Advanced Age-related Macular Degeneration Research Articles

Inflammasome activation aggravates choroidal neovascularization.

Inflammasome activation is implicated in diseases of aberrant angiogenesis such as age-related macular degeneration (AMD), though its precise role in choroidal neovascularization (CNV), a characteristic pathology of advanced AMD, is ill-defined. Reports on inhibition of inflammasome constituents on CNV are variable and the precise role of inflammasome in mediating pathological angiogenesis is unclear. Historically, subretinal injection of inflammasome agonists alone has been used to investigate retinal pigmented epithelium (RPE) degeneration, while the laser photocoagulation model has been used to study pathological angiogenesis in a model of CNV. Here, we report that the simultaneous introduction of any of several disease-relevant inflammasome agonists (Alu or B2 RNA, Alu cDNA, or oligomerized amyloid β (1-40)) exacerbates laser-induced CNV. These activities were diminished or abrogated by genetic or pharmacological targeting of inflammasome signaling constituents including P2rx7, Nlrp3, caspase-1, caspase-11, and Myd88, as well as in myeloid-specific caspase-1 knockout mice. Alu RNA treatment induced inflammasome activation in macrophages within the CNV lesion, and increased accumulation of macrophages in an inflammasome-dependent manner. Finally, IL-1β neutralization prevented inflammasome agonist-induced chemotaxis, macrophage trafficking, and angiogenesis. Collectively, these observations support a model wherein inflammasome stimulation promotes and exacerbates CNV and may be a therapeutic target for diseases of angiogenesis such as neovascular AMD.

Macrophages in age-related macular degeneration: a narrative review

Aging is the major cause of age-related macular degeneration, but its mechanism of action is still unclear. Research has indicated that aging, macrophages and age-related macular degeneration are closely correlated. Owing to the heterogeneity of ocular macrophages and their diverse/plastic phenotypes, recognition of the role of macrophages in age-related macular degeneration is relatively rare, which hinders the development of precision treatments for age-related macular degeneration. In this narrative review, we discuss the classification of retinal macrophages and their diverse polarization states in age-related macular degeneration. To better understand the causal relationship between senescent macrophages and age-related macular degeneration, a novel model for manipulating the macrophage senile state in age-related macular degeneration was proposed. By transplanting senescent macrophages into an age-related macular degeneration model, we can test the ability of senescent macrophages to increase the age-related macular degeneration phenotype; moreover, by replacing senescent macrophages in an age-related macular degeneration model with young macrophages, we can test the necessity of senescent macrophages to cause an age-related macular degeneration phenotype and validate the effectiveness of transplantation of therapeutic macrophages as a treatment for advanced age-related macular degeneration based on the modulation of the inflammatory environment. This proposal is expected to solve the controversy regarding the role of macrophages in age-related macular degeneration and inspire future research on macrophage therapy for senescent diseases.

The role of nutritional factors in transitioning between early, mid, and late stages of age-related macular degeneration: prospective longitudinal analysis

BackgroundTransitions between different stages of age-related macular degeneration (AMD) are not completely captured by traditional survival models with an end point of advanced AMD. ObjectivesThis study aimed to explore the transitions from early and intermediate AMD to higher nonadvanced and advanced stages and determine the contributions of nutritional factors to these outcomes. MethodsEyes with early or intermediate AMD at baseline, classified according to the Age-Related Eye Disease Study severity score, were included in this prospective longitudinal analysis. Foods and the biologically active nutrients associated with AMD [green leafy vegetables, fish, lutein/zeaxanthin (LZ), and ω-3 (n–3) fatty acids] were determined by a baseline food frequency questionnaire. Progression was defined as eyes transitioning to higher severity groups including nonadvanced and advanced stages over 5 y, confirmed at 2 consecutive visits. Cox proportional hazards models for foods and nutrients were analyzed adjusting for demographics, lifestyle, baseline macular status, a family history of AMD, caloric intake, and genetic risk. ResultsAmong 2697 eyes, 616 (23%) progressed to higher severity groups. In the food group model, higher intake of green leafy vegetables reduced incidence of transitions {hazard ratio [HR] (≥2.7 servings/wk compared with none): 0.75; 95% confidence interval [CI]: 0.59, 0.96; P = 0.02}. Higher fish intake was also protective [HR (greater than two 4-ounce servings/wk compared with <2): 0.79; 95% CI: 0.65, 0.95; P = 0.01]. In the nutrient model, LZ intake was protective [HR (≥2 mg/d compared with <2): 0.76; 95% CI: 0.60, 0.96; P = 0.02]. Higher intake of ω-3 fatty acids also tended to be beneficial [HR (≥0.7 g/wk compared with <0.7): 0.85; 95% CI: 0.71, 1.01; P = 0.06]. ConclusionsIncreased consumption of green leafy vegetables, LZ, and fish nutritionally rich in ω-3 fatty acids during the initial stages of AMD may reduce rates of progression to higher severity of this debilitating disease.This trial was registered at clinicaltrials.gov as NCT00594672.

Predict and Protect: Evaluating the Double-Layer Sign in Age-Related Macular Degeneration.

Advanced age-related macular degeneration (AMD) is a major cause of vision loss. Therefore, there is interest in precursor lesions that may predict or prevent the onset of advanced AMD. One such lesion is a shallow separation of the retinal pigment epithelium (RPE) and Bruch's membrane (BM), which is described by various terms, including double-layer sign (DLS). In this article, we aim to examine and clarify the different terms referring to shallow separation of the RPE and BM. We also review current evidence on the outcomes associated with DLS: firstly, whether DLS is predictive of exudative neovascular AMD; and secondly, whether DLS has potential protective properties against geographic atrophy. The range of terms used to describe a shallow separation of the RPE and BM reflects that DLS can present with different characteristics. While vascularised DLS appears to protect against atrophy but can progress to exudation, non-vascularised DLS is associated with an increased risk of atrophy. Optical coherence tomography (OCT) angiography (OCTA) is the principal method for identifying and differentiating various forms of DLS. If OCTA is unavailable or not practically possible, simplified classification of DLS as thick or thin, using OCT, enables the likelihood of vascularisation to be approximated. Research is ongoing to automate DLS detection by applying deep-learning algorithms to OCT scans. The term DLS remains applicable for describing shallow separation of the RPE and BM. Detection and classification of this feature provides valuable information regarding the risk of progression to advanced AMD. However, the appearance of DLS and its value in predicting AMD progression can vary between patients. With further research, individualised risks can be confirmed to inform appropriate treatment.

Correlation between corneal endothelial layer features and age-related macular degeneration severity.

This study aimed to investigate the relationship between corneal endothelial layer features and the severity of age-related macular degeneration (AMD). The study included 119 patients, with 47 females and 72 males. Patients were categorized into four groups based on the AREDS grading system: no AMD (group 1), mild AMD (group 2), moderate AMD (group 3), and advanced AMD (group 4). Only the right eye of patients with both eyes suitable for the study was included. Corneal endothelial cell density (CD), coefficient of variation (CoV), hexagonal cell ratio (HEX), and central corneal thickness (CCT) were measured using specular microscopy (Konan Medical Inc., Nishinomiya, Japan). Group 1 had 40 patients, group 2 had 27 patients, and groups 3 and 4 had 26 patients each. Significant differences were observed between the mean endothelial CD, CoV, and HEX values among the groups, while no significant difference was found in CCT values (p = 0.049, p = 0.002, p = 0.004, and p = 0.883, respectively). A mild negative correlation was observed between AMD severity and CD and HEX values, while a mild positive correlation was found between AMD severity and CoV. Increasing severity of AMD may negatively impact corneal endothelial layer values.

Iron Chelator Deferiprone Restores Iron Homeostasis and Inhibits Retinal Neovascularization in Experimental Neovascular Age-Related Macular Degeneration.

Retinal neovascularization is a significant feature of advanced age-related macular degeneration (AMD) and a major cause of blindness in patients with AMD. However, the underlying mechanism of this pathological neovascularization remains unknown. Iron metabolism has been implicated in various biological processes. This study was conducted to investigate the effects of iron metabolism on retinal neovascularization in neovascular AMD (nAMD). C57BL/6J and very low-density lipoprotein receptor (VLDLR) knockout (Vldlr-/-) mice, a murine model of nAMD, were used in this study. Bulk-RNA sequencing was used to identify differentially expressed genes. Western blot analysis was performed to test the expression of proteins. Iron chelator deferiprone (DFP) was administrated to the mice by oral gavage. Fundus fluorescein angiography was used to evaluate retinal vascular leakage. Immunofluorescence staining was used to detect macrophages and iron-related proteins. RNA sequencing (RNA-seq) results showed altered transferrin expression in the retina and RPE of Vldlr-/- mice. Disrupted iron homeostasis was observed in the retina and RPE of Vldlr-/- mice. DFP mitigated iron overload and significantly reduced retinal neovascularization and vascular leakage. In addition, DFP suppressed the inflammation in Vldlr-/- retinas. The reduced signals of macrophages were observed at sites of neovascularization in the retina and RPE of Vldlr-/- mice after DFP treatment. Further, the IL-6/JAK2/STAT3 signaling pathway was activated in the retina and RPE of Vldlr-/- mice and reversed by DFP treatment. Disrupted iron metabolism may contribute to retinal neovascularization in nAMD. Restoring iron homeostasis by DFP could be a potential therapeutic approach for nAMD.

An Empowerment-Based Physical Activity Intervention for Older People with Advanced Age-Related Macular Degeneration: An Exploratory Qualitative Case Study Design.

Background: Age-related macular degeneration (AMD) is the most common cause of incurable visual impairment and impacts daily life. There are benefits of physical activity for people who are affected with AMD; however, living with AMD is associated with lower levels of physical activity and social isolation. The aim of this study was to explore how older people with AMD in Sweden experienced participation in a 6-month empowerment-based physical activity intervention and how it influenced their physical abilities. Methods: The participants were nine individuals with AMD aged 70-87 years. The intervention comprised physical and social activities in a group twice a week and individual health coaching on three occasions. The study was based on an exploratory qualitative case study design. Results: The findings showed two themes: created meaningfulness in life and creative and playful ways to develop body movements. The findings also showed improved muscle strength after the intervention. Conclusions: The findings showed that participants had increased social connectedness, improved physical self-efficacy and physical ability, as well as improved muscle strength. The empowerment process of the intervention was appreciated by the participants and challenged them to participate in physical activity offered by the municipality for older individuals.

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.

Association between fatty acid intake and age-related macular degeneration: a meta-analysis.

The association of age-related macular degeneration (AMD) with the intake of high and low fatty acids (FAs), respectively, remains controversial. To this end, we performed a comprehensive meta-analysis of all the existing studies on the association of various intake levels of FA subtypes with AMD to determine these associations. A systematic search of PubMed, Web of Science, Cochrane Library, and EMBASE databases was conducted from inception to September 2023. To compare the highest and lowest groups, odds ratio (OR) with 95% confidence intervals (CIs) was analyzed with a random-effects model/fixed-effects model. A high intake of omega-3 LCPUFAs (OR:0.67; 95%CI:[0.51, 0.88]; p = 0.004), DHA (OR:0.80; 95%CI:[0.70, 0.90]; p < 0.001), EPA (OR:0.91; 95%CI:[0.86, 0.97]; p = 0.004), and simultaneous intake of DHA and EPA (OR:0.79; 95%CI:[0.67, 0.93]; p = 0.035) significantly reduced the risk of overall AMD. Conversely, a high intake of trans-FAs (OR: 2.05; 95%CI: [1.29, 3.25]; p = 0.002) was significantly related to an increased risk of advanced AMD compared to the low-intake group. The subgroup analysis results are shown in the articles. Increasing dietary intake of omega-3 LCPUFAs, specifically DHA, and EPA, or the simultaneous intake of DHA and EPA, is significantly associated with a reduced risk of overall AMD. Various subtypes of omega-3 also have a significant association with a reduced risk of different stages of AMD. The high intake of trans-fatty acids (TFAs) is significantly and positively correlated with the risk of advanced AMD. This could further support the idea that consuming foods rich in omega-3 LCPUFAs and reducing consumption of foods rich in TFAs may prevent AMD. https://www.crd.york.ac.uk/prospero/, identifier CRD42023467227.

The role of blood related inflammatory factors on age-related macular degeneration (AMD)

BackgroundAge-related macular degeneration (AMD) is a significant retinal disease that leads to irreversible low vision, particularly in developing countries. The variation in AMD prevalence among different racial groups and highlighted role of inflammation on disease pathology from previous studies which yielded in inconsistent findings, It seems to be of great importance to do more investigation in this field.MethodsThis case control study involved 204 participants, divided into four groups of equal size (51 individuals per group). Three groups represented AMD cases of varying severity according to Beckman classification (3 groups) and one healthy control group. Sampling was conducted exhaustively until the desired sample size was reached. The control group comprised healthy individuals without any infectious or inflammatory systemic, ophthalmic disease. Blood samples were collected to measure inflammatory factors, including lymphocytes, monocytes, neutrophils, neutrophil-to-lymphocyte ratio (NLR), and C-reactive protein (CRP). Collected data were analyzed by statistical methods in SPSS version 21.ResultsOf the participants, 51% were women, and their ages ranged from 47 to 89 years (62.2 ± 8). According to multiple logistic regression analysis, age exhibited a statistically significant positive association with AMD severity (P = 0.038, odds ratio [OR] = 1.034). ANOVA results indicated a significant association between neutrophil count and AMD severity (P < 0.001). As the disease severity increased, the number of neutrophils decreased. The mean ± SD neutrophil counts for early, intermediate and advanced AMD were 3849 ± 800, 3702 ± 734, and 3342 ± 823, respectively. No statistically significant associations were found between lymphocyte count, monocyte count, neutrophil-to-lymphocyte ratio, CRP, and AMD.ConclusionThere was a significant relationship between the number of neutrophils in peripheral blood and the severity of AMD in study participants which needs more evaluation for the potential utility of this factor in the prognosis of AMD. There was not any significant relationship among the other factors and AMD.

Investigating the impact of tadalafil on progression of age-related macular degeneration: a health insurance claims database analysis

PurposeTo assess the effect of tadalafil use on progression of early/intermediate to advanced exudative or non-exudative age-related macular degeneration (AMD) in a real-world population. DesignRetrospective cohort study utilizing Optum's de-identified Clinformatics® Data Mart Database (CDM). MethodsPatients were included from January 2015 to December 2020 aged 55 and older with an index International Classification of Diseases, Tenth Revision (ICD-10) diagnosis of early or intermediate AMD who had a 2-year period of continuous enrollment prior to the index diagnosis date (lookback period), 5 years of continuous follow-up, and who did not meet any exclusion criteria (claims for a phosphodiesterase-5 (PDE-5) inhibitor other than tadalafil during the study, diagnosis of advanced non-exudative or exudative AMD, or claims for exudative AMD treatment during the lookback period). Treated patients with claims for tadalafil during the study period were matched 1:1 to untreated controls by age, sex, race, and smoking status. We assessed the effect of any tadalafil use, high (≥2700 mg) cumulative dose tadalafil vs. matched untreated controls, high (>2700 mg) vs. low (≤2700 mg) cumulative dose tadalafil, and the 2-year cumulative dose of tadalafil (per 100 mg) as a continuous variable on incidence of progression to exudative or advanced non-exudative AMD during the 2-year follow-up. ResultsThere was no significant difference in odds of progression to exudative AMD or advanced non-exudative AMD in the control vs treated groups (OR = 0.802, 95% CI (0.558–1.152), p = 0.233; OR = 1.326, 95% CI (0.757–2.323), p = 0.323). High (≥2700 mg) cumulative dose tadalafil was not associated with a significant difference in odds of progression to exudative AMD or advanced non-exudative AMD when compared to the matched controls (OR = 0.455, 95% CI (0.202–1.025), p = 0.057; OR = 1.000, 95% CI (0.318–3.142), p = 1.000). There was no significant difference in odds of progression to exudative AMD or advanced non-exudative AMD in the high (>2700 mg) vs. low (≤2700 mg) cumulative dose tadalafil (OR = 0.590, 95% CI (0.296–1.177), p = 0.134; OR = 1.039, 95% CI (0.440–2.460), p = 0.931). Lastly, there was no significant difference in odds of progression to exudative AMD or advanced non-exudative AMD when assessing the 2-year cumulative tadalafil dose (per 100 mg) as a continuous variable (OR = 1.000, 95% CI (1.000–1.000), p = 0.305; OR = 1.000, 95% CI (1.000–1.000), p = 0.878). ConclusionIn a retrospective cohort study of a large nationwide health insurance claims database, tadalafil use was not associated with progression of AMD.

Phase 1 Study of JNJ-81201887 Gene Therapy in Geographic Atrophy Secondary to Age-Related Macular Degeneration

ObjectiveTo evaluate the safety and tolerability of a single intravitreal injection of JNJ-81201887 (JNJ-1887) in patients with geographic atrophy (GA) secondary to advanced dry age-related macular degeneration (AMD). DesignPhase 1, open-label, single-center, first-in-human clinical study. SubjectsAdult patients (aged ≥50 years) with GA secondary to AMD in the study-treated eye (treated eye) with a best corrected visual acuity (BCVA) Snellen equivalent of 20/200 or worse in the treated eye (20/80 or worse after the first 3 patients), a total GA lesion size between 5 and 20 mm2 (2-8 disc area), and BCVA of 20/800 or better in fellow, non-treated eye were included. MethodsPatients (N=17) were sequentially enrolled into low (3.56×1010 viral genome [vg]/eye; n=3), intermediate (1.07×1011 vg/eye; n=3), and high (3.56×1011 vg/eye; n=11) dose cohorts without steroid prophylaxis and assessed for safety and tolerability over 24 months. Main Outcome MeasuresSafety and tolerability outcomes included assessment of ocular and non-ocular treatment-emergent adverse events (AEs) over 24 months. Secondary outcomes included GA lesion size and growth rate. ResultsBaseline patient characteristics were consistent with the disease under study, and all enrolled patients had foveal center–involved GA. JNJ-1887 was well tolerated across all cohorts, with no dose-limiting AEs. There were no serious or systemic AEs related to study intervention. Overall, 5/17 (29%) patients experienced 6 events of mild ocular inflammation related to study treatment; exam findings in all resolved, and AEs resolved in 4 of 5 patients following topical steroids or observation. One unresolved vitritis event, managed with observation, occurred in a patient with an unrelated fatal AE. No endophthalmitis or new-onset choroidal neovascularization was reported. GA lesion growth rate was similar among all cohorts over 24 months. For treated eyes in the high-dose cohort, GA lesion growth rate showed continued decline through 24 months, with a reduction in mean square root lesion growth from 0.211 mm at months 0-6 to 0.056 mm at months 18-24. ConclusionsAll 3 studied doses of JNJ-1887 had a manageable safety profile through 24 months of follow-up. Further investigation of JNJ-1887 for the treatment of GA is warranted.

Pilot study evaluating the usability of MonŒil, a ChatGPT-based education tool in ophthalmology

ImportanceThere is an increasing use of artificial intelligence (AI) in ophthalmology to respond to the needs of patients to access reliable, easy-to-understand medical information. ObjectiveTo assess patient satisfaction with the usability of MonŒil, an AI-based platform designed for patient education in ophthalmology. DesignThis was a pilot cross-sectional study of the usability of MonŒil by patients followed for advanced age-related macular degeneration (AMD). MonŒil is based on ChatGPT-4 technology with specific ophthalmology-focused customizations and accessibility enhancements, and is freely available at monoeil.help. Patients were given 20 min of unsupervised interaction with no prior training or guidance, after which their feedback was collected. SettingThe study was performed in the ophthalmology department at the Creteil University Hospital. ParticipantsParticipants included 54 patients diagnosed with advanced AMD defined presenting for follow-up. Patients had to be older than 50 years of age, capable of giving informed consent, and able to understand and interact with MonŒil. Exclusion criteria were severe visual and cognitive impairment that prevented interaction with MonŒil. Main Outcome(s) and Measure(s)The primary outcome was the usability of MonŒil as measured by the System Usability Scale (SUS) questionnaire. ResultsOf the 54 participants, 34 were female (62.96 %). The mean age of the cohort was 77.76±8.14 years (range 58 to 97 years). The mean SUS score was 90.23±12.04 with a median of 92.50 (range 42.50 to 100.00), indicating excellent usability. There was a positive relationship between visual acuity and SUS score (regression coefficient 0.30 (95 % CI 0.08 to 0.51), r2=0.19, p = 0.0077). Conclusions and RelevanceMonŒil demonstrated excellent usability and satisfaction in a sample population of elderly patients with advanced AMD. These results suggest that AI-based tools like MonŒil can enhance patient education with minimal oversight in a complex field like ophthalmology, supporting its use as an adjunct to the physician-patient discussion. Further studies may be necessary to establish the applicability of MonŒil to a broader user base, and to assess its usefulness and clinical impact on patient outcomes such as patient knowledge and vision-related quality of life.

The Fate of RPE Cells Following hESC-RPE Patch Transplantation in Haemorrhagic Wet AMD: Pigmentation, Extension of Pigmentation, Thickness of Transplant, Assessment for Proliferation and Visual Function-A 5 Year-Follow Up.

(1) Background: We reviewed a stem cell-derived therapeutic strategy for advanced neovascular age-related macular degeneration (nAMD) using a human embryonic stem cell-derived retinal pigment epithelium (hESC-RPE) monolayer delivered on a coated, synthetic basement membrane (BM)-the patch-and assessed the presence and distribution of hESC-RPE over 5 years following transplantation, as well as functional outcomes. (2) Methods: Two subjects with acute vision loss due to sub-macular haemorrhage in advanced nAMD received the hESC-RPE patch. Systematic immunosuppression was used peri-operatively followed by local depot immunosuppression. The subjects were monitored for five years with observation of RPE patch pigmentation, extension beyond the patch boundary into surrounding retina, thickness of hESC-RPE and synthetic BM and review for migration and proliferation of hESC-RPE. Visual function was also assessed. (3) Results: The two study participants showed clear RPE characteristics of the patch, preservation of some retinal ultrastructure with signs of remodelling, fibrosis and thinning on optical coherence tomography over the 5-year period. For both participants, there was evidence of pigment extension beyond the patch continuing until 12 months post-operatively, which stabilised and was preserved until 5 years post-operatively. Measurement of hESC-RPE and BM thickness over time for both cases were consistent with predefined histological measurements of these two layers. There was no evidence of distant RPE migration or proliferation in either case beyond the monolayer. Sustained visual acuity improvement was apparent for 2 years in both subjects, with one subject maintaining the improvement for 5 years. Both subjects demonstrated initial improvement in fixation and microperimetry compared to baseline, at year 1, although only one maintained this at 4 years post-intervention. (4) Conclusions: hESC-RPE patches show evidence of continued pigmentation, with extension, to cover bare host basement membrane for up to 5 years post-implantation. There is evidence that this represents functional RPE on the patch and at the patch border where host RPE is absent. The measurements for thickness of hESC-RPE and BM suggest persistence of both layers at 5 years. No safety concerns were raised for the hypothetical risk of RPE migration, proliferation or tumour formation. Visual function also showed sustained improvement for 2 years in one subject and 5 years in the other subject.

Differences in imaging biomarkers between patients with intermediate and advanced non-neovascular age-related macular degeneration (AMD) in the University of Colorado AMD registry.

To quantify and compare the different prevalence rates of specific retinal imaging biomarkers in patients with intermediate AMD (iAMD) and advanced non-neovascular AMD (nnAMD). Cross-sectional study of patients with iAMD and advanced nnAMD. Imaging studies were reviewed for qualitative imaging biomarkers. Choroidal thickness measurements were obtained subfoveally and in 1000 um and 2000 um intervals away from the fovea. The Chi-squared test and Fisher's exact test were used to compare rates of imaging biomarkers among the two cohorts. P-value of <0.05 was considered significant. 376 eyes of 197 patients with iAMD and 187 eyes of 97 patients with advanced nnAMD were recruited. There were significantly lower rates of the following imaging biomarkers in the iAMD compared with the advanced nnAMD cohorts: soft drusen (66.0% vs. 84.2%, p = 0.001), calcified drusen (4.3% vs. 40.0%, p < 0.0001), RPD (26.2% vs. 53.3%, p < 0.0001), ORT (0.5% vs. 46.9%, p < 0.0001), RP (1.1% vs. 46.3%, p < 0.0001), pigment migration (53.2% vs. 100%, p < 0.0001), and iRORA (17.9% vs. 80.2%, p < 0.0001). In the iAMD cohort, choroidal thickness was significantly greater at 188 µm (SD: 60) and 194 µm (SD: 69), compared to the advanced nnAMD with measurements of 153 µm (SD: 68), and 161 µm (SD: 76). This difference was statistically significant (p < 0.0001 and p = 0.0002). Our results highlight significant differences in imaging biomarkers between both cohorts. Key biomarkers, such as iRORA, RPD, pigment migration, and thinner choroidal thickness, were associated with advanced nnAMD. Identifying these biomarkers early may help target patients who could benefit from new treatments, potentially delaying vision loss.

Metrnl inhibits choroidal neovascularization by attenuating the choroidal inflammation via inactivating the UCHL-1/NF-κB signaling pathway.

Choroidal neovascularization (CNV) represents the predominant form of advanced wet Age-related Macular Degeneration (wAMD). Macrophages play a pivotal role in the pathological progression of CNV. Meteorin-like (Metrnl), a novel cytokine known for its anti-inflammatory properties in macrophages, is the focus of our investigation into its mechanism of action and its potential to impede CNV progression. Cell viability was evaluated through CCK-8 and EdU assays following Metrnl treatment. Expression levels of inflammatory cytokines and proteins were assessed using quantitative reverse-transcription polymerase chain reaction(qRT-PCR), enzyme-linked immunosorbent assay (ELISA), and western blot techniques. Protein-protein interactions were identified through protein mass spectrometry and co-immunoprecipitation (Co-IP). Additionally, in vivo and in vitro neovascularization models were employed to evaluate angiogenesis. Our results revealed downregulated Metrnl levels in the choroid-sclera complex of CNV mice, the aqueous humor of wAMD patients, and activated macrophages. Metrnl overexpression demonstrated a reduction in pro-inflammatory cytokine production, influenced endothelial cell function, and suppressed angiogenesis in choroid explants and CNV models. Through protein mass spectrometry and Co-IP, we confirmed Metrnl binds to UCHL-1 to modulate the NF-κB signaling pathway. This interaction inhibited the transcription and expression of pro-inflammatory cytokines, ultimately suppressing angiogenesis. In summary, our findings indicate that Metrnl down-regulates macrophage pro-inflammatory cytokine secretion via the UCHL-1/NF-κB signaling pathway. This mechanism alleviates the inflammatory microenvironment and effectively inhibits choroidal neovascularization.

Drusen in AMD from the Perspective of Cholesterol Metabolism and Hypoxic Response.

Drusen are one of the most characteristic pathologies of precursor lesion of age-related macular degeneration (AMD). Drusen comprise a yellowish white substance that accumulates typically under the retinal pigment epithelium (RPE), and their constituents are lipids, complement, amyloid, crystallin, and others. In the past, many researchers have focused on drusen and tried to elucidate the pathophysiology of AMD because they believed that disease progression from early AMD to advanced AMD might be based on drusen or drusen might cause AMD. In fact, it is well established that drusen are the hallmark of precursor lesion of AMD and a major risk factor for AMD progression mainly based on their size and number. However, the existence of advanced AMD without drusen has long been recognized. For example, polypoidal choroidal vasculopathy (PCV), which comprises the majority of AMD cases in Asians, often lacks drusen. Thus, there is the possibility that drusen might be no more than a biomarker of AMD and not a cause of AMD. Now is the time to reconsider the relationship between AMD and drusen. In this review, we focus on early AMD pathogenesis based on basic research from the perspective of cholesterol metabolism and hypoxic response in the retina, and we discuss the role of drusen.

Defining the structure–function relationship of specific lesions in early and advanced age-related macular degeneration

The objective of this study is to define structure–function relationships of pathological lesions related to age-related macular degeneration (AMD) using microperimetry and multimodal retinal imaging. We conducted a cross-sectional study of 87 patients with AMD (30 eyes with early and intermediate AMD and 110 eyes with advanced AMD), compared to 33 normal controls (66 eyes) recruited from a single tertiary center. All participants had enface and cross-sectional optical coherence tomography (Heidelberg HRA-2), OCT angiography, color and infra-red (IR) fundus and microperimetry (MP) (Nidek MP-3) performed. Multimodal images were graded for specific AMD pathological lesions. A custom marking tool was used to demarcate lesion boundaries on corresponding enface IR images, and subsequently superimposed onto MP color fundus photographs with retinal sensitivity points (RSP). The resulting overlay was used to correlate pathological structural changes to zonal functional changes. Mean age of patients with early/intermediate AMD, advanced AMD and controls were 73(SD = 8.2), 70.8(SD = 8), and 65.4(SD = 7.7) years respectively. Mean retinal sensitivity (MRS) of both early/intermediate (23.1 dB; SD = 5.5) and advanced AMD (18.1 dB; SD = 7.8) eyes were significantly worse than controls (27.8 dB, SD = 4.3) (p < 0.01). Advanced AMD eyes had significantly more unstable fixation (70%; SD = 63.6), larger mean fixation area (3.9 mm2; SD = 3.0), and focal fixation point further away from the fovea (0.7 mm; SD = 0.8), than controls (29%; SD = 43.9; 2.6 mm2; SD = 1.9; 0.4 mm; SD = 0.3) (p ≤ 0.01). Notably, 22 fellow eyes of AMD eyes (25.7 dB; SD = 3.0), with no AMD lesions, still had lower MRS than controls (p = 0.04). For specific AMD-related lesions, end-stage changes such as fibrosis (5.5 dB, SD = 5.4 dB) and atrophy (6.2 dB, SD = 7.0 dB) had the lowest MRS; while drusen and pigment epithelial detachment (17.7 dB, SD = 8.0 dB) had the highest MRS. Peri-lesional areas (20.2 dB, SD = 7.6 dB) and surrounding structurally normal areas (22.2 dB, SD = 6.9 dB) of the retina with no AMD lesions still had lower MRS compared to controls (27.8 dB, SD = 4.3 dB) (p < 0.01). Our detailed topographic structure–function correlation identified specific AMD pathological changes associated with a poorer visual function. This can provide an added value to the assessment of visual function to optimize treatment outcomes to existing and potentially future novel therapies.

A Clinically Explainable AI-Based Grading System for Age-Related Macular Degeneration Using Optical Coherence Tomography.

We propose an automated, explainable artificial intelligence (xAI) system for age-related macular degeneration (AMD) diagnosis. Mimicking the physician's perceptions, the proposed xAI system is capable of deriving clinically meaningful features from optical coherence tomography (OCT) B-scan images to differentiate between a normal retina, different grades of AMD (early, intermediate, geographic atrophy (GA), inactive wet or active neovascular disease [exudative or wet AMD]), and non-AMD diseases. Particularly, we extract retinal OCT-based clinical imaging markers that are correlated with the progression of AMD, which include: (i) subretinal tissue, sub-retinal pigment epithelial tissue, intraretinal fluid, subretinal fluid, and choroidal hypertransmission detection using a DeepLabV3+ network; (ii) detection of merged retina layers using a novel convolutional neural network model; (iii) drusen detection based on 2D curvature analysis; (iv) estimation of retinal layers' thickness, and first-order and higher-order reflectivity features. Those clinical features are used to grade a retinal OCT in a hierarchical decision tree process. The first step looks for severe disruption of retinal layers' indicative of advanced AMD. These cases are analyzed further to diagnose GA, inactive wet AMD, active wet AMD, and non-AMD diseases. Less severe cases are analyzed using a different pipeline to identify OCT with AMD-specific pathology, which is graded as intermediate-stage or early-stage AMD. The remainder is classified as either being a normal retina or having other non-AMD pathology. The proposed system in the multi-way classification task, evaluated on 1285 OCT images, achieved 90.82% accuracy. These promising results demonstrated the capability to automatically distinguish between normal eyes and all AMD grades in addition to non-AMD diseases.

Fluorescence Lifetime Imaging of Human Retinal Pigment Epithelium in Pentosan Polysulfate Toxicity Using Adaptive Optics Scanning Light Ophthalmoscopy.

Fluorescence lifetime ophthalmoscopy (FLIO) is an emerging clinical modality that could provide biomarkers of retinal health beyond fluorescence intensity. Adaptive optics (AO) ophthalmoscopy provides the confocality to measure fluorescence lifetime (FL) primarily from the retinal pigment epithelium (RPE) whereas clinical FLIO has greater influence from fluorophores in the inner retina and lens. Adaptive optics fluorescence lifetime ophthalmoscopy (AOFLIO) measures of FL in vivo could provide insight into RPE health at different stages of disease. In this study, we assess changes in pentosan polysulfate sodium (PPS) toxicity, a recently described toxicity that has clinical findings similar to advanced age-related macular degeneration. AOFLIO was performed on three subjects with PPS toxicity (57-67years old) and six age-matched controls (50-64years old). FL was analyzed with a double exponential decay curve fit and with phasor analysis. Regions of interest (ROIs) were subcategorized based on retinal features on optical coherence tomography (OCT) and compared to age-matched controls. Twelve ROIs from PPS toxicity subjects met the threshold for analysis by curve fitting and 15 ROIs met the threshold for phasor analysis. Subjects with PPS toxicity had prolonged FL compared to age-matched controls. ROIs of RPE degeneration had the longest FLs, with individual pixels extending longer than 900 ps. Our study shows evidence that AOFLIO can provide meaningful information in outer retinal disease beyond what is obtainable from fluorescence intensity alone. More studies are needed to determine the prognostic value of AOFLIO.