The proteomics of drusen.
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ABSTRACT:
SUBMITTER: Crabb JW
PROVIDER: S-EPMC4066642 | biostudies-literature | 2014 May
REPOSITORIES: biostudies-literature
Publications
The formation of extracellular deposits known as drusen below the macular region of the retina correlates with increased risk of severe visual loss from age-related macular degeneration (AMD). Inflammation and complement dysregulation contribute to AMD progression; however, disease mechanisms remain incompletely defined. Multiple genetic and environmental factors influence AMD pathology, and although immune system processes play a central role, multiple molecular mechanisms appear to be involved ...[more]
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Project description:PurposeSpectral domain-optical coherence tomography (SD-OCT) may be useful for efficient measurement of drusen in patients with age-related macular degeneration (AMD). Areas identified as drusen from semiautomated segmentation of drusen on SD-OCT were compared to those identified from review of digital color fundus photographs (CFPs).MethodsTwelve eyes with nonneovascular AMD were prospectively imaged with digital CFP and SD-OCT. For each eye, areas on CFP in which at least two of three retina specialists agreed on drusen presence produced the composite CFP drusen map. Automated image analysis produced another CFP map. Areas identified as drusen by segmentation on SD-OCT B-scans were plotted as the SD-OCT drusen map. The CFP and SD-OCT maps were compared and agreement was quantified. Disagreement was characterized into distinct types, and the frequency of each type was quantified.ResultsThere was general agreement between CFP and SD-OCT in identifying presence and absence of drusen, with mean agreement in 82% ± 9% of total image pixels. Most disagreement (80% ± 15%) occurred at drusen margins. There was a trend toward greater detection of drusen with SD-OCT in eyes with larger drusen and with hyperpigmentation. There was a trend toward greater detection of smaller drusen by CFP.ConclusionsGood agreement was demonstrated in drusen detection between CFP and SD-OCT. Areas of disagreement underscore limitations of CFP-based measurement of drusen, particularly in the sizing of large, soft drusen. SD-OCT shows great promise as an adjunctive tool for assessing drusen burden in AMD. (ClinicalTrials.gov number, NCT00734487.).
| S-EPMC2939301 | biostudies-literature
Project description:Autosomal dominant radial drusen (ADRD), also termed Malattia Leventinese and Doyne honeycomb retinal dystrophy, causes early-onset vision loss because of mutation in EFEMP1. Drusen in an exceedingly rare ADRD human donor eye was compared with eyes affected with age-related macular degeneration (AMD). This study also elucidated whether variations in high-risk AMD genotypes modify phenotypic severity of ADRD.Morphologic and histochemical analyses of drusen in one ADRD donor and seven AMD donors. Evaluation of complement factor H (CFH) and ARMS2/HTRA1 alleles in a cohort of 25 subjects with ADRD.Autosomal dominant radial drusen had unique onion skin-like lamination but otherwise shared many compositional features with hard, nodular drusen and/or diffuse soft drusen with basal deposits. Autosomal dominant radial drusen also possessed collagen type IV, an extracellular matrix protein that is absent in age-related drusen. Antibodies directed against the membrane attack complex showed robust labeling of ADRD. Vitronectin and amyloid P were present in drusen of both types. High-risk alleles in the CFH and ARMS2/HTRA1 genes were not associated with increasing ADRD severity.Drusen from ADRD and AMD exhibit overlap of some major constituents, but ADRD exhibit distinct alterations in the extracellular matrix that are absent in AMD.
| S-EPMC5513174 | biostudies-literature
Project description:PURPOSEAge-related macular degeneration is a common form of vision loss affecting older adults. The etiology of AMD is multifactorial and is influenced by environmental and genetic risk factors. In this study, we examine how 19 common risk variants contribute to drusen progression, a hallmark of AMD pathogenesis.METHODSExome chip data was made available through the International AMD Genomics Consortium (IAMDGC). Drusen quantification was carried out with color fundus photographs using an automated drusen detection and quantification algorithm. A genetic risk score (GRS) was calculated per subject by summing risk allele counts at 19 common genetic risk variants weighted by their respective effect sizes. Pathway analysis of drusen progression was carried out with the software package Pathway Analysis by Randomization Incorporating Structure.RESULTSWe observed significant correlation with drusen baseline area and the GRS in the age-related eye disease study (AREDS) dataset (? = 0.175, P = 0.006). Measures of association were not statistically significant between drusen progression and the GRS (P = 0.54). Pathway analysis revealed the cell adhesion molecules pathway as the most highly significant pathway associated with drusen progression (corrected P = 0.02).CONCLUSIONSIn this study, we explored the potential influence of known common AMD genetic risk factors on drusen progression. Our results from the GRS analysis showed association of increasing genetic burden (from 19 AMD associated loci) to baseline drusen load but not drusen progression in the AREDS dataset while pathway analysis suggests additional genetic contributors to AMD risk.
| S-EPMC4849854 | biostudies-literature
Project description:Background:To investigate whether neovascularization may arise and be detectable in drusen, as reported in histopathologic studies, by OCTA prior to developing exudation and to assess its prevalence in a cohort of patients with intermediate AMD. Methods:Retrospective cross-sectional study of 128 patients with intermediate AMD recruited as part of a separate ongoing clinical trial conducted at multiple large tertiary referral retina clinics. One hundred and twenty-eight consecutive patients with exudative AMD in one eye and intermediate non-exudative AMD in the fellow eye were enrolled and analyzed between September 2015 and March 2017. Results:SD-OCTA identified vascularization within drusen in 7 of 128 eyes, for a prevalence of 5.5%. A total of 12 instances of vascularized drusen were noted. Out of the 12 vascularized drusen noted, 7 were located in the parafoveal region or subfoveal region and 5 was in the extrafoveal region. 9 of 12 instances of vascularized drusen exhibited a uniform sub-RPE hyperreflectivity, whilst 3 of 12 exhibited more heterogenous reflectivity. In all 12 instances, FA images failed to identify the neovascular nature of vascularized drusen. Conclusions:Our results demonstrate the utility of SD-OCTA for the diagnosis of vascularized drusen in patients with intermediate non-exudative AMD. Longitudinal studies are needed to delineate the evolution and conversion risk of these lesions over time, which can be of substantial clinical relevance.
| S-EPMC6702713 | biostudies-literature
Project description:OBJECTIVE: Autosomal dominant drusen is of particular interest because of its phenotypic similarity to age related macular degeneration. Currently, mutation R345W of EFEMP1 and, in a single pedigree, linkage to chromosome 6q14 have been causally related to the disease. We proposed to investigate and quantify the roles of EFEMP1 and the 6q14 locus in dominant drusen patients from the UK and USA. DESIGN: Molecular genetic analysis. PARTICIPANTS: Ten unrelated families and 17 young drusen patients. MAIN OUTCOME MEASURES: Exons 1 and 2 of EFEMP1 were characterised by 5' rapid amplification of cDNA ends and direct sequencing. Exons 1-12 of EFEMP1 were then investigated for mutation by direct sequencing. A HpaII restriction digest test was constructed to detect the EFEMP1 R345W mutation. Marker loci spanning the two dominant drusen linked loci were used to generate haplotype data. RESULTS: Only seven of the 10 families (70%) and one of the 17 sporadic patients (6%) had the R345W mutation. The HpaII restriction digest test was found to be a reliable and quick method for detecting this. No other exonic or splice site mutation was identified. Of the three families without EFEMP1 mutation, two were linked to the 2p16 region. CONCLUSIONS: EFEMP1 R345W accounts for only a proportion of the dominant drusen phenotype. Importantly, other families linked to chromosome 2p16 raise the possibility of EFEMP1 promoter sequence mutation or a second dominant drusen gene at this locus. Preliminary haplotype data suggest that the disease gene at the 6q14 locus is responsible for only a minority of dominant drusen cases.
| S-EPMC1734899 | biostudies-other
Project description:Drusen are extracellular lesions characteristic of aging and age-related maculopathy, a major retinal disease of the elderly. We determined the relative proportions of lipids and proteins in drusen capped with retinal pigment epithelium (RPE) and in RPE isolated from non-macular regions of 36 human retinas with grossly normal maculas obtained <6 hr after death.Druse pellets were examined by light and electron microscopy. Component proteins were extracted using novel methods for preserved tissues, separated, subjected to tryptic digestion and LC-MS(MS)(2) analysis using an ion trap mass spectrometer, and identified with reference to databases. Lipid classes were separated using thin layer chromatography and quantified by densitometry. Major druse components were esterified cholesterol (EC), phosphatidylcholine (PC), and protein (37.5+/-13.7, 36.9+/-12.9, and 43.0+/-11.5 ng/druse, respectively). Lipid-containing particles (median diameter, 77 nm) occupied 37-44% of druse volume. Major proteins include vitronectin, complement component 9, apoE, and clusterin, previously seen in drusen, and ATP synthase subunit beta, scavenger receptor B2, and retinol dehydrogenase 5, previously seen in RPE. Drusen and RPE had similar protein profiles, with higher intensities and greater variability in drusen. C8, part of the complement membrane attack complex, was localized in drusen by immunofluorescence.At least 40% of druse content is comprised by lipids dominated by EC and PC, 2 components that are potentially accounted for by just one pathway, the secretion of lipoproteins by RPE. Manipulating genes encoding apolipoprotein pathways would be a fruitful approach to producing drusen with high EC content in laboratory animals. Therapies that directly mitigate drusen should prepare for the substantial volume of neutral lipids. The catalog of major druse proteins is nearing completion.
| S-EPMC2859054 | biostudies-literature
Project description:Cuticular drusen are part of the spectrum of age-related macular degeneration (AMD) with particular clinical and multimodal imaging characteristics. This drusen subpopulation shares several high-risk single nucleotide polymorphisms with AMD. Despite this feature, they can manifest at a relatively young age, presenting with a female preponderance. Multimodal imaging is essential for characterizing such lesions, using a combination of color fundus photographs, optical coherence tomography (OCT), fluorescein angiography (FA), and fundus autofluorescence (FAF). The classic starry-sky pattern visible on FA and the typical central hypoautofluorescent lesion with hyperautofluorescent rim on FAF is considered the result of a central retinal pigment epithelium (RPE) erosion from these triangular elevations of the RPE-basal lamina. This finding may also be responsible for the typical choroidal hypertransmission appreciated through OCT. The clinical course of cuticular drusen may be relatively benign at early stages, with small drusen presenting at a young age. However, the presence of clinical phenotypes characterized by diffuse involvement and/or accompanying large drusen in patients older than 60 years may confer a significant risk for either macular neovascularization or geographic atrophy.
| S-EPMC8464647 | biostudies-literature
Project description:PURPOSE: The purpose of this study is to optimise the settings of the Retinal Image Analysis Laboratory (RIALAB), a semi-automatic drusen quantification software, in planning for high-throughput quantification of drusen in clinical studies of age-related macular degeneration (AMD). PATIENTS AND METHODS: A comparison of five different settings in RIALAB was made on 67 images from the Rotterdam eye study (population-based study) and 56 images from the fellow eye of patients with active neovascular AMD in King's College Hospital, London (hospital-based study). RESULTS: The 'Few Outer' setting was the best setting, with it being most appropriate for 52 (77.6%) of the Rotterdam cohort and 47 (83.9%) for the London cohort. Pearson's χ(2)-test revealed both results to be statistically significant (P<0.0001). CONCLUSIONS: RIALAB is a viable algorithm and software package that can detect, quantify, and analyse drusen efficiently in both population-based and hospital-based studies. We have shown that the 'Few Outer' drusen setting can be employed as the default setting, with fine-tuning only needed in a minority of cases, thus helping to speed up workflow.
| S-EPMC3625998 | biostudies-other
Project description:PURPOSE:To analyze risk factors for extramacular drusen (EMD) in patients with age-related macular degeneration (AMD) and healthy control individuals. METHODS:This case-control study included 1,520 patients from the prospective multicenter European Genetic Database (EUGENDA). Color fundus photographs and optical coherence tomography scans were evaluated for the presence of AMD and EMD. EMD was considered present if ten or fewer drusen including at least one intermediate-sized drusen were detected outside the macula. Association of EMD was evaluated with various genetic and non-genetic risk factors (31 single nucleotide polymorphisms, systemic complement activation, smoking, cardiovascular factors, and sunlight exposure) using logistic regression models adjusted for age, gender, and AMD. RESULTS:EMD was found in 608 subjects (40%) and AMD in 763 (50%) of 1,520 participants. EMD was strongly associated with AMD (p = 2.83 × 10-63, odds ratio [OR] 7.63). After adjustment for AMD, age (p = 0.06, OR 1.02), female gender (p = 3.34 × 10-24, OR 4.44), history of sunlight exposure ? 8 h /day (p = 0.0004, OR 1.99), serum complement activation (p = 0.004, OR 1.61), and polymorphisms in ARMS2 (p = 0.00016, OR 1.43) and CFI (p = 0.043, OR 1.20) were identified as risk factors for EMD. The final prediction model including these variants showed an area under the curve of 0.820. CONCLUSIONS:The comprehensive analysis of various risk factors revealed a common genetic and pathological pathway of EMD with AMD. Future longitudinal studies are needed to evaluate the role of EMD in otherwise healthy subjects as an expanded phenotype of AMD.
| S-EPMC7553721 | biostudies-literature
Project description:PurposeDrusen are a hallmark of eyes affected by age-related macular degeneration. In previous study, a conformational-specific antibody showed drusen to contain nonfibrillar amyloid structures. The current study was undertaken to assess the presence of additional amyloid structures in drusen.MethodsSections from human donor eyes were reacted with M204, a monoclonal antibody that recognizes nonfibrillar oligomers; OC, a polyclonal antibody that recognizes amyloid fibrils of various molecular weights; and WO1 and WO2, monoclonal antibodies that are specifically reactive to mature amyloid fibrils. Electron microscopy was used as an independent means of investigating the presence of amyloid fibrils in drusen.ResultsThe presence of nonfibrillar oligomers was verified using the M204 antibody. OC and WO antibodies stained a wide spectrum of vesicular structures. OC reactivity showed extensive overlap with Abeta immunoreactivity, whereas a partial overlap was seen between Abeta reactivity and that of the WO antibodies. The presence of amyloid fibrils was also visualized by electron microscopy.ConclusionsThese data reveal the presence of a wide spectrum of amyloid structures in drusen. The results are significant, given that specific conformational forms of amyloid are known to be pathogenic in a variety of neurodegenerative diseases. Deposition of these structures may lead to local toxicity of the retinal pigmented epithelium or induction of local inflammatory events that contribute to drusen biogenesis and the pathogenesis of AMD.
| S-EPMC2840723 | biostudies-literature