UNASSIGNED: Specific genetic factors might serve as markers for risk stratification of AMD progression, but their association with key features of AMD has not been fully elucidated. Thus, we investigated the association between overall and pathway-specific genetic risk scores (GRS) and lead loci (ARMS2, CFH) with AMD stages and features of high-risk nonlate AMD, including reticular pseudodrusen (RPD) and large drusen area (LDA).
UNASSIGNED: We performed a cross-sectional analysis of data from the Rhineland Study, a population-based study in Bonn, Germany. We included 4016 individuals aged 50 years and older of European descent. GRS and pathway-specific subscores were constructed based on a large genome-wide association study of AMD. Subscores were generated based on gene-pathways associations (complement, extracellular matrix remodeling (ECM) and lipid metabolism). Associations were assessed using logistic and multinomial regression.
UNASSIGNED: The mean age of participants was 63.36 years and 1813 (45.1%) were men. The GRS was positive in 48.1% of individuals and increased, but did not fully overlap, across AMD stages. Pathway-specific subscores increased across AMD stages except for the ECM subscore, which only showed a trend for increasing in late AMD. Increasing overall GRS was associated with RPD and LDA (OR [95%CI] for RPD: 1.70 [1.33-2.15], for LDA: 1.64 [1.29-2.07]) among individuals with AMD. Similarly, higher complement and ECM subscores was associated with RPD, while for LDA, only an association with complement subscore was observed.
UNASSIGNED: In a population-based setting, we confirmed higher genetic risk to be associated with more severe AMD and identified associations with high-risk features of intermediate AMD. Conjoint analyses suggested that high-risk features and late AMD might be differentially associated with genetic architecture in AMD, such as ECM remodeling. Incorporation of genetic information such as GRSs might improve AMD risk prediction strategies.

UNASSIGNED: We introduce a deep learning-based biomarker proposal system for the purpose of accelerating biomarker discovery in age-related macular degeneration (AMD).
UNASSIGNED: Retrospective analysis of a large data set of retinal OCT images.
UNASSIGNED: A total of 3456 adults aged between 51 and 102 years whose OCT images were collected under the PINNACLE project.
UNASSIGNED: Our system proposes candidates for novel AMD imaging biomarkers in OCT. It works by first training a neural network using self-supervised contrastive learning to discover, without any clinical annotations, features relating to both known and unknown AMD biomarkers present in 46 496 retinal OCT images. To interpret the learned biomarkers, we partition the images into 30 subsets, termed clusters, that contain similar features. We conduct 2 parallel 1.5-hour semistructured interviews with 2 independent teams of retinal specialists to assign descriptions in clinical language to each cluster. Descriptions of clusters achieving consensus can potentially inform new biomarker candidates.
UNASSIGNED: We checked if each cluster showed clear features comprehensible to retinal specialists, if they related to AMD, and how many described established biomarkers used in grading systems as opposed to recently proposed or potentially new biomarkers. We also compared their prognostic value for late-stage wet and dry AMD against an established clinical grading system and a demographic baseline model.
UNASSIGNED: Overall, both teams independently identified clearly distinct characteristics in 27 of 30 clusters, of which 23 were related to AMD. Seven were recognized as known biomarkers used in established grading systems, and 16 depicted biomarker combinations or subtypes that are either not yet used in grading systems, were only recently proposed, or were unknown. Clusters separated incomplete from complete retinal atrophy, intraretinal from subretinal fluid, and thick from thin choroids, and, in simulation, outperformed clinically used grading systems in prognostic value.
UNASSIGNED: Using self-supervised deep learning, we were able to automatically propose AMD biomarkers going beyond the set used in clinically established grading systems. Without any clinical annotations, contrastive learning discovered subtle differences between fine-grained biomarkers. Ultimately, we envision that equipping clinicians with discovery-oriented deep learning tools can accelerate the discovery of novel prognostic biomarkers.
UNASSIGNED: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Dysregulated macroautophagy/autophagy is one of the hallmarks of aging and has also been linked to higher incidence of several age-associated diseases such as age-related macular degeneration (AMD). The main cell type affected in AMD is the retinal pigment epithelium (RPE), and this disease can lead to central vision loss. Despite affecting around 8.7% of the population between 45-85 years, its etiopathogenesis remains unknown. In our recent manuscript using the pharmacological sodium iodate (SI) model of AMD we identified severe lysosomal membrane permeabilization (LMP) in the RPE, that leads to autophagy flux blockage and proteostasis defects. Treatment with the natural compound urolithin A (UA) reduces RPE cell death and alleviates vision loss, concurrent with full autophagy restoration. While UA was initially described as a specific mitophagy inducer, we now show that it is also able to promote SQSTM1/p62-dependent lysophagy in the context of lysosomal damage and LMP. Genetic downregulation of SQSTM1/p62 fully abolishes the effect of UA on lysophagy while mitophagy stimulation remains unaffected. In summary, these findings highlight the wide range of pathways modulated by UA and its potential implementation in the management of AMD and other diseases involving lysosomal damage.

Glaucine is an aporphine alkaloid with anti-inflammatory, bronchodilator and anti-cancer activities. However, the effects of glaucine in the regulation of age-related macular degeneration (AMD) remain unclear. Herein, we aimed to investigate the anti-angiogenetic and anti-inflammatory effects of glaucine in ARPE-19 cells. ARPE-19 cells were treated with N-(methoxyoxoacetyl)-glycine, methyl ester (DMOG) and cobalt chloride (CoCl2) for induction of hypoxia, while lipopolysaccharide (LPS) treatment was used for elicitation of inflammatory response. Cell viability was analyzed using 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay. The expression of hypoxia-inducible factor (HIF-1α) and vascular endothelial growth factor (VEGF) were measured by Western blot. The secretion of VEGF, interleukin (IL)-6 and monocyte chemoattractant protein-1 (MCP-1) was detected using enzyme-linked immunosorbent assay (ELISA). Human umbilical vein endothelial cells (HUVECs) were used for tube formation analysis. Expression of HIF-1α and secretion of VEGF were significantly increased under DMOG and CoCl2 induction, whereas glaucine significantly attenuated both HIF-1α expression and VEGF secretion by DMOG- and CoCl2-induced ARPE-19 cells. In addition, glaucine suppressed the tube formation by DMOG- and CoCl2-induced HUVEC cells. Moreover, glaucine also attenuated the production of IL-6 and MCP-1 by LPS-induced ARPE-19 cells. This study indicated that glaucine exhibited anti-angiogenic and anti-inflammatory effects, suggesting that glaucine might have benefits for the treatment of AMD.

Age-related macular degeneration (AMD) is one of the leading causes of vision loss in the elderly. This disease involves oxidative stress burden in the retina leading to death of retinal pigment epithelial (RPE) cells and photoreceptors. The retina is susceptible to oxidative stress, in part due to high metabolic activity and high concentration of polyunsaturated fatty acids that undergo lipid peroxidation chain reactions. Antioxidant enzymes exist in the retina to combat this stress, including glutathione peroxidase 4 (GPX4). GPX4 specifically reduces oxidized lipids, protecting against lipid peroxidation-induced oxidative stress, which is noted in dry AMD. We hypothesize that Gpx4 knockout within the RPE will result in an environment of chronic oxidative stress yielding degeneration akin to AMD. C57BL/6J mice with a floxed Gpx4 gene were mated with Rpe65Cre/ER mice. Offspring containing Rpe65Cre ± alleles and either Gpx4 WT or Gpx4 fl/fl alleles were administered tamoxifen to induce Gpx4 knockout in Gpx4 fl/fl mice. At sequential timepoints, retinal phenotypes were assessed via in vivo imaging utilizing confocal scanning laser ophthalmoscopy and optical coherence tomography (OCT), and visual function was probed by electroretinography. Retinas were studied post-mortem by immunohistochemical analyses, electron microscopy, plastic sectioning, and quantitative polymerase chain reaction and Western analyses. The RPE-specific Gpx4 knockout model was validated via Western analysis indicating diminished GPX4 protein only within the RPE and not the neural retina. Following Gpx4 knockout, RPE cells became dysfunctional and died, with significant cell loss occurring 2 weeks post-knockout. Progressive thinning of the photoreceptor layer followed RPE degeneration and was accompanied by loss of visual function. OCT and light microscopy showed hyperreflective foci and enlarged, pigmented cells in and above the RPE layer. Electron microscopy revealed decreased mitochondrial cristae and loss of basal and apical RPE ultrastructure. Finally, there was increased carboxyethylpyrrole staining, indicating oxidation of docosahexaenoic acid, and increased levels of mRNAs encoding oxidative stress-associated genes in the RPE and photoreceptors. Overall, we show that RPE-localized GPX4 is necessary for the health of the RPE and outer retina, and that knockout recapitulates phenotypes of dry AMD.

Purpose: To determine the recurrence rate of neovascular age-related macular degeneration (nAMD) during a 5-year period after the suspension of anti-vascular endothelial growth factor (anti-VEGF) treatments. Methods: Thirty-four eyes of 34 nAMD patients who met the inclusion criteria and were treated by anti-VEGF drugs were studied. All met the treatment suspension criteria and were followed for 5 years after the suspension of the anti-VEGF treatment. Patients with a recurrence within one year were placed in Group A, and patients with a recurrence between 1 and 5 years were placed in Group B. The rate and time of a recurrence were analyzed using the Kaplan-Meier method. We also examined whether there were differences in the baseline factors of age, sex, subtype, treatment period, and treatment interval between Groups A and B. Results: Twenty-five of 34 eyes (73.5%) had a recurrence within 5 years of stopping the anti-VEGF treatments. Thirteen (52.0%) of the 25 eyes had a recurrence within 1 year, 4 (16.0%) eyes between 1 and 2 years, 4 (16.0%) eyes between 2 and 3 years, 2 (8%) between 3 and 4 years, and 2 eyes (8%) between 4 and 5 years. The baseline factors were not significantly different between Groups A and B. Conclusions: The results showed that the recurrence rate was highest within one year after the suspension of the anti-VEGF treatments, with a number of recurrences one year after the suspension. Clinicians should remember that nAMD may recur several years after the suspension of anti-VEGF treatments.

We provide an overview of the expanding literature on the role of cytokines and immune mediators in pathophysiology of age-related macular degeneration (AMD). Although many immunological mediators have been linked to AMD pathophysiology, the broader mechanistic picture remains unclear with substantial variations in the levels of evidence supporting these mediators. Therefore, we reviewed the literature considering the varying levels of supporting evidence. A Medical Subject Headings (MeSH) term-based literature research was conducted in September, 2023, consisting of the MeSH terms \"cytokine\" and \"Age-related macular degeneration\" connected by the operator \"AND\". After screening the publications by title, abstract, and full text, a total of 146 publications were included. The proinflammatory cytokines IL-1β (especially in basic research studies), IL-6, IL-8, IL-18, TNF-α, and MCP-1 are the most extensively characterised cytokines/chemokines, highlighting the role of local inflammasome activation and altered macrophage function in the AMD pathophysiology. Among the antiinflammatory mediators IL-4, IL-10, and TGF-β were found to be the most extensively characterised, with IL-4 driving and IL-10 and TGF-β suppressing disease progression. Despite the extensive literature on this topic, a profound understanding of AMD pathophysiology has not yet been achieved. Therefore, further studies are needed to identify potential therapeutic targets, followed by clinical studies.

Previous observational studies have indicated a correlation between circulating inflammatory proteins and age-related macular degeneration (AMD), yet the causal nature of this relationship remains uncertain. This study aims to investigate the causal link between circulating inflammatory proteins and AMD utilizing a bidirectional two-sample Mendelian randomization approach. The findings indicated that elevated levels of four circulating inflammatory proteins, including C-C Motif Chemokine Ligand 11 (CCL11), Signaling Lymphocytic Activation Molecule Family Member 1 (SLAMF1), TNF Superfamily Member 11 (TRANCE) and Vascular Endothelial Growth Factor A (VEGF-A) lead to the increased risk of AMD, while increased levels of two circulating inflammatory proteins, including Fibroblast Growth Factor 19 (FGF-19) and Interleukin 10 Receptor Subunit Alpha (IL-10RA), resulted in the decreased risk of AMD. Conversely, the results from reverse Mendelian randomization suggested that the presence of AMD lead to the reduction in levels of 15 circulating inflammatory proteins. The findings of this study support the association between elevated levels of circulating inflammatory proteins and the risk of AMD, as well as the potential impact of AMD on reducing circulating inflammatory protein levels. CCL11, SLAMF1, TRANCE and VEGF-A are identified as potential molecular markers in the progression of AMD. These results offer a novel molecular therapeutic target for the prevention and treatment of AMD.

One of the major causes of vision impairment among elderly people in developed nations is age-related macular degeneration (AMD). The distinctive features of AMD are the accumulation of extracellular deposits called drusen and the gradual deterioration of photoreceptors and nearby tissues in the macula. AMD is a complex and multifaceted disease influenced by several factors such as aging, environmental risk factors, and a person\'s genetic susceptibility to the condition. The interaction among these factors leads to the initiation and advancement of AMD, where genetic predisposition plays a crucial role. With the advent of high-throughput genotyping technologies, many novel genetic loci associated with AMD have been identified, enhancing our knowledge of its genetic architecture. The common genetic variants linked to AMD are found on chromosome 1q32 (in the complement factor H gene) and 10q26 (age-related maculopathy susceptibility 2 and high-temperature requirement A serine peptidase 1 genes) loci, along with several other risk variants. This review summarizes the common genetic variants of complement pathways, lipid metabolism, and extracellular matrix proteins associated with AMD risk, highlighting the intricate pathways contributing to AMD pathogenesis. Knowledge of the genetic underpinnings of AMD will allow for the future development of personalized diagnostics and targeted therapeutic interventions, paving the way for more effective management of AMD and improved outcomes for affected individuals.

Neovascular age-related macular degeneration (AMD), a leading cause of blindness, requires frequent intravitreal injection of antivascular endothelial growth factor (anti-VEGF), which could generate a succession of complications with poor patient compliance. The current VEGF-targeting therapies often fail in half of patients due to the complex pathologic microenvironment of excessive reactive oxygen species (ROS) production, and increased levels of inflammation are accompanied by choroidal neovascularization (CNV). We herein reported multifunctional nanotherapeutics featuring superior antioxidant and anti-inflammation properties that aim to reverse the pathological condition, alongside its strong targeted antiangiogenesis to CNV and its ability to provide long-term sustained bioactive delivery via the minimally invasive subconjunctival injection, so as to achieve satisfactory wet AMD treatment effects. Concretely, the nanomedicine was designed by coencapsulation of astaxanthin (AST), a red pigmented carotenoid known for its antioxidative, anti-inflammatory and antiapoptotic properties, and axitinib (AXI), a small molecule tyrosine kinase inhibitor that selectively targets the vascular epidermal growth factor receptor for antiangiogenesis, into the Food and Drug Administration (FDA) approved poly(lactic-co-glycolic acid) (PLGA), which forms the nanodrug of PLGA@AST/AXI. Our results demonstrated that a single-dose subconjunctival administration of PLGA@AST/AXI showed a rational synergistic effect by targeting various prevailing risk factors associated with wet AMD, ensuring persistent drug release profiles, maintaining good ocular biocompatibility, and causing no obvious mechanical damage. Such attributes are vital and hold significant potential in treating ocular posterior segment diseases. Moreover, this nanotherapeutic strategy represents a versatile and broad-spectrum nanoplatform, offering a promising alternative for the complex pathological progression of other neovascular diseases.