Age-related Macular Degeneration Disease Research Articles

Intergrader Agreement in Grading Optical Coherence Tomography Morphologic Features in Eyes With Intermediate Nonexudative Age-Related Macular Degeneration.

To determine the reliability of a nine-point summary scale for grading intermediate age-related macular degeneration (AMD) image morphologic features based on the Early Treatment Diabetic Retinopathy Study (ETDRS) grid. Two trained graders independently divided spectral domain-optical coherence tomography (SD-OCT) scans into nine subfields and then graded each subfield for the presence of intraretinal hyperreflective foci (HRF), reticular pseudodrusen (RPD), and incomplete or complete retinal pigment epithelium and outer retinal atrophy (iRORA or cRORA). Grading results were assessed by summing the subfield grades into a nine-point summary score and also by using an eye-level binary grade for presence of the finding in any subfield. Gwet's first-order agreement coefficient (AC1) was calculated to assess intergrader agreement. Images of 79 eyes from 52 patients were evaluated. Intergrader agreement was higher when the OCT grades were summarized with a nine-point summary score (Gwet's AC1 0.92, 0.89, 0.99, and 0.99 for HRF, RPD, iRORA, and cRORA, respectively) compared with the eye-level binary grade (Gwet's AC1 0.75, 0.76, 0.97, and 0.96 for HRF, RPD, iRORA, and cRORA, respectively), with significant differences detected for HRF and RPD. The use of a nine-point summary score showed higher reliability in grading when compared to the binary subfield- and eye-level data, and thus may offer more precise estimation of AMD disease staging. These findings suggest that a nine-point summary score could be a useful means of disease staging by using findings on OCT in clinical studies of AMD.

Eicosapentaenoic acid-rich omega-3 fatty acids supplementation may improve vision in dry age-related macular degeneration or Stargardt disease, as shown in MADEOS, a prospective, randomized, multicentre, double-blind, placebo-controlled pilot study

BackgroundThis study investigates the effects of eicosapentaenoic acid (EPA)-rich omega-3 fatty acids on dry age-related macular degeneration (AMD) and Stargardt disease. MethodsMADEOS is a prospective, randomized, multicenter, double-blind, placebo-controlled pilot study, which assessed the impact of omega-3 fatty acids on best corrected visual acuity, blood omega-6/omega-3 ratio, and perceived vision and mood using a questionnaire in patients with dry AMD or Stargardt disease. Participants received either the active product (3660 mg of EPA and DHA; 14 patients) or placebo (sunflower oil; 7 patients) daily for 24 weeks. Measurements were taken at screening (Visit 1), 12 weeks (Visit 3), and 24 weeks (Visit 4). Comparisons were made within and between groups. ResultsThe mean letters gained at Visits 3 and 4 were significantly different between the groups (p=0.002). The active group showed a mean gain of 6 ETDRS letters from Visit 1 to Visit 4 (p=0.003). The mean arachidonic acid/EPA ratio in the active group significantly decreased from Visit 1 (5.84 ± 1.05) to Visit 4 (1.47 ± 0.16, p=0.002). The questionnaire scores were similar at Visit 3 but higher for the active group at Visit 4 (9.38 ± 3.35 vs. 7.28 ± 2.36). ConclusionEPA-rich omega-3 supplementation may improve both objective and subjective vision in patients with dry AMD or Stargardt disease, offering a potentially simple, safe, and cost-effective approach to enhancing quality of life.

Levels of the HtrA1 Protein in Serum and Vitreous Humor Are Independent of Genetic Risk for Age-Related Macular Degeneration at the 10q26 Locus.

The purpose of this study was to determine if levels of the HtrA1 protein in serum or vitreous humor are influenced by genetic risk for age-related macular degeneration (AMD) at the 10q26 locus, age, sex, AMD status, and/or AMD disease severity, and, therefore, to determine the contribution of systemic and ocular HtrA1 to the AMD disease process. A custom-made sandwich ELISA assay (SCTM ELISA) for detection of the HtrA1 protein was designed and compared with three commercial assays (R&D Systems, MyBiosource 1 and MyBiosource 2) using 65 serum samples. Concentrations of HtrA1 were thereafter determined in serum and vitreous samples collected from 248 individuals and 145 human donor eyes, respectively. The SCTM ELISA demonstrated high specificity, good recovery, and parallelism within its linear detection range and performed comparably to the R&D Systems assay. In contrast, we were unable to demonstrate the specificity of the two assays from MyBioSource using either recombinant or native HtrA1. Analyses of concentrations obtained using the validated SCTM assay revealed that genetic risk at the 10q26 locus, age, sex, or AMD status are not significantly associated with altered levels of the HtrA1 protein in serum or in vitreous humor (P > 0.05). HtrA1 levels in serum and vitreous do not reflect the risk for AMD associated with the 10q26 locus or disease status. Localized alteration in HTRA1 expression in the retinal pigment epithelium, rather than systemic changes in HtrA1, is the most likely driver of elevated risk for developing AMD among individuals with risk variants at the 10q26 locus.

Decreased Circulating Very Small Low-Density Lipoprotein is Likely Causal for Age-Related Macular Degeneration

Abnormal changes in metabolite levels in serum or plasma have been highlighted in several studies in age-related macular degeneration (AMD), the leading cause of irreversible vision loss. Specific changes in lipid profiles are associated with an increased risk of AMD. Metabolites could thus be used to investigate AMD disease mechanisms or incorporated into AMD risk prediction models. However, whether particular metabolites causally affect the disease has yet to be established. A 3-tiered analysis of blood metabolites in the United Kingdom (UK) Biobank cohort to identify metabolites that differ in AMD patients with evidence for a putatively causal role in AMD. A total of 72376 donors from the UK Biobank cohort including participants with AMD (N=1353) and non-AMD controls (N=71023). We analyzed 325 directly measured or derived blood metabolites from the UK Biobank for 72376 donors to identify AMD-associated metabolites. Genome-wide association studies for 325 metabolites in 98316 European participants from the UK Biobank were performed. The causal effects of these metabolites in AMD were tested using a 2-sample Mendelian randomization approach. The predictive value of these measurements together with sex and age was assessed by developing a machine learning classifier. Evaluating metabolic biomarkers associated with AMD susceptibility and investigating their potential causal contribution to the development of the disease. This study noted age to be the prominent risk factor associated with AMD development. While accounting for age and sex, we identified 84 metabolic markers as significantly (false discovery rate-adjusted P value < 0.05) associated with AMD. Lipoprotein subclasses comprised the majority of the AMD-associated metabolites (39%) followed by several lipoprotein to lipid ratios. Nineteen metabolites showed a likely causative role in AMD etiology. Of these, 6 lipoproteins contain very small, very low-density lipoprotein (VLDL), and phospholipids to total lipid ratio in medium VLDL. Based on this we postulate that depletion of circulating very small VLDLs is likely causal for AMD. The risk prediction model constructed from the metabolites, age and sex, identified age as the primary predictive factor with a much smaller contribution by metabolites to AMD risk prediction. This study underscores the pronounced role of lipids in AMD susceptibility and the likely causal contribution of particular subclasses of lipoproteins to AMD. Our study provides valuable insights into the metabopathological mechanisms of AMD disease development and progression.

LXR/CD38 activation drives cholesterol-induced macrophage senescence and neurodegeneration via NAD+ depletion

Although dysregulated cholesterol metabolism predisposes aging tissues to inflammation and a plethora of diseases, the underlying molecular mechanism remains poorly defined. Here, we show that metabolic and genotoxic stresses, convergently acting through liver X nuclear receptor, upregulate CD38 to promote lysosomal cholesterol efflux, leading to nicotinamide adenine dinucleotide (NAD+) depletion in macrophages. Cholesterol-mediated NAD+ depletion induces macrophage senescence, promoting key features of age-related macular degeneration (AMD), including subretinal lipid deposition and neurodegeneration. NAD+ augmentation reverses cellular senescence and macrophage dysfunction, preventing the development of AMD phenotype. Genetic and pharmacological senolysis protect against the development of AMD and neurodegeneration. Subretinal administration of healthy macrophages promotes the clearance of senescent macrophages, reversing the AMD disease burden. Thus, NAD+ deficit induced by excess intracellular cholesterol is the converging mechanism of macrophage senescence and a causal process underlying age-related neurodegeneration.

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.

Adverse COVID-19 outcomes in American Veterans with age-related macular degeneration: a case–control study

ObjectivesPrior studies suggest that patients with age-related macular degeneration (AMD) have poorer COVID-19 outcomes. This study aims to evaluate whether AMD is associated with adverse COVID-19 outcomes in a large...

Through the Smoke: An In-Depth Review on Cigarette Smoking and Its Impact on Ocular Health.

Smoking is a widespread and pervasive habit, impacting health across various care settings, including acute care, subacute care, home-based care, and long-term care. Smoking is a serious global public health concern that has been related to many chronic diseases. However, the effect of smoking on eye disorders has been less studied. Cigarette smoke contains a complex mixture of harmful constituents, including nicotine and toxic chemicals, which permeate the bloodstream, affecting ocular tissues. The oxidative stress and inflammation induced by smoking are central to its detrimental effects on ocular health. Age-related macular degeneration (AMD), a leading cause of vision loss, exhibits a strong association with smoking. Research consistently demonstrates that smokers face a heightened risk of both early and advanced AMD. Cataracts, another prevalent ocular condition, develop earlier and progress more rapidly in smokers. The oxidative stress on the lens and reduced antioxidants among smokers contribute to the increased severity of cataracts. Moreover, thehealth of the eyes may be compromised by smoking-related chemicals that reduce blood flow and/or hasten thrombus formation in ocular capillaries thus increasing the chance of acquiringglaucoma, cataracts, AMD, and Graves' eye disease. Beyond individual health concerns, the societal implications of smoking on ocular health are substantial, including increased healthcare costs and diminished quality of life for affected individuals. Understanding the underlying mechanisms can provide insights into potential therapeutic interventions for preventing and managing smoking-related ocular damage. Given the global prevalence of smoking, raising awareness about the ocular risks associated with smoking is crucial for promoting eye health. The review underscores the urgent need for comprehensive anti-smoking initiatives and smoking cessation programs to alleviate the burden of ocular diseases associated with smoking.

Deep Learning Approach for Age-related Macular Degeneration Detection Using Retinal Images: Efficacy Evaluation of Different Deep Learning Models

Age-related macular degeneration (AMD) is a typical fundus disease that affects the central vision of elderly people. It causes difficulties in everyday activities such as reading and recognizing faces. AMD can progress slowly or rapidly, and it leads to severe vision loss if left untreated. Therefore, early detection and diagnosis of AMD are crucial to prevent or delay vision impairment in the elderly. To handle this requirement, researchers are exploring deep learning-based models as an AI tool to assist ophthalmologist in AMD diagnosis. However, conducting an appropriate deep learning model for the AMD classification is challenging and cost-intensive. This research aims to evaluate the efficacy of various deep learning models for obtaining the best performance results when identifying AMD disease using retinal images. To meet this objective, the retinal images from the Department of Ophthalmology, the King Chulalongkorn Memorial Hospital, Thailand were collected for transfer learning and other publicly available datasets for testing. Then, seven deep learning models VGG19, Xception, DenseNet201, EfficientNetB7, InceptionV3, NASNetLarge, and ResNet152V2 were chosen to training for the 2-labels (Normal vs. AMD) and the 3-labels (Normal vs. Dry AMD vs. Wet AMD) classifications. From the experimental results, the DenseNet201 model with Dense block in its structure showed the best efficacy in both 2-labels and 3-labels AMD classifications since its performance always include in the Top-3 models accuracy and generalization performance measured by total accuracy and total F1-Score, respectively. Furthermore, the accuracy performance of deep learning models in Top-3 are comparable with the performance of retinal specialist. These results contribute consolidated knowledge to the process of implementation effective deep learning as production that detects AMD automatically in the clinical and enhance the quality of healthcare service.

Identification of the Immune Landscapes and Follicular Helper T Cell-Related Genes for the Diagnosis of Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a progressive ocular ailment causing age-associated vision deterioration, characterized by dysregulated immune cell activity. Notably, follicular helper T (Tfh) cells have emerged as pivotal contributors to AMD pathogenesis. Nonetheless, investigations into Tfh-associated gene biomarkers for this disorder remain limited. Utilizing gene expression data pertinent to AMD procured from the Gene Expression Omnibus (GEO) repository, we employed the "DESeq2" R software package to standardize and preprocess expression levels. Concurrently, CIBERSORT analysis was utilized to compute the infiltration proportions of 22 distinct immune cell types. Subsequent to weighted gene correlation network analysis (WGCNA), coupled with differential expression scrutiny, we pinpointed genes intricately linked with Tfh cells. These potential genes underwent further screening using the MCODE function within Cytoscape software. Ultimately, a judicious selection of pivotal genes from these identified clusters was executed through the LASSO algorithm. Subsequently, a diagnostic nomogram was devised based on these selected genes. Evident Tfh cell disparities between AMD and control cohorts were observed. Our amalgamated analysis, amalgamating differential expression data with co-expression patterns, unveiled six genes closely associated with Tfh cells in AMD. Subsequent employment of the LASSO algo-rithm facilitated identification of the most pertinent genes conducive to predictive modeling. From these, GABRB3, MFF, and PROX1 were elected as prospective diagnostic biomarkers for AMD. This investigation discerned three novel biomarker genes, linked to inflammatory mechanisms and pivotal in diagnosing AMD. Further exploration of these genes holds potential to foster novel therapeutic modalities and augment comprehension of AMD's disease trajectory.

Shedding light on eye disease in obesity: A review.

Obesity is known to be associated with numerous ocular manifestations, including but not limited to, diabetic retinopathy (DR), age-related macular degeneration (AMD), cataracts, glaucoma, and dry eye disease. This review aims to provide an overview of the ophthalmological findings in obesity. A literature search was conducted using PubMed and Cochrane databases for studies describing randomized clinical trials, meta-analyses, systematic reviews, and observational studies published from 1 January 2017 to 1 April 2023. The search terms used included relevant keywords such as 'obesity', 'body mass index', 'waist-to-hip ratio', 'bariatric', 'ophthalmology', 'eye disease', 'myopia', 'retinopathy', 'glaucoma', and 'cataract'. This literature search was performed on 1 April 2023. Obesity is associated with increased risk of developing DR, a sight-threatening complication of diabetes mellitus. Similarly, obesity has been shown to increase risk of AMD, cataracts, glaucoma, and ocular surface disease. Multiple mechanisms linking obesity to ophthalmic disease have been proposed. Adipose tissue produces various inflammatory cytokines that can affect ocular tissues, leading to disease progression. Additionally, obesity is associated with systemic metabolic changes that can influence ocular health. Bariatric surgery has been shown to be protective against development of ophthalmic disease. Obesity is a significant risk factor for several ophthalmological diseases. Healthcare providers should encourage weight loss in patients with overweight or obesity to prevent or delay the onset of ocular complications. Further research is needed to better understand the underlying mechanisms of this association, and to identify effective strategies for preventing or managing ophthalmic disease in patients with obesity.

A semi-automated pipeline for quantifying drusen-like deposits in human induced pluripotent stem cell-derived retinal pigment epithelium cells

Age-Related Macular Degeneration (AMD) is a highly prevalent form of retinal disease amongst Western communities over 50 years of age. A hallmark of AMD pathogenesis is the accumulation of drusen underneath the retinal pigment epithelium (RPE), a biological process also observable in vitro. The accumulation of drusen has been shown to predict the progression to advanced AMD, making accurate characterisation of drusen in vitro models valuable in disease modelling and drug development. More recently, deposits above the RPE in the subretinal space, called reticular pseudodrusen (RPD) have been recognized as a sub-phenotype of AMD. While in vitro imaging techniques allow for the immunostaining of drusen-like deposits, quantification of these deposits often requires slow, low throughput manual counting of images. This further lends itself to issues including sampling biases, while ignoring critical data parameters including volume and precise localization. To overcome these issues, we developed a semi-automated pipeline for quantifying the presence of drusen-like deposits in vitro, using RPE cultures derived from patient-specific induced pluripotent stem cells (iPSCs). Using high-throughput confocal microscopy, together with three-dimensional reconstruction, we developed an imaging and analysis pipeline that quantifies the number of drusen-like deposits, and accurately and reproducibly provides the location and composition of these deposits. Extending its utility, this pipeline can determine whether the drusen-like deposits locate to the apical or basal surface of RPE cells. Here, we validate the utility of this pipeline in the quantification of drusen-like deposits in six iPSCs lines derived from patients with AMD, following their differentiation into RPE cells. This pipeline provides a valuable tool for the in vitro modelling of AMD and other retinal disease, and is amenable to mid and high throughput screenings.

The role of mitochondrial genes on nuclear gene expression in neovascular age related macular degeneration: analysis of nuclear VEGF gene expression after ranibizumab treatment in cytoplasmic hybrid retinal pigment epithelial cell lines correlated with clinical evolution

PurposeThe present study tests the hypothesis that mitochondrial genes have retrograde signaling capacity that influences the expression of nuclear genes related to angiogenesis pathways. Cytoplasmic hybrid (cybrid) in vitro cell lines with patient specific mitochondria inserted into an immortalized retinal pigment epithelial cell line (ARPE-19) were used to test this hypothesis. This type of analysis can provide important information to identify the optimal regimen of anti-VEGF treatment, personalizing age-related macular degeneration (AMD) therapies.MethodsMitochondria deficient ARPE-19 cells (Rho0) were fused with AMD donor’s platelets to create individual cybrid cell lines containing mitochondria from patients with phenotypic AMD disease and nuclear DNA from the immortalized RPE cell line. The cybrids were treated with Ranibizumab (Lucentis, Genentech, San Francisco, CA), at 4 different concentrations for 24 h, and subsequently the levels of reactive oxygen species (ROS), gene expression for VEGF-A, hypoxia-inducible factor 1-alpha (HIF1-a) and manganese superoxide dismutase (SOD2) were measured. The clinical evolution of the two AMD-donors were correlated with the molecular findings found in their ‘personalized’ cybrids.ResultsCybrids from Patient-01 showed down-regulation of gene expression of VEGF-A and HIF-1a at both 1X and 4X Ranibizumab concentrations. Patient-01 AMD cybrid cultures had an increase in the ROS levels at 1X (P = 0.0317), no changes at 2X (P = 0.8350) and a decrease at 4X (P = 0.0015) and 10X (P = 0.0011) of Ranibizumab. Clinically, Patient-01 responded to anti-VEGF therapy but eventually developed geographic atrophy. Patient-02 cybrids demonstrated up-regulation of gene expression of VEGF-A and HIF-1a at Ranibizumab 1X and 4X concentrations. There was decreased ROS levels with Ranibizumab 1X (P = 0.1606), 2X (P = 0.0388), 4X (P = 0.0010) and 10X (P = < 0.0001). Clinically, Patient-02 presented with a neovascular lesion associated with a prominent production of intraretinal fluid in clinical follow-up requiring regular and repeated intravitreal injections of Ranibizumab with recurrent subretinal fluid.ConclusionsOur cybrid model has the potential to help personalize the treatment regimen with anti-VEGF drugs in patients with neovascular AMD. Further investigation is needed to better understand the role that the mitochondria play in the cellular response to anti-VEGF drugs. Future studies that focus on this model have the potential to help personalize anti-VEGF treatment.

Systematic Review of Neovascular Age-Related Macular Degeneration Disease Activity Criteria Use to Shorten, Maintain or Extend Treatment Intervals with Anti-VEGF in Clinical Trials: Implications for Clinical Practice.

Clinical trials in neovascular age-related macular degeneration (nAMD) using anti-vascular endothelial growth factor (ant-VEGF) injections use disease activity (DA) criteria to shorten, maintain or increase the interval between injections. Differences in these DA criteria may contribute to differences in the proportions of patients with macular fluid at key timepoints or achieving extended dosing intervals in these trials. We identified, collated and evaluated DA criteria from pivotal anti-VEGF nAMD trials to understand how differences impact on these studies and real-world visual acuity and extending dosing outcomes. This was a systematic review of literature on Pubmed for randomised clinical trials in nAMD using a proactive treatment regimen. We excluded case reports, review articles and studies on fewer than 50 participants. Twelve clinical trials (LUCAS, VIEW, TREX-AMD, FLUID, TREND, RIVAL, ALTAIR, CANTREAT, ARIES, TREX-Conbercept, HAWK & HARRIER, TENAYA & LUCERNE) investigating anti-VEGF treatment of nAMD were identified according to our search strategy. Different studies utilised a different combination of DA criteria. Specifically, six trials included visual acuity change; four included macular thickness change; one included visual acuity change if associated with macular thickness change; one with qualitative optical coherence tomography (OCT) features; four with qualitative OCT features if also associated with visual acuity change; 10 with macular haemorrhage and five with other fluorescein angiographic features. Different clinical trials use different DA criteria when altering the interval between anti-VEGF injections. This makes it difficult to draw meaningful conclusions about secondary outcomes such as proportion of patients treated at extended dosing intervals or proportions of eyes with persistent subretinal or intraretinal fluid. Standardising DA criteria in clinical trials and preferentially using those easily applied in a real-world setting would lead to results more achievable in real-world settings and for a meaningful comparison of treatment durability.

Fluorescence Lifetime Imaging of Human Sub-RPE Calcification In Vitro Following Chlortetracycline Infusion.

We have shown that all sub-retinal pigment epithelial (sub-RPE) deposits examined contain calcium phosphate minerals: hydroxyapatite (HAP), whitlockite (Wht), or both. These typically take the form of ca. 1 μm diameter spherules or >10 μm nodules and appear to be involved in the development and progression of age-related macular degeneration (AMD). Thus, these minerals may serve as useful biomarkers the for early detection and monitoring of sub-RPE changes in AMD. We demonstrated that HAP deposits could be imaged in vitro by fluorescence lifetime imaging microscopy (FLIM) in flat-mounted retinas using legacy tetracycline antibiotics as selective sensors for HAP. As the contrast on a FLIM image is based on the difference in fluorescence lifetime and not intensity of the tetracycline-stained HAP, distinguishing tissue autofluorescence from the background is significantly improved. The focus of the present pilot study was to assess whether vascular perfusion of the well tolerated and characterized chlortetracycline (widely used as an orally bioavailable antibiotic) can fluorescently label retinal HAP using human cadavers. We found that the tetracycline delivered through the peripheral circulation can indeed selectively label sub-RPE deposits opening the possibility for its use for ophthalmic monitoring of a range of diseases in which deposit formation is reported, such as AMD and Alzheimer disease (AD).

Influence of Clinical and Genetic Factors on the Progression of Age-Related Macular Degeneration: A 3-Year Follow-Up

The aim of the present study was to analyze the relationship of age-related macular degeneration (AMD) progression with clinical characteristics, demographic, and environmental risk factors that would affect disease development. In addition, the influence of three genetic AMD polymorphisms (CFH Y402H, ARMS2 A69S, and PRPH2 c.582-67T>A) on AMD progression was investigated. In total, 94 participants with previously diagnosed early or intermediate AMD in at least one eye were recalled for an updated re-evaluation after 3 years. The initial visual outcomes, medical history, retinal imaging data, and choroidal imaging data were collected to characterize the AMD disease status. Among the AMD patients, 48 demonstrated AMD progression, and 46 showed no disease worsening at 3 years. Disease progression was significantly associated with worse initial visual acuity (OR = 6.74, 95% CI = 1.24-36.79, p = 0.03) and the presence of the wet AMD subtype in fellow eyes (OR = 3.79, 95%CI = 0.94-15.2, p = 0.05). In addition, a higher risk of AMD progression appeared in the patients with active thyroxine supplementation (OR = 4.77, CI = 1.25-18.25, p = 0.002). The CC variant of CFH Y402H was associated with AMD advancement compared to the TC+TT phenotype (OR = 2.76, 95% CI: 0.98-7.79, p = 0.05). Identifying risk factors of AMD progression may lead to earlier intervention and better outcomes, preventing the expansion of the late stage of the disease.

Increased end-stage renal disease risk in age-related macular degeneration: a nationwide cohort study with 10-year follow-up

Common etiologies between age-related macular degeneration (AMD) and kidney disease advocate a close link between AMD and end-stage renal disease (ESRD). However, the risk of ESRD in people with AMD was not reported. Here, we investigated the association between AMD and the risk of ESRD by using a nationwide, population-based cohort data in Korea. 4,206,862 participants aged 50 years or older were categorized by presence of AMD and visual disability. Risk of ESRD was the primary outcome. Cox regression hazard model was used to examine the hazard ratios (HRs) with adjustment for potential confounders. Stratified analyses by age, sex, baseline kidney function, and cardiometabolic comorbidities were performed. During the mean 9.95 years of follow-up, there were 21,759 incident ESRD events (0.52%). AMD was associated with 33% increased risk of ESRD (adjusted HR [aHR] 1.33, 95% confidence interval [CI] 1.24–1.44), and the risk was even higher when accompanied by visual disability (aHR 2.05, 95% CI 1.68–2.50) than when not (aHR 1.26, 95% CI 1.17–1.37). Age, baseline kidney function, and cardiometabolic comorbidities significantly interact between AMD and the risk of ESRD. Our findings have clinical implications on disease prevention and risk factor management of ESRD in patients with AMD.

Repeated Topical Administration of 3 nm Cerium Oxide Nanoparticles Reverts Disease Atrophic Phenotype and Arrests Neovascular Degeneration in AMD Mouse Models.

Increased oxidative stress in the retina and retinal pigment epithelium is implicated in age-related macular degeneration (AMD). Antioxidant cerium oxide nanoparticles (CeO2NPs) have been used to treat degenerative retinal pathologies in animal models, although their delivery route is not ideal for chronic patient treatment. In this work, we prepared a formulation for ocular topical delivery that contains small (3 nm), nonaggregated biocompatible CeO2NPs. In vitro results indicate the biocompatible and protective character of the CeO2NPs, reducing oxidative stress in ARPE19 cells and inhibiting neovascularization related to pathological angiogenesis in both HUVEC and in in vitro models of neovascular growth. In the in vivo experiments, we observed the capacity of CeO2NPs to reach the retina after topical delivery and a subsequent reversion of the altered retinal transcriptome of the retinal degenerative mouse model DKOrd8 toward that of healthy control mice, together with signs of decreased inflammation and arrest of degeneration. Furthermore, CeO2NP eye drops' treatment reduced laser-induced choroidal neovascular lesions in mice by lowering VEGF and increasing PEDF levels. These results indicate that CeO2NP eye drops are a beneficial antioxidant and neuroprotective treatment for both dry and wet forms of AMD disease.

Gene targeting as a therapeutic avenue in diseases mediated by the complement alternative pathway.

The complement alternative pathway (AP) is implicated in numerous diseases affecting many organs, ranging from the rare hematological disease paroxysmal nocturnal hemoglobinuria (PNH), to the common blinding disease age-related macular degeneration (AMD). Critically, the AP amplifies any activating trigger driving a downstream inflammatory response; thus, components of the pathway have become targets for drugs of varying modality. Recent validation from clinical trials using drug modalities such as inhibitory antibodies has paved the path for gene targeting of the AP or downstream effectors. Gene targeting in the complement field currently focuses on supplementation or suppression of complement regulators in AMD and PNH, largely because the eye and liver are highly amenable to drug delivery through local (eye) or systemic (liver) routes. Targeting the liver could facilitate treatment of numerous diseases as this organ generates most of the systemic complement pool. This review explains key concepts of RNA and DNA targeting and discusses assets in clinical development for the treatment of diseases driven by the alternative pathway, including the RNA-targeting therapeutics ALN-CC5, ARO-C3, and IONIS-FB-LRX, and the gene therapies GT005 and HMR59. These therapies are but the spearhead of potential drug candidates that might revolutionize the field in coming years.

Regulation of oxidative stress and inflammatory responses in human retinal pigment epithelial cells.

Age-related macular degeneration (AMD) is an eye disease, which causes impaired vision that can lead to blindness. The incidence of AMD increases with age. Retinal pigment epithelial (RPE) cells maintain retinal homeostasis and support the functionality of photoreceptors. In the pathogenesis of AMD, the degeneration of the RPE cells precedes photoreceptor cell death. RPE cells are susceptible to oxidative stress, and chronic inflammation involving nucleotide-binding domain, leucine-rich repeat and pyrin domain 3 (NLRP3) inflammasome activation and impaired autophagy are challenges faced by aged RPE cells in AMD. There are two types of AMD, dry (85-90%) and wet (10-15%) disease forms. Choroidal neovascularization is typical for wet AMD, and anti-vascular endothelial growth factor (anti-VEGF) injections are used to prevent the progression of the disease but there is no curative treatment. There is no cure for the dry disease form, but antioxidants have been proposed as a potential treatment option. Ageing is the most important risk factor of AMD, and tobacco smoke is the most important environmental risk factor that can be controlled. Hydroquinone is a cytotoxic, immunotoxic, carcinogenic and pro-oxidative component of tobacco smoke. The aim of this PhD thesis was to study hydroquinone-induced oxidative stress and NLRP3 inflammasome activation in human RPE cells (ARPE-19 cells). An age-related eye disease study (AREDS) formulation (incl. omega-3 fatty acids, vitamin C and E, copper, zinc, lutein and zeaxanthin), which is clinically investigated p.o. dosing combination of dietary supplements for AMD patients, has been evaluated as a possible treatment and restraining option for AMD. Resvega (4.1.1, Table 2) is a similar kind of product to AREDS with added resveratrol, and many of the components incorporated within Resvega can be considered as belonging to the normal antioxidative defence system of the retina. Another aim was to evaluate the effects of Resvega on hydroquinone-induced oxidative stress or NLRP3 inflammasome activation induced by impaired protein clearance. The results of this study reveal that hydroquinone elevated the activity of NADPH oxidase which subsequently mediated the production of reactive oxygen species (ROS) and predisposed RPE cells to degeneration by reducing levels of vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF). Hydroquinone induced an NLRP3-independent IL-18 release and NLRP3 accumulation inside the IL-1α-primed cells. Resvega treatment reduced the extent of hydroquinone-induced ROS production and NLRP3 inflammasome activation evoked by impaired protein clearance. Thus, Resvega alleviated hydroquinone- and impaired protein clearance-induced stress in human RPE cells, but more studies are needed, for example, to reveal the most optimal route of administration for targeting the cells in the retina, since both oxidative stress and NLRP3 inflammasome activation are important contributors to the development of AMD and represent significant treatment targets.