Key Points
Question
What are the incidence and risk factors of reticular pseudodrusen using multimodal imaging in an elderly French population?
Findings
This cohort study found an annual incidence of reticular pseudodrusen per participant of 2.9% and an estimated 5-year incidence of 13.5%. Age, choroidal thinning, and genetic background were found to be associated with incident reticular pseudodrusen, whereas lipophilic statin therapy was associated with a lower risk.
Meaning
This study, based on reticular pseudodrusen diagnosed via multimodal imaging, reports a higher incidence of reticular pseudodrusen than in previous studies based on fundus color images, confirms most known risk factors, and suggests a role for lipid metabolism in the pathophysiologic characteristics of reticular pseudodrusen.
Abstract
Importance
Although retinal multimodal imaging is needed for diagnosing reticular pseudodrusen (RPD), the incidence of RPD in the general population typically has been assessed only using fundus photographs, which may underestimate their incidence.
Objectives
To describe the incidence of RPD using retinal color photographs, spectral-domain optical coherence tomography scans, fundus autofluorescence, and near-infrared reflectance images among individuals 77 years of age or older and to analyze the associated risk factors of RPD.
Design, Setting, and Participants
The ALIENOR (Antioxydants, Lipides Essentiels, Nutrition et Maladies Oculaires) Study is a cohort of French individuals 77 years of age or older. Data for this study were collected between February 22, 2011, and February 15, 2017, with a mean (SD) follow-up of 3.7 (1.0) years (range, 1.2-5.6 years). At baseline, 501 individuals were eligible to participate. Of 1002 eyes, 197 had prevalent RPD, advanced age-related macular degeneration, or ungradable images. Of the remaining 805 eyes, 333 were missing follow-up data; therefore, the statistical analyses included data from 472 eyes. Data management and statistical analyses were performed between March 15, 2017, and April 5, 2019.
Main Outcomes and Measures
Reticular pseudodrusen were considered as present if detected by at least 2 of the following imaging methods: color fundus photographs, fundus autofluorescence, near-infrared reflectance, and spectral-domain optical coherence tomography images.
Results
Of the 472 eyes analyzed, 263 (55.7%) were from female participants, and the mean (SD) age was 81.9 (3.2) years. Forty-three eyes developed RPD, corresponding to an annual incidence rate of 2.9% (95% CI, 1.9%-4.4%) per participant and an estimated 5-year risk of 13.5%. In multivariable analysis, 4 risk factors of incident RPD were identified: subfoveal choroidal thinning (hazard ratio [HR], 0.99; 95% CI, 0.99-1.00 per 10-μm decrease in thickness; P = .02) and the presence of the minor allelic variants rs10490924 for ARMS2 (HR, 3.57; 95% CI, 1.80-7.10; P < .001), rs1061170 for CFH (HR, 2.12; 95% CI, 1.02-4.41; P = .04), and rs10468017 for LIPC (HR, 2.57; 95% CI, 1.37-4.82; P = .003). Lipophilic statin therapy was associated with a lower incidence of RPD (HR, 0.13; 95% CI, 0.02-0.74; P = .02).
Conclusions and Relevance
With the use of multimodal imaging, the RPD incidence rate was higher than previously reported in other population-based studies using fundus color images. Individuals with subfoveal choroidal thinning or carrying minor allelic variants for ARMS2, CFH, or LIPC had an increased risk for RPD, whereas lipophilic statin therapy was associated with a lower incidence.
This cohort study describes the incidence of reticular pseudodrusen using retinal color photographs, spectral-domain optical coherence tomography scans, fundus autofluorescence, and near-infrared reflectance images among individuals 77 years of age or older and analyzes the associated risk factors.
Introduction
Age-related macular degeneration (AMD) is the third most common cause of visual impairment worldwide, and the number of people with AMD is expected to increase by approximately 40% between 2020 and 2040.1 Early AMD is clinically characterized by the presence of yellowish drusen,2 which are accumulations of extracellular material between the retinal pigment epithelium–basal lamina and the inner collagenous layer of the Bruch membrane. A specific category of drusen called reticular pseudodrusen (RPD),3 or subretinal drusenoid deposits,4 corresponds to drusen-like, granular hyperreflective material located not beneath but above the retinal pigment epithelium.5 Early identification of RPD is important because they have been shown to be a major risk factor of advanced AMD, compared with other drusen,6 with a cumulative incidence risk ranging from 33.9% to 54.5% at 5 years.7,8
The reported prevalence of RPD in population-based studies has been variable according to the different imaging tools used for RPD detection and the characteristics of the participants studied. Considering the main studies based solely on retinal photographs, RPD prevalence was estimated at 0.7% among individuals aged 43 to 86 years in the Beaver Dam Eye Study,9 0.41% in the Melbourne Collaborative Cohort Study,10 and 1.95% in the Blue Mountains Eye Study.7 In the Rotterdam Eye Study,11 RPD detection was based not only on retinal photographs but also on near-infrared reflectance (NIR) imaging, and the observed prevalence of RPD increased up to 4.9% after 65 years. The ALIENOR (Antioxydants, Lipides Essentiels, Nutrition et Maladies Oculaires) Study,12 which used multimodal imaging combining retinal photographs, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF), and NIR images for RPD detection, showed that RPD prevalence was even higher, at 13.4% after 77 years. The sensitivity of color photographs for RPD detection has been shown to vary between 29% and 88%, whereas that of NIR or SD-OCT ranges between 71% and 100%.8,12 Several studies have recommended the use of multimodal imaging (and ≥2 imaging modalities) for accurate RPD identification.12,13,14,15
The incidence of RPD was only assessed, to date, in 2 population-based studies, the Beaver Dam Eye Study and the Blue Mountains Eye Study, with the limitation of a diagnosis based only on retinal photographs,7,9,16 and these previous analyses may therefore have underestimated the incidence of RPD. In the literature, several risk factors of RPD have been identified, although some are still being debated. The main reported risk factors are increasing age, female sex, decrease in subfoveal choroidal thickness, high body mass index, low educational level, history of smoking, cardiovascular risk factors, and allelic variants of the age-related maculopathy susceptibility-2 (ARMS2; OMIM 611313) and complement factor H (CFH; OMIM 134370) genes.4,6,17 The aim of our study was thus to estimate the incidence of RPD in a population-based study of elderly French individuals using multimodal imaging and to further analyze their potential associated risk factors.
Methods
Study Participants
Participants in the ALIENOR Study were recruited from an ongoing population-based study (Three-City [3C] Study) on the vascular risk factors of dementia.18 The ALIENOR Study consists of periodic eye examinations performed on all participants of the 3C Study cohort in Bordeaux, France, since 2006.19
In the present study, we used the fifth follow-up of the 3C Study as baseline (2011-2012) because SD-OCT, FAF, and NIR imaging were systematically performed from that point forward. Of the 1235 participants of the 3C Study cohort in Bordeaux who were still alive, 759 (61.5%) participated in this eye examination (baseline). Two follow-up examinations were performed from 2013 to 2015 and from 2015 to 2017. Participants’ inclusion required a baseline examination and at least 1 gradable follow-up examination (first follow-up visit, second follow-up visit, or both). Data collection was performed from February 22, 2011, to February 15, 2017. This research followed the tenets of the Declaration of Helsinki.20 Participants provided written informed consent. The design of the ALIENOR Study was approved by the Ethical Committee of Bordeaux in May 2006.
Eye Examination
All eye examinations were performed in the Department of Ophthalmology of Bordeaux University Hospital by the same experienced technician. Examinations included the recording of ophthalmic history, a slitlamp examination, an axial length measurement, and—after pupil dilation—45° retinal photographs using a nonmydriatic fundus camera (TRC-NW6S; Topcon) and SD-OCT, FAF, and NIR imaging using a Spectralis device (software version 5.4.7.0; Heidelberg) as previously described.12,21
Retinal photographs were interpreted in duplicate by 2 specially trained technicians. Inconsistencies between the 2 interpretations were adjudicated by a senior grader (J.-F.K., M.-B.R., C. Delcourt, or M.-N.D.). All cases of advanced AMD and other retinal diseases were reviewed and confirmed by retina specialists (J.-F.K., M.-B.R., and M.-N.D.).
Spectral-domain optical coherence tomography, FAF, and NIR images were interpreted by 3 independent retina specialists (C. Dutheil, J.-F.K., and M.-N.D.) in a masked fashion. In each image series, RPD was deemed absent, present, questionable, or ungradable. In the present study, questionable abnormalities were considered as absent. Subfoveal choroidal thickness was measured manually by 1 ophthalmologist (S.G.), on 1 enhanced depth imaging horizontal optical coherence tomography B-scan crossing the fovea, as previously described.22
Multimodal Definition of RPD and Incidence
On retinal photographs, RPD were identified as yellowish interlacing networks ranging from 125 to 250 μm in width.3,23 On SD-OCT scans, they were identified as well-defined round or triangular hyperreflective deposits localized between the retinal pigment epithelium and the boundary between the inner and outer segments of photoreceptors (inner segment–outer segment boundary) and as small mounds that broke through the inner segment–outer segment boundary in more advanced stages.5 On FAF and NIR images, RPD were identified as an area of iso-autofluorescence or reflectance surrounded by halos of reduced autofluorescence or reflectance, which are associated with the “target” aspect.4 As previously described,12 RPD were defined as definite if they were classified as present with at least 2 imaging methods among photographs and FAF, NIR, and SD-OCT images. Reticular pseudodrusen were considered ungradable when they were judged ungradable by at least 3 methods. The Figure illustrates the typical aspect of RPD through multimodal imaging.
Figure. Multimodal Imaging of Reticular Pseudodrusen (RPD).
A, Color fundus photography shows a yellowish interlacing network superior to the macular area. B, Fundus autofluorescence shows a cluster of ill-defined hypofluorescent lesions. C, Using near-infrared reflectance, the lesions appear isoreflectant and are surrounded by halos of hyporeflectance, which are associated with the “target” aspect. D, On spectral-domain optical coherence tomography horizontal B-scan, different stages of RPD are observed: hyperreflective deposits between the retinal pigment epithelium and the ellipsoid zone (stage 1) or triangular deposits breaking through the ellipsoid zone (stage 3).
Incidence of RPD was defined as eyes progressing from no RPD at baseline to RPD at any point during the study period. The date of RPD occurrence was calculated as the midpoint of the interval between the last visit without RPD and the first visit with RPD. For incidence analyses and Cox proportional hazards regression modeling, follow-up ended at the date of RPD occurrence or the date of the last gradable examination. Eyes with RPD or a nongradable examination at baseline were excluded from the analysis.
AMD Classification
As previously described,21 AMD was graded according to international classifications into 5 exclusive categories: absent, early stage 1 (soft distinct drusen without pigmentary abnormalities or pigmentary abnormalities without large drusen [>125 μm]), early stage 2 (soft indistinct drusen and/or reticular drusen and/or soft distinct drusen with pigmentary abnormalities), advanced atrophic, or neovascular. Classification of advanced atrophic or neovascular AMD was based on all available information (ophthalmologic history and treatments, retinal photographs, and SD-OCT scans), as previously detailed.21,24 All cases of advanced AMD were confirmed by a retina specialist (J.-F.K., M.-B.R., and M.-N.D.).
Assessment of Risk Factors
Clinical risk factors (smoking, hypertension, diabetes, dyslipidemia, and educational level) were collected during the fifth follow-up of the 3C Study by trained psychologists or nurses (eAppendix 1 in the Supplement). Plasma lipid levels were measured from fasting blood samples collected in 2011. Genome wide-scan analysis was performed as previously described.25 Analyzed single-nucleotide variations (formerly single-nucleotide polymorphisms) are listed in eAppendix 2 in the Supplement.
Statistical Analysis
The characteristics of the eyes included in our study were compared with those excluded using logistic generalized estimating equations models.26 Incidence rate, progression rate, and 95% CIs of RPD per eye were obtained using Poisson regression models for correlated data, as previously published.21 The cumulative 5-year incidence (CI-5) was derived from the incidence rate (IR) using the following exponential formula: CI-5 = 1 − exp (−IR × 5).21,27
Associations between RPD occurrence and sociodemographic, medical, and genetic data were estimated using Cox proportional hazards regression models with delayed entry and age as the time scale. Hazard ratios (HRs) and 95% CIs for the occurrence of RPD were estimated using the individual eye as the unit of analysis, using PROC-PHREG in SAS software, version 9.4 (SAS Institute Inc) with the covariance aggregate option to take into account intraindividual correlations.28 For genetic variables, single-nucleotide variations were coded by the number of minor alleles (0, 1, and 2). First, the association with each risk factor was assessed independently using sex-adjusted models. Second, all variables associated with P < .10 were entered in the multivariable model. Sex and axial length were forced into the multivariable model because of the well-known strong association with subfoveal choroidal thickness.22,29,30 In all Cox proportional hazards regression models, the proportional hazard assumption was checked using the Schoenfeld residuals test. The log-linearity of quantitative variables was also checked. Data management and statistical analyses were performed between March 15, 2017, and April 5, 2019. Statistical analyses were performed using SAS software, version 9.4 (SAS Institute Inc). All P values were from 2-sided tests and results were deemed statistically significant at P < .05.
Results
Study Sample
Of the 759 participants at baseline, 258 were examined only at home and therefore had only visual acuity and color images available. Of the remaining 1002 eyes of the remaining 501 participants with multimodal imaging at baseline, 197 presented with prevalent RPD or advanced AMD or had ungradable images (eFigure 1 in the Supplement). Of the remaining 805 eyes, 216 had no follow-up data, 98 were examined only at home after baseline, and 19 had ungradable images. Thus, 472 eyes of 247 participants were included for RPD incidence analyses. Of these 247 participants, 241 were examined at the first follow-up visit and 153 at the second follow-up visit; 147 participants returned for all follow-up visits.
A comparison of demographic characteristics between included and nonincluded eyes of ALIENOR Study participants is summarized in Table 1. Included and nonincluded eyes differed significantly for mean (SD) participant age (81.9 [3.2] vs 84.4 [3.9] years; P < .001), mean (SD) total cholesterol level (207.8 [42.3] vs 217.2 [44.7] mg/dL [to convert to millimoles per liter, multiply by 0.0259]; P = .02), and mean low-density lipoprotein cholesterol level (128.7 [36.8] vs 135.9 [37.9] mg/dL [to convert to millimoles per liter, multiply by 0.0259]; P = .04). The mean (SD) duration of follow-up was 3.7 (1.0) years (range, 1.2-5.6 years).
Table 1. Baseline Characteristics of Included and Nonincluded Eyes.
| Characteristic | Eyes, Total No. | Eyes, No. (%) | P Valuea | ||
|---|---|---|---|---|---|
| Included | Nonincluded | Included (n = 472) | Nonincluded (n = 530) | ||
| Age, mean (SD), y | 472 | 530 | 81.9 (3.2) | 84.4 (3.9) | <.001 |
| Female sex | 472 | 530 | 263 (55.7) | 329 (62.1) | .14 |
| Educational level | 472 | 530 | |||
| None or primary | 28 (5.9) | 40 (7.5) | .52 | ||
| Secondary | 215 (45.6) | 257 (48.5) | |||
| High school or university | 229 (48.5) | 233 (44.0) | |||
| Cataract extraction | 453 | 496 | 230 (50.8) | 296 (59.7) | .99 |
| Subfoveal choroidal thickness, mean (SD), μm | 448 | 460 | 219.9 (82.3) | 192.3 (76.8) | .12 |
| AMD status | 445 | 493 | |||
| None | 361 (81.1) | 298 (60.4) | Selection criterionb | ||
| Early stage 1 | 63 (14.2) | 67 (13.6) | |||
| Early stage 2 | 21 (4.7) | 63 (12.8) | |||
| Late | 65 (13.2) | ||||
| Axial length, mean (SD), mm | 472 | 274 | 23.5 (1.4) | 23.6 (1.5) | .75 |
| Smoking status, pack-years | 466 | 526 | |||
| Nonsmoker | 315 (67.6) | 331 (62.9) | .12 | ||
| <20 | 64 (13.7) | 108 (20.5) | |||
| ≥20 | 87 (18.7) | 87 (16.5) | |||
| BMI, mean (SD) | 448 | 500 | 26.2 (4.0) | 25.6 (4.2) | .11 |
| Diabetes | 464 | 508 | 41 (8.8) | 67 (13.2) | .11 |
| Hypertension | 439 | 481 | 254 (57.9) | 290 (60.3) | .59 |
| Antihypertensive therapy | 464 | 508 | 296 (63.8) | 338 (66.5) | .52 |
| Plasma lipid concentration, mean (SD), mg/dL | |||||
| Cholesterol | |||||
| Total | 408 | 448 | 207.8 (42.3) | 217.2 (44.7) | .02 |
| HDL | 408 | 448 | 56.5 (13.9) | 57.9 (14.9) | .31 |
| LDL | 408 | 446 | 128.7 (36.8) | 135.9 (37.9) | .04 |
| Triglycerides | 408 | 448 | 112.6 (44.4) | 116.7 (51.5) | .36 |
| Statin therapy | 464 | 506 | 141 (30.4) | 145 (28.7) | .67 |
| Lipophilic | 84 (18.1) | 86 (17.0) | .74 | ||
| Hydrophilic | 57 (12.3) | 59 (11.7) | .83 | ||
| Fibrate therapy | 464 | 506 | 42 (9.1) | 40 (7.9) | .64 |
| CFH rs1061170 | 439 | 479 | |||
| CC | 51 (11.6) | 53 (11.1) | .44 | ||
| TC | 179 (40.8) | 223 (46.5) | |||
| TT | 209 (47.6) | 203 (42.4) | |||
| ARMS2 rs10490924 | 401 | 425 | |||
| GG | 279 (69.6) | 273 (64.2) | .08 | ||
| GT | 114 (28.4) | 128 (30.1) | |||
| TT | 8 (2.0) | 24 (5.7) | |||
| Complement factor C3 rs2230199 | 390 | 414 | |||
| CC or GC | 90 (23.1) | 132 (31.9) | .06 | ||
| GG | 300 (76.9) | 282 (68.1) | |||
| Complement factor B rs641153 | 401 | 425 | |||
| AA or GA | 122 (30.4) | 100 (23.5) | .05 | ||
| GG | 279 (69.6) | 325 (76.5) | |||
| ApoE4 | 446 | 488 | 86 (19.3) | 80 (16.4) | .40 |
| LIPC rs493258 | 401 | 425 | |||
| CC | 99 (24.7) | 123 (29.0) | .33 | ||
| CT | 212 (52.9) | 216 (50.8) | |||
| TT | 90 (22.4) | 86 (20.2) | |||
| LIPC rs10468017 | 401 | 421 | |||
| CC | 192 (47.9) | 228 (54.1) | .20 | ||
| TC | 179 (44.6) | 167 (39.7) | |||
| TT | 30 (7.5) | 26 (6.2) | |||
| LPL rs12678919 | 388 | 414 | |||
| AA | 290 (74.7) | 326 (78.7) | .57 | ||
| GG or AG | 98 (25.3) | 88 (21.3) | |||
| CETP rs3764261 | 394 | 416 | |||
| AA | 36 (9.1) | 38 (9.1) | .24 | ||
| AC | 151 (38.3) | 191 (45.9) | |||
| CC | 207 (52.6) | 187 (45.0) | |||
| ABCA1 rs1883025 | 401 | 425 | |||
| CC | 212 (52.9) | 226 (53.2) | .48 | ||
| CT | 160 (39.9) | 148 (34.8) | |||
| TT | 29 (7.2) | 51 (12.0) | |||
Abbreviations: ABCA1, adenosine triphosphate-binding cassette transporter 1; AMD, age-related macular degeneration; ApoE4, apolipoprotein E4; ARMS2, age-related maculopathy susceptibility-2; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); CETP, cholesteryl ester transfer protein; CFH, complement factor H; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LIPC, lipase C precursor; LPL, lipoprotein lipase.
SI conversion factors: To convert total cholesterol, HDL, and LDL to millimoles per liter, multiply by 0.0259; and triglycerides to millimoles per liter, multiply by 0.0113.
Obtained using generalized estimating equations model.
No P value.
Annual Incidence and 5-Year Cumulative Incidence of RPD
As shown in Table 2, incident RPD were identified in 43 of the 472 analyzed eyes (9.1%) between baseline (2011-2012) and the last follow-up visit (2015-2017), with an overall annual incidence of 2.1% (95% CI, 1.4%-3.1%) per eye and an estimated 5-year incidence of 9.7% (eFigure 2 in the Supplement). When analyzing at the person level (≥1 eye with incident RPD in a participant without RPD in any eye at baseline), the annual incidence rate was 2.9% (95% CI, 1.9%-4.4%) and the estimated 5-year incidence was 13.5%. The annual incidence per eye tended to be higher in women (2.6%; 95% CI, 1.6%-4.3%) than in men (1.4%; 95% CI, 0.7%-2.8%) (P = .23) and increased with age, up to 4.8% (95% CI, 2.2%-10.6%) in individuals 85 years or older (P < .05). eFigure 3 in the Supplement illustrates the case of 2 participants with incident RPD during follow-up.
Table 2. Annual and 5-Year Cumulative Incidence of RPD per Eye According to Sex and Age Range in the ALIENOR Study, 2011-2017.
| Characteristic | No. of Incident RPD Cases | No. at Risk, Person-Years | Incidence | |
|---|---|---|---|---|
| Annual, % (95% CI) | 5-y, % | |||
| Sex | ||||
| Male | 15 | 209 | 1.4 (0.7-2.8) | 6.9 |
| Female | 28 | 263 | 2.6 (1.6-4.3) | 12.2 |
| Age, y | ||||
| <85 | 31 | 398 | 1.6 (1.0-2.6) | 7.9 |
| ≥85 | 12 | 74 | 4.8 (2.2-10.6) | 21.5 |
| Total | 43 | 472 | 2.1 (1.4-3.1) | 9.7 |
Abbreviations: ALIENOR, Antioxydants, Lipides Essentiels, Nutrition et Maladies Oculaires; RPD, reticular pseudodrusen.
Of the 43 eyes that developed incident RPD, 22 had no AMD signs, 7 had early stage 1 AMD, and 11 had early stage 2 AMD at baseline. Data on AMD status were missing for the 3 remaining eyes. A total of 32 cases of AMD were incident bilateral cases (16 participants), 3 had already prevalent late AMD in the fellow eye (ie, fellow eye excluded at baseline), and 8 were strictly unilateral.
Characteristics of Eyes With Incident RPD
In the sex-adjusted model (Table 3), incident RPD were found to be associated with subfoveal choroidal thinning (HR, 0.995; 95% CI, 0.99-1.00; P = .03). In the subgroup of eyes with an axial length measurement available (40 of 43 incident RPD cases), adjustment of subfoveal choroidal thickness data on axial length increased the significance of the association (HR, 0.993; 95% CI, 0.99-0.998; P = .002). A reduced risk for incident RPD was observed specifically with lipophilic statin therapy (HR, 0.13; 95% CI, 0.02-0.95; P = .04). Among the genetic factors analyzed, the risk of incident RPD was increased with the at-risk alleles of rs10490924 for ARMS2 (HR, 3.06; 95% CI, 1.48-6.33; P = .003) and rs10468017 for LIPC (lipase C) (HR, 2.25; 95% CI, 1.10-4.58; P = .03).
Table 3. Associations of Incident RPD per Eye With Potential Risk Factors in the ALIENOR Study, 2011-2017a.
| Characteristic | Eyes, Total No. | Eyes, No. (%) | HR (95% CI) | P Value | ||
|---|---|---|---|---|---|---|
| Incident RPD | Nonincident RPD | Incident RPD | Nonincident RPD | |||
| Age, mean (SD), y | 43 | 429 | 83.7 (3.3) | 81.7 (3.1) | NAb | NA |
| Female sex | 43 | 429 | 28 (65.1) | 235 (54.8) | 1.56 (0.68-3.59) | .29 |
| Educational level | 43 | 429 | ||||
| None or primary | 2 (4.6) | 26 (6.1) | 1 [Reference] | .54 | ||
| Secondary | 15 (34.9) | 200 (46.6) | 0.90 (0.12-6.90) | |||
| High school or university | 26 (60.5) | 203 (47.3) | 1.41 (0.19-10.40) | |||
| Cataract extraction | 42 | 411 | 28 (66.7) | 202 (49.1) | 1.62 (0.75-3.48) | .22 |
| Subfoveal choroidal thickness, mean (SD), μm | 40 | 408 | 186.5 (78.4) | 223.4 (82.1) | 0.995 (0.99-1.00)c | .03 |
| Axial length, mean (SD), mm | 43 | 429 | 23.2 (1.1) | 23.6 (1.4) | 0.80 (0.56-1.15) | .23 |
| Smoking status, pack-years | 41 | 425 | ||||
| Nonsmoker | 25 (61.0) | 290 (68.2) | 1 [Reference] | .08 | ||
| <20 | 3 (7.3) | 61 (14.4) | 0.73 (0.20-2.74) | |||
| ≥20 | 13 (31.7) | 74 (17.4) | 2.77 (0.99-7.69) | |||
| BMI, mean (SD) | 43 | 405 | 26.3 (4.3) | 26.2 (4.0) | 1.25 (0.92-1.15) | .67 |
| Cardiovascular diseasesd | 41 | 417 | 1 (2.4) | 19 (4.6) | 0.51 (0.09-2.74) | .43 |
| Diabetes | 43 | 421 | 3 (7.1) | 38 (9.0) | 0.77 (0.24-2.50) | .66 |
| Hypertension | 38 | 401 | 20 (52.6) | 234 (58.4) | 0.80 (0.35-1.83) | .60 |
| Antihypertensive therapy | 43 | 421 | 28 (65.1) | 268 (63.6) | 1.26 (0.52-3.07) | .61 |
| Plasma lipid concentration, mean (SD), mg/dL | ||||||
| Cholesterol | ||||||
| Total | 37 | 371 | 201.3 (46.9) | 208.4 (41.9) | 0.99 (0.98-1.01) | .26 |
| HDL | 37 | 371 | 61.2 (15.5) | 56.1 (13.7) | 1.02 (0.99-1.06) | .25 |
| LDL | 37 | 371 | 119.7 (38.9) | 129.6 (36.5) | 0.99 (0.98-1.00) | .10 |
| Triglycerides | 37 | 371 | 101.7 (37.0) | 113.6 (45.0) | 1.00 (0.99-1.01) | .41 |
| Statin therapy | 43 | 421 | 10 (23.3) | 131 (31.1) | 0.87 (0.36-2.15) | .77 |
| Lipophilic | 43 | 421 | 1 (2.3) | 83 (19.7) | 0.13 (0.02-0.95) | .04 |
| Hydrophilic | 43 | 421 | 9 (20.9) | 48 (11.4) | 2.23 (0.81-6.18) | .12 |
| Fibrate therapy | 43 | 421 | 2 (4.6) | 40 (9.5) | 0.42 (0.08-2.34) | .32 |
| CFH rs1061170 | 41 | 398 | 1.86 (0.98-3.53)e | .06 | ||
| CC (2) | 11 (26.8) | 40 (10.1) | ||||
| TC (1) | 18 (43.9) | 161 (40.4) | ||||
| TT (0) | 12 (29.3) | 197 (49.5) | ||||
| ARMS2 rs10490924 | 38 | 363 | ||||
| GG (0) | 20 (52.6) | 259 (71.4) | 3.06 (1.48-6.33)e | .003 | ||
| GT (1) | 13 (34.2) | 101 (27.8) | ||||
| TT (2) | 5 (13.2) | 3 (0.8) | ||||
| Complement factor C3 rs2230199 | 38 | 352 | ||||
| GG (0) | 27 (71.1) | 273 (77.6) | 1.17 (0.52-2.66)e | .71 | ||
| GC (1) | 11 (28.9) | 75 (21.3) | ||||
| CC (2) | 0 (0.0) | 4 (1.1) | ||||
| Complement factor B rs641153 | 38 | 363 | ||||
| GG (0) | 31 (81.6) | 243 (68.3) | 0.52 (0.19-1.44)e | .21 | ||
| AG (1) | 5 (13.2) | 107 (29.5) | ||||
| AA (2) | 2 (5.2) | 8 (2.2) | ||||
| ApoE4 | 41 | 405 | 6 (14.6) | 80 (19.8) | 0.72 (0.25-2.08) | .55 |
| LIPC rs493258 | 38 | 363 | ||||
| CC (0) | 8 (21.1) | 91 (25.1) | 1.54 (0.82-2.89)e | .18 | ||
| CT (1) | 16 (42.3) | 196 (54.0) | ||||
| TT (2) | 14 (36.8) | 76 (20.9) | ||||
| LIPC rs10468017 | 38 | 363 | ||||
| CC (0) | 14 (36.8) | 178 (49.0) | 2.25 (1.10-4.58)e | .03 | ||
| TC (1) | 17 (46.7) | 162 (44.6) | ||||
| TT (2) | 7 (18.4) | 23 (6.3) | ||||
| LPL rs12678919 | 34 | 354 | ||||
| AA (0) | 30 (88.2) | 260 (73.4) | 0.34 (0.09-1.34)e | .12 | ||
| AG (1) | 4 (11.8) | 92 (26.0) | ||||
| GG (2) | 0 | 2 (0.6) | ||||
| CETP rs3764261 | 36 | 358 | ||||
| AA (2) | 3 (8.3) | 33 (9.2) | 0.62 (0.26-1.49)e | .29 | ||
| AC (1) | 8 (22.2) | 143 (39.9) | ||||
| CC (0) | 25 (69.5) | 182 (50.8) | ||||
| ABCA1 rs1883025 | 38 | 363 | ||||
| CC (0) | 24 (63.2) | 188 (51.8) | 0.71 (0.30-1.64)e | .42 | ||
| CT (1) | 11 (28.9) | 149 (41.0) | ||||
| TT (2) | 3 (7.9) | 26 (7.2) | ||||
Abbreviations: ALIENOR, Antioxydants, Lipides Essentiels, Nutrition et Maladies Oculaires; ABCA1, adenosine triphosphate-binding cassette transporter 1; ApoE4, apolipoprotein E4; ARMS2, age-related maculopathy susceptibility-2; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); CETP, cholesteryl ester transfer protein; CFH, complement factor H; HDL, high-density lipoprotein; HR, hazard ratio; LDL, low-density lipoprotein; LIPC, lipase C precursor; LPL, lipoprotein lipase; NA, not applicable; RPD, reticular pseudodrusen.
Cox proportional hazards regression model with age as the time scale, adjusted for sex.
Could not be calculated for age because age was used as the time scale.
Measured per 10-μm decrease.
Cardiovascular diseases included angina pectoris, myocardial infarction, coronary angioplasty or bypass, and stroke.
Obtained from the number of minor alleles (0, 1, or 2).
Table 4 displays the results of the multivariable analysis with forced entry for sex and axial length. Four risk factors for incident RPD were identified in our population: subfoveal choroidal thinning (HR, 0.994; 95% CI, 0.99-1.00; P = .02) and the presence of the minor alleles of rs10490924 for ARMS2 (HR, 3.57; 95% CI, 1.80-7.10; P < .001), rs10468017 for LIPC (HR, 2.57; 95% CI, 1.37-4.82; P = .003), and rs1061170 for CFH (HR, 2.12; 95% CI, 1.02-4.41; P = .04). Conversely, lipophilic statin therapy (HR, 0.13; 95% CI, 0.02-0.74; P = .02) was associated with a lower incidence of RPD.
Table 4. Associations of Incident Reticular Pseudodrusen per Eye With Potential Risk Factors in the ALIENOR Study, 2011-2017a.
| Characteristic | HR (95% CI) | P Value |
|---|---|---|
| Female sex | 1.13 (0.36-3.57) | .84 |
| Axial length, mm | 0.63 (0.40-0.99) | .046 |
| Subfoveal choroidal thickness, μm | 0.994 (0.99-1.00)b | .02 |
| ARMS2 rs10490924 | 3.57 (1.80-7.10) | <.001 |
| LIPC rs10468017 | 2.57 (1.37-4.82) | .003 |
| CFH rs1061170 | 2.12 (1.02-4.41) | .04 |
| Smoking status, pack-years | ||
| Nonsmoker | 1 [Reference] | .27 |
| <20 | 0.84 (0.28-2.50) | |
| ≥20 | 2.41 (0.76-7.59) | |
| Lipophilic statin therapy | 0.13 (0.02-0.74) | .02 |
Abbreviations: ALIENOR, Antioxydants, Lipides Essentiels, Nutrition et Maladies Oculaires; ARMS2, age-related maculopathy susceptibility-2; CFH, complement factor H; HR, hazard ratio; LIPC, lipase C precursor.
Multivariable model; axial length and sex forced into the model.
Measured per 10-μm decrease.
Discussion
This study analyzed the incidence of RPD using multimodal imaging in a population of elderly individuals. To our knowledge, up to now, reported data in the literature on the incidence of RPD were based only on interpretation of retinal photographs. Hence, the Beaver Dam Eye Study reported a 15-year RPD incidence of 6.6% after 75 years.9 In the Blue Mountains Eye Study, the 5-year incidence was 2.0%, the 15-year cumulative incidence at any age was 4.0%, and the 15-year cumulative incidence after 75 years was 4.9%.7,16 In our cohort, the RPD annual incidence rate was 2.9% and the estimated cumulative 5-year incidence rate was 13.5% in individuals 77 years or older. The higher rate observed in our study may be explained mainly by 2 factors. First, the systematic use of multimodal imaging for RPD assessment has undoubtedly increased the sensitivity of RPD detection.12,13,14,15 Second, the short intervals between eye examinations (1-2 years) have minimized survival bias compared with the Beaver Dam Eye Study and the Blue Mountains Eye Study. In those 2 cohorts, follow-up examinations were performed at 5-year intervals, which may have led to increased survival bias and subsequent decreased incidence rates, as some participants may have developed RPD and died within the 5-year interval and therefore not have been counted as incident cases.
Identified risk factors associated with incident RPD in our cohort were older age, subfoveal choroidal thinning, and ARMS2, CFH, or LIPC allelic variants. Lipophilic statin therapy was associated with a lower RPD incidence. Several constitutive, genetic, and acquired—either environmental or behavioral—risk factors have been described in the literature in association with RPD.6,17 Most studies agree that RPD prevalence10,11,12,23,31,32 and incidence7,9 increase with age and female sex. In our study, RPD incidence increased with age and tended to be higher in women than in men, although this difference was not maintained in the multivariable model. Besides age and sex, choroidal thinning was most often found to be associated with RPD.4,6,15,17,23,31,33,34,35 However, causality between choroidal thinning and RPD remains elusive; RPD were alternatively proposed to be a consequence23,36,37,38 or a cause39 of choroidal thinning. Our prospective analyses rule out this last hypothesis because baseline reduced choroidal thickness was associated with an increased risk of developing RPD during follow-up, therefore suggesting that choroidal modifications precede RPD occurrence. However, underlying pathophysiological mechanisms remain to be elucidated and the influence of a third factor associated with both choroidal thinning and RPD cannot be excluded.40
A predisposing genetic background has been documented in age-related retinal lesions.2 Variants in the ARMS241 and CFH42,43 genes have been strongly associated with AMD. The same allelic variants have also been found to be associated with RPD.4,6,17 Whereas ARMS2 is almost constantly associated with a higher risk of RPD,7,10,11,31,32,44,45,46 controversial data on CFH have been reported, with CFH being alternatively significantly associated with RPD7,10,11,45,46 or not,32,47 and when associated with RPD, described either as a risk factor7,10,11,46 or a protective factor.45 Our results are in line with the literature, demonstrating a strong increased risk of RPD in eyes with the ARMS2 variant, both in the sex-adjusted and the multivariable models. The CFH variant was found to be associated with a higher incidence of RPD only in the multivariable analysis. Besides ARMS2 and CFH, we further identified an association with an LIPC variant that persisted after multivariable analysis. LIPC encodes a hepatic triglyceride lipase expressed in the liver, the retina, and the subretinal space, which would be involved in high-density lipoprotein cholesterol metabolism.48,49 LIPC variants (rs10468017 and rs493258) have been reported to be associated with a decreased risk of early and advanced AMD25,50 but never with RPD.45 In our analyses, only LIPC variant rs10468017 was found to be associated with incident RPD, but as a risk factor. The reasons for the association of LIPC with RPD or other types of drusen or advanced AMD remain to be confirmed and further analyzed.
A potential role of lipid metabolism in the occurrence of RPD is further suggested by the protective role of lipophilic statin therapy that we observed. Recently, a similar association of RPD prevalence with statin therapy was reported.51 The association of statin therapy with AMD was analyzed in several studies with conflicting results, in which statins were reported to be associated with AMD52,53,54,55,56,57 or not.52,53,55 Moreover, when statins were found to be associated with AMD, they were described either as a protective factor52,53,54,55,56,57 or as a risk factor.58,59 Such discrepancies in the literature may be due to the nature of the analyzed statins. Hydrophilic and lipophilic statins exhibit different chemical properties with subsequently different metabolic effects. A combined analysis of the association of the 2 statin subgroups with RPD without any distinction may therefore obscure any specific subgroup properties. Nevertheless, an inverse association of RPD with lipophilic statin therapy needs to be confirmed in larger samples.
Strengths and Limitations
The main strengths of our study include its population-based older cohort sample with a follow-up at 3 time points, the systematic use of multimodal imaging at all examinations, and the short intervals between eye examinations (1-2 years) that limited survival bias. We also chose to analyze our results per eye and not per participant to use all available information and thus more precisely analyze associations with risk factors. This study also has some limitations. First, the follow-up rate was 58.5%. Second, the small number of incident RPD cases (n = 43) may have induced insufficient statistical power for detecting some associations. Third, we did not correct for multiple testing, which may have led to associations observed by chance alone. Associations observed in this study therefore need to be replicated in other cohorts. Fourth, another limitation comes from the representativeness of the population sample. The ALIENOR Study subsample tends to overrepresent younger individuals and those of high socioeconomic status compared with the parent cohort (the 3C Study).19 The individuals included in this study may accordingly be healthier and have different lifestyles, in particular concerning diet or physical activity, compared with the general population. However, for most parameters of interest in our study, individuals included in the ALIENOR Study were not different from those who did not participate.19
Conclusions
In this population-based study of elderly French individuals who underwent retinal multimodal imaging, the incidence of RPD was higher than previously reported in the literature. Incident RPD were strongly associated with allelic variants in the ARMS2 gene, with allelic variants in the CFH and LIPC genes, and with choroidal thinning. Lipophilic statin therapy was associated with a lower incidence of RPD, suggesting a role of lipid metabolism in their pathophysiology. Further studies are warranted to confirm these results.
eAppendix 1. Assessment of Risk Factors for Incident Reticular Pseudodrusen
eAppendix 2. Genome Wide-Scan Analysis and List of Analyzed Genotypes
eFigure 1. Flow Chart Showing Selection of Eyes at Baseline
eFigure 2. Age-Specific Cumulative Incidence of Reticular Pseudodrusen per Eye
eFigure 3. Examples of Two Participants Who Developed Incident Reticular Pseudodrusen (RPD) During Follow-up
References
- 1.Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014;2(2):e106-e116. doi: 10.1016/S2214-109X(13)70145-1 [DOI] [PubMed] [Google Scholar]
- 2.Lim LS, Mitchell P, Seddon JM, Holz FG, Wong TY. Age-related macular degeneration. Lancet. 2012;379(9827):1728-1738. doi: 10.1016/S0140-6736(12)60282-7 [DOI] [PubMed] [Google Scholar]
- 3.Mimoun G, Soubrane G, Coscas G. Macular drusen [in French]. J Fr Ophtalmol. 1990;13(10):511-530. [PubMed] [Google Scholar]
- 4.Spaide RF, Ooto S, Curcio CA. Subretinal drusenoid deposits aka pseudodrusen. Surv Ophthalmol. 2018;63(6):782-815. doi: 10.1016/j.survophthal.2018.05.005 [DOI] [PubMed] [Google Scholar]
- 5.Zweifel SA, Spaide RF, Curcio CA, Malek G, Imamura Y. Reticular pseudodrusen are subretinal drusenoid deposits. Ophthalmology. 2010;117(2):303-12.e1. doi: 10.1016/j.ophtha.2009.07.014 [DOI] [PubMed] [Google Scholar]
- 6.Sivaprasad S, Bird A, Nitiahpapand R, Nicholson L, Hykin P, Chatziralli I; Moorfields UCL AMD Consortium . Perspectives on reticular pseudodrusen in age-related macular degeneration. Surv Ophthalmol. 2016;61(5):521-537. doi: 10.1016/j.survophthal.2016.02.005 [DOI] [PubMed] [Google Scholar]
- 7.Joachim N, Mitchell P, Rochtchina E, Tan AG, Wang JJ. Incidence and progression of reticular drusen in age-related macular degeneration: findings from an older Australian cohort. Ophthalmology. 2014;121(4):917-925. doi: 10.1016/j.ophtha.2013.10.043 [DOI] [PubMed] [Google Scholar]
- 8.Gil JQ, Marques JP, Hogg R, et al. Clinical features and long-term progression of reticular pseudodrusen in age-related macular degeneration: findings from a multicenter cohort. Eye (Lond). 2017;31(3):364-371. doi: 10.1038/eye.2016.207 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Klein R, Meuer SM, Knudtson MD, Iyengar SK, Klein BEK. The epidemiology of retinal reticular drusen. Am J Ophthalmol. 2008;145(2):317-326. doi: 10.1016/j.ajo.2007.09.008 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Finger RP, Chong E, McGuinness MB, et al. Reticular pseudodrusen and their association with age-related macular degeneration: the Melbourne Collaborative Cohort Study. Ophthalmology. 2016;123(3):599-608. doi: 10.1016/j.ophtha.2015.10.029 [DOI] [PubMed] [Google Scholar]
- 11.Buitendijk GHS, Hooghart AJ, Brussee C, et al. Epidemiology of reticular pseudodrusen in age-related macular degeneration: the Rotterdam Study. Invest Ophthalmol Vis Sci. 2016;57(13):5593-5601. doi: 10.1167/iovs.15-18816 [DOI] [PubMed] [Google Scholar]
- 12.Chan H, Cougnard-Grégoire A, Delyfer M-N, et al. Multimodal imaging of reticular pseudodrusen in a population-based setting: the Alienor Study. Invest Ophthalmol Vis Sci. 2016;57(7):3058-3065. doi: 10.1167/iovs.16-19487 [DOI] [PubMed] [Google Scholar]
- 13.Smith RT, Sohrab MA, Busuioc M, Barile G. Reticular macular disease. Am J Ophthalmol. 2009;148(5):733-743.e2. doi: 10.1016/j.ajo.2009.06.028 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Ueda-Arakawa N, Ooto S, Tsujikawa A, Yamashiro K, Oishi A, Yoshimura N. Sensitivity and specificity of detecting reticular pseudodrusen in multimodal imaging in Japanese patients. Retina. 2013;33(3):490-497. doi: 10.1097/IAE.0b013e318276e0ae [DOI] [PubMed] [Google Scholar]
- 15.De Bats F, Mathis T, Mauget-Faÿsse M, Joubert F, Denis P, Kodjikian L. Prevalence of reticular pseudodrusen in age-related macular degeneration using multimodal imaging. Retina. 2016;36(1):46-52. doi: 10.1097/IAE.0000000000000648 [DOI] [PubMed] [Google Scholar]
- 16.Mitchell P, Wang JJ, Foran S, Smith W. Five-year incidence of age-related maculopathy lesions: the Blue Mountains Eye Study. Ophthalmology. 2002;109(6):1092-1097. doi: 10.1016/S0161-6420(02)01055-2 [DOI] [PubMed] [Google Scholar]
- 17.Rabiolo A, Sacconi R, Cicinelli MV, Querques L, Bandello F, Querques G. Spotlight on reticular pseudodrusen. Clin Ophthalmol. 2017;11:1707-1718. doi: 10.2147/OPTH.S130165 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Antoniak M, Pugliatti M, Hubbard R, et al. ; 3C Study Group . Vascular factors and risk of dementia: design of the Three-City Study and baseline characteristics of the study population. Neuroepidemiology. 2003;22(6):316-325. doi: 10.1159/000072920 [DOI] [PubMed] [Google Scholar]
- 19.Delcourt C, Korobelnik J-F, Barberger-Gateau P, et al. Nutrition and age-related eye diseases: the Alienor (Antioxydants, Lipides Essentiels, Nutrition et maladies OculaiRes) Study. J Nutr Health Aging. 2010;14(10):854-861. doi: 10.1007/s12603-010-0131-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.World Medical Association World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191-2194. doi: 10.1001/jama.2013.281053 [DOI] [PubMed] [Google Scholar]
- 21.Saunier V, Merle BMJ, Delyfer M-N, et al. Incidence of and risk factors associated with age-related macular degeneration: four-year follow-up from the ALIENOR Study. JAMA Ophthalmol. 2018;136(5):473-481. doi: 10.1001/jamaophthalmol.2018.0504 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Gattoussi S, Cougnard-Grégoire A, Korobelnik J-F, et al. Choroidal thickness, vascular factors, and age-related macular degeneration: the ALIENOR Study. Retina. 2019;39(1):34-43. doi: 10.1097/IAE.0000000000002237 [DOI] [PubMed] [Google Scholar]
- 23.Arnold JJ, Sarks SH, Killingsworth MC, Sarks JP. Reticular pseudodrusen: a risk factor in age-related maculopathy. Retina. 1995;15(3):183-191. doi: 10.1097/00006982-199515030-00001 [DOI] [PubMed] [Google Scholar]
- 24.Seddon JM, Sharma S, Adelman RA. Evaluation of the clinical age-related maculopathy staging system. Ophthalmology. 2006;113(2):260-266. doi: 10.1016/j.ophtha.2005.11.001 [DOI] [PubMed] [Google Scholar]
- 25.Merle BM, Maubaret C, Korobelnik JF, et al. Association of HDL-related loci with age-related macular degeneration and plasma lutein and zeaxanthin: the Alienor Study. PLoS One. 2013;8(11):e79848. doi: 10.1371/journal.pone.0079848 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Zeger SL, Liang KY, Albert PS. Models for longitudinal data: a generalized estimating equation approach. Biometrics. 1988;44(4):1049-1060. doi: 10.2307/2531734 [DOI] [PubMed] [Google Scholar]
- 27.Rothman KJ, Greenland S, eds. Modern Epidemiology. 2nd ed Philadelphia, PA: Lippincott-Raven Publishers; 1998:37-41. [Google Scholar]
- 28.Glynn RJ, Rosner B. Regression methods when the eye is the unit of analysis. Ophthalmic Epidemiol. 2012;19(3):159-165. doi: 10.3109/09286586.2012.674614 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Barteselli G, Chhablani J, El-Emam S, et al. Choroidal volume variations with age, axial length, and sex in healthy subjects: a three-dimensional analysis. Ophthalmology. 2012;119(12):2572-2578. doi: 10.1016/j.ophtha.2012.06.065 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Hirata M, Tsujikawa A, Matsumoto A, et al. Macular choroidal thickness and volume in normal subjects measured by swept-source optical coherence tomography. Invest Ophthalmol Vis Sci. 2011;52(8):4971-4978. doi: 10.1167/iovs.11-7729 [DOI] [PubMed] [Google Scholar]
- 31.Yoneyama S, Sakurada Y, Mabuchi F, et al. Genetic and clinical factors associated with reticular pseudodrusen in exudative age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 2014;252(9):1435-1441. doi: 10.1007/s00417-014-2601-y [DOI] [PubMed] [Google Scholar]
- 32.Boddu S, Lee MD, Marsiglia M, Marmor M, Freund KB, Smith RT. Risk factors associated with reticular pseudodrusen versus large soft drusen. Am J Ophthalmol. 2014;157(5):985-993.e2. doi: 10.1016/j.ajo.2014.01.023 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Yun C, Ahn J, Kim M, Hwang S-Y, Kim S-W, Oh J. Ocular perfusion pressure and choroidal thickness in early age-related macular degeneration patients with reticular pseudodrusen. Invest Ophthalmol Vis Sci. 2016;57(15):6604-6609. doi: 10.1167/iovs.16-19989 [DOI] [PubMed] [Google Scholar]
- 34.Spaide RF. Choriocapillaris flow features follow a power law distribution: implications for characterization and mechanisms of disease progression. Am J Ophthalmol. 2016;170:58-67. doi: 10.1016/j.ajo.2016.07.023 [DOI] [PubMed] [Google Scholar]
- 35.Cheung CMG, Gan A, Yanagi Y, Wong TY, Spaide R. Association between choroidal thickness and drusen subtypes in age-related macular degeneration. Ophthalmol Retina. 2018;2(12):1196-1205. doi: 10.1016/j.oret.2018.06.014 [DOI] [PubMed] [Google Scholar]
- 36.Garg A, Oll M, Yzer S, et al. Reticular pseudodrusen in early age-related macular degeneration are associated with choroidal thinning. Invest Ophthalmol Vis Sci. 2013;54(10):7075-7081. doi: 10.1167/iovs.13-12474 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Sohrab MA, Smith RT, Salehi-Had H, Sadda SR, Fawzi AA. Image registration and multimodal imaging of reticular pseudodrusen. Invest Ophthalmol Vis Sci. 2011;52(8):5743-5748. doi: 10.1167/iovs.10-6942 [DOI] [PubMed] [Google Scholar]
- 38.Alten F, Clemens CR, Heiduschka P, Eter N. Localized reticular pseudodrusen and their topographic relation to choroidal watershed zones and changes in choroidal volumes. Invest Ophthalmol Vis Sci. 2013;54(5):3250-3257. doi: 10.1167/iovs.13-11923 [DOI] [PubMed] [Google Scholar]
- 39.Spaide RF. Outer retinal atrophy after regression of subretinal drusenoid deposits as a newly recognized form of late age-related macular degeneration. Retina. 2013;33(9):1800-1808. doi: 10.1097/IAE.0b013e31829c3765 [DOI] [PubMed] [Google Scholar]
- 40.Mrejen S, Spaide RF. The relationship between pseudodrusen and choroidal thickness. Retina. 2014;34(8):1560-1566. doi: 10.1097/IAE.0000000000000139 [DOI] [PubMed] [Google Scholar]
- 41.Fritsche LG, Loenhardt T, Janssen A, et al. Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA. Nat Genet. 2008;40(7):892-896. doi: 10.1038/ng.170 [DOI] [PubMed] [Google Scholar]
- 42.Seddon JM, Reynolds R, Rosner B. Peripheral retinal drusen and reticular pigment: association with CFHY402H and CFHrs1410996 genotypes in family and twin studies. Invest Ophthalmol Vis Sci. 2009;50(2):586-591. doi: 10.1167/iovs.08-2514 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308(5720):385-389. doi: 10.1126/science.1109557 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Ueda-Arakawa N, Ooto S, Nakata I, et al. Prevalence and genomic association of reticular pseudodrusen in age-related macular degeneration. Am J Ophthalmol. 2013;155(2):260-269.e2. doi: 10.1016/j.ajo.2012.08.011 [DOI] [PubMed] [Google Scholar]
- 45.Lin LY, Zhou Q, Hagstrom S, et al. ; CATT Research Group . Association of single-nucleotide polymorphisms in age-related macular degeneration with pseudodrusen: secondary analysis of data from the comparison of AMD treatments trials. JAMA Ophthalmol. 2018;136(6):682-688. doi: 10.1001/jamaophthalmol.2018.1231 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Puche N, Blanco-Garavito R, Richard F, et al. Genetic and environmental factors associated with reticular pseudodrusen in age-related macular degeneration. Retina. 2013;33(5):998-1004. doi: 10.1097/IAE.0b013e31827b6483 [DOI] [PubMed] [Google Scholar]
- 47.Wu Z, Ayton LN, Luu CD, Baird PN, Guymer RH. Reticular pseudodrusen in intermediate age-related macular degeneration: prevalence, detection, clinical, environmental, and genetic associations. Invest Ophthalmol Vis Sci. 2016;57(3):1310-1316. doi: 10.1167/iovs.15-18682 [DOI] [PubMed] [Google Scholar]
- 48.Neale BM, Fagerness J, Reynolds R, et al. Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proc Natl Acad Sci U S A. 2010;107(16):7395-7400. doi: 10.1073/pnas.0912019107 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Zheng W, Reem RE, Omarova S, et al. Spatial distribution of the pathways of cholesterol homeostasis in human retina. PLoS One. 2012;7(5):e37926. doi: 10.1371/journal.pone.0037926 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50.Lou L-X, Hu K-M, Jin K, Zhang S-Z, Ye J. The relationship between hepatic lipase gene variant and advanced age-related macular degeneration: a meta-analysis. JAMA Ophthalmol. 2014;132(10):1226-1231. doi: 10.1001/jamaophthalmol.2014.1752 [DOI] [PubMed] [Google Scholar]
- 51.Gabrielle PH, Seydou A, Arnould L, et al. Subretinal drusenoid deposits in the elderly in a population-based study (the Montrachet Study). Invest Ophthalmol Vis Sci. 2019;60(14):4838-4848. doi: 10.1167/iovs.19-27283 [DOI] [PubMed] [Google Scholar]
- 52.Tan JSL, Mitchell P, Rochtchina E, Wang JJ. Statins and the long-term risk of incident age-related macular degeneration: the Blue Mountains Eye Study. Am J Ophthalmol. 2007;143(4):685-687. doi: 10.1016/j.ajo.2006.11.021 [DOI] [PubMed] [Google Scholar]
- 53.Tsao SW, Fong DS. Do statins have a role in the prevention of age-related macular degeneration? Drugs Aging. 2013;30(4):205-213. doi: 10.1007/s40266-013-0061-4 [DOI] [PubMed] [Google Scholar]
- 54.Guymer RH, Baird PN, Varsamidis M, et al. Proof of concept, randomized, placebo-controlled study of the effect of simvastatin on the course of age-related macular degeneration. PLoS One. 2013;8(12):e83759. doi: 10.1371/journal.pone.0083759 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55.Barbosa DTQ, Mendes TS, Cíntron-Colon HR, et al. Age-related macular degeneration and protective effect of HMG Co-A reductase inhibitors (statins): results from the National Health and Nutrition Examination Survey 2005-2008. Eye (Lond). 2014;28(4):472-480. doi: 10.1038/eye.2014.8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56.Ma L, Wang Y, Du J, Wang M, Zhang R, Fu Y. The association between statin use and risk of age-related macular degeneration. Sci Rep. 2015;5:18280. doi: 10.1038/srep18280 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57.Vavvas DG, Daniels AB, Kapsala ZG, et al. Regression of some high-risk features of age-related macular degeneration (AMD) in patients receiving intensive statin treatment. EBioMedicine. 2016;5:198-203. doi: 10.1016/j.ebiom.2016.01.033 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 58.Etminan M, Brophy JM, Maberley D. Use of statins and angiotensin converting enzyme inhibitors (ACE-Is) and the risk of age-related macular degeneration: nested case-control study. Curr Drug Saf. 2008;3(1):24-26. doi: 10.2174/157488608783333952 [DOI] [PubMed] [Google Scholar]
- 59.Peiretti E, Mandas A, Abete C, et al. Age-related macular degeneration and cognitive impairment show similarities in changes of neutral lipids in peripheral blood mononuclear cells. Exp Eye Res. 2014;124:11-16. doi: 10.1016/j.exer.2014.04.017 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eAppendix 1. Assessment of Risk Factors for Incident Reticular Pseudodrusen
eAppendix 2. Genome Wide-Scan Analysis and List of Analyzed Genotypes
eFigure 1. Flow Chart Showing Selection of Eyes at Baseline
eFigure 2. Age-Specific Cumulative Incidence of Reticular Pseudodrusen per Eye
eFigure 3. Examples of Two Participants Who Developed Incident Reticular Pseudodrusen (RPD) During Follow-up
