Development Of Age-related Macular Degeneration Research Articles

Machine learning model for age-related macular degeneration based on heavy metals: The National Health and Nutrition Examination Survey 2005 to 2008

Age-related macular degeneration (AMD) is the leading cause of blindness in older people in developed countries. It has been suggested that heavy metal exposure may be associated with the development of AMD, but most studies have focused on the effects of a single metal with traditional methods. In this study, we analyzed the relationship between 13 urinary heavy metal concentrations and AMD using NHANES data between 2005 and 2008. We constructed and compared 11 machine learning models to identify the best model for predicting AMD risk. We further interpreted the models by Permutation Feature Importance (PFI), Partial Dependence Plot (PDP) analysis, and SHapley Additive exPlanations (SHAP) analysis. 216 AMD patients out of 2380 participants. The random forest (RF) model performed optimally in predicting the risk of AMD, with an AUC value of 0.970. PFI analyses revealed that age and urinary cadmium (Cd) were the main factors influencing the risk of AMD. SHAP analyses further confirmed the significance of Cd concentration in predicting the risk of AMD, and we revealed a significant interaction with significant interaction of race. Our study firstly explored the relationship between heavy metal exposure levels and AMD based on machine learning techniques, found that urinary Cd concentration had the greatest impact on AMD, and revealed the superior predictive performance of machine learning methods. Furthermore, our study provided a new perspective for early screening and intervention of AMD.

Levodopa is associated with reduced development of new-onset geographic atrophy in patients with age-related macular degeneration.

Geographic atrophy (GA) is a significant cause of vision loss in patients with age-related macular degeneration (AMD). Current treatments are limited to anti-complement drugs, which have limited efficacy to delay progression with significant risk of complications. Levodopa (L-DOPA) is a byproduct of melanin synthesis that is associated with reduced development of neovascular AMD. In this study, we determined if L-DOPA was associated with a reduced likelihood of new-onset GA. We performed a retrospective analysis in the Vestrum Health Retina Database. We included eyes with non-neovascular AMD without GA and 1-5years of follow-up. Eyes were divided into two groups. Exposed to L-DOPA before or on the date of non-neovascular AMD without GA diagnosis, and eyes not exposed to L-DOPA. We extracted age, sex, AREDS2 status, dry AMD stage, smoking history, and conversion rate to GA at years 1 through 5. Propensity score matching was used to match L-DOPA and control groups. Cox proportional hazard regression, adjusting for age, sex, AMD severity, AREDS2 use, smoking status, and L-DOPA use was employed to calculate hazard ratios for new-onset GA detection. We identified 112,089 control and 844 L-DOPA exposed eyes with non-neovascular AMD without GA. After propensity score matching, 2532 control and 844 L-DOPA exposed eyes remained that were well-matched for age, sex, AMD severity, AREDS2 use, and smoking status. We found that L-DOPA exposure was associated with a significantly reduced likelihood (HR = 0.68, 95% CI: 0.48-0.95, P = 0.025) of new-onset GA detection. L-DOPA use was associated with reduced detection of new-onset GA.

Serum Iron Status and Retinal Degenerative Diseases: A Mendelian Randomization Study on AMD, RP, and DR.

Background: Observational studies have noted that patients with certain retinal degenerative diseases exhibit iron disturbances in the retina or vitreous compared to healthy controls. However, the connection between serum iron status and these diseases remains unclear. This study aims to explore the potential causal relationship between serum iron status biomarkers and the development of age-related macular degeneration (AMD), retinitis pigmentosa (RP), and diabetic retinopathy (DR). Methods: A two-sample Mendelian randomization (MR) analysis was conducted to investigate the causal relationship between serum iron status and several retinal degenerative diseases. Genome-wide association study (GWAS) summary-level data were extracted from public GWAS databases. Inverse-variance weighting (IVW), MR-Egger regressions, Simple model, Weighted median, and Weight mode were used as MR methods. Sensitivity analysis was conducted to confirm the robustness of the results by examining horizontal pleiotropy and heterogeneity through MR-Egger intercept and leave-one-out analysis. Results: The MR analysis revealed causal relationships between genetically predicted serum iron status biomarkers and various retinal diseases. Transferrin was positively associated with the odds of AMD (whether dry or wet) (OR = 1.167, 95% CI = 1.045-1.304, p = 0.006) and wet AMD (OR = 1.194, 95% CI = 1.018-1.402, p = 0.030). Ferritin was negatively associated with the odds of wet AMD (OR = 0.555, 95% CI = 0.333-0.927, p = 0.024). Serum iron (OR = 0.508, 95% CI = 0.260-0.993, p = 0.048) and transferrin saturation (OR = 0.508, 95% CI = 0.260-0.993, p = 0.048) were negatively associated with the odds of RP. Conclusions: These findings provide evidence supporting a potential causal relationship between serum iron status and various retinal degenerative diseases, highlighting a direction for future research into the underlying mechanisms of these diseases.

Immunocorrective effects of Tricor fenofibrate in the treatment of the early and intermediate stages of age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of irreversible visual impairment, blindness and disability in the elderly. Treatment of end-stage AMD is extremely limited and requires invasive interventions. Currently, there is an active search for remedies aimed at preventing the degenerative process in the retina in the early stages of the disease. AMD is a multifactorial pathology, has common mechanisms with diseases associated with aging, metabolic shifts and hemodynamic disorders. The study of the effects of drugs already used to correct these disorders in the general clinic may also be of interest to ophthalmologists. The aim of the work was to study the dynamics of inflammatory markers of activation of the vascular endothelium and cytokines of the immune response in the tear fluid (TF) of patients with initial and intermediate stages of AMD against the background of the use of Tricor fenofibrate. 65 people were examined, divided into three groups according to the AREDS classification: group I – 20 people with early AMD (AREDS2), group II – 16 patients with intermediate AMD (AREDS3), 29 healthy elderly people without ophthalmopathology entered the age control group (AREDS1 – risk group). Patients of groups I and II received Tricor at a dose of 145 mg once a day for 9 months. Tear fluid (TF) was taken twice: before and immediately after the completion of the course of treatment. The determination of sICAM-1, sVCAM-1, sE-, sP-selectin and MCP-1/CCL2 in CS was performed by flow cytometry using a self-constructed multiplex panel from compatible simplex test kits Human FlowCytomixTM Simplex (Bender MedSystem GmbH, Germany); IL-1β, IL-2 IL-6 TNFα was determined within the framework of the Human Flow CytomixTM 15 Flex system (Bender MedSystem GmbH, Germany). Data processing was performed in the FlowCytomix Pro v 6.0 package (Bender Med Systems GmbH, Germany). According to the results of the study, a significant effect of Tricor fenofibrate was found on the initially high levels of local production of IL-1β, IL-2, IL-6, MCP-1/CCL2 and sICAM-1 in the AREDS2 group, which indicated a direct anti-inflammatory, vasoprotective effect in the treatment of the initial stage of AMD; a similar effect of the drug, but less pronounced, noted in the AREDS3 group. The ophthalmological examination data also indicated stabilization of visual functions and the clinical picture of the fundus, improvement of intraocular blood circulation in patients of the main groups. Thus, the use of Tricor can help prevent the degenerative process in the retina in the early stages of AMD development.

The role of oxidative stress in retinal diseases

Oxidative stress plays a key role in the pathogenesis of many diseases associated with aging, including atherosclerosis, neurodegenerative diseases, diabetes, and retinal diseases. The retina is a tissue that is particularly susceptible to the adverse effects of oxidative stress, as it is characterized by high metabolic rate and high oxygen consumption compared to other body tissues. This review article discusses the relationship between the cellular mechanisms of impaired prooxidant-antioxidant homeostasis and the development of age-related macular degeneration and diabetic retinopathy. Natural defense mechanisms of maintaining redox homeostasis and therapeutic strategies based on the use of antioxidants are also described.

Pharmacologic Treatments for Dementia and the Risk of Developing Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness among people aged 50 years or older worldwide. There is a need for new strategies for the prevention and treatment of AMD. There is some limited evidence to suggest the possibility of a protective association of dementia medications with the development of some types of AMD, but the evidence is weak. To investigate whether the dementia medications memantine and donepezil are associated with the risk of developing AMD. Three population-based cohort studies were performed using data from the Clinical Practice Research Datalink GOLD and Aurum databases from May 15, 2002, to June 21, 2022. Participants included individuals with dementia (vascular dementia, nonvascular dementia, or Alzheimer disease) aged 40 years or older. Statistical analysis was carried out between February and November 2023. Exposures were dementia medications. Cohort 1 compared patients prescribed donepezil with those prescribed rivastigmine or galantamine using the new-user design. Cohort 2 compared memantine with donepezil, rivastigmine, or galantamine using the prevalent new-user design. In a sensitivity analysis, cohort 3 compared memantine with rivastigmine or galantamine only. New diagnosis of AMD. There were 132 846 individuals (mean [SD] age, 80.4 [7.6] years; 61.8% women; mean [SD] body mass index [BMI], 25.5 [4.6]) with a diagnosis of dementia included in cohort 1, 159 419 individuals (mean [SD] age, 81.2 [7.6] years; 59.7% women; mean [SD] body mass index [BMI], 25.6 [4.7]) with a diagnosis of dementia included in cohort 2, and 92 328 individuals with a diagnosis of dementia included in cohort 3 (mean [SD] age, 80.9 [7.7] years; 58.5% women; mean [SD] body mass index [BMI], 25.5 [4.7]). The adjusted hazard ratio (HR) for donepezil compared with rivastigmine or galantamine (cohort 1) was 0.95 (95% CI, 0.67-1.35). The adjusted HR for memantine compared with donepezil, rivastigmine, or galantamine (cohort 2) was 1.03 (95% CI, 0.83-1.27). The adjusted HR for memantine vs rivastigmine or galantamine only (cohort 3) was 1.24 (95% CI, 0.83-1.86). This cohort study of patients with dementia found no significant associations between memantine or donepezil compared with other dementia medications and the risk of development of AMD. Further research is recommended to examine any possible pathophysiological protective action of memantine and other dementia medications against the development of AMD.

The Impact of ARMS2 (rs10490924), VEGFA (rs3024997), TNFRSF1B (rs1061622), TNFRSF1A (rs4149576), and IL1B1 (rs1143623) Polymorphisms and Serum Levels on Age-Related Macular Degeneration Development and Therapeutic Responses.

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.

Psoriasis as a Predictor of Neovascular Age-Related Macular Degeneration in Type 2 Diabetes Mellitus: A Nationwide Cohort Study

PurposeThe objective of this study is to evaluate the relationship of psoriasis and neovascular Age-related Macular Degeneration (AMD) in diabetic mellitus (DM) population. DesignNationwide, population-based, retrospective cohort study. MethodsRecords of patients who had been diagnosed with type 2 diabetes mellitus over 40 years of age from January 2009 to December 2012 were analyzed. The incidence of neovascular AMD was observed from the index year to December 2018 in all subjects. We compared the incidence rate of neovascular AMD among the psoriasis group and control group. Covariates include age, sex, BMI, income level, smoking status, drinking status, regular exercise habits, hypertension, dyslipidemia, end-stage renal disease, diabetic retinopathy, glucose level, the prescription of more than three oral hypoglycemic agents, and a history of diabetes mellitus exceeding five years. ResultsOf 2,245,358 type 2 DM patients, 20,853 patients were classified in the psoriasis group, and the other 2,224,505 individuals in the control group. A total of 105 neovascular AMD cases occurred in the psoriasis group and 7,459 cases in the control group. According to multivariable Cox proportional hazard models, individuals with psoriasis had a significantly higher risk for neovascular AMD compared to controls (HR=1.329, 95% confidence interval: 1.096-1.612) after adjustments for covariates. ConclusionThis study demonstrated that psoriasis was an independent risk factor for developing neovascular AMD in DM patients. Therefore, physicians should be alert to the development of neovascular AMD in DM patients who also have psoriasis.

βA3/A1-crystallin is an epigenetic regulator of histone deacetylase 3 (HDAC3) in the retinal pigmented epithelial (RPE) cells.

The retinal pigmented epithelial (RPE) cells maintain retinal homeostasis, and alterations in their function contribute to non-exudative age-related macular degeneration (AMD) 1,2 . Here, we explore the intricate relationship between RPE cells, epigenetic modifications, and the development of AMD. Importantly, the study reveals a substantial decrease in histone deacetylase 3 (HDAC3) activity and elevated histone acetylation in the RPE of human AMD donor eyes. To investigate epigenetic mechanisms in AMD development, we used a mouse model with RPE-specific Cryba1 knockout 3-5 , revealing that the loss of βA3/A1-crystallin selectively reduces HDAC3 activity, resulting in increased histone acetylation. βA3/A1-crystallin activates HDAC3 by facilitating its interaction with the casein kinase II (CK2) and phosphorylating HDAC3, as well as by regulating intracellular InsP6 (phytic acid) levels, required for activating HDAC3. These findings highlight a novel function of βA3/A1-crystallin as an epigenetic regulator of HDAC3 in the RPE cells and provide insights into potential therapeutic strategies in non-exudative AMD.

Summary of the Therapeutic Options for Patients with Dry and Neovascular AMD.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness worldwide and a severe medical and social problem. The steadily increasing number of patients is related to the aging of the population. So far, many factors affecting the development of AMD have been identified, which can be divided into non-modifiable, including genetic factors, age, and sex, and modifiable or environmental factors, such as smoking, poor diet, and hypertension. Early stages of age-related macular degeneration are characterized by fundus drusen and abnormalities in the retinal pigment epithelium. In late stages, geographic atrophy and choroidal neovascularization (CNV) are observed. The treatment of AMD, especially its advanced forms, is very challenging. Intensive research has made it possible to treat advanced stages of the dry form of AMD with pegcetacoplan and avacincaptad pegol, new drugs approved for use in the US. Pegcetacoplan targets the C3 and avacincaptad pegol targets the C5, the pivotal proteins of the complement cascade. The drugs are administered by intravitreal injection. The gold standard for neovascular AMD (nAMD) consists of intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) drugs such as bevacizumab, ranibizumab, aflibercept, brolucizumab, and faricimab. Treatment can be administered according to the fixed, pro-re-nata, and treat-and-extend regimens. The latter seems to have the best effect on improving visual acuity (VA) and the maximum therapeutic benefit. The search continues for the best ways to deliver intravitreal drugs. Current methods include sustained-release implants and hydrogel platforms for drug release, while the most promising future pathways for treating dry and nAMD are stem cell and gene therapy.

Janus Kinase Inhibitor Therapy and Risk of Age-Related Macular Degeneration in Autoimmune Disease

The involvement of chronic inflammation in the pathogenesis of age-related macular degeneration (AMD) opens therapeutic possibilities to AMD management. To determine whether Janus kinase inhibitors (JAKis) are associated with a reduced risk of AMD development in patients with autoimmune diseases. This retrospective observational cohort study used administrative claims data from Merative MarketScan research databases (Commercial and Medicare Supplemental) and Optum Clinformatics Data Mart databases between January 1, 2010, and January 31, 2022. Patients with autoimmune diseases satisfying study eligibility criteria and who received JAKi treatment (9126 in MarketScan and 5667 in Optum) were propensity score matched (1:1) to identical numbers of study-eligible patients who received non-JAKi-based immunotherapy. Treatment duration of 6 months or longer. Incidence rates of AMD (exudative and nonexudative) over the first 6 to 18 months of treatment were determined, and bayesian Poisson regression models were used to estimate incidence rate ratios, 95% CIs, and posterior probabilities of AMD. After matching, female sex represented the majority of the patient population in both MarketScan and Optum (14 019/18 252 [76.6%] and 8563/3364 [75.2%], respectively in the JAKi patient population). More than 60% of the patient population was older than 55 years of age in both cohorts. Over the specified treatment period, a 49% relative reduction in incidence of AMD was observed among patients who received JAKi therapy (10/9126 events; adjusted incidence rate ratio [AIRR], 0.51; 95% CI, 0.19-0.90) vs those who received non-JAKi therapy (43/9126 events; AIRR, 1 [reference]) in MarketScan, and a 73% relative reduction in incidence of AMD was observed among patients who received JAKi therapy (3/5667 events; AIRR, 0.27; 95% CI, 0.03-0.74) vs those who received non-JAKi therapy (21/5667 events; AIRR, 1 [reference]) in Optum. The absolute percentage reductions were 0.36% (MarketScan) and 0.32% (Optum), favoring patients who received JAKi therapy. Posterior probabilities of the adjusted risk being less than unity were 97.6% (MarketScan) and 98.9% (Optum) for those who received JAKi therapy vs those who received non-JAKi therapy in MarketScan and Optum, respectively. JAKi use may be associated with a reduced risk of incident AMD in US adults with major autoimmune diseases. The absolute percentage reduction is consistent with a potential role for JAKi in this population. Future studies with long-term follow-up are recommended to investigate the association between JAKi use and incident AMD in other disease indications. Investigation into the role of systemic inflammation and JAK-signal transducers and activators of transcription signaling in AMD may improve understanding of the pathophysiology of AMD and lead to new treatment options.

Vitamin D alleviation of oxidative stress in human retinal pigment epithelial cells.

Oxidative stress-induced retinal pigment epithelium (RPE) cell damage is a major factor in age-related macular degeneration (AMD). Vitamin D3 (VD3) is a powerful antioxidant and it has been suggested to have anti-aging properties and potential for treating AMD. This study aimed to investigate the effect of VD3 on RPE cell oxidative apoptosis of RPE cells in order to provide experimental evidence for the treatment of AMD. Human retinal pigment epithelial cell 19 (ARPE-19) cells were divided into four groups: blank group (untreated), model group (incubated in medium with 400μmol/L H2O2 for 1h), VD3 group (incubated in medium with 100μmol/L VD3 for 24h), and treatment group (incubated in medium with 400μmol/L H2O2 for 1h and 100μmol/L VD3 for 24h). Cell viability, cell senescence, ROS content, expression levels of vitamin D specific receptors, Akt, Sirt1, NAMPT, and JNK mRNA expression levels, SOD activity, and MDA, GSH, and GPX levels were measured. We first established an ARPE-19 cell stress model with H2O2. Our control experiment showed that VD3 treatment had no significant effect on ARPE-19 cell viability within 6-48h. Treating the stressed ARPE-19 cells with VD3 showed mixed results; caspase-3 expression was decreased, Bcl-2 expression was increased, MDA level of ARPE-19 cells was decreased, GSH-PX, GPX and SOD levels were increased, the relative mRNA expression levels of Akt, Sirt1, NAMPT were increased (P < 0.05), and the relative mRNA expression level of JNK was decreased (P < 0.05). VD3 can potentially slow the development of AMD.

The relationship between metformin administration and age-related macular degeneration; a systematic review and meta-analysis of observational studies

Introduction: Vision loss due to age-related macular degeneration (AMD) is a major and growing health issue. Given that no definitive treatment is available for AMD, this study aims to evaluate the association between metformin use and AMD risk using a systematic review and meta-analysis approach. Materials and Methods: In this study, databases including ProQuest, PubMed, Web of Science, Cochrane, and Google Scholar search engines were searched without time restriction until April 20, 2024, based on PRISMA statement guidelines. Data were analyzed using STATA 14 software at a significance level of P &lt; 0.05. Results: Overall, metformin administration reduced the risk of AMD (OR: 0.86, 95% CI: 0.80, 0.94). Concerning the dosage, a metformin dose of 1-270 g per 2 years (OR: 0.93, 95% CI: 0.90, 0.96) and 271-600 g per 2 years (OR: 0.91, 95% CI: 0.89, 0.94) mitigated the risk of AMD. Metformin use in women increased the risk of AMD (OR: 1.14, 95% CI: 1.09, 1.18). However, no significant relationship was noticed between metformin use and AMD risk in men (OR: 0.86, 95% CI: 0.73, 1.01). In addition, metformin was associated with a lower risk of AMD in case-control (OR: 0.93, 95% CI: 0.89, 0.97) and cohort (OR: 0.69, 95% CI: 0.51, 0.95) studies. Likewise, metformin use was associated with a lower risk of AMD in the age groups of 50-59 years (OR: 0.54, 95% CI: 0.50, 0.58) and 70-79 years (OR: 0.90, 95% CI: 0.84, 0.97). Conclusion: Metformin administration lowered the risk of AMD by 14%. Moreover, female gender was identified as a risk factor for AMD development. However, further studies are required on this subject to reach a definite conclusion. Registration: This study has been compiled based on the PRISMA checklist, and its protocol was registered on the PROSPERO (ID: CRD42024539904) and Research Registry (UIN: reviewregistry1824) website.

Systemic infection in aged mice causes upregulation of crystallin alpha A in the RPE/choroid

Aging changes the responsiveness of our immune defense, and this decline in immune reactivity plays an important role in the increased susceptibility to infections that marks progressing age. Aging is also the most pronounced risk factor for development of age-related macular degeneration (AMD), a disease that is characterized by dysfunctional retinal pigment epithelial (RPE) cells and loss of central vision. We have previously shown that acute systemic viral infection has a large impact on the retina in young mice, leading to upregulation of chemokines in the RPE/choroid (RPE/c) and influx of CD8 T cells in the neuroretina. In this study, we sought to investigate the impact of systemic infection on the RPE/c in aged mice to evaluate whether infection in old age could play a role in the pathogenesis of AMD. We found that systemic infection in mice led to upregulation of genes from the crystallin family in the RPE/c from aged mice, but not in the RPE/c from young mice. Crystallin alpha A (CRYAA) was the most upregulated gene, and increased amounts of CRYAA protein were also detected in the aged RPE/c. Increased CRYAA gene and protein expression has previously been found in drusen and choroid from AMD patients, and this protein has also been linked to neovascularization. Since both drusen and neovascularization are important hallmarks of advanced AMD, it is interesting to speculate if upregulation of crystallins in response to infection in old age could be relevant for the pathogenesis of AMD.

Immunogenetic and Environmental Factors in Age-Related Macular Disease.

Age-related macular degeneration (AMD) is a chronic disease, which often develops in older people, but this is not the rule. AMD pathogenesis changes include the anatomical and functional complex. As a result of damage, it occurs, in the retina and macula, among other areas. These changes may lead to partial or total loss of vision. This disease can occur in two clinical forms, i.e., dry (progression is slowly and gradually) and exudative (wet, progression is acute and severe), which usually started as dry form. A coexistence of both forms is possible. AMD etiology is not fully understood. Extensive genetic studies have shown that this disease is multifactorial and that genetic determinants, along with environmental and metabolic-functional factors, are important risk factors. This article reviews the impact of heavy metals, macro- and microelements, and genetic factors on the development of AMD. We present the current state of knowledge about the influence of environmental factors and genetic determinants on the progression of AMD in the confrontation with our own research conducted on the Polish population from Kuyavian-Pomeranian and Lubusz Regions. Our research is concentrated on showing how polluted environments of large agglomerations affects the development of AMD. In addition to confirming heavy metal accumulation, the growth of risk of acute phase factors and polymorphism in the genetic material in AMD development, it will also help in the detection of new markers of this disease. This will lead to a better understanding of the etiology of AMD and will help to establish prevention and early treatment.

Melatonin and Risk of Age-Related Macular Degeneration

Melatonin has been shown to oppose several processes that are known to mediate age-related macular degeneration (AMD), but whether melatonin can confer benefits against AMD remains unclear. To examine the association between melatonin supplementation and the risk of the development or progression of AMD. This retrospective cohort study accessed data from TriNetX, a national database of deidentified electronic medical records from both inpatient and outpatient health care organizations across the US, between December 4, 2023, and March 19, 2024. Patients aged 50 years or older, 60 years or older, and 70 years or older with no history of AMD (AMD-naive group) and with a history of nonexudative AMD (nonexudative AMD group) were queried for instances of melatonin medication codes between November 14, 2008, and November 14, 2023. Patients were then classified into either a melatonin group or a control group based on the presence of medication codes for melatonin. Propensity score matching (PSM) was performed to match the cohorts based on demographic variables, comorbidities, and nonmelatonin hypnotic medication use. The presence of at least 4 instances of melatonin records that each occurred at least 3 months apart. After PSM, the melatonin and the control cohorts were compared to evaluate the risk ratios (RRs) and the 95% CIs of having an outcome. For the AMD-naive group, the outcome was defined as a new diagnosis of any AMD, whereas for the nonexudative AMD group, the outcome was progression to exudative AMD. Among 121 523 patients in the melatonin-naive group aged 50 years or older (4848 in the melatonin cohort [4580 after PSM; mean (SD) age, 68.24 (11.47) years; 2588 female (56.5%)] and 116 675 in the control cohort [4580 after PSM; mean (SD) age, 68.17 (10.63) years; 2681 female (58.5%)]), melatonin use was associated with a reduced risk of developing AMD (RR, 0.42; 95% CI, 0.28-0.62). Among 66 253 patients aged 50 years or older in the nonexudative AMD group (4350 in the melatonin cohort [4064 after PSM; mean (SD) age, 80.21 (8.78) years; 2482 female (61.1%)] and 61 903 in the control cohort [4064 patients after PSM; mean (SD) age, 80.31 (8.03) years; 2531 female (62.3%)]), melatonin was associated with a reduced risk of AMD progression to exudative AMD (RR, 0.44; 95% CI, 0.34-0.56). The results were consistent among subsets of individuals aged 60 years or older (AMD-naive cohort: RR, 0.36 [95% CI, 0.25-0.54]; nonexudative AMD cohort: RR, 0.38 [95% CI, 0.30-0.49]) and 70 years or older (AMD-naive cohort: RR, 0.35 [95% CI, 0.23-0.53]; nonexudative AMD cohort: RR, 0.40 [95% CI, 0.31-0.51]). Melatonin use was associated with a decreased risk of development and progression of AMD. Although lifestyle factors may have influenced this association, these findings provide a rationale for further research on the efficacy of using melatonin as a preventive therapy against AMD.

Clinical performance of predicting late age-related macular degeneration development using multimodal imaging.

To examine whether the clinical performance of predicting late age-related macular degeneration (AMD) development is improved through using multimodal imaging (MMI) compared to using colour fundus photography (CFP) alone, and how this compares with a basic prediction model using well-established AMD risk factors. Individuals with AMD in this study underwent MMI, including optical coherence tomography (OCT), fundus autofluorescence, near-infrared reflectance and CFP at baseline, and then at 6-monthly intervals for 3-years to determine MMI-defined late AMD development. Four retinal specialists independently assessed the likelihood that each eye at baseline would progress to MMI-defined late AMD over 3-years with CFP, and then with MMI. Predictive performance with CFP and MMI were compared to each other, and to a basic prediction model using age, presence of pigmentary abnormalities, and OCT-based drusen volume. The predictive performance of the clinicians using CFP [AUC = 0.75; 95% confidence interval (CI) = 0.68-0.82] improved when using MMI (AUC = 0.79; 95% CI = 0.72-0.85; p = 0.034). However, a basic prediction model outperformed clinicians using either CFP or MMI (AUC = 0.85; 95% CI = 0.78-91; p ≤ 0.002). Clinical performance for predicting late AMD development was improved by using MMI compared to CFP. However, a basic prediction model using well-established AMD risk factors outperformed retinal specialists, suggesting that such a model could further improve personalised counselling and monitoring of individuals with the early stages of AMD in clinical practice.

Effect of Low-Dose Aspirin on the Course of Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in old age. There is no proven intervention to prevent AMD and, apart from lifestyle, nutritional, and supplement advice, there is no intervention to delay its progression. To determine the impact of long-term low-dose aspirin on the incidence and progression of AMD. The Aspirin in Reducing Events in the Elderly-AMD (ASPREE-AMD) study was an Australian-based substudy of the ASPREE trial, a multicenter, international, randomized, double-masked, placebo-clinical trial investigating the efficacy of low-dose aspirin in prolonging disability-free survival among older individuals. Retinal photography was conducted at baseline from March 2010 to January 2015, then 3 and 5 years after randomization. AMD status was determined using color retinal images and treatment records. Australian participants in ASPREE aged 70 years and older without dementia, independence-limiting physical disability, cardiovascular disease, or chronic illness limiting 5-year survival and with gradable retinal images at baseline were included. Data were analyzed from December 2022 to December 2023. Aspirin (100 mg daily, enteric coated) or placebo. Incidence of AMD and progression from early/intermediate to late AMD. Outcomes were analyzed by modified intention-to-treat analysis. A total of 4993 participants were enrolled in this substudy. Baseline characteristics were similar between groups. At the time of sponsor-determined trial termination, retinal follow-up data were available for 3208 participants, 3171 of whom were analyzed for AMD incidence and progression, with a median (IQR) age of 73.5 (71.5-76.4) years and even sex distribution (1619 [51%] female). Median (IQR) follow-up time was 3.1 (3.0-3.5) years. Cumulative AMD incidence was 195 of 1004 (19.4%) in the aspirin group and 187 of 979 (19.1%) in the placebo group (relative risk [RR], 1.02; 95% CI, 0.85-1.22; P = .86). Cumulative progression from early/intermediate AMD to late AMD was observed in 14 of 615 (2.3%) participants in the aspirin group and 18 of 573 (3.1%) in the placebo group (RR, 0.72; 95% CI, 0.36-1.44; P = .36). In this trial, low-dose aspirin administered for 3 years did not affect the incidence of AMD. The evidence was weaker for progression of AMD due to low number of progressed cases. Overall, these results do not support suggestion that low-dose daily aspirin prevents the development or progression of AMD. anzctr.org Identifier: ACTRN12613000755730.

Circulating Anti-Endothelial Cell Antibodies in Patients with Geographic Atrophy Related to Dry Age-Related Macular Degeneration.

Background and Objectives: Age-related macular degeneration (AMD) is one of the leading causes of central vision loss among elderly patients, and its dry form accounts for the majority of cases. Although several causes and mechanisms for the development and progression of AMD have previously been identified, the pathogenesis of this complex disease is still not entirely understood. As inflammation and immune system involvement are strongly suggested to play a central role in promoting the degenerative process and stimulating the onset of complications, we aimed to analyze the frequency of serum anti-retinal (ARAs) and anti-endothelial cell antibodies (AECAs) in patients with dry AMD and to determine their relationship with the clinical features of the disease, notably the area of geographic atrophy (GA). Materials and Methods: This study included 41 patients with advanced-stage dry AMD and 50 healthy controls without AMD, matched for gender and age. ARAs were detected by indirect immunofluorescence using monkey retina as an antigen substrate, and the presence of AECAs was determined using cultivated human umbilical vein endothelial cells and primate skeletal muscle. Results: ARAs were detected in 36 (87.8%) AMD patients (titers ranged from 1:20 to 1:320) and in 16 (39.0%) (titers ranged from 1:10 to 1:40) controls (p = 0.0000). Twenty of the forty-one patients (48.8%) were positive for AECAs, while in the control group, AECAs were present only in five sera (10.0%). The titers of AECAs in AMD patients ranged from 1:100 to 1:1000, and in the control group, the AECA titers were 1:100 (p = 0.0001). There were no significant correlations between the presence of AECAs and disease activity. Conclusions: This study demonstrates a higher prevalence of circulating AECAs in patients with dry AMD; however, no correlation was found between the serum levels of these autoantibodies and the area of GA.

CYTOR-NFAT1 feedback loop regulates epithelial-mesenchymal transition of retinal pigment epithelial cells.

Epithelial mesenchymal transition (EMT) occurring in retinal pigment epithelial cells (RPE) is a crucial mechanism that contributes to the development of age-related macular degeneration (AMD), a pivotal factor leading topermanent vision impairment. Long non-coding RNAs (lncRNAs) have emerged as critical regulators orchestrating EMT in RPE cells. In this study, we explored the function of the lncRNA CYTOR (cytoskeleton regulator RNA) in EMT of RPE cells and its underlying mechanisms. Through weighted correlation network analysis, we identified CYTOR as an EMT-related lncRNA associated with AMD. Experimental validation revealed that CYTOR orchestrates TGF-β1-induced EMT, as well as proliferation and migration of ARPE-19 cells. Further investigation demonstrated the involvement of CYTOR in regulating the WNT5A/NFAT1 pathway and NFAT1 intranuclear translocation in the ARPE-19 cell EMT model. Mechanistically, CHIP, EMSA and dual luciferase reporter assays confirmed NFAT1's direct binding to CYTOR's promoter, promoting transcription. Reciprocally, CYTOR overexpression promoted NFAT1 expression, while NFAT1 overexpression increased CYTOR transcription. These findings highlight a mutual promotion between CYTOR and NFAT1, forming a positive feedback loop that triggers the EMT phenotype in ARPE-19 cells. These discoveries provide valuable insights into the molecular mechanisms of EMT and its association with AMD, offering potential avenues for targeted therapies in EMT-related conditions, including AMD.