Progression Of Age-related Macular Degeneration Research Articles

Effect of Low-Dose Aspirin on the Course of Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in old age. There is no proven intervention to prevent AMD and, apart from lifestyle, nutritional, and supplement advice, there is no intervention to delay its progression. To determine the impact of long-term low-dose aspirin on the incidence and progression of AMD. The Aspirin in Reducing Events in the Elderly-AMD (ASPREE-AMD) study was an Australian-based substudy of the ASPREE trial, a multicenter, international, randomized, double-masked, placebo-clinical trial investigating the efficacy of low-dose aspirin in prolonging disability-free survival among older individuals. Retinal photography was conducted at baseline from March 2010 to January 2015, then 3 and 5 years after randomization. AMD status was determined using color retinal images and treatment records. Australian participants in ASPREE aged 70 years and older without dementia, independence-limiting physical disability, cardiovascular disease, or chronic illness limiting 5-year survival and with gradable retinal images at baseline were included. Data were analyzed from December 2022 to December 2023. Aspirin (100 mg daily, enteric coated) or placebo. Incidence of AMD and progression from early/intermediate to late AMD. Outcomes were analyzed by modified intention-to-treat analysis. A total of 4993 participants were enrolled in this substudy. Baseline characteristics were similar between groups. At the time of sponsor-determined trial termination, retinal follow-up data were available for 3208 participants, 3171 of whom were analyzed for AMD incidence and progression, with a median (IQR) age of 73.5 (71.5-76.4) years and even sex distribution (1619 [51%] female). Median (IQR) follow-up time was 3.1 (3.0-3.5) years. Cumulative AMD incidence was 195 of 1004 (19.4%) in the aspirin group and 187 of 979 (19.1%) in the placebo group (relative risk [RR], 1.02; 95% CI, 0.85-1.22; P = .86). Cumulative progression from early/intermediate AMD to late AMD was observed in 14 of 615 (2.3%) participants in the aspirin group and 18 of 573 (3.1%) in the placebo group (RR, 0.72; 95% CI, 0.36-1.44; P = .36). In this trial, low-dose aspirin administered for 3 years did not affect the incidence of AMD. The evidence was weaker for progression of AMD due to low number of progressed cases. Overall, these results do not support suggestion that low-dose daily aspirin prevents the development or progression of AMD. anzctr.org Identifier: ACTRN12613000755730.

Circulating Anti-Endothelial Cell Antibodies in Patients with Geographic Atrophy Related to Dry Age-Related Macular Degeneration.

Background and Objectives: Age-related macular degeneration (AMD) is one of the leading causes of central vision loss among elderly patients, and its dry form accounts for the majority of cases. Although several causes and mechanisms for the development and progression of AMD have previously been identified, the pathogenesis of this complex disease is still not entirely understood. As inflammation and immune system involvement are strongly suggested to play a central role in promoting the degenerative process and stimulating the onset of complications, we aimed to analyze the frequency of serum anti-retinal (ARAs) and anti-endothelial cell antibodies (AECAs) in patients with dry AMD and to determine their relationship with the clinical features of the disease, notably the area of geographic atrophy (GA). Materials and Methods: This study included 41 patients with advanced-stage dry AMD and 50 healthy controls without AMD, matched for gender and age. ARAs were detected by indirect immunofluorescence using monkey retina as an antigen substrate, and the presence of AECAs was determined using cultivated human umbilical vein endothelial cells and primate skeletal muscle. Results: ARAs were detected in 36 (87.8%) AMD patients (titers ranged from 1:20 to 1:320) and in 16 (39.0%) (titers ranged from 1:10 to 1:40) controls (p = 0.0000). Twenty of the forty-one patients (48.8%) were positive for AECAs, while in the control group, AECAs were present only in five sera (10.0%). The titers of AECAs in AMD patients ranged from 1:100 to 1:1000, and in the control group, the AECA titers were 1:100 (p = 0.0001). There were no significant correlations between the presence of AECAs and disease activity. Conclusions: This study demonstrates a higher prevalence of circulating AECAs in patients with dry AMD; however, no correlation was found between the serum levels of these autoantibodies and the area of GA.

Age- and sex- divergent translatomic responses of the mouse retinal pigmented epithelium

Aging is the main risk factor for age-related macular degeneration (AMD), a retinal neurodegenerative disease that leads to irreversible blindness, particularly in people over 60 years old. Retinal pigmented epithelium (RPE) atrophy is an AMD hallmark. Genome-wide chromatin accessibility, DNA methylation, and gene expression studies of AMD and control RPE demonstrate epigenomic/transcriptomic changes occur during AMD onset and progression. However, mechanisms by which molecular alterations of normal aging impair RPE function and contribute to AMD pathogenesis are unclear.Here, we specifically interrogate the RPE translatome with advanced age and across sexes in a novel RPE reporter mouse model. We find differential age- and sex- associated transcript expression with overrepresentation of pathways related to inflammation in the RPE. Concordant with impaired RPE function, the phenotypic changes in the aged translatome suggest that aged RPE becomes immunologically active, in both males and females, with some sex-specific signatures, which supports the need for sex representation for in vivo studies.

Drusen in AMD from the Perspective of Cholesterol Metabolism and Hypoxic Response.

Drusen are one of the most characteristic pathologies of precursor lesion of age-related macular degeneration (AMD). Drusen comprise a yellowish white substance that accumulates typically under the retinal pigment epithelium (RPE), and their constituents are lipids, complement, amyloid, crystallin, and others. In the past, many researchers have focused on drusen and tried to elucidate the pathophysiology of AMD because they believed that disease progression from early AMD to advanced AMD might be based on drusen or drusen might cause AMD. In fact, it is well established that drusen are the hallmark of precursor lesion of AMD and a major risk factor for AMD progression mainly based on their size and number. However, the existence of advanced AMD without drusen has long been recognized. For example, polypoidal choroidal vasculopathy (PCV), which comprises the majority of AMD cases in Asians, often lacks drusen. Thus, there is the possibility that drusen might be no more than a biomarker of AMD and not a cause of AMD. Now is the time to reconsider the relationship between AMD and drusen. In this review, we focus on early AMD pathogenesis based on basic research from the perspective of cholesterol metabolism and hypoxic response in the retina, and we discuss the role of drusen.

Longitudinal Evaluation of the Distribution of Intraretinal Hyper-Reflective Foci in Eyes with Intermediate Age-Related Macular Degeneration

Purpose Intraretinal hyper-reflective foci (IHRF) are optical coherence tomography (OCT) risk factors for progression of age-related macular degeneration (AMD). In this study we assess the change in the number and distribution of IHRF over two years. Methods The axial distribution of IHRF were quantified in eyes with intermediate AMD (iAMD) at baseline and 24 months, using a series of 5 sequential equidistant en face OCT retinal slabs generated between the outer border of the internal limiting membrane (ILM) and the inner border of the retinal pigment epithelium (RPE). Following thresholding and binarization, IHRF were quantified in each retinal slab using ImageJ. The change in IHRF number in each slab between baseline and month 24 was calculated. Results Fifty-two eyes showed evidence of IHRF at baseline, and all continued to show evidence of IHRF at 24 months (M24). The total average IHRF count/eye increased significantly from 4.67 ± 0.63 at baseline to 11.62 ± 13.86 at M24 (p < 0.001) with a mean increase of 6.94 ± 11.12 (range: - 9 to + 60). Overall, at M24, 76.9% eyes showed an increase in IHRF whereas 15.4% of eyes showed a decrease (3 eyes [5.7%] showed no change). There was a greater number of IHRF and a greater increase in IHRF over M24 in the outer slabs. Conclusions IHRF are most common in the outer retinal layers and tend to increase in number over time. The impact of the distribution and frequency of these IHRF on the overall progression of AMD requires further study.

Inhibition of HDAC1 and 3 in the Presence of Systemic Inflammation Reduces Retinal Degeneration in a Model of Dry Age-Related Macular Degeneration.

Purpose: Previously, we identified increased retinal degeneration and cytokine response in a mouse model of dry age-related macular degeneration (AMD) in the presence of systemic inflammation from rheumatoid arthritis (RA). Histone deacetylases (HDACs) regulate cytokine production by reducing acetylation and are found to be dysregulated in inflammatory diseases, including RA and AMD. Therefore, this current study investigates the effect of HDAC inhibition on AMD progression in the presence of systemic inflammation. Methods: Collagen induced arthritis (CIA) was induced in C57BL6J mice, followed by sodium iodate (NaIO3)-induced retinal degeneration. Mice were treated with a selective HDAC class I inhibitor, MS-275, and retinal structure [optical coherence tomography (OCT)], function (electroretinography), and molecular changes quantitative real-time polymerase chain reaction (RT-qPCR, Western Blot) were assessed. Results: NaIO3 retinal damage was diminished in CIA mice treated with MS-275 (P ≤ 0.05). While no significant difference was observed in retinal pigment epithelium (RPE) function, a trend in increased c-wave amplitude was detected in CIA + NaIO3 mice treated with MS-275. Finally, we identified decreased Hdac1, Hdac3, and Cxcl9 expression in CIA + NaIO3 mouse RPE/choroid when treated with MS-275 (P ≤ 0.05). Conclusions: Our data demonstrate that HDAC inhibition can reduce the additive effect of NaIO3-induced retinal degeneration in the presence of systemic inflammation by CIA as measured by OCT analysis. In addition, HDAC inhibition in CIA + NaIO3 treated mice resulted in reduced cytokine production. These findings are highly innovative and provide additional support to the therapeutic potential of HDAC inhibitors for dry AMD treatment.

A Clinically Explainable AI-Based Grading System for Age-Related Macular Degeneration Using Optical Coherence Tomography.

We propose an automated, explainable artificial intelligence (xAI) system for age-related macular degeneration (AMD) diagnosis. Mimicking the physician's perceptions, the proposed xAI system is capable of deriving clinically meaningful features from optical coherence tomography (OCT) B-scan images to differentiate between a normal retina, different grades of AMD (early, intermediate, geographic atrophy (GA), inactive wet or active neovascular disease [exudative or wet AMD]), and non-AMD diseases. Particularly, we extract retinal OCT-based clinical imaging markers that are correlated with the progression of AMD, which include: (i) subretinal tissue, sub-retinal pigment epithelial tissue, intraretinal fluid, subretinal fluid, and choroidal hypertransmission detection using a DeepLabV3+ network; (ii) detection of merged retina layers using a novel convolutional neural network model; (iii) drusen detection based on 2D curvature analysis; (iv) estimation of retinal layers' thickness, and first-order and higher-order reflectivity features. Those clinical features are used to grade a retinal OCT in a hierarchical decision tree process. The first step looks for severe disruption of retinal layers' indicative of advanced AMD. These cases are analyzed further to diagnose GA, inactive wet AMD, active wet AMD, and non-AMD diseases. Less severe cases are analyzed using a different pipeline to identify OCT with AMD-specific pathology, which is graded as intermediate-stage or early-stage AMD. The remainder is classified as either being a normal retina or having other non-AMD pathology. The proposed system in the multi-way classification task, evaluated on 1285 OCT images, achieved 90.82% accuracy. These promising results demonstrated the capability to automatically distinguish between normal eyes and all AMD grades in addition to non-AMD diseases.

Eye Drop with Fas-Blocking Peptide Attenuates Age-Related Macular Degeneration.

Age-related macular degeneration (AMD), characterized by macular retinal degeneration, poses a significant health concern due to the lack of effective treatments for prevalent dry AMD. The progression of AMD is closely linked to reactive oxygen species and Fas signaling, emphasizing the need for targeted interventions. In this study, we utilized a NaIO3-induced retinal degeneration mouse model to assess the efficacy of Fas-blocking peptide (FBP). Intravitreal administration of FBP successfully suppressed Fas-mediated inflammation and apoptosis, effectively arresting AMD progression in mice. We developed a 6R-conjugated FBP (6R-FBP) for eye drop administration. 6R-FBP, administered as an eye drop, reached the retinal region, attenuating degeneration by modulating the expression of inflammatory cytokines and blocking Fas-mediated apoptosis in rodent and rabbit NaIO3-induced retinal degeneration models to address practical concerns. Intravitreal FBP and 6R-FBP eye drops effectively reduced retinal degeneration and improved retinal thickness in rodent and rabbit models. This study highlights the therapeutic potential of FBP, particularly 6R-FBP as an eye drop, in inhibiting Fas-mediated cell signaling and protecting against retinal cell death and inflammation in dry AMD. Future investigations should explore the translational prospects of this approach in primates with eye structures comparable to those of humans.

Oxidized-LDL Induces Metabolic Dysfunction in Retinal Pigment Epithelial Cells.

Recently, mitochondrial dysfunction has gained attention as a causative factor in the pathogenesis and progression of age-related macular degeneration (AMD). Mitochondrial damage plays a key role in metabolism and disrupts the balance of intracellular metabolic pathways, such as oxidative phosphorylation (OXPHOS) and glycolysis. In this study, we focused on oxidized low-density lipoprotein (ox-LDL), a major constituent of drusen that accumulates in the retina of patients with AMD, and investigated whether it could be a causative factor for metabolic alterations in retinal pigment epithelial (RPE) cells. We found that prolonged exposure to ox-LDL induced changes in fatty acid β-oxidation (FAO), OXPHOS, and glycolytic activity and increased the mitochondrial reactive oxygen species production in RPE cells. Notably, the effects on metabolic alterations varied with the concentration and duration of ox-LDL treatment. In addition, we addressed the limitations of using ARPE-19 cells for retinal disease research by highlighting their lower barrier function and FAO activity compared to those of induced pluripotent stem cell-derived RPE cells. Our findings can aid in the elucidation of mechanisms underlying the metabolic alterations in AMD.

Identification of key lncRNAs in age-related macular degeneration through integrated bioinformatics and experimental validation.

This study aimed to identify key long noncoding RNAs (lncRNAs) in age-related macular degeneration (AMD) patients and to identify relevant pathological mechanisms of AMD development. We identified 407 differentially expressed mRNAs and 429 differentially expressed lncRNAs in retinal pigment epithelium (RPE) and retina in the macular region of AMD patients versus controls (P < 0.05 and |log2FC| > 0.585) from GSE135092. A total of 14 key differentially expressed mRNAs were obtained through external data validation from GSE115828. A miRNA-mRNA and miRNA-lncRNA network containing 52 lncRNA nodes, 49 miRNA nodes, 14 mRNA nodes and 351 edges was constructed via integrated analysis of these components. Finally, the LINC00276-miR-619-5p-IFIT3 axis was identified via protein-protein network analysis. In the t-BH-induced ARPE-19 senescent cell model, LINC00276 and IFIT3 were downregulated. Overexpression of LINC00276 could accelerate cell migration in combination with IFIT3 upregulation. This compelling finding suggests that LINC00276 plays an influential role in the progression of AMD, potentially through modulating senescence processes, thereby setting a foundation for future investigative efforts to verify this relationship.

Risk Factors of Age-Related Macular Degeneration in a Population-Based Study: Results from SHIP-TREND-1 (Study of Health in Pomerania-TREND-1).

BACKGROUND Age-related macular degeneration (AMD) is the most common cause of visual impairment in the elderly population in industrialized countries. The Study of Health in Pomerania (SHIP) with its cohort SHIP-TREND was designed to investigate risk factors and clinical disorders in the general population of northeast Germany. This work focused on the first follow-up of SHIP-TREND and determined associated modifiable risk factors of AMD. Modifying risk factors is important to slow the progression of early AMD as there is currently no treatment for the late stage of geographic atrophy. Understanding AMD-associated risk factors also plays an important role in the development of therapeutic concepts. MATERIAL AND METHODS Between 2016 and 2019, data were collected from a total of 2507 initially randomly selected subjects from the general population aged 28 to 89 years. Non-mydriatic fundus photography of the right eye was performed in 2489 subjects. Grading of AMD was performed using the Rotterdam classification system. RESULTS We included 1418 gradable fundus photographs in the analysis. The risk of AMD changes increased with age and was positively correlated with HDL cholesterol, fT3, and low educational level. In men, BMI and cigarette smoking were also positively associated with AMD changes. CONCLUSIONS This study emphasizes the consideration of various metabolic pathways for the development of therapeutic concepts.

Identification of Genetic Variants for Risk Prediction and Early Diagnosis of Age-Related Macular Degeneration in the Taiwanese Population.

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly worldwide. The prevalence and phenotypes of AMD differ among populations, including between people in Taiwan and other regions. We performed a genome-wide association study to identify genetic variants and to develop genetic models to predict the risk of AMD development and progression in the Taiwanese population. In total, 4039 patients with AMD and 16,488 non-AMD controls (aged ≥ 65 years) were included. We identified 31 AMD-associated variants (p < 5 × 10-8) on chromosome 10q26, surrounding PLEKHA1-ARMS2-HTRA1. Two genetic models were constructed using the clump and threshold method. Model 1 included the single nucleotide polymorphism rs11200630 and showed a 1.31-fold increase in the risk of AMD per risk allele (95% confidence interval (CI) = 1.20-1.43, p < 0.001). In model 2, 1412 single-nucleotide polymorphisms were selected to construct a polygenic risk score (PRS). Individuals with the top 5% PRS had a 1.40-fold higher AMD risk compared with that of individuals with a PRS in the bottom quartile (95% CI = 1.04-1.89, p = 0.025). Moreover, the PRS in the upper quartile was related to a decreased age at AMD diagnosis by 0.62 years (95% CI = -1.15, -0.09, p = 0.023). Both genetic models provide useful predictive power for populations at high risk of AMD, affording a basis for identifying patients requiring close follow-up and early intervention.

Prevalence and Risk Factors of Age-Related Macular Degeneration in South Korea: Korea National Health and Nutrition Examination Survey

ABSTRACT Purpose To evaluate the prevalence and risk factors of age-related macular degeneration (AMD) in the Korean population. Methods In this cross-sectional study based on the Korea National Health and Nutrition Examination Survey (2017–2020) data 13,737 participants aged ≥ 40 years with assessable fundus images were included. The prevalence and risk factors of AMD were evaluated. The prevalence of early AMD, geographic atrophy (GA), and neovascular AMD were also assessed. Logistic regression analyses were used to identify risk factors. Results The prevalence (95% confidence interval [CI]) of AMD was 13.94% (13.15–14.72). The prevalence (95% CI) of early AMD, GA, and neovascular AMD was 13.07% (12.29–13.85), 0.26% (0.17–0.35), and 0.61% (0.47–0.75), respectively. The prevalence increased with age; it was 3.61%, 11.33%, 20.31%, 31.37%, and 33.98% in participants in their 40s, 50s, 60s, 70s, and ≥ 80 years, respectively. In multivariate analysis, AMD was positively associated with older age (p < 0.001; odds ratio [OR], 1.08; 95% CI, 1.07–1.09), male sex (p = 0.014; OR, 1.27; 95% CI, 1.05–1.53), and lower degree of education (p < 0.001; OR, 1.36 (for junior high school graduates); 95% CI, 1.12–1.65). Conclusions AMD was detected in approximately one-third of individuals aged ≥ 70 years, thus indicating that AMD is a common disease among older Koreans. Regular fundus examinations in populations with risk factors for AMD as well as education on methods to prevent or delay AMD progression, such as the Mediterranean diet, are necessary.

Establishing chronic models of age-related macular degeneration via long-term iron ion overload.

Age-related macular degeneration (AMD) is characterized by the degenerative senescence in the retinal pigment epithelium (RPE) and photoreceptors, which is accompanied by the accumulation of iron ions in the aging retina. However, current models of acute oxidative stress are still insufficient to simulate the gradual progression of AMD. To address this, we established chronic injury models by exposing the aRPE-19 cells, 661W cells, and mouse retina to iron ion overload over time. Investigations at the levels of cell biology and molecular biology were performed. It was demonstrated that long-term treatment of excessive iron ions induced senescence-like morphological changes, decreased cell proliferation, and impaired mitochondrial function, contributing to apoptosis. Activation of the mitogen-activated protein kinase (MAPK) pathway and the downstream molecules were confirmed both in the aRPE-19 and 661W cells. Furthermore, iron ion overload resulted in dry AMD-like lesions and decreased visual function in the mouse retina. These findings suggest that chronic exposure to overloading iron ions plays a significant role in the pathogenesis of retinopathy and provide a potential model for future studies on AMD.NEW & NOTEWORTHY To explore the possibility of constructing reliable research carriers on age-related macular degeneration (AMD), iron ion overload was applied to establish models in vitro and in vivo. Subsequent investigations into cellular physiology and molecular biology confirmed the presence of senescence in these models. Through this study, we hope to provide a better option of feasible methods for future researches into AMD.

DeepAlienorNet: A deep learning model to extract clinical features from colour fundus photography in age-related macular degeneration.

This study aimed to develop a deep learning (DL) model, named 'DeepAlienorNet', to automatically extract clinical signs of age-related macular degeneration (AMD) from colour fundus photography (CFP). The ALIENOR Study is a cohort of French individuals 77 years of age or older. A multi-label DL model was developed to grade the presence of 7 clinical signs: large soft drusen (>125 μm), intermediate soft (63-125 μm), large area of soft drusen (total area >500 μm), presence of central soft drusen (large or intermediate), hyperpigmentation, hypopigmentation, and advanced AMD (defined as neovascular or atrophic AMD). Prediction performances were evaluated using cross-validation and the expert human interpretation of the clinical signs as the ground truth. A total of 1178 images were included in the study. Averaging the 7 clinical signs' detection performances, DeepAlienorNet achieved an overall sensitivity, specificity, and AUROC of 0.77, 0.83, and 0.87, respectively. The model demonstrated particularly strong performance in predicting advanced AMD and large areas of soft drusen. It can also generate heatmaps, highlighting the relevant image areas for interpretation. DeepAlienorNet demonstrates promising performance in automatically identifying clinical signs of AMD from CFP, offering several notable advantages. Its high interpretability reduces the black box effect, addressing ethical concerns. Additionally, the model can be easily integrated to automate well-established and validated AMD progression scores, and the user-friendly interface further enhances its usability. The main value of DeepAlienorNet lies in its ability to assist in precise severity scoring for further adapted AMD management, all while preserving interpretability.

Risk factors for development of hyper-reflective foci overlying drusen in eyes with intermediate age-related macular degeneration

AimsThe aim of this study is to assess baseline characteristics of drusen preceding the development of intraretinal hyper-reflective foci (IHRF) in eyes with intermediate age-related macular degeneration (AMD).MethodsIn this retrospective...

Associations of drusen location with risk factors and incidence of late age-related macular degeneration in the Alienor study.

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. 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). 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. Central drusen were strongly associated with AMD risk factors and incident late AMD, suggesting that it represents a key marker for AMD progression.

Levels of complement factor H-related 4 protein do not influence susceptibility to age-related macular degeneration or its course of progression

Dysregulation of the alternative pathway (AP) of the complement system is a significant contributor to age-related macular degeneration (AMD), a primary cause of irreversible vision loss worldwide. Here, we assess the contribution of the liver-produced complement factor H-related 4 protein (FHR-4) to AMD initiation and course of progression. We show that FHR-4 variation in plasma and at the primary location of AMD-associated pathology, the retinal pigment epithelium/Bruch’s membrane/choroid interface, is entirely explained by three independent quantitative trait loci (QTL). Using two distinct cohorts composed of a combined 14,965 controls and 20,741 cases, we ascertain that independent QTLs for FHR-4 are distinct from variants causally associated with AMD, and that FHR-4 variation is not independently associated with disease. Additionally, FHR-4 does not appear to influence AMD progression course among patients with disease driven predominantly by AP dysregulation. Modulation of FHR-4 is therefore unlikely to be an effective therapeutic strategy for AMD.

Recent Advances in Our Understanding of Age-Related Macular Degeneration: Mitochondrial Dysfunction, Redox Signaling, and the Complement System.

Age-related macular degeneration (AMD) is a prevalent degenerative disorder of the central retina, which holds global significance as the fourth leading cause of blindness. The condition is characterized by a multifaceted pathophysiology that involves aging, oxidative stress, inflammation, vascular dysfunction, and complement activation. The complex interplay of these factors contributes to the initiation and progression of AMD. Current treatments primarily address choroidal neovascularization (CNV) in neovascular AMD. However, the approval of novel drug therapies for the atrophic and more gradual variant, known as geographic atrophy (GA), has recently occurred. In light of the substantial impact of AMD on affected individuals' quality of life and the strain it places on healthcare systems, there is a pressing need for innovative medications. This paper aims to provide an updated and comprehensive overview of advancements in our understanding of the etiopathogenesis of AMD. Special attention will be given to the influence of aging and altered redox status on mitochondrial dynamics, cell death pathways, and the intricate interplay between oxidative stress and the complement system, specifically in the context of GA. Additionally, this review will shed light on newly approved therapies and explore emerging alternative treatment strategies in the field. The objective is to contribute to the ongoing dialogue surrounding AMD, offering insights into the latest developments that may pave the way for more effective management and intervention approaches.

Influence of drusenoid pigment epithelial detachments on the progression of age-related macular degeneration and visual acuity

ObjectiveTo analyze the presence and morphologic characteristics of drusenoid pigment epithelial detachments (DPEDs) in spectral-domain optical coherence tomography (SD-OCT) in Caucasian patients with early and intermediate age-related macular degeneration (AMD) as well as the influence of these characteristics on best-corrected visual acuity (BCVA) and disease progression. DesignProspective observational cohort study. Participants: 89 eyes of 56 patients with early and intermediate AMD. MethodsExaminations consisted of BCVA, SD-OCT, and indocyanine green angiography. Evaluated parameters included drusen type, mean drusen height and -volume, the presence of DPED, DPED maximum height, -maximum diameter, -volume, topographic location, the rate of DPED collapse, and the development of macular neovascularization (MNV) or geographic atrophy (GA). ResultsDPED maximum height (162.34 µm ± 75.70 μm, p = 0.019) was significantly associated with the development of GA and MNV. For each additional 100 μm in maximum height, the odds of developing any late AMD (GA or MNV) increased by 2.23 (95% CI = 1.14–4.35). The presence of DPED (44 eyes, p = 0.01), its volume (0.20 mm ± 0.20 mm, p = 0.01), maximum diameter (1860.87 μm ± 880.74 μm, p = 0.03), maximum height (p < 0.001) and topographical location in the central millimetre (p = 0.004) of the Early Treatment Diabetic Retinopathy Study (ETDRS)-Grid were significantly correlated with BCVA at the last follow-up (0.15logMAR ± 0.20logMAR; Snellen equivalent approximately 20/28). DPEDs occurred significantly less in the outer quadrants than in the central millimetre and inner quadrants of ETDRS-Grid (all p values < 0.001). ConclusionsThe height of drusen and DPEDs is a biomarker that is significantly associated with the development of late AMD and visual loss. DPEDs affect predominantly the center and inner quadrants of the ETDRS-Grid.