Search Results (1,344)

Background: Age-related macular degeneration (AMD) is a complex eye disorder with an environmental and genetic origin, affecting millions worldwide. The study aims to explore the association between retinal morphology and the polygenic risk score (PRS) for AMD using fundus images and deep learning techniques. Methods: The study used and pre-processed 23,654 fundus images from 332 subjects (235 patients with AMD and 97 controls), ultimately selecting 558 high-quality images for analysis. The fine-tuned DenseNet121 deep learning model was employed to estimate PRS from single fundus images. After training, deep features were extracted, fused, and used in machine learning regression models to estimate PRS for each subject. The Grad-CAM technique was applied to examine the relationship between areas of increased model activity and the retina’s morphological features specific to AMD. Results: Using the hybrid approach improved the results obtained by DenseNet121 in 5-fold cross-validation. The final evaluation metrics for all predictions from the best model from each fold are MAE = 0.74, MSE = 0.85, RMSE = 0.92, R² = 0.18, MAPE = 2.41. Grad-CAM heatmap evaluation showed that the model decisions rely on lesion area, focusing mostly on the presence of drusen. The proposed approach was also shown to be sensitive to artifacts present in the image. Conclusions: The findings indicate an association between fundus images and AMD PRS, suggesting that deep learning models may effectively estimate genetic risk for AMD from retinal images, potentially aiding in early detection and personalized treatment strategies. Full article

Natural products with high antioxidant activity are considered as innovative prevention strategies to effectively prevent age-related macular degeneration (AMD) in the early stage because the generation of reactive oxygen species (ROS) leading to the development of drusen is reported as an important cause of this disease. To investigate the prevention effects of the methanol extracts of Euphorbia heterophylla L. (MEE) on AMD, its effects on the antioxidant activity, inflammatory response, apoptosis pathway, neovascularization, and retinal tissue degeneration were analyzed in N-retinylidene-N-retinylethanolamine (A2E)-landed spontaneously arising retinal pigment epithelia (ARPE)-19 cells and BALB/c mice after exposure to blue light (BL). The MEE contained 10 active components and showed high free radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and nitric oxide (NO) radicals. The pretreatments of high-dose MEE remarkably suppressed the production of intracellular ROS (88.2%) and NO (25.2%) and enhanced (SOD) activity (84%) and the phosphorylation of nuclear factor erythroid 2–related factor 2 (Nrf2) in A2E + BL-treated ARPE-19 cells compared to Vehicle-treated group. The activation of the inducible nitric oxide synthase (iNOS)-induced cyclooxygenase-2 (COX-2) mediated pathway, inflammasome activation, and expression of inflammatory cytokines was significantly inhibited in A2E + BL-treated ARPE-19 cells after the MEE pretreatment. The activation of the apoptosis pathway and increased expression of neovascular proteins (36% for matrix metalloproteinase (MMP)-9) were inhibited in the MEE pretreated groups compared to the Vehicle-treated group. Furthermore, the thickness of the whole retina (31%), outer nuclear layer (ONL), inner nuclear layer (INL), and photoreceptor layer (PL) were significantly increased by the MEE pretreatment of BALB/c mice with BL-induced retinal degeneration. Therefore, these results suggest that the MEE, with its high antioxidative activity, protects against BL-induced retinal degeneration through the regulation of the antioxidative system, inflammatory response, apoptosis, and neovascularization in the AMD mouse model. Full article

Glaucoma stands as a primary cause of irreversible blindness globally, characterized by the progressive dysfunction and loss of retinal ganglion cells (RGCs). While current treatments primarily focus on controlling intraocular pressure (IOP), many patients continue to experience vision loss. Therefore, the research focus has shifted to therapeutic targets aimed at preventing or delaying RGC death and optic nerve degeneration to slow or halt disease progression. Traditional ocular drug administration, such as eye drops or oral medications, face significant challenges due to the eye’s unique structural and physiological barriers, which limit effective drug delivery. Invasive methods like intravitreal injections can cause side effects such as bleeding, inflammation, and infection, making non-invasive delivery methods with high bioavailability very desirable. Nanotechnology presents a promising approach to addressing these limitations in glaucoma treatment. This review summarizes current approaches involving neuroprotective drugs combined with nanocarriers, and their impact for future use. Full article

Age-related macular degeneration (AMD) is a major global health problem as it is the leading cause of irreversible loss of central vision in the aging population. Anti-vascular endothelial growth factor (anti-VEGF) therapies are effective but do not respond optimally in all patients. This study investigates the genetic factors associated with susceptibility to AMD and response to treatment, focusing on key polymorphisms in the ARMS2 (rs10490924), IL1B1 (rs1143623), TNFRSF1B (rs1061622), TNFRSF1A (rs4149576), VEGFA (rs3024997), ARMS2, IL1B1, TNFRSF1B, TNFRSF1A, and VEGFA serum levels in AMD development and treatment efficacy. This study examined the associations of specific genetic polymorphisms and serum protein levels with exudative and early AMD and the response to anti-VEGF treatment. The AA genotype of VEGFA (rs3024997) was significantly associated with a 20-fold reduction in the odds of exudative AMD compared to the GG + GA genotypes. Conversely, the TT genotype of ARMS2 (rs10490924) was linked to a 4.2-fold increase in the odds of exudative AMD compared to GG + GT genotypes. In females, each T allele of ARMS2 increased the odds by 2.3-fold, while in males, the TT genotype was associated with a 5-fold increase. Lower serum IL1B levels were observed in the exudative AMD group compared to the controls. Early AMD patients had higher serum TNFRSF1B levels than controls, particularly those with the GG genotype of TNFRSF1B rs1061622. Exudative AMD patients with the CC genotype of TNFRSF1A rs4149576 had lower serum TNFRSF1A levels compared to the controls. Visual acuity (VA) analysis showed that non-responders had better baseline VA than responders but experienced decreased VA after treatment, whereas responders showed improvement. Central retinal thickness (CRT) reduced significantly in responders after treatment and was lower in responders compared to non-responders after treatment. The T allele of TNFRSF1B rs1061622 was associated with a better response to anti-VEGF treatment under both dominant and additive genetic models. These findings highlight significant genetic and biochemical markers associated with AMD and treatment response. This study found that the VEGFA rs3024997 AA genotype reduces the odds of exudative AMD, while the ARMS2 rs10490924 TT genotype increases it. Lower serum IL1B levels and variations in TNFRSF1B and TNFRSF1A levels were linked to AMD. The TNFRSF1B rs1061622 T allele was associated with better anti-VEGF treatment response. These markers could potentially guide risk assessment and personalized treatment for AMD. Full article

Purpose: To investigate the influence of intraretinal fluid (IRF) on change in retinal nerve fiber layer (RNFL) and retinal ganglion cell layer (RGCL) and thickness in patients with naive neovascular AMD under anti-VEGF treatment. Design: post hoc analysis. Methods: 97 eyes of 83 patients on continuous therapy with intravitreal anti-vascular endothelial growth factors (anti-VEGF) and a follow-up of 24 months were included. RGCL and RNFL thickness in the perifoveal (-O), parafoveal (PF), and nasal areas and number of injections (IVI) were recorded before the first IVI as well as 1 and 2 years after initiating treatment and compared longitudinally and between groups with and without IRF. Results: The group with IRF at baseline had a higher RNFL thickness at baseline and showed a significant reduction in RNFL-PF between baseline and first and second follow-ups (p < 0.001) but not between first and second follow-ups. The group without IRF showed no significant reduction in RNFL over time. The presence of IRF was not associated with a reduction in RNFL-O or RNFL-nasal. RGCL thickness decreased significantly in both groups with and without IRF after 2 years. Number of IVIs showed no significant correlation to RNFL or RGCL after stratification for the presence of IRF. Conclusions: The presence of IRF has a significant influence on RNFL thickness at baseline as well as on its changes over time during anti-VEGF therapy. The preoperative presence of IRF should be considered when comparing changes in RNFL thickness after IVI. Full article

Inherited retinal degenerations (IRDs) are a group of genetic disorders characterized by the progressive degeneration of retinal cells, leading to irreversible vision loss. SLC4A7 has emerged as a candidate gene associated with IRDs, yet its mechanisms remain largely unknown. This study aims to investigate the role of slc4a7 in retinal development and its associated molecular pathogenesis in zebrafish. Morpholino oligonucleotide knockdown, CRISPR/Cas9 genome editing, quantitative RT-PCR, eye morphometric measurements, immunofluorescent staining, TUNEL assays, visual motor responses, optokinetic responses, rescue experiments, and bulk RNA sequencing were used to assess the impact of slc4a7 deficiency on retinal development. Our results demonstrated that the knockdown of slc4a7 resulted in a dose-dependent reduction in eye axial length, ocular area, and eye-to-body-length ratio. The fluorescence observations showed a significant decrease in immunofluorescence signals from photoreceptors and in mCherry fluorescence from RPE in slc4a7-silenced morphants. TUNEL staining uncovered the extensive apoptosis of retinal cells induced by slc4a7 knockdown. Visual behaviors were significantly impaired in the slc4a7-deficient larvae. GO and KEGG pathway analyses reveal that differentially expressed genes are predominantly linked to aspects of vision, ion channels, and phototransduction. This study demonstrates that the loss of slc4a7 in larvae led to profound visual impairments, providing additional insights into the genetic mechanisms predisposing individuals to IRDs caused by SLC4A7 deficiency. Full article

Background/objectives: To compare the prevalence of intra-ocular inflammation (IOI) between brolucizumab and aflibercept in neovascular age-related macular degeneration (nAMD) after intra-vitreal injections (IVI) and to compare the IOI odds ratios (ORs) of both therapies with the prevalence of septic endophthalmitis after IVI that was previously reported in the literature. Methods: A total of 468 IVI of brolucizumab (117 eyes) were compared with 2884 IVI of aflibercept (305 eyes) regarding IOI and occlusive retinal vasculitis (RV) from December 2021 to June 2023 in this retrospective study. The OR was calculated for both anti-VEGF agents and was compared with the relative risk of septic endophthalmitis after IVI. Results: There were four eyes with unilateral IOI related to brolucizumab (3.42%), one presenting uveitis (0.85%), two vitritis (1.71%) and the last one presenting occlusive RV (0.85%), compared with two eyes presenting unilateral IOI (anterior uveitis, 0.66%) and none with RV from the aflibercept cohort. The incidence of IOI per injection with brolucizumab (0.855%) was significantly higher compared with aflibercept (0.069%, p = 0.004). The OR of IOI related to brolucizumab IVI compared with septic endophthalmitis was 20 times greater (1.49 for aflibercept, p = 0.646, versus 20.15 for brolucizumab, p < 0.001). The OR of RV with brolucizumab compared with septic endophthalmitis was 4.6. Conclusion: Data from our department suggest a much higher risk of IOI and occlusive retinal vasculitis after brolucizumab when compared with aflibercept. The risk of IOI and severe sight-threatening complications related to brolucizumab is greater than the risk of septic endophthalmitis after any IVI. Full article

The management of vision-threatening retinal diseases remains challenging due to the lack of an effective drug delivery system. Encapsulated cell therapy (ECT) offers a promising approach for the continuous delivery of therapeutic agents without the need for immunosuppressants. In this context, an injectable and terminable collagen–alginate composite (CAC) ECT gel, designed with a Tet-on pro-caspase-8 system, was developed as a safe intraocular drug delivery platform for the sustained release of glial-cell-line-derived neurotrophic factor (GDNF) to treat retinal degenerative diseases. This study examined the potential clinical application of the CAC ECT gel, focusing on its safety, performance, and termination through doxycycline (Dox) administration in the eyes of healthy New Zealand White rabbits, as well as its therapeutic efficacy in rabbits with sodium-iodate (SI)-induced retinal degeneration. The findings indicated that the CAC ECT gel can be safely implanted without harming the retina or lens, displaying resistance to degradation, facilitating cell attachment, and secreting bioactive GDNF. Furthermore, the GDNF levels could be modulated by the number of implants. Moreover, Dox administration was effective in terminating gel function without causing retinal damage. Notably, rabbits with retinal degeneration treated with the gels exhibited significant functional recovery in both a-wave and b-wave amplitudes and showed remarkable efficacy in reducing photoreceptor apoptosis. Given its biocompatibility, mechanical stability, controlled drug release, terminability, and therapeutic effectiveness, our CAC ECT gel presents a promising therapeutic strategy for various retinal diseases in a clinical setting, eliminating the need for immunosuppressants. Full article

Background: The aim of this paper was to investigate the protein concentrations of high-temperature requirement A 1 (HTRA1) and transforming growth factor-$\mathsf{\beta }$ (TGF-$\mathsf{\beta }$) in the vitreous humor of patients with chorioretinal vascular diseases. Methods: This study measured protein concentrations of HTRA1, TGF-${\mathsf{\beta }}_{1-3}$, and vascular endothelial growth factor A (hereinafter called VEGF) in the vitreous humor from seven eyes of patients with chorioretinal vascular diseases (age-related macular degeneration, diabetic macular edema, and retinal vein occlusion) and six control eyes (idiopathic epiretinal membrane and macular hole). We analyzed the mutual relationship among the protein levels. Results: The protein levels of HTRA1 and VEGF were significantly increased in the chorioretinal vascular disease group compared with the control group (1.57 ± 0.79 $\times {10}^{-9}$ mol/mL vs. 0.68 ± 0.79 $\times {10}^{-9}$ mol/mL, p = 0.039; 3447.00 ± 3423.47 pg/mL vs. 35.33 ± 79.01 pg/mL, p = 0.046, respectively). TGF-${\mathsf{\beta }}_2$ levels were not significantly different between groups (2222.71 ± 1151.25 pg/mL for the chorioretinal vascular disease group vs. 1918.83 ± 744.01 pg/mL for the control group, p = 0.62). The concentration of HTRA1 was strongly associated with TGF-${\mathsf{\beta }}_2$ levels in the vitreous humor, independent of VEGF (r = 0.80, p = 0.0010). Conclusions: We revealed that vitreous HTRA1 was increased in patients with chorioretinal vascular diseases and strongly correlated with TGF-${\mathsf{\beta }}_2$. Full article

Mitochondrial malfunction, excessive production of reactive oxygen species (ROS), deficient autophagy/mitophagy, and chronic inflammation are hallmarks of age-related macular degeneration (AMD). Metformin has been shown to activate mitophagy, alleviate inflammation, and lower the odds of developing AMD. Here, we explored the ability of metformin to activate mitophagy and alleviate inflammation in retinal pigment epithelium (RPE) cells. Human ARPE-19 cells were pre-treated with metformin for 1 h prior to exposure to antimycin A (10 µM), which induced mitochondrial damage. Cell viability, ROS production, and inflammatory cytokine production were measured, while autophagy/mitophagy proteins were studied using Western blotting and immunocytochemistry. Metformin pre-treatment reduced the levels of proinflammatory cytokines IL-6 and IL-8 to 42% and 65% compared to ARPE-19 cells exposed to antimycin A alone. Metformin reduced the accumulation of the autophagy substrate SQSTM1/p62 (43.9%) and the levels of LC3 I and II (51.6% and 48.6%, respectively) after antimycin A exposure. Metformin also increased the colocalization of LC3 with TOM20 1.5-fold, suggesting active mitophagy. Antimycin A exposure increased the production of mitochondrial ROS (226%), which was reduced by the metformin pre-treatment (84.5%). Collectively, metformin showed anti-inflammatory and antioxidative potential with mitophagy induction in human RPE cells suffering from mitochondrial damage. Full article

Recovery after visual loss is a key goal of neuroscience and treatments able to improve visual function are still largely lacking. Glaucoma, one of the leading causes of visual disability in the world, is usually associated with elevated intraocular pressure (IOP), but a subset of “normal tension glaucoma” patients develop damage without ever manifesting high IOP. Sometimes, even in patients with good control of IOP, retinal ganglion cell degeneration can progress to forward blindness. Moreover, usually the damage already caused by the disease remains. These considerations underline the need to find new, effective treatments and solutions to add to the standard ones. In this paper, we expose the most important data supporting the use of alternating current stimulation, including the theoretical bases of this approach, in glaucoma. Full article

Our previous study discussed crystallin family induction in an experimental rat model of retinal detachment. Therefore, we attempted to evaluate the role of α-crystallin in photoreceptor survival in an experimental model of retinal detachment, as well as its association with the intrinsically neuroprotective protein Fas-apoptotic inhibitory molecule 2 (FAIM2). Separation of retina and RPE was induced in rat and mouse eyes by subretinal injection of hyaluronic acid. Retinas were subsequently analyzed for the presence αA-crystallin (HSPB4) and αB-crystallin (HSPB5) proteins using immunohistochemistry and immunoblotting. Photoreceptor death was analyzed using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) staining and cell counts. The 661W cells subjected to FasL were used as a cell model of photoreceptor degeneration to assess the mechanisms of the protective effect of αA-crystallin and its dependence on its phosphorylation on T148. We further evaluated the interaction between FAIM2 and αA-crystallin using a co-immunoprecipitation assay. Our results showed that α-crystallin protein levels were rapidly induced in response to retinal detachment, with αA-crystallin playing a particularly important role in protecting photoreceptors during retinal detachment. Our data also show that the photoreceptor intrinsically neuroprotective protein FAIM2 is induced and interacts with α-crystallins following retinal detachment. Mechanistically, our work also demonstrated that the phosphorylation of αA-crystallin is important for the interaction of αA-crystallin with FAIM2 and their neuroprotective effect. Thus, αA-crystallin is involved in the regulation of photoreceptor survival during retinal detachment, playing a key role in the stabilization of FAIM2, serving as an important modulator of photoreceptor cell survival under chronic stress conditions. Full article

Rotenone is a mitochondrial complex I inhibitor that causes retinal degeneration. A study of a rat model of rotenone-induced retinal degeneration suggested that this model is caused by indirect postsynaptic N-methyl-D-aspartate (NMDA) stimulation triggered by oxidative stress-mediated presynaptic intracellular calcium signaling. To elucidate the mechanisms by which rotenone causes axonal degeneration, we investigated morphological changes in optic nerves and the change in retinal ganglion cell (RGC) number in rats. Optic nerves and retinas were collected 3 and 7 days after the intravitreal injection of rotenone. The cross-sections of the optic nerves were subjected to a morphological analysis with axon quantification. The axons and somas of RGCs were analyzed immunohistochemically in retinal flatmounts. In the optic nerve, rotenone induced axonal swelling and degeneration with the incidence of reactive gliosis. Rotenone also significantly reduced axon numbers in the optic nerve. Furthermore, rotenone caused axonal thinning, fragmentation, and beading in RGCs on flatmounts and decreased the number of RGC soma. In conclusion, the intravitreal injection of rotenone in rats induced morphological abnormities with a reduced number of optic nerve axons and RGC axons when the RGC somas were degenerated. These findings help elucidate the pathogenesis of optic neuropathy induced by mitochondrial dysfunction. Full article

Glaucoma and age-related macular degeneration (AMD) are progressive retinal diseases characterized by increased oxidative stress, inflammation, and mitochondrial dysfunction. This review investigates the potential therapeutic benefits of NAD+ and niacin supplementation in managing glaucoma and AMD. A literature search was conducted encompassing keywords such as “niacin”, “NAD”, “glaucoma”, “AMD”, and “therapeutics”. NAD+ depletion is associated with increased oxidative stress and mitochondrial dysfunction in glaucoma and AMD. Niacin, a precursor to NAD+, has shown promise in replenishing NAD+ levels, improving choroidal blood flow, and reducing oxidative damage. Animal studies in glaucoma models indicate that nicotinamide (NAM) supplementation preserves RGC density and function. Large-scale population-based studies indicate an inverse correlation between niacin intake and glaucoma prevalence, suggesting a preventative role. Randomized controlled trials assessing niacin supplementation showed significant improvements in visual field sensitivity and inner retinal function, with a dose-dependent relationship. In AMD, nicotinamide supplementation may improve rod cell function and protect against oxidative stress-induced damage. Cross-sectional studies reveal that individuals with AMD have a lower dietary intake of niacin. Further studies suggest niacin’s role in improving choroidal blood flow and dilating retinal arterioles, potentially mitigating ischemic damage and oxidative stress in AMD. Beyond current management strategies, NAD+ and niacin supplementation may offer novel therapeutic avenues for glaucoma and AMD. Further research is warranted to elucidate their efficacy and safety in clinical settings. Full article

Background: The purpose of this study was to compare geographic atrophy (GA) area semi-automatic measurement using fundus autofluorescence (FAF) versus optical coherence tomography (OCT) annotation with the cRORA (complete retinal pigment epithelium and outer retinal atrophy) criteria. Methods: GA findings on FAF and OCT were semi-automatically annotated at a single time point in 36 pairs of FAF and OCT scans obtained from 36 eyes in 24 patients with dry age-related macular degeneration (AMD). The GA area, focality, perimeter, circularity, minimum and maximum Feret diameter, and minimum distance from the center were compared between FAF and OCT annotations. Results: The total GA area measured on OCT was 4.74 ± 3.80 mm². In contrast, the total GA measured on FAF was 13.47 ± 8.64 mm² (p < 0.0001), with a mean difference of 8.72 ± 6.35 mm². Multivariate regression analysis revealed a significant correlation between the difference in area between OCT and FAF and the total baseline lesion perimeter and maximal lesion diameter measured on OCT (adjusted r²: 0.52; p < 0.0001) and the total baseline lesion area measured on FAF (adjusted r²: 0.83; p < 0.0001). Conclusions: We report that the GA area measured on FAF differs significantly from the GA area measured on OCT. Further research is warranted in order to determine the clinical relevance of these findings. Full article