Nonexudative Age-related Macular Degeneration Research Articles

Laser speckle flowgraphy reveals widespread reductions in ocular blood flow in non-exudative age-related macular degeneration.

To evaluate whether and where laser speckle flowgraphy (LSFG)-derived indices of ocular blood flow are reduced in non-exudative age-related macular degeneration (AMD) compared with age-matched control subjects. Retrospective case-control study PARTICIPANTS: 39 eyes of 24 subjects with AMD and 41 eyes of 21 healthy controls were included. Subjects with non-exudative AMD in the early, intermediate, or advanced stage underwent blood flow imaging with LSFG and were compared to age-matched control subjects. Mixed-effects models accounted for correlations between eyes in the same patient. Logistic regression evaluated the effect of ocular perfusion pressure and other factors associated with blood flow. Blood flow data was analyzed in two ways: by binary threshold for the primary analysis and through a superpixel-based method to map the territory of very low flow. Choroidal blood flow and inner retinal blood flow in AMD and control eyes. Choroidal blood flow as measured by the LSFG in arbitrary units (AU) was reduced by 33% in AMD patients vs controls (5.3±0.3 AU vs 7.9±0.5 AU respectively, P = .00005). Inner retinal blood flow was also significantly reduced in AMD (12.5±0.6 vs 15.6±0.5 AU, P = .004). Ocular perfusion pressure showed no significant difference between AMD and control groups (50±5.5 vs 53±6.7 mmHg respectively, P = .17), indicating that neither elevated intraocular pressure nor low blood pressure could account for the reduced blood flow. In most cases, the area of lowest blood flow was large and diffuse, exceeding the abnormal area affected by non-exudative AMD. Controlling for other subject and eye characteristics, an eye with 10%, 25%, or 50% below the average normal choroidal blood flow was more likely to have AMD, with an odds ratio of 2.27, 7.76, and 60.1, respectively (P = .026). Laser speckle flowgraphy showed lower choroidal and inner retinal blood flow in non-exudative AMD patients compared to age-matched controls, not explained by low perfusion pressure. Areas of reduced blood flow greatly exceeded the territory of choroidal atrophy, emphasizing its role as a risk factor for the development and potential progression of dry AMD.

Photobiomodulation Therapy for Non-exudative Age-related Macular Degeneration.

Age-related macular degeneration (AMD) is a chronic condition that causes gradual central vision loss, most commonly in patients 50 years or older. This disease is commonly classified as either dry (non-exudative) or wet (exudative). Most patients with AMD have the non-exudative form, characterized by the presence of drusen in the macula. These patients can be further subclassified based on drusen size into early, intermediate, or late stages. The pathogenesis of this disease is quite complex and has been linked to genetic variations, dysfunction of normal retinal homeostasis, chronic inflammation, and mitochondrial dysfunction. Current treatment options for patients with intermediate dry AMD are limited to lifestyle modifications and vitamin supplementation. Photobiomodulation therapy (PBT) has been proposed as an additional therapy for this disease. Early animal and human studies have shown that PBT can alter many of the pathways implicated in the pathogenesis of AMD including improving mitochondrial function, decreasing inflammation, and promoting wound healing. Clinical trials investigating the use of PBT in patients with non-exudative AMD have shown promising results. Many of these trials showed improvement in both clinical (visual acuity and contrast sensitivity) as well as anatomic (drusen volume and area geographic atrophy) variables. Most, however, are limited by sample size, differences in treatment algorithm, and populations tested. Ongoing clinical trials aim to expand on this work with longer follow-up, larger sample sizes, and studying a global population. Further work is needed to determine ideal treatment algorithms and patient populations that may benefit the most from this technology.

Association between Obstructive Sleep Apnea and Age-related Macular Degeneration Development and Progression.

Evaluate the risk of age-related macular degeneration (AMD) development and progression in individuals with diagnosed obstructive sleep apnea (OSA). Retrospective cohort study. 60,652 and 1,173,723 individuals with OSA or not, respectively, were included in the study before propensity score matching (PSM). After PSM and applying inclusion/exclusion criteria, 58,700 individuals in each cohort were subsequently analyzed. Collected data using TriNetX (Cambridge, MA, USA), a deidentified electronic health records research network. Individuals with an ICD-10 code for OSA confirmed with polysomnography and an additional code for CPAP use were compared to individuals without diagnosed OSA (control cohort) for the development of main outcome measures at five years. Secondary analyses were included to assess non-advanced AMD progression in individuals with and without diagnosed OSA at five years. The main outcome measures were the incidence of AMD, macular hemorrhage, legal blindness, and requiring anti-vascular endothelial factor (VEGF) intervention at five years. Individuals with non-advanced AMD with and without an OSA diagnosis were separately analyzed for progression to late AMD, and the development of macular hemorrhage, legal blindness, and requiring anti-VEGF therapy at five years. At five years, individuals with diagnosed OSA had a significantly elevated risk of nonexudative AMD (HR, 2.64, 95% CI, 2.37 - 2.96; P<.001), exudative AMD (HR, 2.48, 95% CI, 1.99 - 3.11; P=.002) and requiring anti-VEGF therapy (HR, 2.85, 95% CI, 2.26 - 3.59; P<.001) compared to the control cohort. In the secondary analysis, individuals with non-advanced AMD with diagnosed OSA were associated with an elevated risk of geographic atrophy (GA; HR, 7.00, 95% CI, 4.47 - 11.0; P=.03), exudative AMD (HR, 2.87, 95% CI, 2.37 - 3.48; P=.03), and requiring anti-VEGF injections (HR, 4.72, 95% CI, 3.59 - 6.22; P=.02) compared to those with non-advanced AMD without diagnosed OSA CONCLUSIONS: In a large, heterogenous database, an elevated risk of developing AMD and progression to later stages of the disease was observed among individuals with diagnosed OSA.

Risk of Age-Related Macular Degeneration in Patients with Exfoliation Syndrome: The Utah Project on Exfoliation Syndrome (UPEXS)

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.

Looking beyond the eyes of the patient: The importance of effective communication in the treatment of age-related macular degeneration.

Patients with exudative and nonexudative age-related macular degeneration (AMD) can experience physical, mental, social, administrative or financial burden that are associated with the treatment of this progressive chronic disease. The role of healthcare providers in supporting patients who experience high treatment burden can be important, especially when it comes to effective communication. Despite previous research underlining the need to improve patient-provider communication in AMD care, patient experiences with communication, and how these are related to perceived treatment burden, remain underexplored. A survey was distributed among Dutch patients with AMD, which contained questions on several aspects of communication with the patient's ophthalmologist, such as the Quality Of communication Through the patients' Eyes (QUOTE-COMM, including task-, affect- and therapy-oriented communication) questionnaire. Patients were primarily enlisted through a patient association. A total of 162 patients completed the questionnaire, of which 133 provided fully completed responses. While patients reported positive experiences with affect-oriented communication of their ophthalmologist, they rated task- and therapy-oriented communication as below their expectations. Most patients wished to receive (additional) information on AMD-related costs (71%), future perspectives (71%) and coping with negative emotions pertaining to the disease (68%). Both lower experience scores on task- and affect-oriented communication and lower self-efficacy were associated with higher administrative burden and mental burden among patients. Our study shows that current communication, information provision and decision-making do not fully meet patients' needs and preferences. Enhancing patient-provider communication seems important, as effective dialogue is likely to diminish patients' perceived treatment burden.

INCIDENCE AND PROGRESSION OF AGE-RELATED MACULAR DEGENERATION AMONG PATIENTS WITH AND WITHOUT OBSTRUCTIVE SLEEP APNEA: A National Cohort Study.

Obstructive sleep apnea (OSA) may increase the risk of age-related macular degeneration (AMD) due to repetitive oxygen deprivation or other mechanisms, though whether OSA increases the risk of AMD progression is unknown. The authors analyzed associations between OSA and AMD risk in the Taiwanese population. The authors identified patients diagnosed with OSA between 2000 and 2018 in the Taiwan National Health Insurance Research Database and used 1:1 propensity score matching on demographics and comorbidities to create a non-OSA cohort. The authors used Cox proportional hazard modeling to investigate the risk of AMD and the risk of progression from nonexudative to exudative AMD in OSA versus non-OSA patients. A total of 66,869 OSA patients were matched with 66,869 non-OSA patients. The hazard ratio of AMD in the OSA cohort was 1.36 (95% confidence interval, 1.29-1.43, P < 0.0001). The hazard ratio for progression from nonexudative to exudative AMD for the OSA cohort was 0.94 (95% confidence interval, 0.77-1.14, P = 0.5073). Obstructive sleep apnea is associated with a higher risk of developing AMD. However, no increased risk of AMD progression is observed among people with OSA and existing nonexudative AMD.

Comparison Between Optical Coherence Tomography B-scan and En Face Imaging for the Diagnosis of Early Macular Atrophy in Age-Related Macular Degeneration

The gradings of complete retinal pigment epithelium (RPE) and outer retinal atrophy (cRORA) and incomplete RPE and outer retinal atrophy (iRORA) on spectral domain optical coherence tomography (SD-OCT) B-scans were compared with the grading of persistent choroidal hypertransmission defects (hyperTDs) on swept-source optical coherence tomography angiography (SS-OCTA) en face images. Comparative diagnostic analysis of prospective study data. Patients with late nonexudative age-related macular degeneration underwent same-day 6×6-mm macular scans using both SD-OCT (Spectralis Heidelberg, 512×97, automatic real-time tracking: 9) and SS-OCTA (PLEX Elite 9000, Carl Zeiss Meditec, 500×500 angio pattern) instruments. SS-OCTA and SD-OCT en face images were generated from a sub-RPE slab positioned 64 to 400 µm below Bruch's membrane. SD-OCT B-scan gradings, which included an inspection of neighboring B-scans for the diagnosis of cRORA and iRORA, were performed at the Moran Eye Center, and gradings of en face images to identify persistent choroidal hyperTDs were performed at the Bascom Palmer Eye Institute and Tel Aviv Medical Center. There was a high degree of agreement (99.6%) between the gradings of cRORA lesions and persistent hyperTDs. However, 27.4% of iRORA lesions were found to be contained within persistent hyperTDs. This discrepancy was due to the finding that 27.5% of iRORA lesions were diagnosed as having a greatest linear horizontal dimension of <250 µm on B-scans, but on en face images, these B-scan-defined iRORA lesions were found to have the greatest linear dimensions in the nonhorizontal dimension that were ≥250 µm. This report demonstrates the benefits of using en face OCT imaging to identify cRORA lesions and highlights the need to acquire dense raster B-scans with the grading neighboring B-scans when identifying iRORA lesions to assess the full extent of the iRORA lesions in the nonhorizontal dimension. Although neighboring B-scans were inspected, 27.5% of iRORA lesions were actually part of larger cRORA lesions when graded using an en face strategy.

APPLICATIONS OF MULTIMODAL GENERATIVE ARTIFICIAL INTELLIGENCE IN A REAL-WORLD RETINA CLINIC SETTING.

This study evaluates a large language model, Generative Pre-trained Transformer 4 with vision, for diagnosing vitreoretinal diseases in real-world ophthalmology settings. A retrospective cross-sectional study at Bascom Palmer Eye Clinic, analyzing patient data from January 2010 to March 2023, assesses Generative Pre-trained Transformer 4 with vision's performance on retinal image analysis and International Classification of Diseases 10th revision coding across 2 patient groups: simpler cases (Group A) and complex cases (Group B) requiring more in-depth analysis. Diagnostic accuracy was assessed through open-ended questions and multiple-choice questions independently verified by three retina specialists. In 256 eyes from 143 patients, Generative Pre-trained Transformer 4-V demonstrated a 13.7% accuracy for open-ended questions and 31.3% for multiple-choice questions, with International Classification of Diseases 10th revision code accuracies at 5.5% and 31.3%, respectively. Accurately diagnosed posterior vitreous detachment, nonexudative age-related macular degeneration, and retinal detachment. International Classification of Diseases 10th revision coding was most accurate for nonexudative age-related macular degeneration, central retinal vein occlusion, and macular hole in OEQs, and for posterior vitreous detachment, nonexudative age-related macular degeneration, and retinal detachment in multiple-choice questions. No significant difference in diagnostic or coding accuracy was found in Groups A and B. Generative Pre-trained Transformer 4 with vision has potential in clinical care and record keeping, particularly with standardized questions. Its effectiveness in open-ended scenarios is limited, indicating a significant limitation in providing complex medical advice.

Identifiable Historic and Observable Factors May Predict Progression to Exfoliation Glaucoma in Newly Diagnosed Exfoliation Patients

To identify clinical factors associated with conversion to exfoliation glaucoma (XFG) in exfoliation syndrome (XFS) patients most at risk of progression to XFG within 3 years for increased surveillance and early preventive interventions. A retrospective patient cohort study design was employed. A source population of XFS patients 50 years and older was identified from electronic medical records in the Utah Population Database. From this, 487 study patients with one or more dilated eye exams prior to chart-confirmed XFS onset in 2011 or later, and three or more years of subsequent eye exams, were selected for study. We implemented a binomial linear mixed models with L1-penalized estimation to select variables associated with conversion. Models included a random intercept to account for within-patient correlation for eye-level data. Candidate demographic, lifestyle, systemic and ocular comorbidities data were obtained and diagnoses categorized as binary (history or no history). These potential factors between conversion and non-conversion patients were used in model selection of variables jointly predictive of conversion. Odds ratios and confidence intervals were calculated using the link logit. To determine the main outcome of conversion to XFG following an index diagnosis of XFS compared with nonconversion within 3 years, clinical records of each subject's left and right eyes were assessed to confirm XFS and date of onset and date of XFG onset, if conversion occurred. Clinical measurements, e.g. intraocular pressure (IOP), cup to disc ratio, provider notes and IOP-lowering procedures and medications were used to corroborate conversion status. Eighteen variables jointly predicted XFG conversion within 3 years correctly in 71% of patient eyes. Odds of conversion was highest for exudative age-related macular degeneration (AMD), 2.3-fold (P=0.004). Other predictive variables included nonexudative AMD (P=0.05), primary open angle glaucoma (P<0.001), obstructive sleep apnea (P=0.03), and ocular hypertension (P=0.003) diagnosed prior to XFS onset. We determined a set of clinically relevant factors that predicted which newly-diagnosed XFS patients progressed to XFG within 3 years. A planned validation will independently confirm if these prognostic indicators hold promise in other settings.

OCTA: Essential or Gimmick?

This commentary article delves into the transformative role of optical coherence tomography angiography (OCTA) in diagnosing and managing a wide array of eye conditions, including diabetic retinopathy, age-related macular degeneration, retinal vein occlusions, and white dot syndromes. Developed in 2005, OCTA has emerged as a non-invasive, high-resolution imaging technique that offers advantages over traditional fluorescein angiography (FA), providing quicker and safer monitoring of ocular conditions with similar diagnostic accuracy. In diabetic retinopathy, OCTA has been instrumental in early identification of retinal changes, offering quantifiable metrics including perfused capillary density (PCD) for assessing vascular alterations. For age-related macular degeneration (AMD), OCTA has deepened our understanding of non-exudative neovascular AMD, allowing for more effective monitoring and potential earlier initiation of treatment. In cases of retinal vein occlusions, OCTA can reveal specific microvascular features and allow for depth-resolved measurements of the foveal avascular zone, providing significant prognostic implications. OCTA has also been invaluable in studying rare white dot syndromes, enabling nuanced differentiation between conditions that often present similarly. Emerging research also suggests that OCTA can have potential utility in neurodegenerative diseases like Alzheimer's, where retinal vascular patterns could offer diagnostic insights. While OCTA is revolutionizing ophthalmic care, further clinical trials and standardization are needed for its broader adoption into clinical practice.

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.

Comparison between Spectral-Domain and Swept-Source OCT Angiography for the Measurement of Persistent Hypertransmission Defects in Age-Related Macular Degeneration

Spectral-domain OCT angiography (SD-OCTA) scans were tested in an algorithm developed for use with swept-source OCT angiography (SS-OCTA) scans to determine if SD-OCTA scans yielded similar results for the detection and measurement of persistent choroidal hypertransmission defects (hyperTDs). Retrospective study. Forty pairs of scans from 32 patients with late-stage nonexudative age-related macular degeneration (AMD). Patients underwent both SD-OCTA and SS-OCTA imaging at the same visit using the 6× 6 mm OCTA scan patterns. Using a semiautomatic algorithm that helped with outlining the hyperTDs, 2 graders independently validated persistent hyperTDs, which are defined as having a greatest linear dimension ≥250 μm on the en face images generated using a slab extending from 64 to 400 μm beneath Bruch's membrane. The number of lesions and square root (sqrt) total area of the hyperTDs were obtained from the algorithm using each imaging method. The mean sqrt area measurements and the number of hyperTDs were compared. The number of lesions and sqrt total area of the hyperTDs were highly concordant between the 2 instruments (rc= 0.969 and rc= 0.999, respectively). The mean number of hyperTDs was 4.3 ± 3.1 for SD-OCTA scans and 4.5 ± 3.3 for SS-OCTA scans (P= 0.06). The mean sqrt total area measurements were 1.16 ± 0.64 mm for the SD-OCTA scans and 1.17 ± 0.65 mm for the SS-OCTA scans (P < 0.001). Because of the small standard error of the differences, the mean difference between the scans was statistically significant but not clinically significant. Spectral-domain OCTA scans provide similar results to SS-OCTA scans when used to obtain the number and area measurements of persistent hyperTDs through a semiautomated algorithm previously developed for SS-OCTA. This facilitates the detection of atrophy with a more widely available scan pattern and the longitudinal study of early to late-stage AMD. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Pre-Clinical Studies of a Novel Bispecific Fusion Protein Targeting C3b and VEGF in Neovascular and Nonexudative AMD Models.

KNP-301 is a bi-specific fragment crystallizable region (Fc) fusion protein, which inhibits both C3b and vascular endothelial growth factor (VEGF) simultaneously for patients with late-stage age-related macular degeneration (AMD). The present study evaluated in vitro potency, in vivo efficacy, intravitreal pharmacokinetics (IVT PK), and injectability of KNP-301. C3b and VEGF binding of KNP-301 were assessed by surface plasmon resonance (SPR) and enzyme-linked immunosorbent assay (ELISA), and cellular bioassays. A laser-induced choroidal neovascularization (CNV) model and a sodium iodate-induced nonexudative AMD model were used to test the in vivo efficacy of mouse surrogate of KNP-301. Utilizing fluorescein angiography (FA) and spectral-domain optical coherence tomography (SD-OCT) scans, the reduction in disease lesions were analyzed in a CNV mouse model. In the nonexudative AMD mouse model, outer nuclear layer (ONL) was assessed by immunofluorescence staining. Lastly, intravitreal pharmacokinetic study was conducted with New Zealand white rabbits via IVT administration of KNP-301 and injectability of KNP-301 was examined by a viscosity test at high concentrations. KNP-301 bound C3b selectively, which resulted in a blockade of the alternative pathway, not the classical pathway. KNP-301 also acted as a VEGF trap, impeding VEGF-mediate signaling. Our dual-blockade strategy was effective in both neovascular and nonexudative AMD models. Moreover, KNP-301 had an advantage of potentially less frequent dosing due to the long half-life in the intravitreal chamber. Our viscosity assessment confirmed that KNP-301 meets the criteria of the IVT injection. Unlike current therapies, KNP-301 is expected to cover patients with late-stage AMD of both neovascular and nonexudative AMD, and its long-term PK profile at the intravitreal chamber would allow convenience in the dosing interval of patients.

The Discrepancy Between Visual Acuity Decline and Foveal Involvement in Geographic Atrophy

To investigate the discrepancy between visual acuity (VA) decline and foveal involvement in geographic atrophy (GA) secondary to non-exudative age-related macular degeneration (AMD), and to explore how early retinal changes impact the progression of visual impairment. Retrospective, longitudinal cohort study. This study evaluated 80 eyes from 60 patients (mean age 74.2±10 years) with progressing non-neovascular AMD using blue-light fundus autofluorescence (FAF) and spectral-domain optical coherence tomography (SD-OCT). The study monitored the onset of foveal involvement and analyzed VA changes over an average follow-up of 60±26.4 months, encompassing 785 observations. Mixed-effects models with natural splines assessed the effects of demographic and ocular characteristics on baseline VA and its rate of decline. Survival analyses compared the timing of anatomical changes with the most rapid functional declines, indicated by the highest first derivative of VA trajectories. Discrepancies between visual and anatomical changes were explored using generalized linear mixed-effects models. VA declined consistently by an average of 0.010 LogMAR per month (SE: 0.0003, p<0.001). The onset of foveal involvement significantly exacerbated this decline, adding an average loss of 0.15 LogMAR (SE: 0.02, p<0.001). Stabilization of VA typically occurred around 41 months post-foveal involvement. Significant factors associated with worse baseline VA were older age, female gender, unifocal GA morphology, and drusen-associated forms of GA (p<0.05). The most rapid declines in VA typically occurred about 9 months (IQR 0-27 months) prior to detectable subfoveal changes. The reticular FAF pattern (27/46 [59%] vs. 2/13 [15%], p=0.02) and smaller baseline GA lesions (p=0.01) were associated with faster deterioration preceding visible foveal damage. This study demonstrates that significant VA loss in GA can precede detectable foveal involvement, suggesting a window for early interventions to slow the progression of visual impairment. Identifying specific GA characteristics and FAF patterns as predictors of rapid VA decline supports the need for personalized treatment strategies to optimize outcomes for patients with non-exudative AMD.

Intergrader Agreement in Grading Optical Coherence Tomography Morphologic Features in Eyes With Intermediate Nonexudative Age-Related Macular Degeneration.

To determine the reliability of a nine-point summary scale for grading intermediate age-related macular degeneration (AMD) image morphologic features based on the Early Treatment Diabetic Retinopathy Study (ETDRS) grid. Two trained graders independently divided spectral domain-optical coherence tomography (SD-OCT) scans into nine subfields and then graded each subfield for the presence of intraretinal hyperreflective foci (HRF), reticular pseudodrusen (RPD), and incomplete or complete retinal pigment epithelium and outer retinal atrophy (iRORA or cRORA). Grading results were assessed by summing the subfield grades into a nine-point summary score and also by using an eye-level binary grade for presence of the finding in any subfield. Gwet's first-order agreement coefficient (AC1) was calculated to assess intergrader agreement. Images of 79 eyes from 52 patients were evaluated. Intergrader agreement was higher when the OCT grades were summarized with a nine-point summary score (Gwet's AC1 0.92, 0.89, 0.99, and 0.99 for HRF, RPD, iRORA, and cRORA, respectively) compared with the eye-level binary grade (Gwet's AC1 0.75, 0.76, 0.97, and 0.96 for HRF, RPD, iRORA, and cRORA, respectively), with significant differences detected for HRF and RPD. The use of a nine-point summary score showed higher reliability in grading when compared to the binary subfield- and eye-level data, and thus may offer more precise estimation of AMD disease staging. These findings suggest that a nine-point summary score could be a useful means of disease staging by using findings on OCT in clinical studies of AMD.

Estimating Uncertainty of Geographic Atrophy Segmentations with Bayesian Deep Learning

To apply methods for quantifying uncertainty of deep learning segmentation of geographic atrophy (GA). Retrospective analysis of OCT images and model comparison. One hundred twenty-six eyes from 87 participants with GA in the SWAGGER cohort of the Nonexudative Age-Related Macular Degeneration Imaged with Swept-Source OCT (SS-OCT) study. The manual segmentations of GA lesions were conducted on structural subretinal pigment epithelium en face images from the SS-OCT images. Models were developed for 2 approximate Bayesian deep learning techniques, Monte Carlo dropout and ensemble, to assess the uncertainty of GA semantic segmentation and compared to a traditional deep learning model. Model performance (Dice score) was compared. Uncertainty was calculated using the formula for Shannon Entropy. The output of both Bayesian technique models showed a greater number of pixels with high entropy than the standard model. Dice scores for the Monte Carlo dropout method (0.90, 95% confidence interval 0.87-0.93) and the ensemble method (0.88, 95% confidence interval 0.85-0.91) were significantly higher (P<0.001) than for the traditional model (0.82, 95% confidence interval 0.78-0.86). Quantifying the uncertainty in a prediction of GA may improve trustworthiness of the models and aid clinicians in decision-making. The Bayesian deep learning techniques generated pixel-wise estimates of model uncertainty for segmentation, while also improving model performance compared with traditionally trained deep learning models. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Retro Mode Imaging for Detection and Quantification of Sub-RPE Drusen and Subretinal Drusenoid Deposits in Age-Related Macular Degeneration.

Background: Drusen and drusenoid deposits are a hallmark of age-related macular degeneration (AMD). Nowadays, a multimodal retinal imaging approach enables the detection of these deposits. However, quantitative data on subretinal drusenoid deposits (SDDs) are still missing. Here, we compare the capability of en-face drusen and SDD area detection in eyes with non-exudative AMD using conventional imaging modalities versus Retro mode imaging. We also quantitatively assess the topographic distribution of drusen and SDDs. Methods: In total, 120 eyes of 90 subjects (mean age ± standard deviation = 74.6 ± 8.6 years) were included. Coherent en-face drusen and SDD areas were measured via near-infrared reflectance, green (G-) and blue (B-) fundus autofluorescence (AF), and Retro mode imaging. Drusen phenotypes were classified by correlating en-face drusen areas using structural high-resolution spectral domain optical coherence tomography. The topographic distribution of drusen was analyzed according to a modified ETDRS (Early Treatment of Diabetic Retinopathy Study) grid. Intraclass correlation coefficient (ICC) analysis was applied to determine the inter-reader agreement in the SDD en-face area assessment. Results: The largest coherent en-face drusen area was found using Retro mode imaging with a mean area of 105.2 ± 45.9 mm2 (deviated left mode (DL)) and 105.4 ± 45.5 mm2 (deviated right mode (DR)). The smallest en-face drusen areas were determined by GAF (50.9 ± 42.6 mm2) and BAF imaging (49.1 ± 42.9 mm2) (p < 0.001). The inter-reader agreement for SDD en-face areas ranged from 0.93 (DR) to 0.70 (BAF). The topographic analysis revealed the highest number of SDDs in the superior peripheral retina, whereas sub-retinal pigment epithelium drusen were mostly found in the perifoveal retina. Retro mode imaging further enabled the detection of the earliest SDD stages. Conclusions: Retro mode imaging allows for a detailed detection of drusen phenotypes. While hundreds/thousands of SDDs can be present in one eye, the impact of SDD number or volume on AMD progression still needs to be evaluated. However, this new imaging modality can add important knowledge on drusen development and the pathophysiology of AMD.

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.

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.

An ethologically relevant paradigm to assess defensive response to looming visual contrast stimuli

In the animal kingdom, threat information is perceived mainly through vision. The subcortical visual pathway plays a critical role in the rapid processing of visual information-induced fear, and triggers a response. Looming-evoked behavior in rodents, mimicking response to aerial predators, allowed identify the neural circuitry underlying instinctive defensive behaviors; however, the influence of disk/background contrast on the looming-induced behavioral response has not been examined, either in rats or mice. We studied the influence of the dark disk/gray background contrast in the type of rat and mouse defensive behavior in the looming arena, and we showed that rat and mouse response as a function of disk/background contrast adjusted to a sigmoid-like relationship. Both sex and age biased the contrast-dependent response, which was dampened in rats submitted to retinal unilateral or bilateral ischemia. Moreover, using genetically manipulated mice, we showed that the three type of photoresponsive retinal cells (i.e., cones, rods, and intrinsically photoresponsive retinal ganglion cells (ipRGCs)), participate in the contrast-dependent response, following this hierarchy: cones > > rods > > > ipRGCs. The cone and rod involvement was confirmed using a mouse model of unilateral non-exudative age-related macular degeneration, which only damages canonical photoreceptors and significantly decreased the contrast sensitivity in the looming arena.