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The delivery of therapeutic agents to the eye presents significant challenges due to various anatomical and physiological barriers, leading to low bioavailability in conventional formulations. Polymeric nanoparticles (PNPs) offer a promising solution for overcoming these obstacles in ocular drug delivery. These submicron-sized particles, composed of biocompatible and biodegradable polymers, can encapsulate a wide range of therapeutic compounds, including proteins, genes, and small molecules, allowing for targeted and sustained delivery to specific ocular tissues. The advantages of PNPs include enhanced drug bioavailability, prolonged retention time, and reduced systemic side effects, which are critical in treating major ocular diseases such as glaucoma, cataracts, age-related macular degeneration, dry eye syndrome, and diabetic retinopathy. The selection of polymers like chitosan, polyethylene glycol, and poly (lactic-co-glycolic acid) is crucial due to their biocompatibility and biodegradability, ensuring safe and effective ocular treatment. Moreover, surface modifications, such as PEGylation and ligand attachment, enhance the targeting and therapeutic efficacy of PNPs. Despite these advancements, challenges in drug encapsulation efficiency, stability during storage, and maintaining sterility remain. Nonetheless, the development of PNP-based formulations represents a significant advancement in ophthalmic therapeutics, offering the potential for improved patient outcomes in the management of ocular diseases. [ABSTRACT FROM AUTHOR]

Ginsenosides, constituting 2–3% of Panax ginseng Meyer, are noteworthy for their anticancer and antioxidant effects. Despite demonstrating promise in various diseases, their specific impact on age-related macular degeneration (AMD) remains unclear. This research investigates whether ginsenosides can inhibit the progression of dry AMD and explores the mechanisms by which they influence apoptosis, providing insight into their regulatory role in programmed cell death. Human retinal pigment epithelial (ARPE-19) cells were pre-treated with ginsenosides, followed by induction of oxidative stress using hydrogen peroxide. Pre-treatment with 20(S)-ginsenoside Rg3 significantly increased cell viability and reduced apoptotic markers, including Annexin V, Bax, Bim S, cleaved caspase 3, cleaved caspase 9, and cleaved PARP. Furthermore, 20(S)-ginsenoside Rg3 effectively diminished the activation of the ERK and NF-κB signaling pathways. 20(S)-ginsenoside Rg3 could be a good prevention for AMD by modulating apoptosis, offering valuable therapeutic insights for AMD. [ABSTRACT FROM AUTHOR]

This study investigates the efficacy of predicting age-related macular degeneration (AMD) activity through deep neural networks (DNN) using a cross-instrument training dataset composed of Optical coherence tomography-angiography (OCTA) images from two different manufacturers. A retrospective cross-sectional study analyzed 2D vascular en-face OCTA images from Heidelberg Spectralis (1478 samples: 1102 training, 276 validation, 100 testing) and Optovue Solix (1003 samples: 754 training, 189 validation, 60 testing). OCTA scans were labeled based on clinical diagnoses and adjacent B-scan OCT fluid information, categorizing activity into normal, dry AMD, active wet AMD, and wet AMD in remission. Experiments explored cross-instrument disease classification using separate and combined datasets for training the DNN. Testing involved 100 Heidelberg and 60 Optovue samples. Training on Heidelberg data alone yielded 73% accuracy on Heidelberg images and 60% on Optovue images. Training on Optovue data alone resulted in 34% accuracy on Heidelberg and 85% on Optovue images. Combined training data from both instruments achieved 78% accuracy on Heidelberg and 76% on Optovue test sets. Results indicate that cross-instrument classifier training demonstrates high classification prediction accuracy, making cross-instrument training viable for future clinical applications. This implies that vascular morphology in OCTA can predict disease progression. [ABSTRACT FROM AUTHOR]

To identify genetic influences on subfoveal choroidal thickness of older adults using a genome-wide association study (GWAS). We recruited 300 participants from the population-based Korean Longitudinal Study on Health and Aging (KLoSHA) and Korean Longitudinal Study on Cognitive Aging and Dementia (KLOSCAD) cohort studies and 500 participants from the Bundang age-related macular degeneration (AMD) cohort study dataset. We conducted a GWAS on older adult populations in the KLoSHA and KLOSCAD cohorts. Single nucleotide polymorphisms (SNPs) associated with choroidal thickness were identified with P values < 1.0 × 10−4 in both the right and left eyes, followed by validation using the Bundang AMD cohort dataset. This association was further confirmed by a functional in vitro study using human umbilical vein endothelial cells (HUVECs). The ages of the cohort participants in the discovery and validation datasets were 73.5 ± 3.3 and 71.3 ± 7.9 years, respectively. In the discovery dataset, three SNPs (rs1916762, rs7587019, and rs13320098) were significantly associated with choroidal thickness in both eyes. This association was confirmed for rs1916762 (genotypes GG, GA, and AA) and rs7587019 (genotypes GG, GA, and AA), but not for rs13320098. The mean choroidal thickness decreased by 56.7 μm (AA, 73.8%) and 31.1 μm (GA, 85.6%) compared with that of the GG genotype of rs1916762, and by 55.4 μm (AA, 74.2%) and 28.2 μm (GA, 86.7%) compared with that of the GG genotype of rs7587019. The SNPs rs1916762 and rs7587019 were located close to the FAM124B gene near its cis-regulatory region. Moreover, FAM124B was highly expressed in vascular endothelial cells. In vitro HUVEC experiments showed that the inhibition of FAM124B was associated with decreased vascular endothelial proliferation, suggesting a potential mechanism of choroidal thinning. FAM124B was identified as a susceptibility gene affecting subfoveal choroidal thickness in older adults. This gene may be involved in mechanisms underlying retinal diseases associated with altered choroidal thickness, such as age-related macular degeneration. [ABSTRACT FROM AUTHOR]

The ocular condition known as age-related macular degeneration (AMD) affects the retina and impairs vision in the elderly. For both controlling and detecting retinal illnesses like AMD, optical coherence tomography (OCT) is an important investigative tool. The accurate segmentation of retinal layers is critical, as accurately segmenting the layers helps ophthalmologists for early diagnosis of AMD. An accurate and effective detection technique is created using the proposed Water Cycle Corona Virus Optimization-based Deep Residual Network (WCCVO-based DRN) to address these problems and identify AMD at the early stages. In the first step, the active contour model is used to segment the layers, and features such as reflectivity, thickness, curvature, statistical features, and the devised Local Directional Gradient Pattern Histogram (LDGPH) are retrieved. The LDGPH is designed based on the concept of Local Directional pattern (LDP) and Local Gradient pattern (LGP). At last, for the AMD detection DRN classifier is used, which is trained by the devised WCCVO. The accuracy, sensitivity, and specificity metrics for the WCCVO-based DRN achieved satisfactory performance with values of 0.916, 0.923, and 0.919. [ABSTRACT FROM AUTHOR]

Cell adhesion to the extracellular matrix and its natural outcome of cell spreading, along with the maintenance of barrier activity, are essential behaviors of epithelial cells, including retinal pigment epithelium (RPE). Disruptions in these characteristics can result in severe vision-threatening diseases such as diabetic macular edema and age-related macular degeneration. However, the precise mechanisms underlying how RPE cells regulate their barrier integrity and cell spreading are not fully understood. This study aims to elucidate the relative importance of upper glycolytic components in governing these cellular behaviors of RPE cells. Electric Cell-Substrate Impedance Sensing (ECIS) technology was utilized to assess in real-time the effects of targeting various upper glycolytic enzymes on RPE barrier function and cell spreading by measuring cell resistance and capacitance, respectively. Specific inhibitors used included WZB117 for Glut1 inhibition, Lonidamine for Hexokinase inhibition, PFK158 for PFKFB3/PFK axis inhibition, and TDZD-8 for Aldolase inhibition. Additionally, the viability of RPE cells was evaluated using a lactate dehydrogenase (LDH) cytotoxicity assay. The most significant decrease in electrical resistance and increase in capacitance of RPE cells were observed due to dose-dependent inhibition of Glut1 using WZB117, as well as Aldolase inhibition with TDZD-8. LDH level analysis at 24–72 h post-treatment with WZB117 (1 and 10 μM) or TDZD-8 (1 μM) showed no significant difference compared to the control, indicating that the disruption of RPE functionality was not attributed to cell death. Lastly, inhibition of other upper glycolytic components, including PFKFB3/PFK with PFK158 or Hexokinase with Lonidamine, did not significantly affect RPE cell behavior. This study provides insights into the varied roles of upper glycolytic components in regulating the functionality of RPE cells. Specifically, it highlights the critical roles of Glut1 and Aldolase in preserving barrier integrity and promoting RPE cell adhesion and spreading. Such understanding will guide the development of safe interventions to treat RPE cell dysfunction in various retinal disorders. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is one of the leading causes of blindness. AMD is currently incurable; the best solution is to prevent its occurrence. To develop drugs for AMD, it is crucial to have a model system that mimics the symptoms and mechanisms in patients. It is most important to develop safer and more effective anti-AMD drug. In this study, the dose of A2E and the intensity of blue light were evaluated to establish an appropriate atrophic in vitro model of AMD and anti-AMD effect and therapeutic mechanism of Codonopsis lanceolata. The experimental groups included a control group an AMD group treated with A2E and blue light, a lutein group treated with 25 μM lutein after AMD induction, and three groups treated with different doses of C. lanceolata (10, 20, and 50 μg/mL) after AMD induction. Intrinsic apoptotic pathway (Bcl-2 family), anti-oxidative system (Keap1/Nrf2/HO-1 antioxidant response element), and anti-carbonyl effect (4-hydroxynonenal [4-HNE]) were evaluated using immunofluorescence, MTT, TUNEL, FACS, and western blotting analyses. A2E accumulation in the cytoplasm of ARPE-19 cells depending on the dose of A2E. Cell viability of ARPE-19 cells according to the dose of A2E and/or blue light intensity. The population of apoptotic or necrotic cells increased based on the A2E dose and blue light intensity. Codonopsis lanceolata dose-dependently prevented cell death which was induced by A2E and blue light. The antiapoptotic effect of that was caused by activating Keap1/Nrf2/HO-1 pathway, suppressing 4-HNE, and modulating Bcl-2 family proteins like increase of antiapoptotic proteins such as Bcl-2 and Bcl-XL and decrease of proapoptotic protein such as Bim. Based on these findings, 30 μM A2E and 20 mW/cm2 blue light on adult retinal pigment epithelium-19 cells was an appropriate condition for AMD model and C. lanceolata shows promise as an anti-AMD agent. [ABSTRACT FROM AUTHOR]

This paper provides a systematic survey of artificial intelligence (AI) models that have been proposed over the past decade to screen retinal diseases, which can cause severe visual impairments or even blindness. The paper covers both the clinical and technical perspectives of using AI models in hosipitals to aid ophthalmologists in promptly identifying retinal diseases in their early stages. Moreover, this paper also evaluates various methods for identifying structural abnormalities and diagnosing retinal diseases, and it identifies future research directions based on a critical analysis of the existing literature. This comprehensive study, which reviews both the conventional and state-of-the-art methods to screen retinopathy across different modalities, is unique in its scope. Additionally, this paper serves as a helpful guide for researchers who want to work in the field of retinal image analysis in the future. [ABSTRACT FROM AUTHOR]

Photochemical damage to retinal pigment epithelial (RPE) cells is implicated in the pathogenesis of age-related macular degeneration. This study investigated the protective effect of mangiferin on RPE cells subjected to blue light-induced damage. Using human-derived acute RPE 19 (ARPE-19) cells as an in vitro model, we incubated ARPE-19 cells with mangiferin and subsequently subjected those cells to damage-inducing blue light irradiation. Cell viability was measured by Cell Counting Kit-8. Intracellular reactive oxygen species (ROS) level was analyzed using flow cytometry. The results indicate that mangiferin can protect ARPE-19 cell growth after blue light-induced damage. However, the preincubation of ARPE-19 cells with lutein did not demonstrate the same protective effect against photo-induced damage. Lutein increased ROS generation and reduced cell viability (72 h), but mangiferin reduced the ROS level compared with the blank control. Our results demonstrate that mangiferin had a protective effect on blue light-induced RPE cell damage. [ABSTRACT FROM AUTHOR]

The underlying causes of age-related macular degeneration (AMD) remain elusive and treatment options of it are limited, while atorvastatin (AT) is expected to improve AMD. Our study sought to uncover the specific mechanisms that initiate pyroptosis in AMD and elucidate whether AT ameliorates Aβ1-40-induced retinal damage by inhibiting pyroptosis. An animal model of AMD was triggered by Aβ1-40, and the therapeutic efficacy of AT was evaluated by hematoxylin and eosin staining (H&E), Optical Coherence Tomography (OCT), Electroretinogram (ERG) and other methods. Utilizing network pharmacology in conjunction with transcriptomics, we identified potential therapeutic pathways. we employed Western blotting (WB) and quantitative real-time PCR (qPCR) methodologies to evaluate the levels of pyroptosis. In vitro system of retinal pigment epithelium (RPE) cells injury was caused by Aβ1-40 and subsequently treated with AT or JC2-11. The extent of pyroptosis was quantified using enzyme-linked immunosorbent assay (ELISA), immunofluorescence staining and WB. Cell morphological changes were examined using light microscopy and scanning electron microscopy. Network pharmacology and transcriptomics identified AIM2/Caspase-1/GSDMD as the key pathway. AT improved the retinal morphological and functional damage caused by Aβ1-40, and decreased the production of AIM2, Asc, Caspase-1, GSDMD-N, Cleaved Caspase-1 and cytokines to exert an anti-inflammatory effect. In addition, AT improved the ruptured membrane of RPE cells caused by Aβ1-40. The use of JC2-11 further demonstrated that AT inhibits pyroptosis of RPE via AIM2/Caspase-1/GSDMD pathway activated by Aβ1-40. These discoveries illuminate the retinal conservation role of AT by effectively hindering the progression of pyroptosis. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is an illness involving the degeneration of the macula of the retina. Fundus photography is the most affordable and convenient way to monitor individuals, in which AMD symptoms segmentation is necessary to assist clinical diagnosis. This study conducted a large number of experimental discussions on the annotation quality and symptoms categories to find a reliable learning strategy, and then applied it to early detection of AMD. Specifically, we discuss the inference of the representational power of the deep neural network, loss function selection, the preprocessing scheme of annotation augmentation, and the annotation quality of the dataset on prediction performance. This paper verified that different learning strategies need to be selected for the AMD symptoms segmentation tasks with varying characteristics of database, which can be used as a reference for developing the related research in the future. On the other hand, we demonstrated that current medical datasets suffer from annotation quality uncertainty, leading to limited learning capabilities. In the future, it is necessary to develop methods to overcome the impact of datasets with poor annotation quality. [ABSTRACT FROM AUTHOR]

One type of age-related macular degeneration (AMD), neovascular (nAMD), characterized by choroidal neovascularization (CNV), accounts for the majority of the severe central vision impairment associated with AMD. Endothelial cells (ECs) in direct contact with retinal pigment epithelial (RPE) cells are more prone to the pathological angiogenesis involved in CNV. Herein, we investigated the effect of crosstalk between RPE cells and choroidal endothelial cells (CECs) via the ANXA1/FPR2/NLRP3 inflammasome/pyroptosis axis on the development of choroidal neovascularization (CNV) in vitro and in vivo. ANXA1 expression and secretion from ARPE-19 cells were upregulated by hypoxia. FPR2 expression, especially on the plasma membrane, in HCECs was upregulated under hypoxic conditions. ANXA1 secreted from ARPE-19 cells inhibited NLRP3 inflammasome activation and NLRP3 inflammasome-mediated pyroptosis in HCECs by activating the FPR2/SHP2 axis. Moreover, ANXA1 secreted by ARPE-19 cells promoted behaviors of HCECs, including proliferation, migration, and tube formation, by activating the FPR2/SHP2 axis and inhibiting NLRP3 inflammasome-mediated pyroptosis. Inhibiting the upregulated ANXA1/FPR2/SHP2/NLRP3 inflammasome/pyroptosis axis decreased the volume of CNV. Our data suggest that the crosstalk between RPE cells and CECs via the ANXA1/FPR2/NLRP3 inflammasome/pyroptosis axis promotes CNV. This finding could identify a potential target for the prevention and treatment of CNV. [ABSTRACT FROM AUTHOR]

Aging, chronic oxidative stress, and inflammation are major pathogenic factors in the development and progression of age-related macular degeneration (AMD) with the loss of retinal pigment epithelium (RPE). The human RPE contains a subpopulation of progenitors (i.e., RPE stem cells—RPESCs) whose role in the RPE homeostasis is under investigation. We evaluated the paracrine effects of mature RPE cells exposed to oxidative stress (H2O2) on RPESCs behavior through co-cultural, morphofunctional, and bioinformatic approaches. RPESCs showed a decline in proliferation, an increase of the senescence-associated β-galactosidase activity, the acquisition of a senescent-like secretory phenotype (SASP), and the reduction of their stemness and differentiation competencies. IL-6 and Superoxide Dismutase 2 (SOD2) seem to be key molecules in RPESCs response to oxidative stress. Our results get insight into stress-induced senescent-associated molecular mechanisms implicated in AMD pathogenesis. The presence of chronic oxidative stress in the microenvironment reduces the RPESCs abilities, inducing and/or maintaining a pro-inflammatory retinal milieu that in turn could affect AMD onset and progression. [ABSTRACT FROM AUTHOR]

Purpose: To investigate whether previously reported seasonal variation and winter-dominant prevalence of acute massive submacular hemorrhages (SMHs) caused by age-related macular degeneration (AMD) disappeared, and those caused by retinal microaneurysms (RMAs) emerged. Method: The medical charts of 95 patients (95 eyes) with SMH caused by AMD and 76 patients (76 eyes) with SMH caused by RMAs in 2012–2019 were retrospectively reviewed. For each subject, the month of onset, the mean ambient temperature of that month were recorded. Results: The monthly numbers of cases of SMHs caused by AMD from January to December were 6, 8, 4, 9, 7, 10, 9, 11, 7, 11, 3, and 10. No significant seasonal variation in the monthly incidence was identified (Roger's R = 1.89, p = 0.39). The monthly numbers of SMHs caused by RMAs from January to December were 3, 11, 11, 8, 7, 8, 5, 5, 2, 4, 7, and 5. There was significant seasonal variation in the monthly incidence (Roger's R = 7.67, p = 0.02). There was no significant correlation between the monthly incidence of SMHs caused by RMAs and mean ambient temperature. Conclusion: Our previous study conducted for cases obtained in 1998–2005 showed seasonal cyclic trend in the number of SMHs caused by AMD, with the peak in winter. However, that significant seasonal variation disappeared in 2012–2019 in the present study. Common usage of OCT devices and anti-VEGF drugs might be the reason for the lack of seasonal variation in the cases of SMH caused by AMD. [ABSTRACT FROM AUTHOR]

The most common retinal diseases that are to be diagnosed are Diabetic Retinopathy (DR), Age-related Macular Degeneration (AMD) and Choroidal Neovascularization (CNV). For the people above 60 years of age, detection of these retinal diseases is an important task for treatment that reduces the risk of vision loss. Retinal fundus images play a significant role in the detection of DR, AMD and CNV disease diagnosis and treatment. The existing techniques for the detection of DR, AMD and CNV have not fulfilled with the classification accuracy of the retinal diseases effectively. This research work proposes an efficient classification framework for retinal fundus image recognition to overcome these drawbacks. Initially, the input image from the publicly available STARE database is preprocessed with the following three steps (a) Specular reflection removal and smoothing, (b) contrast enhancement and (c) retinal region expansion. With the preprocessed image, the features are extracted using Multi-Scale Discriminative Robust Local Binary Pattern (MS-DRLBP), based on RGB component selection, Gradient operation, and LBP descriptor. Finally, classification was done using hybrid Convolution Neural Network (CNN) and Radial Basis Function (RBF) model (CNN-RBF) which classifies the retinal fundus images into four classes such as DR, AMD, CNV and Normal (NR). Experimental results of the proposed method gives an accuracy of 97.22% compared with the existing other methodologies. [ABSTRACT FROM AUTHOR]

Purpose: To assess disease stability (absence of intra- and/or subretinal fluid) and the portion of eyes being capable to extend their treatment interval to ≥ 12 weeks in exudative age-related macular degeneration (AMD). Methods: A systematic literature search was performed in NCBI, PubMed, CENTRAL, and ClinicalTrials.gov to identify clinical studies reporting treatment outcomes for ranibizumab, aflibercept, and brolucizumab in exudative AMD under a treat-and-extend protocol and a follow-up of ≥ 12 months. Weighted mean differences and subgroup comparisons were used to integrate the different studies. Results: This meta-analysis refers to 29 published series, including 27 independent samples and 5629 patients. In the pooled group, disease stability was reported in 62.9% and 56.0%, respectively, after 12 and 24 months of treatment, whereas treatment intervals were extended to ≥ 12 weeks in 37.7% and 42.6%, respectively. Ranibizumab, aflibercept, and brolucizumab differed regarding their potential to achieve disease stability (56.3%, 64.5%, and 71.5% after 12, and 50.0%, 52.7% and 75.7% after 24 months; p = < 0.001) and to allow an interval extension to ≥ 12 weeks (28.6%, 34.2%, and 53.3% after 12, and 34.2%, 47.7%, and 41.7% after 24 months; p = < 0.001). Conclusion: The portion of eyes achieving disease stability regressed in the second year, whereas the portion of eyes under a ≥ 12-week interval increased. This discrepancy may reflect the challenges in balancing between under-treatment and a reduced treatment burden. [ABSTRACT FROM AUTHOR]

Purpose: The treatment guidelines for many macular diseases rely on frequent monitoring with optical coherence tomography (OCT). However, the burden of frequent disease control leads to low therapy adherence in real life. OCT home monitoring would address this issue but requires an inexpensive and self-operable device. With self-examination low-cost full-field OCT (SELFF-OCT), our group has introduced a novel technology that may fulfill both requirements. In this pilot study, we report the initial experiences with a clinical prototype. Methods: Fifty-one patients with different macular diseases were recruited in a cross-sectional study. The most common diseases were age-related macular degeneration (AMD; 39/51), diabetic macular edema (DME; 6/51), and retinal vein occlusion (RVO; 3/51). Patients received a short training in device usage and then performed multiple self-scans with the SELFF-OCT device. For comparison, scans with a standard clinical spectral domain (SD-)OCT were taken. Results: After a brief training, 77% of the patients were able to successfully acquire images that were clinically gradable. No significant influence on success could be found for age (p = 0.08) or BCVA (p = 0.97). Relevant disease biomarkers in the most common retinal diseases could be detected. Conclusions: SELFF-OCT was used successfully for retinal self-examination and in the future could be used for retinal home monitoring. Future improvements in technology are expected to improve success rates and image quality. Trial registration: The Trial was registered in the German Trial Register under the number DRKS00013755 on 14.03.2018. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is one of the leading causes of irreversible blindness and is characterized by fluid-related accumulations such as intra-retinal fluid (IRF), subretinal fluid (SRF), and pigment epithelial detachment (PED). Spectral-domain optical coherence tomography (SD-OCT) is the primary modality used to diagnose AMD, yet it does not have algorithms that directly detect and quantify the fluid. This work presents an improved convolutional neural network (CNN)-based architecture called RetFluidNet to segment three types of fluid abnormalities from SD-OCT images. The model assimilates different skip-connect operations and atrous spatial pyramid pooling (ASPP) to integrate multi-scale contextual information; thus, achieving the best performance. This work also investigates between consequential and comparatively inconsequential hyperparameters and skip-connect techniques for fluid segmentation from the SD-OCT image to indicate the starting choice for future related researches. RetFluidNet was trained and tested on SD-OCT images from 124 patients and achieved an accuracy of 80.05%, 92.74%, and 95.53% for IRF, PED, and SRF, respectively. RetFluidNet showed significant improvement over competitive works to be clinically applicable in reasonable accuracy and time efficiency. RetFluidNet is a fully automated method that can support early detection and follow-up of AMD. [ABSTRACT FROM AUTHOR]

Purpose: To describe the clinical and multimodal imaging (MMI) features of age-related macular degeneration (AMD) eyes presenting with intraretinal exudation and no evidence of neovascularization or structural alterations of native retinal vessels. Methods: This was a retrospective review of the MMI and electronic health records for 3 consecutive patients presenting with unilateral exudative non-neovascular age-related macular degeneration. MMI included confocal color fundus photography (CFP), fundus autofluorescence (FAF), fluorescein angiography (FA), spectral domain optical coherence tomography (SD-OCT), swept-source optical coherence tomography angiography (SS-OCTA), and spectral domain optical coherence tomography angiography (SD-OCTA). Dense B-scan OCTA (DB-OCTA) patterns and implemented image post-processing were used to improve spatial resolution in the OCTA analysis and remove projection artifacts. Results: Three eyes of 3 patients (1 male and 2 females, ages 72–87) developed intraretinal fluid (IRF) producing retinal edema during regular follow-up for non-neovascular AMD. FA, SS-OCTA, and DB-OCTA demonstrated no evidence of macular neovascularization or discrete retinal vascular abnormalities that could explain the IRF accumulation. Two eyes received intravitreal anti-VEGF therapy and demonstrated prompt resolution of IRF with periodic recurrences over time. Conclusion: Exudative non-neovascular AMD is a novel clinical phenotype characterized by the presence of non-neovascular intraretinal exudation producing macular edema. Differentiating this condition from other manifestations of AMD requires appropriate use of MMI. Further study is needed to assess the clinical impact and optimal management of exudative non-neovascular AMD. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is the leading cause of central vision loss in the developed world. Wet AMD can be managed through serial intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents. However, sometimes the treatment is ineffective. Given that the half-life of the drug is limited, inefficient mixing of the injected drug in the vitreous chamber of the eye may contribute to the ineffectiveness. Here, we introduce thermal heating as a means of enhancing the mixing-process in the vitreous chamber and investigate parameters that potentially influence its effectiveness. Our in vitro studies reveal the importance of the heating location on the eye. A significant increase in the mixing and delivery of drugs to the targeted area (the macula) could be achieved by placing heating pads to induce a current, against gravity, in the vitreous. The presented results can potentially help in the development of a better strategy for intravitreal injection, subsequently improving the quality of patient care. [ABSTRACT FROM AUTHOR]

Fibulin-3 (F3) is an extracellular matrix glycoprotein found in basement membranes across the body. An autosomal dominant R345W mutation in F3 causes a macular dystrophy resembling dry age-related macular degeneration (AMD), whereas genetic removal of wild-type (WT) F3 protects mice from sub-retinal pigment epithelium (RPE) deposit formation. These observations suggest that F3 is a protein which can regulate pathogenic sub-RPE deposit formation in the eye. Yet the precise role of WT F3 within the eye is still largely unknown. We found that F3 is expressed throughout the mouse eye (cornea, trabecular meshwork (TM) ring, neural retina, RPE/choroid, and optic nerve). We next performed a thorough structural and functional characterization of each of these tissues in WT and homozygous (F3−/−) knockout mice. The corneal stroma in F3−/− mice progressively thins beginning at 2 months, and the development of corneal opacity and vascularization starts at 9 months, which worsens with age. However, in all other tissues (TM, neural retina, RPE, and optic nerve), gross structural anatomy and functionality were similar across WT and F3−/− mice when evaluated using SD-OCT, histological analyses, electron microscopy, scotopic electroretinogram, optokinetic response, and axonal anterograde transport. The lack of noticeable retinal abnormalities in F3−/− mice was confirmed in a human patient with biallelic loss-of-function mutations in F3. These data suggest that (i) F3 is important for maintaining the structural integrity of the cornea, (ii) absence of F3 does not affect the structure or function of any other ocular tissue in which it is expressed, and (iii) targeted silencing of F3 in the retina and/or RPE will likely be well-tolerated, serving as a safe therapeutic strategy for reducing sub-RPE deposit formation in disease. Key messages: • Fibulins are expressed throughout the body at varying levels. • Fibulin-3 has a tissue-specific pattern of expression within the eye. • Lack of fibulin-3 leads to structural deformities in the cornea. • The retina and RPE remain structurally and functionally healthy in the absence of fibulin-3 in both mice and humans. [ABSTRACT FROM AUTHOR]

To examine whether free fatty acid receptor 4 (FFAR4) activation can protect against choroidal neovascularization (CNV), which is a common cause of blindness, and to elucidate the mechanism underlying the inhibition, we used the mouse model of laser-induced CNV to mimic angiogenic aspects of age-related macular degeneration (AMD). Laser-induced CNV was compared between groups treated with an FFAR4 agonist or vehicle, and between FFAR4 wild-type (Ffar4+/+) and knock out (Ffar4−/−) mice on a C57BL/6J/6N background. The ex vivo choroid-sprouting assay, including primary retinal pigment epithelium (RPE) and choroid, without retina was used to investigate whether FFAR4 affects choroidal angiogenesis. Western blotting for pNF-ĸB/NF-ĸB and qRT-PCR for Il-6, Il-1β, Tnf-α, Vegf, and Nf-ĸb were used to examine the influence of FFAR4 on inflammation, known to influence CNV. RPE isolated from Ffar4+/+ and Ffar4−/− mice were used to assess RPE contribution to inflammation. The FFAR4 agonist suppressed laser-induced CNV in C57BL/6J mice, and CNV increased in Ffar4−/− compared to Ffar4+/+ mice. We showed that the FFAR4 agonist acted through the FFAR4 receptor. The FFAR4 agonist suppressed mRNA expression of inflammation markers (Il-6, Il-1β) via the NF-ĸB pathway in the retina, choroid, RPE complex. The FFAR4 agonist suppressed neovascularization in the choroid-sprouting ex vivo assay and FFAR4 deficiency exacerbated sprouting. Inflammation markers were increased in primary RPE cells of Ffar4−/− mice compared with Ffar4+/+ RPE. In this mouse model, the FFAR4 agonist suppressed CNV, suggesting FFAR4 to be a new molecular target to reduce pathological angiogenesis in CNV. [ABSTRACT FROM AUTHOR]

Lipocalins are a family of secreted adipokines which play important roles in various biological processes. Lipocalin-2 (LCN-2) has been shown to be involved in acute and chronic inflammation. This particular protein is critical in the pathogenesis of several diseases including cancer, diabetes, obesity, and multiple sclerosis. Herein, we discuss the general molecular basis for the involvement of LCN-2 in acute infections and chronic disease progression and also ascertain the probable role of LCN-2 in ocular diseases, particularly in age-related macular degeneration (AMD). We elaborate on the signaling cascades which trigger LCN-2 upregulation in AMD and suggest therapeutic strategies for targeting such pathways. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is a complex eye disease underlined by the death of photoreceptors and degeneration of retinal pigment epithelium (RPE) and choriocapillaris (CC). The mechanism(s) responsible for massive and progressive retinal degeneration is not completely known. Senescence, a state of permanent inhibition of cell growth, may be induced by many factors important for AMD pathogenesis and results in senescence-associated secretory phenotype (SASP) that releases growth factors, cytokines, chemokines, proteases and other molecules inducing inflammation and other AMD-related effects. These effects can be induced in the affected cell and neighboring cells, leading to progression of AMD phenotype. Senescent cells also release reactive oxygen species that increase SASP propagation. Many other pathways of senescence-related AMD pathogenesis, including autophagy, the cGAS–STING signaling, degeneration of CC by membrane attack complex, can be considered. A2E, a fluorophore present in lipofuscin, amyloid-beta peptide and humanin, a mitochondria-derived peptide, may link AMD with senescence. Further studies on senescence in AMD pathogenesis to check the possibility of opening a perspective of the use of drugs killing senescent cells (senolytics) and terminating SASP bystander effects (senostatics) might be beneficial for AMD that at present is an incurable disease. [ABSTRACT FROM AUTHOR]

Purpose: To compare treatment efficacy of anti-VEGF medications following pro re nata (PRN, "as needed", monthly injections only in case of active disease) or treat and extend (T&E, progressive extension of treatment intervals up to 12 weeks depending on the clinical findings) treatment protocols in real-world conditions. Methods: Retrospective, observational study. Patients diagnosed with age-related macular degeneration and without pre-treatment undergoing routine anti-VEGF treatment in one eye clinic in Switzerland were included. Treatment was performed according to local practices, using ranibizumab or aflibercept, and following T&E or PRN regimens. Changes in logMAR and injection intervals (time between two injections) for specific treatment periods were evaluated descriptively and using mixed models. Results: In total, 1071 patients with 1332 treated eyes (ranibizumab/PRN 722, ranibizumab/T&E 191, aflibercept/T&E 419) were included in the analyses. At baseline, logMAR (mean ± SD) was similar in both ranibizumab treatment groups (PRN 0.63 ± 0.43, T&E 0.57 ± 0.42). In the ranibizumab/PRN group, logMAR was about 0.1 lower for all time intervals in the initial and maintenance phases in comparison with baseline, indicating an improvement in VA. By comparison, logMAR improved more strongly in the ranibizumab/T&E group (16 to < 22 months, − 0.19 [− 0.23–0.15]) in comparison with baseline. Comparing ranibizumab/T&E vs. aflibercept/T&E groups, improvements in logMAR were similar over time. In the maintenance phase, the rate of patients with a clinically relevant improvement in visual acuity (> 0.2 logMAR) was higher in both T&E groups compared with the ranibizumab/PRN group. Injection intervals in the maintenance phase in ranibizumab/T&E group gradually expanded over time; whereas in the aflibercept/T&E group, injection intervals remained relatively stable. Conclusions: Ranibizumab used according to T&E protocol yielded a stronger improvement in logMAR, compared with PRN protocol with longer injection intervals than aflibercept/T&E. This large real-world data assessment supports previous data on the superiority of T&E treatment. [ABSTRACT FROM AUTHOR]

Background: Age-related macular degeneration (AMD) causes reading impairment, reduced quality of life (QoL), and secondary depression. We have shown that support with magnifying aids improved reading speed (RS), emotional and cognitive status, and QoL. The present study investigates whether additional reading training (RT) (after adapting to appropriate visual aids) can further improve vision rehabilitation. Methods: Patients with dry AMD were randomly assigned to 2 groups. The primary RT group (P-RTG, n = 25) trained with sequentially presented text (RSVP), and the control group (CG, n = 12) performed placebo training (crossword puzzles) and later crossed over to RT, so that altogether 37 participants performed reading training. Patients trained at home on a PC for 6 weeks. RS was assessed during reading printed paragraphs of text aloud. Using a scanning laser ophthalmoscope, we examined fixation stability and preferred retinal locus (PRL) for fixating a cross, as well as PRL and eye movements during reading single words. We assessed emotional status by Montgomery–Åsberg Depression Rating Scale (MADRS), cognitive status by dementia detection test (DemTect) and QoL by Impact of Vision Impairment (IVI) profile. Visual acuity and magnification requirement were examined by standard procedures. All variables were measured before and after placebo training, before and after RT, and after 6 weeks without training (follow-up). Results: RS improved significantly in the P-RTG during RT, but not in the CG during placebo training. The effect remained stable at follow-up. Fixation performance and eye movement variables did not change. Emotional status (MADRS) improved in P-RTG during RT and showed a significant difference of the change of scores between the 2 groups. Complete IVI scores improved significantly during RT and remained stable. Conclusion: The results indicate that patients with AMD, who already use magnifying aids, benefit from additional RT and that it can contribute in preventing depression and improve QoL. Trial registration: The study was registered at the German Clinical Trials Register (DRKS00015609). [ABSTRACT FROM AUTHOR]

Background: Age-related macular degeneration (AMD) is a complex disease, and recent studies have shown role of complement system genes in its development. Complement factor I regulates the complement pathways, and relationship between CFI polymorphisms and AMD is controversial. We evaluated the possible association of complement factor I rs141853578 (G119R) variation with advanced AMD in Iranian patients.Materials and methods: We included 371 case-control samples consisting of 220 advanced AMD patients and 151 genetically unrelated healthy controls. Extracted DNA samples amplified to obtain fragment including the polymorphic complement factor I rs141853578 (G119R) region.Results: The distribution of the genotypes was significantly different in the AMD patients compared to that of controls (p = 0.035). The TT genotype frequencies for CFI were significantly higher in AMD group (7.7 vs. 2%, OR 4.67, CI 1.33-16.45, p = 0.016). This significant difference was maintained after adjustment for the effects of age and gender (OR 5.09, CI 1.42-18.20, p = 0.012). The minor allele frequency (T allele) was also significantly higher in AMD patients compared to that of controls (29.3 vs. 21.5% OR 1.51, CI 1.07-2.13, p = 0.018).Conclusion: Current study showed that CFI rs141853578 (G119R) is a risk factor for developing advanced type AMD. This study also suggests that the frequency of G119R polymorphism in our population is not as rare as reported from other populations. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the efficacy of intravitreal aflibercept therapy using a treat-and-extend regimen on treatment-naïve pachychoroid neovasculopathy (PNV) and Type 1 neovascular age-related macular degeneration (AMD).Methods: We retrospectively studied 42 eyes with PNV and 60 eyes with Type 1 neovascular AMD. We assessed best-corrected visual acuity (BCVA), central macular thickness (CMT), central choroidal thickness (CCT), and total number of injections over 2 years.Results: The BCVA and CMT improvements during the 2-year treatment period did not differ significantly between PNV and AMD; however, CCT decreased significantly in PNV than in AMD (P<0.05). Management of PNV required significantly fewer injections than AMD during the 2-year period (P<0.05). There were no significant differences in BCVA, CMT and CCT changes between PNV with and without polypoidal lesions (28 vs. 14 eyes) during the 2 year period. Significantly fewer injections were needed for PNV with polypoidal lesions than for PNV without (P<0.01). There were no significant differences in BCVA, CMT and CCT changes, or in the number of injections during the 2-year treatment period, between AMD with and without polypoidal lesions (30 vs. 30 eyes).Conclusion: Treat-and-extend regimen of intravitreal aflibercept injection may be equally effective in terms of improvement of BCVA and exudative changes both in eyes with PNV and those with Type 1 neovascular AMD requiring fewer injections for the former. Among eyes with PNV, those with polypoidal lesions needed fewer injections than those without polypoidal lesions. [ABSTRACT FROM AUTHOR]

Purpose: To report research participants’ baseline characteristics in the AMD2000 study, a prospective, multicenter, 5-year, observational cohort study of Japanese age-related macular degeneration (AMD). The characteristics were determined using multimodal imaging.Methods: Patients with AMD were recruited at 18 clinical sites in Japan between April 2006 and March 2009. Each patient underwent a complete ophthalmic examination, including measurement of best-corrected visual acuity (Landolt chart), indirect ophthalmoscopy, slit-lamp biomicroscopy with a contact lens, optical coherence tomography imaging, fundus photography, and fluorescein and indocyanine green angiography.Results: Four hundred sixty participants (326 men [70.9%]) were included in the study. At enrollment, 131 eyes (28.5%) had hard drusen and 125 eyes (27.2%) had soft drusen in the macular area. A total of 455 eyes (98.9%) were diagnosed as having wet AMD, and 5 eyes (1.1%), as having dry AMD. Of the 455 eyes with wet AMD, 209 eyes (45.4%) had typical AMD, 228 eyes (49.6%) had polypoidal choroidal vasculopathy (PCV), and 18 eyes (3.9%) had retinal angiomatous proliferation. The size of choroidal neovascularization (CNV) was significantly smaller with indocyanine green angiography than with fluorescein angiography (P < 0.001). Poor baseline visual acuity was associated with cystoid macular edema, older age, scar, extrafoveal macular edema, subfoveal CNV, large branching vascular network, and hard exudates.Conclusion: Japanese patients with AMD are predominantly male, lack drusen, and have a high rate of PCV. [ABSTRACT FROM AUTHOR]

Purpose: To compare the published results of studies on the genotype association of ARMS2/LOC387715 A69S, CFH Y402H, and CFH I62V in cases diagnosed as retinal angiomatous proliferation (RAP) versus neovascular age-related macular degeneration (AMD) or healthy controls. Methods: Heterogeneity of studies was evaluated using Cochran's Q test and I-square index. To modify the heterogeneity in the variables, we used random effects model. Meta-analysis was performed using STATA. Results: Four studies were included with 1076 neovascular AMD patients, 222 RAP cases, and 2276 control subjects. Pooled overall odds ratios for RAP/AMD were 1.15 (95% CI 0.60-2.18) for GT versus GG, 3.52 (95% CI 1.25-9.91) for TT versus GG ARMS2, 0.98 (95% CI 0.22-4.29) for GA versus AA, 1.00 (95% CI 0.25-4.02) for GG versus AA CFHI62V, 0.57 (95% CI 0.35-0.93) for CT versus TT CFH Y402H, and 0.40 (95% CI 0.22-0.74) for CC versus TT CFH Y402H. Regression analysis showed that ARMS2 TT genotype has a statistically significant effect on RAP versus AMD compared to CFH genotypes ( P < 0.001). Conclusion: This meta-analysis disclosed a stronger effect of ARMS2 genotypes in RAP cases compared with CFH Y402H and I62V genotypes. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate the efficacy of standard induction therapy with intravitreal aflibercept (IVA) in patients with exudative age-related macular degeneration (AMD) at 6 months after completion of induction therapy. Eleven eyes with typical AMD (tAMD) and 13 eyes with polypoidal choroidal vasculopathy (PCV) received three monthly doses of IVA (2 mg/0.05 ml in weeks 0, 4, and 8) for treatment of exudative AMD. Best-corrected visual acuity (BCVA) was measured, and optical coherence tomography was performed at baseline and at each monthly visit until 6 months after IVA. Treatment failure was defined as persistent or recurrent AMD that presented with cystoid macular edema, serous retinal detachment, and pigment epithelium detachment. Mean logMAR BCVA was improved from 0.62 ± 0.46 at baseline to 0.54 ± 0.43 at 6 months after IVA ( p < 0.05). The success rate was 95.8 % at 3 months and 75.0 % at 6 months after IVA. Failure of IVA was positively associated with the absence of PVD before treatment ( r = 0.35) and with the AMD type (tAMD, r = 0.43) by univariate analysis. Cox proportional hazards analysis demonstrated that the absence of PVD before treatment was associated with an increased risk of failure of IVA (OR = 33.17, p = 0.0219). Three months of induction IVA achieved a high success rate in patients with AMD monitored for up to 6 months. Factors associated with failure of IVA were the absence of PVD and the presence of tAMD. Accordingly, continuation of IVA following induction therapy may be beneficial to manage AMD in patients with tAMD or those without PVD. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is the leading cause of vision loss and blindness among the elderly. Although the pathogenesis of this disease remains still obscure, several researchers have report that death of retinal pigmented epithelium (RPE) caused by excessive accumulation of A2E is crucial determinants of AMD. In this study, the preventive effect of Vaccinium uliginosum L. (V.U) extract and its fractions on AMD was investigated in blue light-irradiated human RPE cell (ARPE-19 cells). Blue light-induced RPE cell death was significantly inhibited by the treatment of V.U extract or its fraction. To identify the mechanism, FAB-MS analysis revealed that V.U inhibits the photooxidation of N-retinyl- N-retinylidene ethanolamine (A2E) induced by blue light in cell free system. Moreover, monitoring by quantitative HPLC also revealed that V.U extract and its fractions reduced intracellular accumulation of A2E, suggesting that V.U extract and its fractions inhibit not only blue light-induced photooxidation, but also intracellular accumulation of A2E, resulting in RPE cell survival after blue light exposure. A2E-laden cell exposed to blue light induced apoptosis by increasing the cleaved form of caspase-3, Bax/Bcl-2. Additionally, V.U inhibited by the treatment of V.U extract or quercetin-3-O-arabinofuranoside. These results suggest that V.U extract and its fractions have preventive effect on blue light-induced damage in RPE cells and AMD. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the plasma levels of amyloid beta (Aβ) and select inflammatory mediators in patients with various stages of AMD compared to that of age-matched controls, and discern a relationship to disease severity. Methods: Plasma samples were obtained from AMD subjects at various stages of disease-early (drusen only), geographic atrophy (GA), neovascular AMD (CNV)-and from controls of similar age without AMD. Samples were analyzed using a commercially available ELISA kit (sixteen cytokines) or LC/MS/MS (Aβ isotypes). Descriptive statistics were compiled on all analytes. Analysis of covariance (ANCOVA) was conducted to compare each analyte across AMD groups while adjusting for sex and age of the patients, and in comparison to the control group. Receiver operating characteristics plots were generated for the strongest predictor variables. Results: Levels of alternative spliced CC3 proteins were significantly different between controls and CNV groups ( p < 0.05), with median levels almost twice higher in CNV than in controls. There was an increasing trend for plasma levels of Αβ isotypes across AMD progressive stages ( p values ranged from 0.052 to 0.0012) (ANCOVA). When adjusted for multiple comparisons analysis, plasma Aβ 1-42 levels, and its ratio with Aβ 1-40 were the most significantly associated with late AMD stages. Consistently with the ANCOVA results for Αβ isotypes, the ROC curve showed a moderate prediction (AUC = - ~ 0.78) of AMD vs control using the Aβ 1−42 isotype. Conclusion: Plasma Aβ 1-42 may have utility as a systemic biomarker for AMD. [ABSTRACT FROM AUTHOR]

Amyloid is a generic term for insoluble, often intensely hydrophobic, fibrous protein aggregates that arise from inappropriately folded versions of naturally-occurring polypeptides. The abnormal generation and accumulation of amyloid, often referred to as amyloidogenesis, has been associated with the immune and pro-inflammatory pathology of several progressive age-related diseases of the human central nervous system (CNS) including Alzheimer's disease (AD) and age-related macular degeneration (AMD). This 'research perspective' paper reviews some of the research history, biophysics, molecular-genetics and environmental factors concerning the contribution of amyloid beta (Aβ) peptides, derived from beta-amyloid precursor protein (βAPP), to AD and AMD that suggests an extensive similarity in immune and inflammatory degenerative mechanisms between these two CNS diseases. [ABSTRACT FROM AUTHOR]

Purpose: This study evaluates the potential of serum pro-inflammatory cytokines as AMD biomarkers. Methods: Serum samples from 30 age-related macular degeneration (AMD) patients and 15 age-matched controls were examined for 16 inflammatory cytokines using multiplex ELISA. Patients were divided into three subgroups (improvement/no change/deterioration during anti-VEGF treatment) by OCT and funduscopy, and correlated to the cytokine levels. Results: Serum concentrations of IL-1α, IL-1β, IL-4, IL-5, IL-10, IL-13, and IL-17 were significantly higher in AMD patients than in controls. None of the co-variables expressed a significant effect on the tested cytokines. Only IL-1a and IL-17 showed a statistically significant difference between groups (improved, unchanged, deteriorated) as determined by one-way ANOVA. Patients with increased macular thickness during treatment showed significantly lower levels of IL-17 compared to improved cases and to unchanged cases ( p = 0.004, 0.03 respectively, Dunnett's T3 post hoc multiple test). TNF-α was significantly higher in improved cases compared to deteriorated cases ( p =0.03, Dunnett's T3 post hoc multiple test). IL-17 was a significant predictor for macular oedema using linear regression (β = −0.888, p <0.05). Conclusion: Elevation of IL-1α, IL-1β, IL-4, IL-5, IL-10, IL-13, and IL-17 in the serum of AMD patients supports the hypothesis of AMD as an inflammatory disease. Patients with high IL-17 and TNF-α serum levels were more likely to have a favourable course under VEGF therapy. These cytokines may be used as easy-to-obtain biomarkers. [ABSTRACT FROM AUTHOR]

The opportunity to undergo an induced pluripotent stem cell-based autologous transplant can strike patients as a chance for a cure from a debilitating condition with few options for respite. However, when clinical studies of this caliber present themselves, patients and researchers, each with their own set of motives, may find it difficult to take a balanced approach to evaluating them. We present a patient-centered risk-benefit analysis of the iPSC-based clinical research currently underway in Japan, including a survey of in vitro and in vivo tests that support this project, an in-depth discussion of risks, and further elucidation of considerations patients may wish to consider. The arguments presented will assist patients in undertaking a more informed decision-making process. [ABSTRACT FROM AUTHOR]

Physiological stress response and oxidative damage are factors for aging processes and, as such, are thought to contribute to neovascular age-related macular degeneration (AMD). Paraoxonase 1 (PON1) is an enzyme that plays an important role in oxidative stress and aging. We investigated association of DNA sequence variants (SNP) within the upstream regulatory region of the PON1 gene with neovascular AMD in 305 patients and 288 controls. Four of the seven tested SNPs (rs705379, rs705381, rs854573, and rs757158) were more frequently found in AMD patients compared to controls ( P = 0.0099, 0.0295, 0.0121, and 0.0256, respectively), and all but one (SNP rs757158) are in linkage disequilibrium. Furthermore, haplotype TGGCCTC conferred protection (odds ratio (OR) = 0.76, (CI) = 0.60-0.97) as it was more frequently found in control individuals, while haplotype CGATGCT increased the risk (OR = 1.55, CI = 1.09-2.21) for AMD. These results were also reflected when haplotypes for the untranscribed and the 5′untranslated regions (5′UTR) were analyzed separately. To assess haplotype correlation with levels of gene expression, the three SNPs within the 5′UTR were tested in a luciferase reporter assay. In retinal pigment epithelium-derived ARPE19 cells, we were able to measure significant differences in reporter levels, while this was not observed in kidney-derived HEK293 cells. The presence of the risk allele A (SNP rs705381) caused an increase in luciferase activity of approximately twofold. Our data support the view that inflammatory reactions mediated through anti-oxidative activity may be relevant to neovascular age-related macular degeneration. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is still an incurable blinding eye disease because of complex pathogenic mechanisms and unusual diseased regions. With the use of chemical biology tools, great progress has been achieved in improving the understanding of AMD pathogenesis. The severity of AMD is, at least in part, linked to the non-degradable lipofuscin bis-retinoids in retinal pigment epithelial (RPE). This material is thought to result from the lifelong accumulation of lysosomal residual bodies containing the end products derived from the daily phagocytosis of rod outer segments by RPE cells. Here, we present previously recognized bis-retinoids with focus on structures and biosynthetic pathways. In addition to a brief discussion on the mutual conversion relationships of bis-retinoids, future perspectives and the medical relevance of such studies on these lipofuscin constituents are also highlighted. [ABSTRACT FROM AUTHOR]

Background: To investigate a possible structural difference in the retina of hydroxychloroquine (Plaquenil)-treated patients as an explanation for the protective effect of this medication against age-related macular degeneration (AMD). Methods: In this retrospective study, we compared the mean thickness of the retinal outer band (consisting of the Bruch's membrane and retinal pigment epithelium layer), as measured by optical coherence tomography (OCT), of 54 eyes of 27 hydroxychloroquine-treated rheumatoid arthritis patients (study group), 40 eyes of 20 healthy similar aged individuals (control group I), and 22 eyes of 11 non-hydroxychloroquine-treated rheumatoid arthritis patients (control group II). Results: The mean thicknesses of the outer band of the retinal pigment epithelium layer was 60.4 ± 7.4, 43.3 ± 2.7, and 39.7 ± 3.6 μm for the study group, control group I, and control group II, respectively. P values for differences in mean thicknesses were < 0.0001 between the study group and each of the control groups, and 0.086 between the two control groups. Conclusion: Treatment with hydroxychloroquine was associated with increased thickness of the outer band of the retinal pigment epithelium layer. This finding may explain the protective effect of hydroxychloroquine against age-related macular degeneration (AMD). [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) causes progressive impairment of central vision and is the leading cause of vision loss in older individuals. Although the etiology of AMD has not been clearly elucidated, genetic and environmental factors have been implicated. Vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF), a major regulator of vascular permeability and angiogenesis, have been suggested to play an important role in the pathogenesis of AMD. This study was performed to determine whether VEGF and PEDF variations are associated with AMD in the Korean population. Four SNPs of both the VEGF gene the PEDF gene were used to screen for genetic variation. This analysis was performed using polymerase chain reaction-restriction fragment length polymorphism, direct sequencing and an allele-specific oligonucleotide analysis. The study investigated four SNPs in VEGF and PEDF in Korean patients with AMD. The frequency of the TT genotype of rs1413711 and the recessive VEGF allele significantly differed between the patient and control groups. The TT genotype of rs1136287 (M72T) in PEDF significantly differed between the patient and control groups. Six haplotypes in the VEGF gene and two haplotypes in the PEDF gene were significantly associated with AMD. In this study, rs1413711 of VEGF, rs1136287 of PEDF and haplotypes were identified as candidate variants associated with AMD in Korean patients. [ABSTRACT FROM AUTHOR]

Background: The use of intravitreal anti-VEGF agents in general, and of bevacizumab (Avastin) in particular, has become the common first-line treatment of neovascular age-related macular degeneration (AMD). Several reports addressed the possible elevation of intraocular pressure (IOP) following intravitreal injection of anti-VEGF. The aim of this study was to determine the prevalence of sustained IOP elevation following intravitreal bevacizumab injections for neovascular AMD and identify possible risk factors for the development of increased IOP. Methods: This retrospective cohort study included 174 consecutive patients (201 eyes) receiving intravitreal bevacizumab (1.25 mg/0.05 ml) as treatment for neovascular AMD. The records of the study patients were reviewed for age, gender, history of glaucoma, phakic status, IOP levels, length of follow-up, total number of injections, intervals between injections, and IOP management in eyes that exhibited IOP elevation. Sustained IOP elevation was defined as IOP ≥22 mmHg and a change from baseline of ≥6 mmHg recorded on at least two consecutive visits and lasting ≥30 days. Risk factors for an IOP increase were identified from the association between the studied variables and IOP elevations. Results: Sustained IOP elevation was found in 22 of 201 eyes (11%). The increased IOP was controlled with topical medications in all eyes. Among the variables studied, only male gender [OR = 3.1, 95% CI (1.1, 8.5) p = 0.029] and length of interval between injections <8 weeks [OR = 3.0, 95%CI (1.1, 7.9), p = 0.028] emerged as risk factors for IOP elevation in a multivariable model. The prevalence of IOP elevation was significantly higher when the interval between injections was <8 weeks than ≥8 weeks (17.6 and 6%, respectively, p = 0.009). Pre-existing glaucoma was not associated with IOP elevation ( p = 0.9). Conclusions: Sustained IOP elevations can occur in normotensive eyes undergoing intravitreal bevacizumab treatment for neovascular AMD. This phenomenon was related to shorter intervals between injections, with 8 weeks being taken as the cut-off point. AMD eyes that receive intravitreal bevacizumab injections need to be monitored for IOP changes, especially those in which the intervals between injections are <8 weeks. [ABSTRACT FROM AUTHOR]

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Purpose: The purpose of this study was to determine the clinical characteristics of age-related macular degeneration (AMD) in patients with diabetic retinopathy (DR). Methods: Retrospective, consecutive case series. Twenty-six eyes of 25 Japanese patients were studied. All patients were diagnosed as having exudative AMD with DR. Patients with no apparent DR, dry AMD, neovascular maculopathy associated with high myopia, and age <50 years were excluded. The clinical characteristics of AMD in patients with DR, e.g., gender, age, stage of DR, and type of AMD were evaluated. Results: In the 26 eyes, 2 eyes (7.7%) were classified as mild nonproliferative DR (NPDR), 7 (27.0%) with moderate NPDR, 16 (61.5%) with severe NPDR and 1 eye (3.8%) with PDR. Of the 26 eyes with exudative AMD, 21 eyes (80.8%) were classified as neovascular AMD, 4 (15.4%) as polypoidal choroidal vasculopathy and 1 eye (3.8%) as a retinal angiomatous proliferation. Among the eyes with neovascular AMD, 9 eyes (42.9%) were classified as predominantly classic choroidal neovascularization (CNV). Conclusions: There is a predominance of men, neovascular AMD and predominantly classic CNV in Japanese AMD patients with DR. The exudative AMD in patients with DR may have different clinical characteristics from those without DR. [ABSTRACT FROM AUTHOR]

Conditions resulting in retinal angiogenesis and edema (exudative age-related macular degeneration, diabetic retinopathy, retinal vein occlusion and retinopathy of prematurity) are major causes of visual impairment, with significant impact on quality of life. There has been increasing clinical usage of anti-vascular endothelial growth factor (anti-VEGF) agents to stop retinal angiogenesis and resolve intraretinal fluid arising from these conditions. However, anti-VEGFs have not been completely successful in curing these conditions, and a range of emerging treatments aimed at supplementing or competing with anti-VEGF agents are being developed. We will discuss the proposed merits these emerging agents bring to the treatment arsenal and how they compare with anti-VEGFs with regards to therapeutic activity, potency, specificity and safety. This review will also highlight recent pre-clinical research findings and suggest where future research might be directed. [ABSTRACT FROM AUTHOR]

Background: Automatically measurements of retinal thickness by optical coherence tomography (OCT) facilitate the assessment of various retinal diseases.The aim of this retrospective study was to report macular thickness measurements in eyes with vascular pigment epithelial detachment (PED) due to age-related macular degeneration (AMD) by using two different commercially available spectral domain (SD) OCT instruments and to consequently point out differences in their algorithm software.systems. Methods: OCT images of patients with vascular PED due to AMD, obtained with Cirrus and Spectralis OCT, were retrospectively analyzed. Main objectives were to observe differences in central retinal thickness (CRT) values and failures in automated threshold delineation, as well as central point thickness values obtained after manual correction of threshold lines. Scanning with the Cirrus HD OCT was performed with the 512 × 128 scan pattern; scans performed with the Spectralis OCT were 20 × 15 degree raster scans consisting of 19 high-speed line scans. Results: OCT images of 34 eyes of 28 patients with a mean age of 71 years and a mean distance visual acuity (VA) of 0.70 ETDRS were analyzed. Mean central retinal thickness (CRT) was 262.38 μm ± 133.18 (176-507 μm) in Cirrus and 337.82 μm ± 137.75 (277-790 μm) in Spectralis scans,mainly caused by different software approaches in positioning the posterior threshold line, following the PED in Cirrus OCT whereas remaining unelevated in Spectralis OCT. There were failures in positioning the outer retinal boundary line in 50% of Cirrus scans and in 73.52% of Spectralis scans. We obtained the mean value of central point neurosensory retinal thickness of each central single scan after manual delineation, and found a significant correlation ( r = 0.819, p < 0.001). Conclusions: Our study indicates that there are significant differences in CRT values in patients with vascular PED, due to different segmentation algorithms and a high error rate in automatically set threshold lines. When planning and conducting multicenter studies, one has to be especially aware of the differences in delineating threshold algorithm lines by different SD OCT devices. [ABSTRACT FROM AUTHOR]