Exploring the causal link between long-term elevated plasma caffeine levels and age-related eye diseases using Mendelian randomization.

Exendin-4 alleviates Aβ1-40-induced apoptosis and calcium dysregulation in RPE cells through the CHP1/NHE1 complex.

Oxidative stress is associated with many retinal diseases, including age-related macular degeneration (AMD). The purpose of this study is to investigate the efficacy of oral deuterated docosahexaenoic acid (D-DHA), an oxidation-resistant lipid, in a mouse model with features of dry AMD. We also evaluated whether long-term D-DHA dosing affects normal retinal structure or function. Liver-specific hepcidin (Hepc) and ceruloplasmin/hepcidin (Cp/Hepc) knock-out (KO) mice were fed experimental diet containing 0.25% D-DHA or control containing normal H-DHA during various stages of disease progression. Retinal pigment epithelium (RPE) damage was assessed with in vivo scanning laser ophthalmoscopy (SLO) imaging and histology. For the safety study, wild-type mice were fed the diets beginning in utero or at 3 months of age, continuing for 12 months. These mice were analyzed to assess retinal structure (SLO, optical coherence tomography [OCT], and transmission electron microscopy [TEM]), function (ERG), and gene expression (qPCR). KO mice fed control diet developed expanding autofluorescent patches of hypertrophic RPE cells. This damage was markedly prevented or halted by diet with D-DHA, depending on age at diet onset. Wild-type mice administered diet with D-DHA from age 3 to 15 months had no retinal abnormalities. Mice administered D-DHA beginning in utero had normal retinal development and structure but minor deficits in ERG amplitudes and Rpe65 expression by age 12 months. Oral D-DHA was strongly protective against RPE ferroptosis, with minimal side effects. This study suggests that DHA oxidation is a key mechanism of retinal iron toxicity and supports the potential clinical application of D-DHA for diseases involving retinal oxidative stress.

Approximately 1.5 million Americans over the age of 40 suffer from vision-threatening age-related macular degeneration (AMD), a number expected to rise with aging demographics. AMD exists in two defined forms: dry (non-exudative) which accounts for up to 90% of cases, and wet (exudative). Dry AMD is characterized by the slow buildup of drusen under the retina, eventually leading to geographical atrophy. Wet AMD involves vascular endothelial growth factor (VEGF)-induced blood vessel formation from the choriocapillaris into the subretinal space, a process referred to as neovascularization. These newly formed blood vessels leak fluid into the subretinal space leading to atrophy of the retinal pigment epithelium (RPE) and associated photoreceptors. Despite clinical distinctions, dry and wet AMD share overlapping pathophysiological features, marked by degeneration of the RPE and the overlying photoreceptors. A major feature of the RPE and photoreceptors are their high metabolically activity and their large numbers of mitochondria, which generate reactive oxygen species (ROS) during ATP production. ROS-induced oxidative stress damages lipids, proteins and DNA, resulting in cellular degradation which contributes to AMD. Because of the elevated oxidative stress levels, antioxidants which neutralize ROS are often recommended as a treatment for AMD. A major objective of this review is to examine the role of melatonin, a powerful and multifunctional antioxidant, in altering the trajectory of AMD progression. Melatonin is synthesized in the RPE and photoreceptors of young individuals but its expression declines with age. As shown in an epidemiological report, its loss contributes to age-related degeneration of the RPE and photoreceptors. Moreover, melatonin inhibits VEGF, suggesting that it would be useful as a treatment for wet AMD. This review explores melatonin-mediated protective mechanisms in the retina, a likely mechanistic basis for the already published findings showing that melatonin use by humans is associated with delayed AMD, and potential clinical applications.

Dry age-related macular degeneration (AMD) is characterized by the progressive loss of retinal pigment epithelium cells in the macula, leading to photoreceptor degeneration and loss of central vision. Current treatments only modestly delay disease progression, but once photoreceptors are damaged, vision loss becomes irreversible. Therefore, there is an urgent need to develop therapies that prevent photoreceptor cell death and that may complement current and emerging treatment strategies. A critical step toward this goal is establishing pathophysiologically relevant human disease models for therapeutic testing. In this study, we developed a human induced pluripotent stem cell-derived retinal organoid (RO) model that recapitulates key aspects of AMD-associated photoreceptor degeneration. To mimic environmental stressors relevant to AMD, we treated mature ROs with cigarette smoke extract (CSE), a known oxidative agent and major modifiable risk factor for the disease. CSE exposure induced oxidative stress, mitochondrial membrane depolarization, and cell death primarily in the outer nuclear layer. Photoreceptor degeneration in this model involves the activation of the intrinsic apoptotic pathway and ferroptosis, which is accompanied by lipid peroxidation and dysregulation of the glutathione system. Proteomic profiling confirmed alterations in metabolic, redox, and cell death pathways consistent with AMD pathophysiology, and offered further insight into the mechanistic interplay among these pathways. Furthermore, we integrated this model with robust, quantitative outcome measures in live ROs, offering a powerful platform for preclinical therapeutic screening in dry AMD.

The Effect of Nutrition on Dry Age-Related Macular Degeneration: A Systematic Narrative Review of Evidence and Clinical Implications

This study aimed to identify optical coherence tomography angiography (OCTA) biomarkers associated with disease severity in dry age-related macular degeneration (dAMD). This cross-sectional study included 142 eyes (104 patients) with dAMD, classified as early (n = 34), intermediate (n = 40), or late stage (n = 37) according to the Beckman Classification, and 30 control eyes without AMD. OCTA-images were obtained using the ZEISS PLEX Elite 9000, vascular metrics such as vessel density, total number of junctions, total and average vessel length, junction density, total number of endpoints, and lacunarity were assessed in the superficial capillary plexus, deep capillary plexus (DCP), and choriocapillaris (CC) using AngioTool software. The CC showed the most pronounced changes, with vessel percentage area reduced from 58.98 ± 4.86% in controls to 52.14 ± 10.30% in intermediate and 31.34 ± 11.27% in late AMD (P <.001). Total vessel length declined from 407.52 ± 16.33 mm to 367.09 ± 49.18 mm and 217.23 ± 86.88 mm, respectively (P <.001), while lacunarity increased nearly 50-fold in late AMD (0.56 ± 0.91 vs 0.01 ± 0.00; P <.001). In the DCP, vessel percentage area decreased from 45.68 ± 4.92% in controls to 41.95 ± 5.08% in intermediate and 38.24 ± 6.71% in late AMD (P <.001). Vessel length dropped from 275.21 ± 21.82 mm to 254.13 ± 28.78 mm and 224.68 ± 36.37 mm (P <.001), with increased lacunarity in intermediate and late stages (P <.01). The superficial capillary plexus showed early alterations, with vessel percentage area reduced from 41.46 ± 1.58% in controls to 39.42 ± 3.45% in early AMD (P = .017) and total vessel length decreased from 202.85 ± 10.65 mm to 191.42 ± 18.67 mm and 185.92 ± 18.09 mm in intermediate AMD (P <.001). Mean lacunarity was elevated in all AMD stages (P <.001). OCTA reveals distinct, layer-specific microvascular changes in AMD mainly within DCP and CC. Vessel percentage area, total vessel length, and lacunarity represent sensitive, noninvasive OCTA biomarkers of microvascular impairment in dry AMD, with potential applicability for longitudinal disease monitoring and as quantitative imaging endpoints in future interventional trials.

Age-related Macular Degeneration (AMD) is a major cause of vision impairment and may progress to blindness; thus, accurate differentiation between Dry and Wet AMD is essential for timely clinical decision-making. This study proposes a lightweight multi-class AMD classification framework from fundus images that combines an anatomically consistent Assisted Region of Interest (Assisted-ROI) protocol with a hybrid handcrafted representation. Four public datasets (ODIR, ADAM, FIVES, and RFMiD) were merged to construct a curated dataset of 597 images across three classes (Normal, Dry AMD, and Wet AMD). AMD cases were re-annotated into Dry and Wet subtypes by three ophthalmologists, while Normal labels were retained. The experiments used 5-fold cross-validation under three input scenarios: full-fundus (no ROI), Optic Disc (OD)-guided automatic ROI, and the proposed Assisted-ROI. The no-ROI baseline achieved 80.91% accuracy, the OD-guided ROI achieved 85.27%, and Assisted-ROI delivered the best performance with 90.63% accuracy. Feature ablation under identical controlled settings showed that early fusion of LBP-RIU, Haralick/GLCM texture features, and RGB color moments yielded the most discriminative representation (90.63% accuracy; 89.06% macro-F1), outperforming the best single descriptor (LBP-RIU: 83.09%). Overall, anatomically consistent ROI standardization and complementary handcrafted feature fusion improve robust multi-class AMD recognition on heterogeneous multi-source fundus data under reduced computational cost.

Single intravitreal injection of lipid nanoparticles delivering circular mRNA of nicotinamide phosphoribosyltransferase protects against dry AMD.

Bidirectional causal associations between immune cell phenotypes and age-related macular degeneration subtypes: A mendelian randomization study.

This study evaluated longitudinal choroidal vascular changes in dry age-related macular degeneration (dAMD) eyes using a three-dimensional (3D) algorithm. Patients underwent swept-source optical coherence tomography during two follow-up visits. Choroidal boundaries and vessels were segmented using the ResUNet model and Phansalkar thresholding. 3D choroidal maps were created and divided into five sectors. Mean choroidal vessel diameter (MChVD), inter-vessel distance (IVD), volumetric choroidal thickness (ChT), and choroidal vascularity index (CVI) were measured in both visits. This retrospective cohort study included 30 eyes with AMD. The mean age was 72.8 ± 9.55 years. The mean follow-up duration was 11.6 ± 5.02 months. The mean MChVD increased 16.4 µm (6.8%) over time (239.2 ± 19.8 to 255.6 ± 28.2 µm, P = 0.003), particularly in the nasal and temporal sectors (P < 0.05). The mean IVD increased 21.8 µm (10.8%) over time (201.8 ± 29.0 to 223.7 ± 38.2 µm, P = 0.009), which was significant in the nasal, temporal, and superior sectors (P < 0.05). The ChT showed a decreasing trend, though not statistically significant (190.7 ± 58.0 to 183.4 ± 56.8 µm, P = 0.051). The CVI remained stable during follow-up (0.358 ± 0.034 vs. 0.357 ± 0.040, P = 0.933). MChVD positively correlated with the IVD (r = +0.501, P = 0.005). ChT exhibited a negative correlation with IVD (r = -0.426, P = 0.019). Eyes with dry AMD showed increased MChVD and IVD along with decreased ChT, and we hypothesise that these changes may reflect progressive small-vessel atrophy accompanied by compensatory dilation of larger choroidal vessels during follow-up.

To examine the potential of GPT-4V(ision) in evaluating age-related macular degeneration (AMD) and other ophthalmological pathologies through optical coherence tomography (OCT) images. The study analyzed 90 OCT images, evenly divided among dry AMD, wet AMD, and normal control groups, using the GPT-4V model via the Julius AI platform. Each image was evaluated twice by the model and independently by two ophthalmologists (with a third arbitrating discrepancies) using a standardized set of 20 closed-ended questions covering critical parameters. The outputs were then compared statistically in terms of agreement, sensitivity, specificity, and predictive values to assess the model’s performance in detecting relevant pathological features. The GPT-4V model exhibited agreement rates above 90%, high sensitivity, and specificity values in evaluating image quality, and normal OCT identification, detection of subretinal and intraretinal fluid, ellipsoid zone integrity, and wet-type AMD findings in AMD degeneration OCT images. Additionally, the two ophthalmology specialists exhibited excellent agreement (100%, p < 0.001) in 14 different questions when evaluating OCT images. However, the model’s performance was lower for dry AMD and normal OCT images, with sensitivities of 68.7% and 75.3%, respectively. GPT-4V exhibited a promising performance as a clinical support tool in the evaluation of AMD through OCT images, albeit with limitations in detecting geographic atrophy and assessing dry AMD. However, the generalizabiity of these findings is constrained by the restricted dataset size and limited diagnostic spectrum. The GPT-4V model cannot therefore replace expert evaluation, although it appears promising as a clinical support tool. This study may also serve as a guide for larger-scale research.

Age-related macular degeneration (AMD) represents a multifactorial disease that is influenced by age, genetic, and environmental factors. AMD is characterized by dysfunction of the retinal pigment epithelium (RPE) resulting from oxidative stress, inflammation, and complement activation. As the disease progresses, the loss of the RPE and photoreceptors leads to geographic atrophy, which is a hallmark of dry AMD. Although research is ongoing, there is currently no established effective treatment for dry AMD. Notably, circular RNAs (circRNAs) have been studied in various diseases; however, the role of circRNAs in eye diseases remains poorly understood. To fill this gap, this study aimed to investigate circRNAs as potential therapeutic targets for dry AMD. We identified candidate circRNAs using a laser-induced choroidal neovascularization (CNV) model. The function of circAFF3 was investigated through knockdown experiments in ARPE-19 cells, followed by transcriptomic analysis, pathway enrichment, and functional assays, including qPCR, western blotting, immunofluorescence, monocyte adhesion, and measurements of ROS, iron, lipid peroxidation, and apoptosis. Interaction between circAFF3 and p53 was explored using binding prediction, RNA-binding protein immunoprecipitation, and cycloheximide chase assay. We found that circAff3 levels were downregulated in RPE samples at day 3 after laser injury. Moreover, silencing circAFF3 induced an inflammatory response in ARPE-19 cells. Based on these results, a subsequent transcriptomic analysis of circAFF3 knockdown in ARPE-19 cells was conducted to further elucidate its function. These analyses showed that genes downregulated by circAFF3 knockdown in ARPE-19 cells were significantly associated with retinal degeneration. Additionally, reduced circAFF3 expression promoted a decrease in ID2 levels, resulting in increased oxidative stress and cell death. Our study further demonstrated that circAFF3 directly interacts with p53, thereby regulating ID2 expression in ARPE-19 cells. Collectively, our study reveals that circAFF3 plays a crucial role in RPE dysfunction by modulating a circAFF3/p53/ID2 pathway, suggesting that circAFF3 can serve as a key regulator with therapeutic potential in dry AMD.

Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in elderly individuals for which no effective treatments are currently available. The photoreceptor loss in dry AMD is secondary to the demise of the retinal pigment epithelium (RPE) cells. The accumulation of extracellular deposits, known as drusen, resulting in part from deficient lysosomal and autophagosomal degradation, is a key feature of dry AMD pathogenesis. Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation pathway that maintains proteostasis by targeting specific cytosolic proteins for lysosomal translocation and degradation. LAMP2A (lysosome-associated membrane protein 2A) functions as the key lysosomal receptor required for CMA. Using Lamp2a knockout mouse, we show that selective CMA dysfunction recapitulates AMD-like pathologies, including sub-RPE lipid and protein deposits, RPE atrophy, Bruch's membrane thickening, and impaired autophagic activity. Furthermore, we identify large-conductance Ca²⁺-activated K⁺ (BK) channels as a therapeutic target for restoring autophagic activity. Mechanistically, pharmacological activation of BK channels with the small-molecule agonist GLA-1-1 enhances macroautophagy and stimulates autophagic flux by promoting autophagosome-lysosome fusion. Importantly, oral administration of GLA-1-1 in markedly attenuates structural, functional, and molecular retinal abnormalities in Lamp2a -deficient mice, suggesting that pharmacological activation of macroautophagy through facilitating autophagosome-lysosome fusion can partially compensate for CMA deficiency. Together, these findings demonstrate that pharmacological activation of macroautophagy can ameliorate the retinal phenotype resulting from CMA dysfunction and support BK channel activation by GLA-1-1 as a promising therapeutic strategy for dry AMD.

SYFOVRE, the brand name of pegcetacoplan and the first FDA-approved treatment for geographic atrophy arising from dry age-related macular degeneration, is currently available only in vial format. Consequently, it is often compounded and transferred into syringes. This study aims to identify the optimal syringe type for both storage and intravitreal injection (IVI) of medium- and high-viscosity formulations such as SYFOVRE. SYFOVRE was prepared in four syringe types and stored under refrigeration in amber bags for up to 110 days. Samples were evaluated for potency, aggregation, protein integrity, binding activity, pH, appearance, sterility, and container closure integrity. Syringe particulate contribution was examined using light obscuration. Injectability of each syringe was assessed through administration of 15 cP and 120 cP viscosity mimics into the vitreous of human cadaver eyes, and injection force was recorded over time. Pegcetacoplan remained stable across all syringe types for 110 days. The ClearJect (0.5 mL) syringe exceeded particulate safety limits as defined by USP <789>. Ophthalmic-specific syringes (Zero Residual [0.2 mL] and StaClear [0.25 mL]) required significantly lower injection forces than the BD (1 mL) and ClearJect (0.5 mL) (p < 0.0001). While all syringes preserved stability of SYFOVRE, injection force increased with higher viscosity. The borosilicate syringe (ClearJect) failed particulate testing, disqualifying it as a viable IVI option. Low-volume ophthalmic-specific syringes (Zero Residual and StaClear) demonstrated superior performance, suggesting they should be used for the safer delivery of intravitreal therapies. Notably, Zero Residual is the only IVI-indicated syringe that eliminates silicone oil–associated risks.

ABSTRACT Age‐related macular degeneration (AMD) is a global vision threatening disease affecting the macular region of the retina. AMD is classified into two forms: dry and wet AMD. There are no effective treatment options available for dry AMD (80% of cases). The cellular pathology includes oxidative stress and dysfunctional autophagy challenging the homeostasis of the retinal pigment epithelial (RPE) cells. Clinical findings include the formation of drusen deposits beneath the RPE cells consisting of 42 amino acids long amyloid beta (Aβ) among other components. However, the origin of drusen remains elusive. The 5xFAD (familiar Alzheimer's disease) mouse model of Alzheimer's disease produces abundant levels of Aβ making it an interesting model to study the possible relationship of Aβ to the formation of extracellular deposits and AMD‐like pathology. An immunohistology analysis of the 5xFAD mouse model showed accumulation of autophagic markers SQSTM1 (sequestosome 1) and ubiquitin in the RPE. Concurrently, the markers of secretory autophagy enabling the delivery of the intracellular material to the extracellular lumen were upregulated. Aβ, SQSTM1, ubiquitin, catalase, and TRIM16 (tripartite motif containing 16) shifted age‐dependently from intracellular origin to drusen‐like deposits beneath the RPE cells. Additionally, classical proteins secreted via secretory autophagy, IL‐1β (interleukin 1β), HMGB1 (high mobility group box‐1), and ferritin showed similar accumulation which became visible in fundus age‐dependently. These findings suggest a role for Aβ in the cellular pathogenesis of AMD. Furthermore, this model showed activated secretory autophagy pathway suggesting a role for Aβ in drusen‐like deposition formation.

Objectives: Age-related macular degeneration (AMD) is a major cause of irreversible central vision loss among the elderly, and it significantly affects quality of life. Its pathogenesis involves both modifiable and non-modifiable risk factors, making early detection and prevention essential. This study aims to determine the prevalence of AMD in a tertiary care hospital in western India and to evaluate its association with demographic, systemic and lifestyle factors, including age, gender, diabetes, hypertension, tobacco use and sunlight exposure. Materials and Methods: A cross-sectional observational study was conducted between January 2023 and June 2023 among 150 individuals aged 50 years and above attending the Ophthalmology Department of Jagjivanram Railway Hospital, Mumbai, Maharashtra, India. Detailed demographic, systemic and lifestyle histories were recorded. Fundus examination classified AMD into non-neovascular (dry) or vascular (wet) type and staged it according to age-related eye disease study classification. Statistical analysis was performed using Chi-square and Fisher’s exact tests to assess associations between AMD and risk factors. Results: AMD was detected in 16.7% of participants, with dry AMD in 8.7% and wet AMD in 8.0%. Among these, 24% were early stage, 32% intermediate and 44% late stage. Smoking ( P = 0.014) and sunlight exposure of &lt;2 h daily ( P = 0.038) were significantly associated with AMD, while diabetes showed a borderline association ( P = 0.054). No significant associations were noted with age, gender or hypertension. Conclusion: Approximately one in six elderly individuals in this cohort had AMD, with smoking and inadequate sunlight exposure as significant risk factors. These findings highlight the importance of lifestyle modifications, ultraviolet (UV)-protective practices and targeted screening to prevent progression and late-stage presentation.

Exploring the causal relationship between osteoporosis and age-related macular degeneration: Evidence from observational studies and mendelian randomization.

Butylphthalide nanoemulsion for management of dry age-related macular degeneration via antioxidant and anti-inflammatory mechanisms.

Task-specific neural networks for medical imaging using pretrained fragments.