PANoptosis‐Related Diagnostic Biomarkers in Non‐Neovascular Age‐Related Macular Degeneration: An Integrative Transcriptomic and Experimental Study

Objective: To investigate any relationships between exfoliation syndrome or exfoliation glaucoma and age-related macular degeneration utilizing the Utah population database. Design: This was a retrospective, case–control cohort study. Subjects, Participants, and/or Controls: We identified 3405 patients diagnosed with exfoliation syndrome (XFS) or exfoliation glaucoma (XFG) during a dilated eye exam within the UHealth system from 1996 to 2021, whose dry or wet age-related macular degeneration (AMD) status was assessed. A population-based control pool of 257,714 UHealth patients with no XFS/XFG diagnosis and a dilated eye exam history from 1996 to 2021 was compiled, with its patients randomly selected and individually matched 3:1 to cases based on sex and age at index diagnosis of their respective case. Methods: A covariate analysis was performed of characteristics and risk factors associated with XFS/XFG, which included race/ethnicity, residence location, partner/marital status, and family history of XFS/XFG, obesity, tobacco use, alcohol use, osteoporosis/vitamin D deficiency, primary/essential hypertension, ocular hypertension, and cataract surgery. Main Outcome Measure: We studied the trends of non-exudative (dry) or exudative (wet) AMD in a large Utah population study of XFS/XFG patients and controls. Results: Of 3396 XFS/XFG patients, as well as 10,179 individually matched 3:1 control patients, 64% were female and the average age of XFS onset was 74.3 yrs. In a univariate model, we observed a very modest increased risk of wet AMD in XFS/XFG patients (odds ratio, OR = 1.14, 95% confidence interval (CI) 0.99–1.32), which did not achieve statistical significance (p = 0.07). After adjusting for the main effects of potential confounders, there was no greater presentation of AMD in XFS/XFG patients when compared with controls (dry AMD: OR = 0.94, 95% CI 0.85–1.05, p = 031; wet AMD: OR = 0.98, 95% CI 0.83–1.14, p = 0.76). In XFS/XFG patients compared to controls, the risk of having cataract surgery was elevated (OR = 2.39, 95% CI 2.18–2.62). However, after accounting for an interaction with AMD, XFS/XFG patients who underwent cataract surgery did not exhibit an increased risk of either dry or wet AMD (dry AMD: OR = 0.91, 95% CI 0.80–1.03; wet AMD: OR = 0.89, 95% CI 0.75–1.07). The risk of AMD in XFS/XFG patients vs. controls showed no association with osteoporosis/vitamin D deficiency for dry (OR 0.78 95% CI 0.66–0.92 p = 0.004) or wet AMD (OR = 0.72 95% CI 0.56–0.92 p = 0.01), while we found a borderline positive association with both dry and wet AMD if they had osteoporosis/vitamin D deficiency. Conclusion: Using the Utah Population Database, we found that a cataract surgery history significantly impacts the association between AMD and XFS, and that vitamin D deficiency/osteoporosis is a significant confounder of the association. However, no direct association between XFS and AMD was found in this study.

ROBO1 is a strong candidate gene for age-related macular degeneration (AMD) based upon its location under a linkage peak on chromosome 3p12, its expression pattern, and its purported function in a pathway that includes RORA, a gene previously associated with risk for neovascular AMD. Previously, we observed that expression of ROBO1 and RORA is down-regulated among wet AMD cases, as compared to their unaffected siblings. Thus, we hypothesized that contribution of association signals in ROBO1, and interaction between these two genes may be important for both wet and dry AMD. We evaluated association of 19 single nucleotide polymorphisms (SNPs) in ROBO1 with wet and dry stages of AMD in a sibling cohort and a Greek case-control cohort containing 491 wet AMD cases, 174 dry AMD cases and 411 controls. Association signals and interaction results were replicated in an independent prospective cohort (1070 controls, 164 wet AMD cases, 293 dry AMD cases). The most significantly associated ROBO1 SNPs were rs1387665 under an additive model (meta P = 0.028) for wet AMD and rs9309833 under a recessive model (meta P = 6×10−4) for dry AMD. Further analyses revealed interaction between ROBO1 rs9309833 and RORA rs8034864 for both wet and dry AMD (interaction P<0.05). These studies were further supported by whole transcriptome expression profile studies from 66 human donor eyes and chromatin immunoprecipitation assays from mouse retinas. These findings suggest that distinct ROBO1 variants may influence the risk of wet and dry AMD, and the effects of ROBO1 on AMD risk may be modulated by RORA variants.

Oral Acetylcysteine and the Risk of Age-Related Macular Degeneration: A Retrospective Cohort Study.

Purpose This study aims to evaluate the association between age-related macular degeneration (AMD) and cardiovascular disease by using the noninvasive flow-mediated dilation (FMD) test to show endothelial dysfunction as an indicator of subclinical atherosclerosis. Method Participants in this study included 30 dry AMD patients, 30 wet AMD patients, and 30 healthy controls without any systemic disease, including AMD. FMD and the intima media thickness (IMT) of the carotid artery were compared between the groups. Results Comparison of FMD between the groups showed a 10.96% brachial artery dilation in the healthy controls, 3.99% in the dry AMD group, and 5.03% in the wet AMD group. While a significant difference was not observed between the wet and dry AMD groups, comparison of the control group to the wet and dry AMD groups yielded a significant difference. When brachial artery dilation below 7% was accepted as an abnormal FMD, 26.7% of the healthy controls, 66.7% of the dry AMD patients and 76.7% of the wet AMD patients were found to be abnormal. Similarly, while no significant difference was observed between the wet and dry AMD groups, comparison of the control group with the wet and dry AMD patients yielded a significant difference. When an IMT below 0.7 mm was accepted as abnormal, 26.7% of the healthy controls, 33.3% of the dry AMD, and 43.3% of the wet AMD were found to have an abnormal IMT. However, differences between the groups did not reach statistical significance. Conclusions In this study, use of the FMD test showed endothelial dysfunction among AMD patients. No significant differences were found between the dry and wet AMD patient groups.

Research has suggested a potential relationship between apolipoproteins A (ApoA) and B (ApoB) and age-related macular degeneration (AMD). This study explored the potential causal relationship between ApoA/ApoB levels and AMD/AMD subtypes using two-sample Mendelian randomisation (MR). We selected 308 single nucleotide polymorphisms (SNPs) for ApoA and 198 SNPs for ApoB from the UK Biobank data. Summary statistics for AMD were collected from the genome-wide association study of the FinnGen project. We performed two-sample MR to assess the causal effects of ApoA/ApoB on AMD and its subtypes. Potential confounders, including body mass index, C-reactive protein level, and smoking status, were assessed using a multivariable MR analysis. ApoA showed a significant causal association with AMD (odds ratio [OR] = 1.14, 95% confidence interval [CI] = 1.05-1.25, p = 0.003) and was linked to both dry (p = 0.004) and wet (p = 0.025) AMD. ApoB showed a decreasing trend in dry AMD risk (p = 0.074), though not significant, and was not associated with overall or wet AMD. The multivariable MR analysis showed no significant association of ApoA with any AMD subtype (p > 0.05). ApoB decreased dry AMD risk (OR = 0.89, 95% CI = 0.80-0.99, p = 0.039), with trends for overall and wet AMD that were not significant (p = 0.070 and p = 0.091, respectively). These findings suggest that ApoB is associated with lower AMD risk, particularly for dry AMD. Further research is needed to clarify lipid biomarker's role as AMD risk factors.

This study systematically investigates the causal relationships between 731 immune cell phenotypes and age-related macular degeneration (AMD) using comprehensive Mendelian randomization (MR) analyses. The goal is to identify immune cell factors that contribute to or protect against AMD, thereby clarifying the immunological mechanisms underlying AMD pathophysiology and informing prevention and treatment strategies. Univariable, bidirectional, and multivariable MR analyses were conducted to evaluate the associations between immune cells and AMD. By utilizing publicly available GWAS datasets, we eliminated the need for individual consents. The large-scale MR approach adhered to STROBE-MR guidelines. Immune cell GWAS data were sourced from a study involving 3,757 Sardinians, encompassing a broad spectrum of immune phenotypes, while AMD summary statistics were derived from a GWAS with over 3,763 cases. Instrumental variables (IVs) were carefully selected to comply with MR assumptions, and multiple MR methods were employed to enhance the robustness of causal inferences. Additionally, we supplemented the data for dry AMD (2,469 cases and 206,221 controls) and wet AMD (2,114 cases and 206,601 controls) for validation purposes. Univariable MR analysis identified 17 immune cell phenotypes significantly associated with AMD, including 11 potential risk factors and 6 potential protective factors. Bidirectional MR analysis found no significant effects of AMD on the examined immune cell subsets. Multivariable MR analysis indicated that TD CD4+ %T cells and CD39+ CD8br %T cells likely inhibit AMD development, whereas CD39+ CD8br %CD8br cells and CD45RA on resting Treg cells appear to increase AMD risk. Validation of immune cell subsets in dry and wet AMD revealed significant associations between specific immune cells and both forms of AMD, with some subsets uniquely linked to wet AMD and others to dry AMD. This study addresses a critical gap in understanding the causal relationship between immune cells and AMD, identifying immune cell subsets that may either mitigate or exacerbate AMD risk. Notably, it highlights the potential role of CD39+ CD8+ T cells as anti-inflammatory agents and potential targets for immunotherapy in AMD. The absence of bidirectional causality suggests a complex origin of immune dysregulation in AMD. The differential associations of immune cell subsets with AMD subtypes carry significant implications for precision medicine approaches in ophthalmology, laying a solid foundation for future research focused on understanding the immunological underpinnings of AMD and developing targeted therapeutic strategies.

This study adds to the evidence that elevated levels of high-sensitivity C-reactive protein (hsCRP) predict future risk of age-related macular degeneration (AMD). This information might shed light on underlying pathological mechanisms involving inflammation and could be of clinical utility in the identification of persons at high risk of AMD who may benefit from increased adherence to lifestyle recommendations, eye examination schedules, and therapeutic protocols. To investigate the relationship between hsCRP and future risk of AMD in US men and women. Pooled analysis of prospective nested case-control data from the Women's Health Study and 4 other cohorts, the Physicians' Health Study, Women's Antioxidant and Folic Acid Cardiovascular Study, Nurses' Health Study, and Health Professionals Follow-up Study. A prospective nested case-control study within 5 large cohorts. Patients were initially free of AMD. We prospectively identified 647 incident cases of AMD and selected age- and sex-matched controls for each AMD case (2 controls for each case with dry AMD or 3 controls for each case of neovascular AMD). MAIN OUTCOME MEASURES We measured hsCRP in baseline blood samples. We used conditional logistic regression models to examine the relationship between hsCRP and AMD and pooled findings using meta-analytic techniques. After adjusting for cigarette smoking status, participants with high (>3 mg/L) compared with low (<1 mg/L) hsCRP levels had cohort-specific odds ratios (ORs) for incident AMD ranging from 0.94 (95% CI, 0.58-1.51) in the Physicians' Health Study to 2.59 (95% CI, 0.58-11.67) in the Women's Antioxidant and Folic Acid Cardiovascular Study. After testing for heterogeneity between studies (Q = 5.61; P = .23), we pooled findings across cohorts and observed a significantly increased risk of incident AMD for high vs low hsCRP levels (OR, 1.49; 95% CI, 1.06-2.08). Risk of neovascular AMD was also increased among those with high hsCRP levels (OR, 1.84; 95% CI, 1.14-2.98). Overall, these pooled findings from 5 prospective cohorts add further evidence that elevated levels of hsCRP predict greater future risk of AMD. This information might shed light on underlying mechanisms and could be of clinical utility in the identification of persons at high risk of AMD who may benefit from increased adherence to lifestyle recommendations, eye examination schedules, and therapeutic protocols.

Objective: Genetic variants in the adenosine triphosphate-binding cassette transporter A1( ABCA1 ) is associated with higher concentrations of high-density lipoprotein (HDL) cholesterol. Higher HDL cholesterol concentrations are observationally and genetically associated with higher risk of age-related macular degeneration (AMD). However, whether amino acid changing genetic variants in ABCA1 associated with high HDL cholesterol concentrations confer a higher risk of AMD in the general population is currently unknown. We tested this hypothesis. Methods: We genotyped all amino acid changing ABCA1 variants with a minor allele frequency above 0.002, measured plasma HDL cholesterol and other plasma lipids, and used Cox regression to assess risk of AMD. We created an HDL cholesterol weighted allele score and tested the association with risk of AMD on a continuous scale and in tertiles. Further, we performed mediation analyses. Main outcome measures: 1,554 AMD events. Median follow-up of 10 years. Results: Of 90,344 study participants, 55% were women. Median age was 58 (interquartile range: 47-67) years. On a continuous scale, higher concentrations of genetically determined HDL cholesterol were associated with higher risk of all-cause AMD, dry AMD, and wet AMD both in an age- and sex adjusted model and in a multivariable adjusted model (See Figure). The ABCA1 allele score for the third versus the first tertile was associated with HRs (95% confidence intervals (CIs)) of 1.30 (1.14-1.49) for all-cause AMD, 1.26 (1.06-1.50) for dry AMD, and 1.31 (1.12-1.53) for wet AMD in a multivariable adjusted model. 6-8% of the effect was mediated through HDL cholesterol. There was no interaction between weighted allele score tertiles and confounding factors on risk of AMD. Conclusions: Amino acid changing genetic variants in ABCA1 which were associated with higher HDL cholesterol concentrations, were also associated with higher risk of AMD, both on a weighted allele score continuously and when divided into tertiles.

To assess the reliability and the diagnostic performance of a novel CE (European Conformity)-marked and FDA (Food and Drug Administration)-cleared dot patient self-monitoring test (Alleye, Oculocare medical Inc.) for the detection and characterization of metamorphopsia in age-related macular degeneration (AMD). Three consecutive tests were performed in 63 wet AMD, 26 dry AMD, and 19 age-matched healthy eyes. In addition, the test was performed in 34 young healthy eyes. The mean Alleye score and standard deviations (SDs) were calculated for each eye and group. We compared and tested healthy with dry and wet AMD eyes and assessed the extent to which the test discriminated between healthy subjects and patients with dry and wet AMD using the area under the receiver operating characteristic curve (AUC). The mean (SD) Alleye score was 49.5 (16.1) in wet AMD eyes, 62.1 (22.5) in dry AMD eyes, 69.8 (10.2) in age-matched healthy eyes, and 85.3 (10.0) in young healthy subjects. Compared to age-matched healthy subjects, the AUC (95% confidence interval) to detect wet AMD was 0.845 (0.759-0.932), and 0.660 (0.520-0.799) to discriminate between dry and wet AMD. Compared to young healthy subjects, the AUC to detect dry AMD was 0.799 (0.675-0.923), and 0.969 (0.940-0.997) to detect wet AMD. This is the first assessment of Alleye in clinical practice. The test is highly accurate to detect wet AMD and reasonably accurate to classify dry vs. wet AMD. Data from longitudinal monitoring and its role in the therapeutic management of AMD is warranted.

Association between glycemic status and age-related macular degeneration: A nationwide population-based cohort study

The Influence of Diabetes, Hypertension, and Hyperlipidemia on the Onset of Age-Related Macular Degeneration in North China: The Kailuan Eye Study

There is a relative lack of head-to-head comparisons of denosumab against other osteoporosis drugs on safety. We aimed to explore ocular outcomes in patients with osteoporosis initiating denosumab vs zoledronic acid. We conducted a cohort study using claims data (2010-15) from two large US commercial insurance databases including patients with osteoporosis who were aged 50 years or older and initiators of denosumab or zoledronic acid. The primary outcomes were (1) receipt of cataract surgery and development of (2) wet age-related macular degeneration and (3) dry age-related macular degeneration within 365 days after initiation of denosumab vs zoledronic acid. Propensity score fine stratification and weighting were used to control for potential confounding, and we calculated the incidence rate and hazard ratio for each outcome in the cohorts. The estimates from the two databases were combined with a fixed-effects model meta-analysis. The study cohort included 50,821 denosumab and 67,471 zoledronic acid initiators. In the propensity score-weighted analysis, compared to zoledronic acid use, denosumab was associated with a modestly decreased risk of undergoing cataract surgery (hazard ratio 0.91; 95% confidence interval 0.85-0.98) but not with the risk of wet age-related macular degeneration (hazard ratio 1.29; 95% confidence interval 0.99-1.70) or dry age-related macular degeneration (hazard ratio 1.03; 95% confidence interval 0.98-1.09). In this large population-based cohort study of 118,292 patients with osteoporosis, initiation of denosumab was associated with a modestly decreased risk of cataract surgery vs zoledronic acid. The risk of age-related macular degeneration was similar between the two drugs.

Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD)

Retinal oxygen saturation (SO2) during flicker light stimulation was measured non-invasively in humans with age-related macular degeneration (AMD). Furthermore, the differences between early and late stages of AMD were evaluated. In 60 eyes of 45 AMD patients (74 ± 8.3 years) and 23 eyes of 23 healthy controls (73.4 ± 7.4 years), the SO2 of arterioles and venules was measured with the oximetry module of the Retinal Vessel Analyzer. Arterial SO2, venous SO2 and arteriovenous SO2 difference at baseline and with the flicker were assessed and compared with controls. From the difference between the arteriovenous SO2 under flicker stimulation and at baseline, the parameter delta av. Diff was calculated. Subgroup analyses of non-exudative (dry) AMD, exudative (wet) AMD and their end stages, geographic atrophy (GA) and disciform scar (DS) were performed. In comparison with healthy subjects (mean - 4.90, CI [- 6.32, - 3.43]), the parameter delta av. Diff was significantly reduced in all AMD patients (mean - 2.20, CI - 3.15, -1.23, p = 0.003), dry AMD (mean - 1.97, CI - 3.31, -0.63, p = 0.013) and wet AMD (mean - 2.35, CI - 3.50, - 1.19, p = 0.025). The comparison between wet and dry AMD revealed no significant results (p = 1). The comparison between AMD subgroups and healthy controls (median (IQR) - 4.29 (- 8.32; - 2.42) %) showed significant differences in non-neovascular (early dry AMD) (median (IQR) - 2.43 (- 4.59; - 0.74) %, p = 0.038), GA (median (IQR) 0.10 (- 4.02; 3.15) %, p = 0.019) and DS (median (IQR) - 1.67 (- 3.52; - 0.12) %, p = 0.03). A nearly significant reduction was observed in exudative (early wet) AMD (median (IQR) - 2.71 (- 5.84; - 0.2) %, p = 0.055). Minimal, not statistically significant differences of delta av. Diff were found between AMD subgroups. None of the baseline parameters was significantly different between patients and healthy controls, even after flicker light stimulation. Non-invasive retinal oximetry with flicker light stimulation seems to be a suitable method to study the pathogenetic mechanisms of AMD. The mathematically derived parameter delta av. Diff appears to be more sensitive than arteriovenous SO2 difference. Results suggest that the regulation of retinal oxygen supply, oxygen consumption or both is impaired in AMD.

Aim:The aim of the study was to evaluate the macular pigment optical density (MPOD) levels in patients with wet age-related macular degeneration (AMD), dry AMD, and also in healthy controls.Settings and Design:This study was conducted at Department of Ophthalmology, and the study design was a prospective study.Patients and Methods:Forty-eight patients with wet AMD, 51 patients with dry AMD, and 50 controls were included in the study. All patients were naive to both previous lutein or zeaxanthin administration and any previous intravitreal injections. Fundus reflectance (VISUCAM 500, reflectance of a single 460 nm wavelength) was used to measure the MPOD levels. Three groups were compared regarding age, gender, serum lutein, and zeaxanthin concentrations as well as MPOD levels.Results:Serum lutein and zeaxanthin levels were significantly higher in control group when compared with wet AMD (Group 1) and dry AMD (Group 2) (P = 0.001 and P < 0.001, respectively). Mean MPOD was found to be similar in all of the three study subgroups (P = 0.630). However, maximum MPOD was significantly higher in control group when compared with Group 1 and 2 (P = 0.003). There was no correlation between serum lutein or zeaxanthin concentrations and mean MPOD levels (P = 0.815, r = 0.014 and P = 0.461, r = 0.043, respectively), but there was a weak correlation between serum zeaxanthin concentration and maximum MPOD level (P = 0.042, r = 0.124). Maximum MPOD level was found to be correlated with the level of AMD (Group 1, 2, and 3; r = 0.184, P = 0.041).Conclusion:Maximum MPOD level was found to be lower in patients with AMD when compared with control cases. Mean MPOD and maximum MPOD levels were similar in wet and dry AMD Groups. These results can be applied clinically keeping in mind that MPOD measurements with one wavelength reflectometry may not be completely reliable.