Dataset Information

Plasma Biomarkers of Reticular Pseudodrusen and the Risk of Progression to Advanced Age-Related Macular Degeneration.

ABSTRACT: Purpose:To determine, using an aptamer-based technology in patients with intermediate age-related macular degeneration (AMD), (1) if there is a difference in plasma levels of 4979 proteins in patients with and without reticular pseudodrusen (RPD), and (2) if plasma levels of proteins are related to time to conversion to advanced AMD. Methods:Patients with intermediate AMD and RPD were identified from an AMD registry. Relative concentrations of each protein were log (base 2) transformed and compared between patients with and without RPD using linear regression. A Cox proportional hazards survival model was fit to each aptamer to quantify associations with time to conversion. A pathway analysis was conducted in converters versus non-converters using the Reactome database. Results:Of the 109 intermediate AMD patients, 39 had bilateral RPD (36%). Two proteins, TCL1A and CNDP1, were lower in patients in the intermediate AMD group with RPD. Twenty-one patients converted to advanced AMD with a median time to conversion of 25.2 months (range, 2.3-48.5 months) and median follow-up time in non-converters of 26.4 months (range, 0.03-49.7 months). Several proteins (lysozyme C, TFF3, RNAS6, and SAP3) distinguished patients who converted from those who did not convert to advanced AMD. The top conversion pathways included tumor necrosis factors bind their physiological receptors, digestion and absorption, signaling by activin, and signaling by TGF-? family members. Conclusions:We identified a protein signature related to RPD, as well as to conversion to advanced AMD. The pathway analysis suggests that dysfunction of critical systemic pathways may have links to conversion to advanced AMD. Translational Relevance:Biomarkers identified in plasma likely reflect systemic alterations in protein expression in patients with intermediate AMD.

SUBMITTER: Lynch AM

PROVIDER: S-EPMC7488626 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Plasma Biomarkers of Reticular Pseudodrusen and the Risk of Progression to Advanced Age-Related Macular Degeneration.

Lynch Anne M AM Wagner Brandie D BD Palestine Alan G AG Janjic Nebojsa N Patnaik Jennifer L JL Mathias Marc T MT Siringo Frank S FS Mandava Naresh N

Translational vision science & technology 20200911 10

<h4>Purpose</h4>To determine, using an aptamer-based technology in patients with intermediate age-related macular degeneration (AMD), (1) if there is a difference in plasma levels of 4979 proteins in patients with and without reticular pseudodrusen (RPD), and (2) if plasma levels of proteins are related to time to conversion to advanced AMD.<h4>Methods</h4>Patients with intermediate AMD and RPD were identified from an AMD registry. Relative concentrations of each protein were log (base 2) transf ...[more]

PMID: 32974084

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Project description:PURPOSE:We investigate whether ocular and person-based characteristics were associated with dark adaptation (DA). DESIGN:Cross-sectional, single-center, observational study. PARTICIPANTS:One hundred sixteen participants older than 50 years of age with a range of age-related macular degeneration (AMD) severity. METHODS:Participants underwent best-corrected visual acuity (BCVA) testing, ophthalmoscopic examination, and multimodal imaging. Presence of reticular pseudodrusen (RPD) was assessed by masked grading of fundus images and was confirmed with optical coherence tomography. Eyes also were graded for AMD features (drusen, pigmentary changes, late AMD) to generate person-based AMD severity groups. One eye was designated the study eye for DA testing. Nonparametric statistical testing was performed on all comparisons. MAIN OUTCOME MEASURES:The primary outcome of this study was the rod intercept time (RIT), which is defined as the time for a participant's visual sensitivity to recover to a stimulus intensity of 5×10(-3) cd/m(2) (a decrease of 3 log units), or until a maximum test duration of 40 minutes was reached. RESULTS:A total of 116 study eyes from 116 participants (mean age, 75.4±9.4 years; 58% female) were analyzed. Increased RIT was associated significantly with increasing AMD severity, increasing age (r = 0.34; P = 0.0002), decreasing BCVA (r = -0.54; P < 0.0001), pseudophakia (P = 0.03), and decreasing subfoveal choroidal thickness (r = -0.27; P = 0.003). Study eyes with RPD (15/116 [13%]) had a significantly greater mean RIT compared with eyes without RPD in any AMD severity group (P < 0.02 for all comparisons), with 80% reaching the DA test ceiling. CONCLUSIONS:Impairments in DA increased with age, worse visual acuity, presence of RPD, AMD severity, and decreased subfoveal choroidal thickness. Analysis of covariance found the multivariate model that best fit the data included age, AMD group, and presence of RPD (R(2) = 0.56), with the presence of RPD conferring the largest parameter estimate.

Project description:PURPOSE:To determine the prevalence of reticular pseudodrusen (RPD) in eyes with age-related macular degeneration (AMD), assess the role of RPD as an independent risk factor for late AMD development, and evaluate genetic association with RPD. DESIGN:Prospective cohort study. PARTICIPANTS:Participants with intermediate AMD in 1 or both eyes enrolled in the Age-Related Eye Disease Study 2 (AREDS2), a 5-year multicenter study of nutritional supplement. METHODS:Fundus autofluorescence (FAF) images from a subset of AREDS2 participants were evaluated at annual visits for presence of RPD. Six single nucleotide polymorphisms-rs10490924 (ARMS2), rs1061170 (CFH), rs2230199 (C3), rs116503776 and rs114254831 (C2/CFB), and rs943080 (VEGF-A)-and the genetic risk score (GRS) were assessed for association with RPD. Development of late AMD, defined as geographic atrophy (GA) or neovascular AMD (NVAMD), was identified. MAIN OUTCOME MEASURES:Prevalence of RPD, odds ratio (OR) of late AMD development, and genetic associations of RPD. RESULTS:The FAF images were evaluated for 5021 eyes (2516 participants). Reticular pseudodrusen were seen in 1186 eyes (24% of eyes, 29% of participants). Prevalence of RPD varied with baseline AREDS AMD severity level: 6% in early AMD (n = 458), 26% in intermediate AMD (n = 2606), 36% in GA (n = 682), and 19% in NVAMD (n = 1246). Mean age of participants with RPD was 79 years (standard deviation [SD], 7) and 75 years (SD, 8) in those without RPD (P < 0.0001). Reticular pseudodrusen were more frequent in female participants (65% RPD vs. 53% no RPD). Odds ratio adjusted for baseline age, gender, race, educational status, smoking, and AMD severity level for 1710 eyes at risk of developing late AMD at the next annual visit was 2.42 (95% confidence interval [CI], 1.80-3.24; P < 0.001) for GA and 1.21 (95% CI, 0.87-1.7; P = 0.26) for NVAMD. Presence of RPD was significantly associated with higher GRS (P < 0.0001) and ARMS2 risk alleles (P < 0.0001) and, at a nominal level, with C3 risk alleles (P = 0.04) and CFH risk alleles (P = 0.048 for homozygotes). CONCLUSIONS:Participants with RPD have an increased risk of progression to GA but not NVAMD. ARMS2 risk alleles and higher GRS were associated with the presence of RPD. This study suggests that RPD are an important risk marker and should be included in classification systems used for patient prognosis.

Project description:BackgroundTo identify novel biomarkers related to the pathogenesis of dry age-related macular degeneration (AMD), we adopted a human retinal pigment epithelial (RPE) cell culture model that mimics some features of dry AMD including the accumulation of intra- and sub-RPE deposits. Then, we investigated the aqueous humor (AH) proteome using a data-independent acquisition method (sequential window acquisition of all theoretical fragment ion mass spectrometry) for dry AMD patients and controls.MethodsAfter uniformly pigmented polarized monolayers of human fetal primary RPE (hfRPE) cells were established, the cells were exposed to 4-hydroxy-2-nonenal (4-HNE), followed by Western blotting, immunofluorescence analysis and ELISA of cells or conditioned media for several proteins of interest. Data-dependent acquisition for identification of the AH proteome and SWATH-based mass spectrometry were performed for 11 dry AMD patients according to their phenotypes (including soft drusen and reticular pseudodrusen [RPD]) and 2 controls (3 groups).ResultsIncreased intra- and sub-RPE deposits were observed in 4-HNE-treated hfRPE cells compared with control cultures based on APOA1, cathepsin D, and clusterin immunoreactivity. Additionally, the differential abundance of proteins in apical and basal chambers with or without 4-HNE treatment confirmed the polarized secretion of proteins from hfRPE cells. A total of 119 proteins were quantified in dry AMD patients and controls by SWATH-MS. Sixty-five proteins exhibited significantly altered abundance among the three groups. A two-dimensional principal component analysis plot was generated to identify typical proteins related to the pathogenesis of dry AMD. Among the identified proteins, eight proteins, including APOA1, CFHR2, and CLUS, were previously considered major components or regulators of drusen. Three proteins (SERPINA4, LUM, and KERA proteins) have not been previously described as components of drusen or as being related to dry AMD. Interestingly, the LUM and KERA proteins, which are related to extracellular matrix organization, were upregulated in both RPD and soft drusen.ConclusionsDifferential protein expression in the AH between patients with drusen and RPD was quantified using SWATH-MS in the present study. Detailed proteomic analyses of dry AMD patients might provide insights into the in vivo biology of drusen and RPD.

Project description:To evaluate the association between pseudodrusen and incidence of late age-related macular degeneration (AMD) in fellow eyes of patients with unilateral neovascular AMD (nAMD).Cohort study within the Comparison of AMD Treatments Trials (CATT).Patients with neither nAMD nor geographic atrophy (GA) in the fellow eye at baseline.Presence and type (dot, reticular, or confluent) of baseline pseudodrusen were assessed using digital color fundus photography (CFP) viewed under full color, green channel, and blue channel; red-free images; and fluorescein angiography (FA). Incidence of nAMD was based on monthly clinical examination and reading center evaluation of images at years 1 and 2. Incidence of GA was based on reading center evaluation of CFP and FA images at years 1 and 2. Associations of baseline pseudodrusen with incident nAMD and GA were summarized with adjusted risk ratios (aRRs) and their 95% confidence intervals (CIs) from multivariate Cox models, with adjustment of covariates identified through backward stepwise selection.Incident nAMD and GA.Among 620 fellow eyes, 176 (28.4%) had baseline pseudodrusen (55% dot, 82% reticular, 35% confluent). Within 2 years, nAMD occurred in 54 eyes (30.7%) with pseudodrusen and in 72 eyes (16.2%) without pseudodrusen (aRR, 2.05; 95% CI, 1.43-2.93); GA occurred in 27 eyes (15.3%) with pseudodrusen and in 37 eyes (8.3%) without pseudodrusen (aRR, 1.89; 95% CI, 1.13-3.17); late AMD occurred in 73 eyes (41.5%) with pseudodrusen and in 101 eyes (22.8%) without pseudodrusen (aRR, 2.07; 95% CI, 1.51-2.83). Dot pseudodrusen were associated independently with nAMD (aRR, 2.53; 95% CI, 1.60-4.00), whereas confluent pseudodrusen were associated independently with GA (aRR, 4.35; 95% CI, 1.69-11.2). Eyes with pseudodrusen had increased incidence of late AMD regardless of whether the Age-Related Eye Diseases Study (AREDS) severity score was 2 (28.7% vs. 10.3%), 3 (34.9% vs. 13.7%), or 4 (50.5% vs. 32.0%).In fellow eyes of CATT participants, pseudodrusen were associated independently with a higher incidence of both nAMD and GA. Dot pseudodrusen were associated with nAMD, whereas confluent pseudodrusen were associated with GA. Pseudodrusen should be considered along with the AREDS severity score for predicting late AMD.

Dataset Information

Plasma Biomarkers of Reticular Pseudodrusen and the Risk of Progression to Advanced Age-Related Macular Degeneration.

Publications

Plasma Biomarkers of Reticular Pseudodrusen and the Risk of Progression to Advanced Age-Related Macular Degeneration.

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