Dataset Information

Complement factors and reticular pseudodrusen in intermediate age-related macular degeneration staged by multimodal imaging.

ABSTRACT: Objective:Systemic activation of the complement system in intermediate age-related macular degeneration (AMD) is understudied. Moreover, links between the presence of reticular pseudodrusen (RPD) and systemic complement dysregulation have not been studied. The aim of this study was to determine if there is a difference in plasma complement factor levels in intermediate AMD compared with controls, and if complement levels are related to the presence of RPD. Methods and analysis:Levels of complement factors C1q (µg/mL), C4 (µg/mL), C2 (µg/mL), Mannose Binding Lectin (ng/mL), C4b (µg/mL), C3 (µg/mL), factor B (µg/mL), factor D (µg/mL), properdin (µg/mL), C3a (ng/mL), iC3b/C3b (ng/mL), Ba (ng/mL), factor H (µg/mL), factor I (µg/mL), C5 (µg/mL), C5a (pg/mL) and SC5b-9 (ng/mL) were measured in plasma. Results:109 cases and 65 controls were included in the study. Thirty-nine (36%) cases had RPD. Significantly lower systemic levels of: C1q (OR 0.96, 95%?CI 0.94?to 0.98), factor B (OR 0.98, 95%?CI 0.96?to 0.99), iC3b/C3b (OR 0.97, 95%?CI 0.95?to 0.98), factor H (OR 0.99, 95%?CI 0.98?to 0.99), factor I (OR 0.83, 95%?CI 0.77?to 0.89) and C5 (OR 0.94, 95%?CI 0.90?to 0.98) were found in cases versus controls. Significantly elevated levels of: C2 (OR 1.29, 95%?CI 1.07?to 1.59), C3a (OR 1.03, 95%?CI 1.01?to 1.05) Ba (OR 1.03, 95%?CI 1.01?to 1.05) and C5a (OR 1.04, 95%?CI 1.02?to 1.07) were found in cases versus controls. Systemic levels of complement factors measured were not related to the presence of RPD. Conclusions:Levels of several systemic complement pathway factors were found to be altered in intermediate AMD. Systemic levels of complement factors were not related to RPD.

SUBMITTER: Lynch AM

PROVIDER: S-EPMC7254108 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Complement factors and reticular pseudodrusen in intermediate age-related macular degeneration staged by multimodal imaging.

Lynch Anne M AM Palestine Alan G AG Wagner Brandie D BD Patnaik Jennifer L JL Frazier-Abel Ashley A AA Mathias Marc T MT Siringo Frank S FS Holers Vernon Michael VM Mandava Naresh N

BMJ open ophthalmology 20200114 1

<h4>Objective</h4>Systemic activation of the complement system in intermediate age-related macular degeneration (AMD) is understudied. Moreover, links between the presence of reticular pseudodrusen (RPD) and systemic complement dysregulation have not been studied. The aim of this study was to determine if there is a difference in plasma complement factor levels in intermediate AMD compared with controls, and if complement levels are related to the presence of RPD.<h4>Methods and analysis</h4>Lev ...[more]

PMID: 32509962

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Project description:PurposeTo determine the interreader agreement for reticular pseudodrusen (RPD) assessment on combined infrared reflectance (IR) and OCT imaging in the early stages of age-related macular degeneration across a range of different criteria to define their presence.DesignInterreader agreement study.ParticipantsTwelve readers from 6 reading centers.MethodsAll readers evaluated 100 eyes from individuals with bilateral large drusen for the following: (1) the presence of RPD across a range of different criteria and (2) the number of Stage 2 or 3 RPD lesions (from 0 to ≥ 5 lesions) on an entire OCT volume scan and on a selected OCT B-scan. Supportive information was available from the corresponding IR image.Main outcome measuresInterreader agreement, as assessed by Gwet's first-order agreement coefficient (AC1).ResultsWhen evaluating an entire OCT volume scan, there was substantial interreader agreement for the presence of any RPD, any or ≥ 5 Stage 2 or 3 lesions, and ≥ 5 definite lesions on en face IR images corresponding to Stage 2 or 3 lesions (AC1 = 0.60-0.72). On selected OCT B-scans, there was also moderate-to-substantial agreement for the presence of any RPD, any or ≥ 5 Stage 2 or 3 lesions (AC1 = 0.58-0.65) and increasing levels of agreement with increasing RPD stage (AC1 = 0.08, 0.56, 0.78, and 0.99 for the presence of any Stage 1, 2, 3, and 4 lesions, respectively). There was substantial agreement regarding the number of Stage 2 or 3 lesions on an entire OCT volume scan (AC1 = 0.68), but only fair agreement for this evaluation on selected B-scans (AC1 = 0.30).ConclusionsThere was generally substantial or near-substantial-but not near-perfect-agreement for assessing the presence of RPD on entire OCT volume scans or selected B-scans across a range of differing RPD criteria. These findings underscore how interreader variability would likely contribute to the variability of findings related to the clinical associations of RPD. The low levels of agreement for assessing RPD number on OCT B-scans underscore the likely challenges of quantifying RPD extent with manual grading.Financial disclosuresProprietary or commercial disclosure may be found after the references.

Project description:PurposeWe investigate whether ocular and person-based characteristics were associated with dark adaptation (DA).DesignCross-sectional, single-center, observational study.ParticipantsOne hundred sixteen participants older than 50 years of age with a range of age-related macular degeneration (AMD) severity.MethodsParticipants 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 measuresThe 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.ResultsA 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.ConclusionsImpairments 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:ImportanceAlthough 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.ObjectivesTo 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 participantsThe 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 measuresReticular 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.ResultsOf 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-?m 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 relevanceWith 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.

Project description:BackgroundTo investigate the characteristics of retinal vessels and retinal thickness in eyes with early age-related macular degeneration (AMD) with or without reticular pseudodrusen.MethodsWe retrospectively evaluated the clinical history and optical coherence tomography (OCT) and OCT angiography images of consecutive patients with early AMD. We calculated the retinal vessel densities of the superficial and deep capillary plexus with the ImageJ software (National Institutes of Health, Bethesda, MD, USA) and investigated the relationship with mean retinal thickness and subfoveal choroidal thickness.ResultsWe included 135 early AMD eyes and classified 60 of them into a reticular pseudodrusen group and 75 into a non-reticular pseudodrusen group. The vascular densities of the superficial and deep capillary plexus in the reticular pseudodrusen group (32.35% ± 3.67 and 26.71% ± 2.88%) were not different from those of the non-reticular pseudodrusen group (33.18% ± 2.2% and % 27.43 ± 1.79%; P = 0.546 and P = 0.318, respectively). The retinal thickness of the reticular pseudodrusen group (287.31 μm ± 24.36 μm) did not differ from that of the non-reticular pseudodrusen group (294.27 μm ± 20.71 μm; P = 0.493), while subfoveal choroidal thickness in the reticular pseudodrusen group (158.13 μm ± 42.53 μm) was lower than that in the non-reticular pseudodrusen group (237.89 μm ± 60.94 μm; P < 0.001). Multivariate analysis revealed that lower vascular density of the superficial capillary plexus and subfoveal choroidal thickness were associated with retinal thinning in reticular pseudodrusen group (P = 0.003 and P = 0.036) and older age was associated with retinal thickness in the non-reticular pseudodrusen group (P = 0.005).ConclusionsRetinal thinning in early AMD patients with reticular pseudodrusen was accompanied by choroidal and retinal vascular loss, which suggests a possible linkage of retinal thinning with vascular alterations.

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.

Dataset Information

Complement factors and reticular pseudodrusen in intermediate age-related macular degeneration staged by multimodal imaging.

Publications

Complement factors and reticular pseudodrusen in intermediate age-related macular degeneration staged by multimodal imaging.

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