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Eye (London, England) Mar 2024To investigate the prevalence of macular lesions associated with age-related macular degeneration (AMD) in eyes with pachydrusen.
BACKGROUND
To investigate the prevalence of macular lesions associated with age-related macular degeneration (AMD) in eyes with pachydrusen.
METHODS
Clinical records and multimodal imaging data of patients over 50 years old with drusen or drusenoid deposits were retrospectively assessed, and eyes with pachydrusen were included in this study. The presence of AMD features, including drusen or drusenoid deposits, macular pigmentary abnormalities, geographic atrophy (GA), and macular neovascularization (MNV), were evaluated.
RESULTS
Out of 967 eyes of 494 patients with drusen or drusenoid deposits, 330 eyes of 183 patients had pachydrusen (34.1%). The mean age was 66.1 ± 9.3 years, and the subfoveal choroidal thickness (SFCT) was 292.7 ± 100.1 μm. The mean number of pachydrusen per eye was 2.22 ± 1.73. The majority of eyes with pachydrusen had no other drusen or drusenoid deposits (95.2%). Only 16 eyes (4.8%) had other deposits, including soft drusen (10 eyes, 3.0%), cuticular drusen (3 eyes, 0.9%), and reticular pseudodrusen (RPD; 3 eyes, 0.9%). Macular pigmentary abnormalities accompanied pachydrusen in 68 eyes (27.4%). None of the eyes had GA, and 82 eyes (24.8%) had MNV. The majority of MNV was polypoidal choroidal vasculopathy (PCV; 65 eyes, 19.7%), followed by type 1 (10 eyes, 3.0%), type 2 (5 eyes, 1.5%), and type 3 MNV (2 eyes, 0.6%).
CONCLUSIONS
Eyes with pachydrusen in Korean population have several characteristic AMD lesions in low frequencies. These findings indicate that pachydrusen might have diagnostic and prognostic values that are different from those of other drusen or drusenoid deposits.
Topics: Humans; Middle Aged; Aged; Retrospective Studies; Tomography, Optical Coherence; Macular Degeneration; Retinal Drusen; Retina; Geographic Atrophy; Neovascularization, Pathologic; Fluorescein Angiography
PubMed: 37773436
DOI: 10.1038/s41433-023-02752-0 -
Investigative Ophthalmology & Visual... Apr 2024Complement dysregulation is a key component in the pathogenesis of age-related macular degeneration (AMD) and related diseases such as early-onset macular drusen (EOMD)....
PURPOSE
Complement dysregulation is a key component in the pathogenesis of age-related macular degeneration (AMD) and related diseases such as early-onset macular drusen (EOMD). Although genetic variants of complement factor H (CFH) are associated with AMD risk, the impact of CFH and factor H-like protein 1 (FHL-1) expression on local complement activity in human retinal pigment epithelium (RPE) remains unclear.
METHODS
We identified a novel CFH variant in a family with EOMD and generated patient induced pluripotent stem cell (iPSC)-derived RPE cells. We assessed CFH and FHL-1 co-factor activity through C3b breakdown assays and measured complement activation by immunostaining for membrane attack complex (MAC) formation. Expression of CFH, FHL-1, local alternative pathway (AP) components, and regulators of complement activation (RCA) in EOMD RPE cells was determined by quantitative PCR, western blot, and immunostaining. Isogenic EOMD (cEOMD) RPE was generated using CRISPR/Cas9 gene editing.
RESULTS
The CFH variant (c.351-2A>G) resulted in loss of CFH and FHL-1 expression and significantly reduced CFH and FHL-1 protein expression (∼50%) in EOMD iPSC RPE cells. These cells exhibited increased MAC deposition upon exposure to normal human serum. Under inflammatory or oxidative stress conditions, CFH and FHL-1 expression in EOMD RPE cells paralleled that of controls, whereas RCA expression, including MAC formation inhibitors, was elevated. CRISPR/Cas9 correction restored CFH/FHL-1 expression and mitigated alternative pathway complement activity in cEOMD RPE cells.
CONCLUSIONS
Identification of a novel CFH variant in patients with EOMD resulting in reduced CFH and FHL-1 and increased local complement activity in EOMD iPSC RPE supports the involvement of CFH haploinsufficiency in EOMD pathogenesis.
Topics: Humans; Complement Factor H; Haploinsufficiency; Retinal Pigment Epithelium; Macular Degeneration; Male; Female; Induced Pluripotent Stem Cells; Complement C3b Inactivator Proteins; Complement Activation; Pedigree; Blotting, Western; Complement System Proteins; Retinal Drusen; Middle Aged; Muscle Proteins; Intracellular Signaling Peptides and Proteins; LIM Domain Proteins
PubMed: 38683564
DOI: 10.1167/iovs.65.4.43 -
Acta Ophthalmologica Mar 2024Age-related macular degeneration (AMD) is a devastating eye disease that causes permanent vision loss in the central part of the retina, known as the macula. Patients...
Age-related macular degeneration (AMD) is a devastating eye disease that causes permanent vision loss in the central part of the retina, known as the macula. Patients with such severe visual loss face a reduced quality of life and are at a 1.5 times greater risk of death compared to the general population. Currently, there is no cure for or effective treatment for dry AMD. There are several mechanisms thought to underlie the disease, for example, ageing-associated chronic oxidative stress, mitochondrial damage, harmful protein aggregation and inflammation. As a way of gaining a better understanding of the molecular mechanisms behind AMD and thus developing new therapies, we have created a peroxisome proliferator-activated receptor gamma coactivator 1-alpha and nuclear factor erythroid 2-related factor 2 (PGC1α/NFE2L2) double-knockout (dKO) mouse model that mimics many of the clinical features of dry AMD, including elevated levels of oxidative stress markers, damaged mitochondria, accumulating lysosomal lipofuscin and extracellular drusen-like structures in retinal pigment epithelial cells (RPE). In addition, a human RPE cell-based model was established to examine the impact of non-functional intracellular clearance systems on inflammasome activation. In this study, we found that there was a disturbance in the autolysosomal machinery responsible for clearing mitochondria in the RPE cells of one-year-old PGC1α/NFE2L2-deficient mice. The confocal immunohistochemical analysis revealed an increase in autophagosome marker microtubule-associated proteins 1A/1B light chain 3B (LC3B) as well as multiple mitophagy markers such as PTE-induced putative kinase 1 (PINK1) and E3 ubiquitin ligase (PARKIN), along with signs of damaged mitochondria. However, no increase in autolysosome formation was detected, nor was there a colocalization of the lysosomal marker LAMP2 or the mitochondrial marker, ATP synthase β. There was an upregulation of late autolysosomal fusion Ras-related protein (Rab7) in the perinuclear space of RPE cells, together with autofluorescent aggregates. Additionally, we observed an increase in the numbers of Toll-like receptors 3 and 9, while those of NOD-like receptor 3 were decreased in PGC1α/NFE2L2 dKO retinal specimens compared to wild-type animals. There was a trend towards increased complement component C5a and increased involvement of the serine protease enzyme, thrombin, in enhancing the terminal pathway producing C5a, independent of C3. The levels of primary acute phase C-reactive protein and receptor for advanced glycation end products were also increased in the PGC1α/NFE2L2 dKO retina. Furthermore, selective proteasome inhibition with epoxomicin promoted both nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and mitochondrial-mediated oxidative stress, leading to the release of mitochondrial DNA to the cytosol, resulting in potassium efflux-dependent activation of the absent in melanoma 2 (AIM2) inflammasome and the subsequent secretion of interleukin-1β in ARPE-19 cells. In conclusion, the data suggest that there is at least a relative decrease in mitophagy, increases in the amounts of C5 and thrombin and decreased C3 levels in this dry AMD-like model. Moreover, selective proteasome inhibition evoked mitochondrial damage and AIM2 inflammasome activation in ARPE-19 cells.
Topics: Humans; Animals; Mice; Infant; Inflammasomes; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Retinal Pigment Epithelium; Thrombin; Proteasome Endopeptidase Complex; Quality of Life; Macular Degeneration; Oxidative Stress; Geographic Atrophy; Biomarkers; Epithelial Cells; Retinal Pigments
PubMed: 38467968
DOI: 10.1111/aos.16661 -
Ophthalmology. Retina Jun 2024To evaluate which OCT prognostic biomarkers best predict the risk of progression from early/intermediate to late age-related macular degeneration (AMD). (Meta-Analysis)
Meta-Analysis Review
TOPIC
To evaluate which OCT prognostic biomarkers best predict the risk of progression from early/intermediate to late age-related macular degeneration (AMD).
CLINICAL RELEVANCE
Among > 100 OCT prognostic biomarkers for AMD, it is unclear which are the most relevant for clinicians and researchers to focus on. This review evaluated which OCT biomarkers confer the greatest magnitude of prediction for progression to late AMD.
METHODS
Study protocol was registered on PROSPERO (CRD42023400166). PubMed and Embase were searched from inception to March 2, 2023, and eligible studies assessed following the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. The primary outcome was any quantified risk of progression from treatment-naive early/intermediate AMD to late AMD, including hazard ratios (HRs), odds ratios (ORs), and standardized mean differences (at baseline, between eyes with versus without progression), subgrouped by each OCT biomarker. Further meta-analyses were subgrouped by progression to geographic atrophy or neovascularization.
RESULTS
A total of 114 quantified OCT prognostic biomarkers were identified. With high GRADE certainty of evidence, the greatest magnitudes of prediction to late AMD belonged to: external limiting membrane abnormality (OR, 15.42 [7.63, 31.17]), ellipsoid zone abnormality (OR, 10.8 [4.58, 25.46]), interdigitation zone abnormality (OR, 7.68 [2.57, 23]), concurrent large drusen and reticular pseudodrusen (HR, 6.73 [1.35, 33.65], hyporeflective drusen cores (HR, 2.48 [1.8, 3.4]; OR 1.85 [1.29, 2.66]), intraretinal hyperreflective foci (IHRF; HR, 2.16 [0.92, 5.07]; OR 5.08 [3.26, 7.92]), and large drusen (HR, 2.01 [1.35, 2.99]); OR, 1.98 [1.27, 3.08]). There was greater risk of geographic atrophy for IHRF and hyporeflective drusen cores (P < 0.05), and neovascularization for ellipsoid zone abnormality (P < 0.05). Other OCT biomarkers such as drusenoid pigment epithelium detachment, shallow irregular retinal pigment epithelium elevations, and nascent geographic atrophy exhibited large magnitudes of risk but required further studies for validation.
CONCLUSION
This review synthesizes the 6 most relevant OCT prognostic biomarkers for AMD with greater predictive ability than large drusen alone, for clinicians and researchers to focus on. Further study is required to validate other biomarkers with less than high certainty of evidence, and assess how the copresence of biomarkers may affect risks.
FINANCIAL DISCLOSURE(S)
The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Topics: Humans; Disease Progression; Prognosis; Tomography, Optical Coherence; Biomarkers; Macular Degeneration
PubMed: 38154619
DOI: 10.1016/j.oret.2023.12.006 -
Acta Ophthalmologica Jan 2024To test the hypothesis that central drusen location is strongly linked with known Age-related Macular Degeneration (AMD) risk factors and risk of incident late AMD.
PURPOSE
To test the hypothesis that central drusen location is strongly linked with known Age-related Macular Degeneration (AMD) risk factors and risk of incident late AMD.
METHODS
The Alienor study is a prospective population-based cohort study of residents of Bordeaux, France, followed from 2009 to 2017. On retinal photographs, we defined central drusen as at least one soft drusen (>63 μm) within 500 μm from fovea and pericentral drusen as at least one drusen 500-3000 μm from fovea, in the absence of any central drusen. Late AMD (atrophic and/or neovascular) was diagnosed using multimodal imaging. In total, 481 eyes were included in the analysis: 160 central and 321 pericentral. We investigated associations with systemic (age, sex, smoking, medical prescriptions, plasma concentrations of lipids and nutrients, UV exposure, blood pressure), ocular (retinal thickness, cataract extraction) and genetic risk scores (GRS).
RESULTS
In multivariate logistic regression central drusen were associated with smoking (OR, 2.95 for smoking more than 20 pack-years, p = 0.02), HDL-cholesterol (OR, 1.57 for 1 standard deviation (SD) increase, p = 0.0048), pulse pressure (OR, 0.77 for 1 SD increase, p = 0.04), Age-Related Maculopathy Susceptibility 2 (ARMS2) GRS (OR, 1.42; 95% CI, 1.11-1.83) and complement GRS (OR, 1.55; 95% CI, 1.15-2.10). In Cox modelling, the central location of drusen (at baseline or during the follow-up) was associated with a 4.41-fold increased risk (95% CI,1.98-9.81) for an incident late AMD.
CONCLUSION
Central drusen were strongly associated with AMD risk factors and incident late AMD, suggesting that it represents a key marker for AMD progression.
PubMed: 38278777
DOI: 10.1111/aos.16645 -
Diagnostics (Basel, Switzerland) Apr 2024The imagistic evaluation of non-neovascular age-related macular degeneration (AMD) is crucial for diagnosis, monitoring progression, and guiding management of the... (Review)
Review
The imagistic evaluation of non-neovascular age-related macular degeneration (AMD) is crucial for diagnosis, monitoring progression, and guiding management of the disease. Dry AMD, characterized primarily by the presence of drusen and retinal pigment epithelium atrophy, requires detailed visualization of the retinal structure to assess its severity and progression. Several imaging modalities are pivotal in the evaluation of non-neovascular AMD, including optical coherence tomography, fundus autofluorescence, or color fundus photography. In the context of emerging therapies for geographic atrophy, like pegcetacoplan, it is critical to establish the baseline status of the disease, monitor the development and expansion of geographic atrophy, and to evaluate the retina's response to potential treatments in clinical trials. The present review, while initially providing a comprehensive description of the pathophysiology involved in AMD, aims to offer an overview of the imaging modalities employed in the evaluation of non-neovascular AMD. Special emphasis is placed on the assessment of progression biomarkers as discerned through optical coherence tomography. As the landscape of AMD treatment continues to evolve, advanced imaging techniques will remain at the forefront, enabling clinicians to offer the most effective and tailored treatments to their patients.
PubMed: 38611677
DOI: 10.3390/diagnostics14070764 -
Bioengineering (Basel, Switzerland) Jul 2023Accurate noninvasive diagnosis of retinal disorders is required for appropriate treatment or precision medicine. This work proposes a multi-stage classification network...
Accurate noninvasive diagnosis of retinal disorders is required for appropriate treatment or precision medicine. This work proposes a multi-stage classification network built on a multi-scale (pyramidal) feature ensemble architecture for retinal image classification using optical coherence tomography (OCT) images. First, a scale-adaptive neural network is developed to produce multi-scale inputs for feature extraction and ensemble learning. The larger input sizes yield more global information, while the smaller input sizes focus on local details. Then, a feature-rich pyramidal architecture is designed to extract multi-scale features as inputs using DenseNet as the backbone. The advantage of the hierarchical structure is that it allows the system to extract multi-scale, information-rich features for the accurate classification of retinal disorders. Evaluation on two public OCT datasets containing normal and abnormal retinas (e.g., diabetic macular edema (DME), choroidal neovascularization (CNV), age-related macular degeneration (AMD), and Drusen) and comparison against recent networks demonstrates the advantages of the proposed architecture's ability to produce feature-rich classification with average accuracy of 97.78%, 96.83%, and 94.26% for the first (binary) stage, second (three-class) stage, and all-at-once (four-class) classification, respectively, using cross-validation experiments using the first dataset. In the second dataset, our system showed an overall accuracy, sensitivity, and specificity of 99.69%, 99.71%, and 99.87%, respectively. Overall, the tangible advantages of the proposed network for enhanced feature learning might be used in various medical image classification tasks where scale-invariant features are crucial for precise diagnosis.
PubMed: 37508850
DOI: 10.3390/bioengineering10070823 -
Frontiers in Bioengineering and... 2023Cell monolayers that form a barrier between two structures play an important role for the maintenance of tissue functionality. In the anterior portion of the eye, the... (Review)
Review
Cell monolayers that form a barrier between two structures play an important role for the maintenance of tissue functionality. In the anterior portion of the eye, the corneal endothelium forms a barrier that controls fluid exchange between the aqueous humor of the anterior chamber and the corneal stroma. This monolayer is central in the pathogenesis of Fuchs endothelial corneal dystrophy (FECD). FECD is a common corneal disease, in which corneal endothelial cells deposit extracellular matrix that increases the thickness of its basal membrane (Descemet's membrane), and forms excrescences (guttae). With time, there is a decrease in endothelial cell density that generates vision loss. Transplantation of a monolayer of healthy corneal endothelial cells on a Descemet membrane substitute could become an interesting alternative for the treatment of this pathology. In the back of the eye, the retinal pigment epithelium (RPE) forms the blood-retinal barrier, controlling fluid exchange between the choriocapillaris and the photoreceptors of the outer retina. In the retinal disease dry age-related macular degeneration (dry AMD), deposits (drusen) form between the RPE and its basal membrane (Bruch's membrane). These deposits hinder fluid exchange, resulting in progressive RPE cell death, which in turn generates photoreceptor cell death, and vision loss. Transplantation of a RPE monolayer on a Bruch's membrane/choroidal stromal substitute to replace the RPE before photoreceptor cell death could become a treatment alternative for this eye disease. This review will present the different biomaterials that are proposed for the engineering of a monolayer of corneal endothelium for the treatment of FECD, and a RPE monolayer for the treatment of dry AMD.
PubMed: 37840667
DOI: 10.3389/fbioe.2023.1269385 -
Clinical Ophthalmology (Auckland, N.Z.) 2023Prior studies have validated ultra-widefield imaging as a remote screening tool for diabetic retinopathy. The aim of this study was to determine its use in screening for...
BACKGROUND
Prior studies have validated ultra-widefield imaging as a remote screening tool for diabetic retinopathy. The aim of this study was to determine its use in screening for any fundus pathology in a routine patient population.
METHODS
In this prospective randomized study, patients underwent both slit lamp indirect ophthalmoscopy and ultra-widefield imaging. Ultra-widefield images were independently reviewed by two optometrists, and discrepancies were adjudicated by a retina specialist. Clinical findings from slit-lamp examiners and image-reviewers were coded into themes and clinically meaningful findings were extracted. Cohen's kappa was used to estimate agreement for these findings between the two image-reviewers and between the image-reviewers and slit-lamp examiners.
RESULTS
Nine-hundred eyes of 450 patients were examined and imaged, of which 616 eyes were analyzed. At least one abnormal fundus finding was present on ophthalmoscopy in 71 eyes (11%) and on adjudicated image interpretation in 166 eyes (27%). Agreement between the two image-reviewers was moderate to substantial for most clinically meaningful findings, including optic disc hemorrhage (κ = 0.8), macular exudates (κ = 0.7), and macular pigmentary changes (κ = 0.7). Agreement between examiners and image-reviewers was moderate to substantial for optic disc hemorrhage (κ = 1), indistinct optic disc margins (κ = 0.5), drusen (κ = 0.4), pigmentary changes (κ = 0.4), and hemorrhage (κ = 0.8). A total of 187 findings were detected by imaging but not examination, compared with 42 that were detected on examination but not imaging.
CONCLUSION
In a routine patient population, ultra-widefield imaging agreed with standard-of-care slit-lamp examinations and detected more fundus findings.
PubMed: 37927576
DOI: 10.2147/OPTH.S433864 -
The British Journal of Ophthalmology Nov 2023To report prevalence and risk factor associations for age-related macular degeneration (AMD) and AMD features from multimodal retinal grading in a multidisciplinary...
Prevalence and risk factors for age-related macular degeneration in a population-based cohort study of older adults in Northern Ireland using multimodal imaging: NICOLA Study.
PURPOSE
To report prevalence and risk factor associations for age-related macular degeneration (AMD) and AMD features from multimodal retinal grading in a multidisciplinary longitudinal population-based study of aging in Northern Ireland.
STUDY DESIGN
Population-based longitudinal cohort study.
METHODS
Retinal imaging at the Norther Ireland Cohort for the Longitudinal Aging Study health assessment included stereo Colour Fundus Photography (CFP) (Canon CX-1, Tokyo, Japan) and Spectral-Domain Optical Coherence Tomography (SD-OCT) ((Heidelberg Retinal Angopgraph (HRA)+OCT; Heidelberg Engineering, Heidelberg, Germany). Medical history and demographic information was obtained during a home interview. Descriptive statistics were used to describe the prevalence of AMD and individual AMD features. Multiple imputation followed by multiple regression modelling was used to explore risk factor associations including relationships with AMD genetic risk score.
RESULTS
Retinal images from 3386 participants were available for analysis. Mean age of the sample was 63.4 (SD 9.01, range: 36-99). Population weighted prevalence of AMD using colour grading in those over 55 years was: no drusen: 6 0.4%; drusen <63 μm: 15.9%; drusen 63-125 µm: 13.7%; drusen >125 µm or pigmentary changes: 8.3%; late AMD: 1.6%. Prevalence of AMD features in those over 55 years was: OCT drusen 27.5%, complete outer retinal pigment epithelium and outer retinal atrophy (cRORA) on OCT was 4.3%, reticular drusen 3.2% and subretinal drusenoid deposits 25.7%. The genetic risk score was significantly associated with drusen and cRORA but less so for SDD alone and non-significant for hyperpigmentation or vitelliform lesions.
CONCLUSIONS
Multimodal imaging-based classification has provided evidence of some divergence of genetic risk associations between classical drusen and SDD. Our findings support an urgent review of current AMD severity classification systems.
Topics: Humans; Aged; Retinal Drusen; Cohort Studies; Longitudinal Studies; Prevalence; Northern Ireland; Macular Degeneration; Risk Factors; Tomography, Optical Coherence; Fluorescein Angiography
PubMed: 36216411
DOI: 10.1136/bjo-2021-320469