retinal function and a plausible candidate mechanism involved in forming extracellular cholesterol-containing lesions in ARM. The pigmentary retinopathy and neuropathy of abetalipoproteinemia (Mendelian Inheritance of Man 200100; Bassen-Kornzwieg disease), which is caused by mutations in the MTP gene, may involve loss of function at the retina.

Basal deposits and drusen in eyes with age-related maculopathy: evidence for solid lipid particles

Neutral lipid, including esterified cholesterol, and apolipoproteins B and E are abundant in basal deposits and drusen of aged and age-related maculopathy (ARM) eyes. The principal component of basal linear deposit (BlinD), a specific ARM lesion, is membranous debris, which if actually derived from membranes cannot account for extracellular neutral lipid. We therefore used a lipid-preserving ultrastructural method to obtain improved images of membranous debris. Maculas from 44 human donors (71–96 yr) were preserved <7·5 hr after death. Blocks were post-fixed in 2% osmium or osmium-tannic acid-paraphenylenediamine (OTAP) to preserve neutral lipid for thin-section transmission electron microscopic (TEM) examination. Solid particles identified by OTAP were considered closest to the in vivo state of extracellular lipids. Micrographs were examined for intermediate forms, with greatest weight given to comparable images from different preparations of same or fellow eyes. Twenty eyes of older adults (12 with ARM including fellows treated with photodynamic and radiation therapies) had adequately preserved extracellular lipid. The exterior surface of membranous debris was thicker and more electron-dense than basal infoldings of retinal pigment epithelium (RPE) cells. By OTAP, individual membranous debris profiles were solid (diameters, 80–200 nm) and formed tracks across or aggregations within basal laminar deposits. Solid particles and/or pools of neutral lipid were visible in BlinD and drusen. When processed to preserve lipid, membranous debris resembles neither membranes of surrounding cells nor vesicles possessing aqueous interiors but rather solid particles. These results are consistent with recent evidence implicating lipoprotein particles of intra-ocular origin as a potential source of neutral lipids, including esterified cholesterol, in the specific lesions of ARM.

14-Year Incidence, Progression, and Visual Morbidity of Age-Related Maculopathy: The Copenhagen City Eye Study

To describe the 14-year incidence of age-related maculopathy (ARM) lesions and the related visual loss. Population-based cohort study. Nine hundred forty-six residents (age range, 60-80 years) of Copenhagen participated in the study from 1986 through 1988. Excluding participants who had died since baseline, 359 persons (97.3% of survivors) were reexamined from 2000 through 2002. Participants underwent extensive ophthalmologic examinations. Age-related maculopathy lesions were determined by grading color fundus photographs from the examinations using a modified Wisconsin Age-Related Maculopathy Grading System. Incidence of drusen type and size, pigmentary abnormalities, pure geographic atrophy, exudative ARM, visual impairment, and blindness. The 14-year incidences of early and late ARM were 31.5% and 14.8%, respectively. Individuals 75 to 80 years of age at baseline had significantly (P< or =0.05) higher 14-year incidences of the following lesions than those aged 60 to 64 years: medium or large drusen (> or =125 microm; 34.2% vs. 12.8%, respectively), soft drusen (45.2% vs. 21.4%), pigmentary abnormalities (31.4% vs. 17.0%), pure geographic atrophy (17.4% vs. 1.0%), and exudative ARM (23.3% vs. 5.7%). Severe drusen type, large drusen, and retinal pigmentary abnormalities at baseline were important predictors of incident late ARM. The 14-year incidences of visual impairment (<20/40 but >20/200) or legal blindness from late ARM were 6.0% and 3.4%, respectively. Late ARM caused 35.7% of all visual impairment and 66.7% of all blindness. There is a high incidence of ARM lesions in this elderly white population. Severe drusen type and size or a combination of drusen and pigmentary abnormalities significantly increases the risk of developing late ARM, the most frequent cause of legal blindness in this population.

Location of lesions associated with age-related maculopathy over a 10-year period: the Beaver Dam Eye Study.

To describe cumulative incidence and changes in retinal lesions associated with age-related maculopathy (ARM) by location over a 10-year period and to examine the relation of location of those lesions to progression of ARM. Persons ranging in age from 43 to 84 years and living in Beaver Dam, Wisconsin, at the time of a census (1987-1988) were examined two to three times over a 10-year period (n = 3684). Drusen area, size, and type; retinal pigment epithelium depigmentation; increased pigment; geographic atrophy; and neovascular macular degeneration were determined in each of nine macular subfields: central, inner and outer superior, inner and outer nasal, inner and outer inferior, and inner and outer temporal by grading of stereoscopic color fundus photographs. Late ARM was defined as presence of either geographic atrophy or neovascular ARM. Lesions were more likely to change or develop in specific locations. Drusen area increased most in the central circle. Compared with other quadrants, drusen greater than 125 micro m in diameter and soft indistinct or reticular drusen were most likely to develop in the superior or temporal quadrants, whereas pigmentary abnormalities were most likely to occur in the nasal or superior quadrants. In general, large drusen, soft indistinct drusen, and pigmentary abnormalities were more likely to develop in the inner circle versus the central and outer circles. The quadrant location of early ARM lesions in 72 persons in whom late ARM developed was generally similar to that in persons who did not have late ARM. However, persons who had geographic atrophy were more likely to have large drusen in the inner circle than in the outer circle, while those who did not have late ARM were more likely to have large drusen in the outer circle. Lesions associated with early ARM were more likely to develop in specific locations in the macular area, and persons with lesions closer to the fovea may be related to a higher risk of development of late ARM. The quadrant location of early ARM lesions does not appear to add additional information to the risk of development of late ARM.

Five-year incidence of age-related maculopathy: The Visual Impairment Project

Purpose To describe the 5-year incidence of age-related maculopathy (ARM) and the progression of the early stages of ARM lesions in Melbourne, Australia. Design Population-based cohort study. Participants A total of 3271 participants aged 40 years and older from Melbourne, Victoria, Australia. Main outcome measures The 5-year incidence and progression of ARM lesions. Methods Participants were recruited through a cluster random sampling from 9 urban clusters. Baseline examinations were conducted from 1992 through 1994, and the follow-up data were collected from 1997 through 1999. Presence of ARM lesions was graded from color stereo fundus photographs according to the International Classification and Grading System. Results The overall cumulative 5-year incidence of age-related macular degeneration (AMD) was 0.49% (95% confidence interval [CI], 0.2–0.8) and that of early ARM was 17.3% (95% CI, 8.7–26.0). The incidence of all ARM lesions increased with age (all P<0.001). The 5-year incidence of AMD was 0%, 0.69%, 1.7%, and 6.3% and that of early ARM was 13%, 22.7%, 29.8%, and 20% for participants aged 60 years and younger, aged 60 to 69 years, aged 70 to 79 years, and aged 80 years and older at baseline, respectively. People with soft indistinct drusen with pigmentary abnormalities had a 9.5 times (95% CI, 1.9–45.6) higher risk of developing AMD compared with people with soft drusen or pigmentary abnormalities. After adjusting for age, people with unilateral early ARM at baseline were 3 times (95% CI, 0.98–8.0) as likely to have early ARM in their second eye when compared with people with no ARM in both eyes. Conclusions These data suggest that 1 in 3 persons aged 70 years or older will have ARM lesions over a 5-year period and that the disease will progress to a more severe form after the age of 80 years. The presence of soft indistinct drusen with pigmentary abnormalities significantly increased the risk for development of AMD.

Cataract surgery and the 5-year incidence of late-stage age-related maculopathy: Pooled findings from the Beaver Dam and Blue Mountains eye studie

Purpose To assess whether cataract surgery in older persons increases risk for the development of late-stage age-related maculopathy (ARM). Design Combined analysis of longitudinal data from two population-based cohorts, the Beaver Dam Eye Study and Blue Mountains Eye Study. Participants The Beaver Dam Eye Study examined 4926 persons aged 43 years or older at baseline and re-examined 3684 after 5 years. The Blue Mountains Eye Study examined 3654 persons aged 49 years or older at baseline and re-examined 2335 after 5 years. Methods The two studies used similar protocols for retinal photography and photographic grading. We defined incident late-stage ARM as the development of neovascular ARM or geographic atrophy in eyes without either lesion type at baseline that was confirmed by consensus between the study investigators. Nonphakic eyes included eyes that were aphakic or pseudophakic at baseline. Eye-specific data were analyzed. Age- and study site–adjusted relative risks were calculated using the Cochran-Mantel-Haenszel method. Multivariate-adjusted odds ratios (ORs) were also estimated using generalized estimating equation models. Results Of the 6019 participants examined after 5 years, 11,391 eyes were considered at risk for developing late-stage ARM, including 315 nonphakic and 11,076 phakic eyes. Late-state ARM (either neovascular ARM or geographic atrophy) developed in 6.0% to 7.5% of nonphakic eyes (10 of 168 right and 11 of 147 left eyes), compared with 0.7% of phakic eyes (40 of 5504 right and 37 of 5572 left eyes) during the 5-year period. Age- and study site–adjusted 5-year relative risks were 2.8 (95% confidence interval [CI], 1.6–5.1) for right and 3.7 (95% CI, 2.1–6.4) for left eyes. After further adjustment for gender, smoking, and the presence of indistinct or reticular drusen or pigmentary abnormalities at baseline, nonphakic eyes had a substantially higher risk for developing either late-stage ARM lesion compared with phakic eyes, OR = 5.7 (95% CI, 2.4–13.6). Conclusions Pooled findings from these two large population-based cohorts support the hypothesis that cataract surgery in older persons may be associated with an increased subsequent risk for developing late-stage ARM, particularly neovascular ARM.

The relationship between iris color, hair color, and skin sun sensitivity and the 10-year incidence of age-related maculopathy: The Beaver Dam Eye Study

Purpose To examine the association between iris color, hair color, and skin sun sensitivity and the 10-year incidence of age-related maculopathy (ARM). Design Population-based cohort study. Participants A population of 4926 adults (range, 43–86 years of age at baseline) living in Beaver Dam, Wisconsin, was studied at baseline (1988–1990); of these, 3684 and 2764 subjects, respectively, participated in 5-year and 10-year follow-up examinations. Methods Data on hair color at age 15 years and skin responsiveness to sun exposure were obtained from a standardized questionnaire administered at the baseline examination. Iris color was determined with penlight illumination during the baseline examination by using photographic standards. Age-related maculopathy status was determined by grading stereoscopic color fundus photos with the Wisconsin Age-Related Maculopathy Grading System. Main outcome measures Incidence and progression of ARM. Results When controlling for age and gender, people with brown eyes were significantly more likely to develop soft indistinct drusen (risk ratio [RR], 1.53; 95% confidence interval [CI], 1.19–1.97; P < 0.01) than were people with blue eyes. However, people with brown eyes were significantly less likely to develop retinal pigment epithelial depigmentation (RR, 0.58; 95% CI, 0.41–0.82; P < 0.01) than were people with blue eyes. When compared with persons with blond hair, persons with brown hair were at decreased risk of developing pigmentary abnormalities (RR, 0.73; 95% CI, 0.53–1.00; P = 0.05). Iris color, hair color, and skin sun sensitivity were not associated with the development of late ARM. Conclusion Iris color and hair color were found to be associated with the 10-year incidence of pigmentary abnormalities. Iris color seems to be inconsistently related to the 10-year incidence of early ARM lesions and the progression of ARM.

Five-year incidence of age-related maculopathy in relation to iris, skin or hair colour, and skin sun sensitivity: the Blue Mountains Eye Study.

This study aimed to assess longitudinal associations between iris,hair and skin colour, plus skin sensitivity to sun and the 5-year incidence of age-related maculopathy (ARM). Of 3654 baseline Blue Mountains Eye Study participants (aged 49+ years), 2335 survivors (75.1%) were re-examined after 5 years. Retinal photographs were graded using the Wisconsin ARM Grading System and incident ARM lesions confirmed using side-by-side grading.Iris/skin/hair colour was assessed and skin sensitivity questions were asked at baseline. After adjusting for age, sex and smoking, no significant associations were found between iris or hair colour and incident late or early ARM. Compared to persons with fair skin, those with very fair skin had an increased risk of developing geographical atrophy (odds ratio [OR] 3.5,95% confidence interval [CI] 1.2-10.4).However, persons with sun-related skin damage were less likely than those without to develop indistinct soft drusen (OR 0.6, 95% CI 0.4-0.9). Longitudinal data provide no support for the previously reported cross-sectional association between iris colour and ARM.

Inter- and intra-observer variability in grading lesions of age-related maculopathy and macular degeneration.

To introduce a revised version of the grading system established by the International ARM Epidemiological Study Group for identifying and quantifying abnormalities of age-related maculopathy (ARM) and age-related degeneration (AMD) and to investigate its reliability, specifically the inter- and intra-observer variability. Fifty eyes of 25 patients with ARM or AMD in at least one eye were randomly selected from a large ongoing collection of clinical data and DNA in a tertiary referral UK population. Stereoscopic color fundus photographs were taken with a 30 degrees fundus camera and were centered on the macula. Presence and severity of fundus abnormalities in ARM and AMD were graded using a grid to define macular subfields and standard circles to define the size of lesions. Inter-observer variability was assessed by having three retinal specialists evaluate the color slides and intra-observer variability by re-grading the same set. The inter-observer agreement for all subfields was fair to substantial for small hard drusen (70-89%; kappa=0.26-0.63) and intermediate soft drusen (76-94%; kappa=0.27-0.69). Agreement ranged between 87% and 100%, between 50% and 92%, and between 78% and 100% for larger drusen, the presence of hyperpigmentation, and the presence of hypopigmentation, respectively. Agreement was moderate to almost perfect for the presence of geographic atrophy (88-98%; kappa=0.60-0.95) and substantial to almost perfect for the presence of choroidal neovascularization (84-100%; kappa=0.62-1.00). The intra-observer variability for the grading of drusen characteristics and pigmentary changes was similar in magnitude, but slightly greater for features of advanced AMD. Reproducibility was achieved using a revised version of the grading system established by the International ARM Epidemiological Study Group. This grading system may therefore be used for phenotyping of ARM and AMD.

Smoking and the 5-year incidence of age-related maculopathy: the Blue Mountains Eye Study.

To assess the relationship between baseline smoking and the 5-year incidence of late and early age-related maculopathy (ARM) in an older population cohort. The Blue Mountains Eye Study examined 3654 participants aged 49 years or older during 1992 to 1994 and then 2335 survivors (75.1%) after 5 years. Retinal photographs were graded using the Wisconsin Age-Related Maculopathy Grading System. Those with any ARM lesions at either examination were regraded in detail using a side-by-side method similar to that developed for the Beaver Dam Eye Study. We also used similar definitions for incident ARM lesions. Smoking status was recorded at interview. Age-standardized incidence rates for any late ARM lesions were 3.1%, 1.2%, and 1.4%, respectively, among baseline current, past, or never smokers. Corresponding age-standardized incidence rates for early ARM were 10.6%, 8.2%, and 9.3%, respectively. The mean age for cases with incident late ARM was 67 years for baseline current smokers, 73 years for past smokers, and 77 years for those who had never smoked (P =.02). After adjusting for age, current smokers, compared with never smokers, had an increased risk of incident geographic atrophy (age-adjusted relative risk [RR], 3.6; 95% confidence interval [CI], 1.1-11.3) and any late ARM lesions (RR, 2.5; 95% CI, 1.0-6.2). Current smokers had an increased risk of incident retinal pigmentary abnormalities (RR, 1.7; 95% CI, 1.1-2.7), with the risk higher in men (RR, 2.8; 95% CI, 1.4-5.6). Five-year incidence of early ARM, late ARM, and ARM lesions. In this cohort, persons who were current smokers had an increased risk of 5-year incident late ARM lesions and retinal pigmentary abnormalities. Current smokers developed late ARM at a significantly earlier age than never or past smokers.