Autophagy in dry AMD: A promising therapeutic strategy for retinal pigment epithelial cell damage.

Dry age-related macular degeneration (AMD) is a prevalent clinical condition that leads to permanent damage to central vision and poses a significant threat to patients' visual health. Although the pathogenesis of dry AMD remains unclear, there is consensus on the role of retinal pigment epithelium (RPE) damage. Oxidative stress and chronic inflammation are major contributors to RPE cell damage, and the NOD-like receptor thermoprotein structural domain-associated protein 3 (NLRP3) inflammasome mediates the inflammatory response leading to apoptosis in RPE cells. Furthermore, lipofuscin accumulation results in oxidative stress, NLRP3 activation, and the development of vitelliform lesions, a hallmark of dry AMD, all of which may contribute to RPE dysfunction. The process of autophagy, involving the encapsulation, recognition, and transport of accumulated proteins and dead cells to the lysosome for degradation, is recognized as a significant pathway for cellular self-protection and homeostasis maintenance. Recently, RPE cell autophagy has been discovered to be closely linked to the development of macular degeneration, positioning autophagy as a cutting-edge research area in the realm of dry AMD. In this review, we present an overview of how lipofuscin, oxidative stress, and the NLRP3 inflammasome damage the RPE through their respective causal mechanisms. We summarized the connection between autophagy, oxidative stress, and NLRP3 inflammatory cytokines. Our findings suggest that targeting autophagy improves RPE function and sustains visual health, offering new perspectives for understanding the pathogenesis and clinical management of dry AMD.

Deep-learning automated quantification of longitudinal OCT scans demonstrates reduced RPE loss rate, preservation of intact macular area and predictive value of isolated photoreceptor degeneration in geographic atrophy patients receiving C3 inhibition treatment.

OBJECTIVE: To evaluate the role of automated optical coherence tomography (OCT) segmentation, using a validated deep-learning model, for assessing the effect of C3 inhibition on the area of geographic atrophy (GA); the constituent features of GA on OCT (photoreceptor degeneration (PRD), retinal pigment epithelium (RPE) loss and hypertransmission); and the area of unaffected healthy macula.To identify OCT predictive biomarkers for GA growth. METHODS: Post hoc analysis of the FILLY trial using a deep-learning model for spectral domain OCT (SD-OCT) autosegmentation. 246 patients were randomised 1:1:1 into pegcetacoplan monthly (PM), pegcetacoplan every other month (PEOM) and sham treatment (pooled) for 12 months of treatment and 6 months of therapy-free monitoring. Only participants with Heidelberg SD-OCT were included (n=197, single eye per participant).The primary efficacy endpoint was the square root transformed change in area of GA as complete RPE and outer retinal atrophy (cRORA) in each treatment arm at 12 months, with secondary endpoints including RPE loss, hypertransmission, PRD and intact macular area. RESULTS: Eyes treated PM showed significantly slower mean change of cRORA progression at 12 and 18 months (0.151 and 0.277 mm, p=0.0039; 0.251 and 0.396 mm, p=0.039, respectively) and RPE loss (0.147 and 0.287 mm, p=0.0008; 0.242 and 0.410 mm, p=0.00809). PEOM showed significantly slower mean change of RPE loss compared with sham at 12 months (p=0.0313). Intact macular areas were preserved in PM compared with sham at 12 and 18 months (p=0.0095 and p=0.044). PRD in isolation and intact macula areas was predictive of reduced cRORA growth at 12 months (coefficient 0.0195, p=0.01 and 0.00752, p=0.02, respectively) CONCLUSION: The OCT evidence suggests that pegcetacoplan slows progression of cRORA overall and RPE loss specifically while protecting the remaining photoreceptors and slowing the progression of healthy retina to iRORA.

Choroidal Hyper-Reflective Foci in Geographic Atrophy.

Purpose: The purpose of this study was to describe the presence of choroidal hyper-reflective foci (HRF) on optical coherence tomography (OCT) in patients with geographic atrophy (GA). The relationship between the presence and quantity of choroidal HRF and other clinical and imaging factors was also investigated. Methods: A total of 40 participants (40 eyes) with GA and age-related macular degeneration (AMD) were retrospectively analyzed. OCT images were reviewed for the presence, characteristics, and localization of choroidal HRF. The amount of choroidal HRF was quantified in different choroidal layers by two different (i.e. threshold reflectivity and manual counting) methodologies. The primary outcome was to describe and quantify choroidal HRF and correlate them with GA lesion size. Results: Structural OCT images showed that all patients had multiple hyper-reflective deposits in different layers of the choroid. These hyper-reflective deposits in the choroid were located near Bruch's membrane or the edges of the blood vessels, particularly in the Sattler's layer, and none were observed inside the vessels. Choroidal HRF exhibited variable size and shape and varying effects on the posterior signal, including shadowing or hypertransmission. Mean ± SD number of choroidal HRF per B-scan was 21.5 ± 15.4 using the threshold reflectivity methodology and 25.1 ± 16.0 using the manual counting methodology. A significant correlation between the untransformed GA size and number of HRF was found, considering both quantitative strategies. Conclusions: Hyper-reflective dots in the choroid of subjects with GA may be readily identified with structural OCT. These HRF might represent a natural component of the choroid that becomes more visible due to the absence of the retinal pigment epithelium.

Therapeutic targeting of the complement system in ocular disease.

The complement system is involved in the pathogenesis of several ocular diseases, providing a rationale for the investigation of complement-targeting therapeutics for these conditions. Dry age-related macular degeneration, as characterised by geographic atrophy (GA), is currently the most active area of research for complement-targeting therapeutics, with a complement C3 inhibitor approved in the United States earlier this year marking the first approved therapy for GA. This review discusses the role of complement in ocular disease, provides an overview of the complement-targeting agents currently under development for ocular conditions, and reflects on the lessons that can be learned from the preclinical investigations and clinical trials conducted in this field to date.

Novel Fractal-Based Sub-RPE Compartment OCT Radiomics Biomarkers Are Associated With Subfoveal Geographic Atrophy in Dry AMD.

OBJECTIVE: The purpose of this study was to quantitatively characterize the shape of the sub-retinal pigment epithelium (sub-RPE, i.e., space bounded by RPE and Bruch's membrane) compartment on SD-OCT using fractal dimension (FD) features and evaluate their impact on risk of subfoveal geographic atrophy (sfGA) progression. METHODS: This was an IRB-approved retrospective study of 137 subjects with dry age-related macular degeneration (AMD) with subfoveal GA. Based on sfGA status at year five, eyes were categorized as "Progressors" and "Non-progressors". FD analysis allows quantification of the degree of shape complexity and architectural disorder associated with a structure. To characterize the structural irregularities along the sub-RPE surface between the two groups of patients, a total of 15 shape descriptors of FD were extracted from the sub-RPE compartment of baseline OCT scans. The top four features were identified using minimum Redundancy maximum Relevance (mRmR) feature selection method and evaluated with Random Forest (RF) classifier using three-fold cross validation from the training set (N = 90). Classifier performance was subsequently validated on the independent test set (N = 47). RESULTS: Using the top four FD features, a RF classifier yielded an AUC of 0.85 on the independent test set. Mean fractal entropy (p-value = 4.8e-05) was identified as the most significant biomarker; higher values of entropy being associated with greater shape disorder and risk for sfGA progression. CONCLUSIONS: FD assessment holds promise for identifying high-risk eyes for GA progression. SIGNIFICANCE: With further validation, FD features could be potentially used for clinical trial enrichment and assessments for therapeutic response in dry AMD patients.

Bilateral plaque like macular atrophy and pigmentary retinopathy in an infant with a missense mutation in the MFF gene.

PURPOSE: Ocular involvement has been shown in many of the primary mitochondrial diseases. Herein, we report a pediatric case of an extraordinary fundus appearance of bilateral plaque-like macular atrophy and hypopigmented flecks with homozygous MFF gene mutation. METHODS: A case report. RESULTS: An eighteen-month-old male infant presented with a lack of object tracking which was recognized in the last few months. Along with regression in normal development, myoclonic epilepsy signs and encephalomyelopathy were detected. Therefore, the patient was evaluated for mitochondrial diseases. Fundus examination revealed bilateral fine hypopigmented lesions in retinal pigment epithelium at midperiphery and periphery. Additionally, there was bilateral geographic atrophy that was separated from the adjacent normal retina with distinct borders in the fovea. Homozygous pT198A (c.592A>G) missense variation was detected in the MFF gene. CONCLUSION: Maculopathy could be encountered in patients with MFF gene variation. Specific variants or some undiscovered genomic mutations may be the reason for this novel clinical appearance.

A laser-induced mouse model of progressive retinal degeneration with central sparing displays features of parafoveal geographic atrophy.

There are no disease-modifying treatments available for geographic atrophy (GA), the advanced form of dry age-related macular degeneration. Current murine models fail to fully recapitulate the features of GA and thus hinder drug discovery. Here we describe a novel mouse model of retinal degeneration with hallmark features of GA. We used an 810 nm laser to create a retinal lesion with central sparing (RLCS), simulating parafoveal atrophy observed in patients with progressive GA. Laser-induced RLCS resulted in progressive GA-like pathology with the development of a confluent atrophic lesion. We demonstrate significant changes to the retinal structure and thickness in the central unaffected retina over a 24-week post-laser period, confirmed by longitudinal optical coherence tomography scans. We further show characteristic features of progressive GA, including a gradual reduction in the thickness of the central, unaffected retina and of total retinal thickness. Histological changes observed in the RLCS correspond to GA pathology, which includes the collapse of the outer nuclear layer, increased numbers of GFAP + , CD11b + and FcγRI + cells, and damage to cone and rod photoreceptors. We demonstrate a laser-induced mouse model of parafoveal GA progression, starting at 2 weeks post-laser and reaching confluence at 24 weeks post-laser. This 24-week time-frame in which GA pathology develops, provides an extended window of opportunity for proof-of-concept evaluation of drugs targeting GA. This time period is an added advantage compared to several existing models of geographic atrophy.

Geographic Atrophy Phenotypes in Subjects of Different Ethnicity: Asia-Pacific Ocular Imaging Society Work Group Report 3.

OBJECTIVE: To characterize geographic atrophy (GA) and evaluate differences between Asians and non-Asians. DESIGN: Multicenter, retrospective case series. PARTICIPANTS: Subjects aged ≥ 50 years with GA secondary to age-related macular degeneration in the absence of neovascularization in the study eye and follow-up of ≥ 2 years. METHODS: The GA lesion characterized at baseline and last follow-up based on multimodal imaging (fundus autofluorescence [FAF], near infrared [NIR], and spectral domain-OCT). Patients were grouped as either Asian or non-Asian. MAIN OUTCOME MEASURES: Comparison of (1) phenotypes of GA lesions (size, foveal involvement, number of foci, drusen background, and choroid background) and (2) growth rates of GA. RESULTS: A total of 144 patients (169 eyes) with distribution of 50.9% Asians and 49.1% non-Asians. The age and sex were similar between Asians and non-Asians (Asians: mean age, 77.2 ± 10.1 years, 47.9% female; non-Asians: mean age, 79.7 ± 8.4 years, 58.7% female). Asians exhibited thicker choroids (167 ± 74 versus [vs.] 134 ± 56 µm; P < 0.01) and lower prevalence of drusen (40.7% vs. 66.3%; P < 0.01). At baseline, the GA area was smaller in Asians vs. non-Asians (NIR, 3.7 ± 4.6 vs. 6.3 ± 6.8 mm2; P = 0.01: FAF, 2.4 ± 3.4 vs. 8.4 ± 9.6 mm2; P < 0.01). Asians had fewer GA foci (1.7 ± 1.3 vs. 2.7 ± 2.2; P < 0.01) compared to non-Asians. The proportion with diffused or banded FAF junctional zone pattern was similar between Asians and non-Asians (44.2% vs. 60.2%; P = 0.20). Asians had a slower GA lesion growth rate than non-Asians (NIR, 0.7 vs. 1.9 mm2/year; P < 0.01: FAF, 0.3 vs. 2.0 mm2/year; P < 0.01: NIR, 0.2 vs. 0.4 mm/year; P < 0.01 square root transformed: FAF, 0.1 vs. 0.3 mm/year; P < 0.01 square root transformed). The factors associated with GA lesion growth rate are (from the highest effect size) ethnicity, junctional zone FAF pattern, baseline GA area, and number of GA foci. Higher GA lesion growth rate was observed in both Asian and non-Asian subgroups, with drusen or lesion size and FAF patterns meeting inclusion criteria of recent therapeutic trials, but growth rate remained significantly slower in Asians. Eyes with baseline lesion ≥ 5 mm2 showed the highest growth rate, and the difference between ethnicities was no longer significant (2.6 vs. 3.3 mm2/year; P = 0.14). CONCLUSIONS: There are differences in GA lesion phenotype, associated features, and growth rate between Asians and non-Asian subjects. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Reverse engineering for reconstructing baseline features of dry age-related macular degeneration in optical coherence tomography.

Age-related macular degeneration (AMD) is the most widespread cause of blindness and the identification of baseline AMD features or biomarkers is critical for early intervention. Optical coherence tomography (OCT) imaging produces a 3D volume consisting of cross sections of retinal tissue while fundus fluorescence (FAF) imaging produces a 2D mapping of retina. FAF has been a good standard for assessing dry AMD late-stage geographic atrophy (GA) while OCT has been used for assessing early AMD biomarkers beyond as well. However, previous approaches in large extent defined AMD features subjectively based on clinicians' observation. Deep learning-an objective artificial intelligence approach, may enable to discover 'true' salient AMD features. We develop a novel reverse engineering approach which bases on the backbone of a fully convolutional neural network to objectively identify and visualize AMD early biomarkers in OCT from baseline exams before significant atrophy occurs. Utilizing manually annotated GA regions on FAF from a follow-up visit as ground truth, we segment GA regions and reconstruct early AMD features in baseline OCT volumes. In this preliminary exploration, compared with ground truth, we achieve baseline GA segmentation accuracy of 0.95 and overlapping ratio of 0.65. The reconstructions consistently highlight that large druse and druse clusters with or without mixed hyper-reflective focus lesion on baseline OCT cause the conversion of GA after 12 months. However, hyper-reflective focus lesions and subretinal drusenoid deposit lesions alone are not seen such conversion after 12 months. Further research with larger dataset would be needed to verify these findings.

Does the Outer Retinal Thickness Around Geographic Atrophy Represent Another Clinical Biomarker for Predicting Growth?

PURPOSE: To determine whether the outer retinal layer (ORL) thickness around geographic atrophy (GA) could serve as a clinical biomarker to predict the annual enlargement rate (ER) of GA. DESIGN: Retrospective analysis of a prospective, observational case series. METHODS: Eyes with GA were imaged with a swept-source OCT 6 × 6 mm scan pattern. GA lesions were measured from customized en face OCT images and the annual ERs were calculated. The ORL was defined and segmented from the inner boundary of outer plexiform layer (OPL) to the inner boundary of retinal pigment epithelium (RPE) layer. The ORL thickness was measured at different subregions around GA. RESULTS: A total of 38 eyes from 27 participants were included. The same eyes were used for the choriocapillaris (CC) flow deficit (FD) analysis and the RPE to the Bruch membrane (RPE-BM) distance measurements. A negative correlation was observed between the ORL thickness and the GA growth. The ORL thickness in a 300-µm rim around GA showed the strongest correlation with the GA growth (r = -0.457, P = .004). No correlations were found between the ORL thickness and the CC FDs; however, a significant correlation was found between the ORL thickness and the RPE-BM distances around GA (r = -0.398, P = .013). CONCLUSIONS: ORL thickness showed a significant negative correlation with annual GA growth, but also showed a significant correlation with the RPE-BM distances, suggesting that they were dependently correlated with GA growth. This finding suggests that the loss of photoreceptors was associated with the formation of basal laminar deposits around GA.

Histologic Cell Shape Descriptors for the Retinal Pigment Epithelium in Age-Related Macular Degeneration: A Comparison to Unaffected Eyes.

Purpose: Phenotype alterations of the retinal pigment epithelium (RPE) are a main characteristic of age-related macular degeneration (AMD). Individual RPE cell shape descriptors may help to delineate healthy from AMD-affected cells in early disease stages. Methods: Twenty-two human RPE flatmounts (7 eyes with AMD [early, 3; geographic atrophy, 1; neovascular, 3); 15 unaffected eyes [8 aged ≤51 years; 7 aged >80 years)] were imaged at the fovea, perifovea, and near periphery (predefined sample locations) using a laser-scanning confocal fluorescence microscope. RPE cell boundaries were manually marked with computer assistance. For each cell, 11 shape descriptors were calculated and correlated with donor age, cell autofluorescence (AF) intensity, and retinal location. Statistical analysis was performed using an ensemble classifier based on logistic regression. Results: In AMD, RPE was altered at all locations (most pronounced at the fovea), with area, solidity, and form factor being the most discriminatory descriptors. In the unaffected macula, aging had no significant effect on cell shape factors; however, with increasing distance to the fovea, area, solidity, and convexity increased while form factor decreased. Reduced AF in AMD was significantly associated with decreased roundness and solidity. Conclusions: AMD results in an altered RPE with enlarged and deformed cells that could precede clinically visible lesions and thus serve as early biomarkers for AMD onset. Our data may also help guide the interpretation of RPE morphology in in vivo studies utilizing high-resolution single-cell imaging. Translational Relevance: Our histologic RPE cell shape data have the ability to identify robust biomarkers for the early detection of AMD-affected cells, which also could serve as a basis for automated segmentation of RPE sheets.

Cell culture models to study retinal pigment epithelium-related pathogenesis in age-related macular degeneration.

Age-related macular degeneration (AMD) is a disease that affects the macula - the central part of the retina. It is a leading cause of irreversible vision loss in the elderly. AMD onset is marked by the presence of lipid- and protein-rich extracellular deposits beneath the retinal pigment epithelium (RPE), a monolayer of polarized, pigmented epithelial cells located between the photoreceptors and the choroidal blood supply. Progression of AMD to the late nonexudative "dry" stage of AMD, also called geographic atrophy, is linked to progressive loss of areas of the RPE, photoreceptors, and underlying choriocapillaris leading to a severe decline in patients' vision. Differential susceptibility of macular RPE in AMD and the lack of an anatomical macula in most lab animal models has promoted the use of in vitro models of the RPE. In addition, the need for high throughput platforms to test potential therapies has driven the creation and characterization of in vitro model systems that recapitulate morphologic and functional abnormalities associated with human AMD. These models range from spontaneously formed cell line ARPE19, immortalized cell lines such as hTERT-RPE1, RPE-J, and D407, to primary human (fetal or adult) or animal (mouse and pig) RPE cells, and embryonic and induced pluripotent stem cell (iPSC) derived RPE. Hallmark RPE phenotypes, such as cobblestone morphology, pigmentation, and polarization, vary significantly betweendifferent models and culture conditions used in different labs, which would directly impact their usability for investigating different aspects of AMD biology. Here the AMD Disease Models task group of the Ryan Initiative for Macular Research (RIMR) provides a summary of several currently used in vitro RPE models, historical aspects of their development, RPE phenotypes that are attainable in these models, their ability to model different aspects of AMD pathophysiology, and pros/cons for their use in the RPE and AMD fields. In addition, due to the burgeoning use of iPSC derived RPE cells, the critical need for developing standards for differentiating and rigorously characterizing RPE cell appearance, morphology, and function are discussed.

Deuterated docosahexaenoic acid protects against oxidative stress and geographic atrophy-like retinal degeneration in a mouse model with iron overload.

Oxidative stress plays a central role in age-related macular degeneration (AMD). Iron, a potent generator of hydroxyl radicals through the Fenton reaction, has been implicated in AMD. One easily oxidized molecule is docosahexaenoic acid (DHA), the most abundant polyunsaturated fatty acid in photoreceptor membranes. Oxidation of DHA produces toxic oxidation products including carboxyethylpyrrole (CEP) adducts, which are increased in the retinas of AMD patients. In this study, we hypothesized that deuterium substitution on the bis-allylic sites of DHA in photoreceptor membranes could prevent iron-induced retinal degeneration by inhibiting oxidative stress and lipid peroxidation. Mice were fed with either DHA deuterated at the oxidation-prone positions (D-DHA) or control natural DHA and then given an intravitreal injection of iron or control saline. Orally administered D-DHA caused a dose-dependent increase in D-DHA levels in the neural retina and retinal pigment epithelium (RPE) as measured by mass spectrometry. At 1 week after iron injection, D-DHA provided nearly complete protection against iron-induced retinal autofluorescence and retinal degeneration, as determined by in vivo imaging, electroretinography, and histology. Iron injection resulted in carboxyethylpyrrole conjugate immunoreactivity in photoreceptors and RPE in mice fed with natural DHA but not D-DHA. Quantitative PCR results were consistent with iron-induced oxidative stress, inflammation, and retinal cell death in mice fed with natural DHA but not D-DHA. Taken together, our findings suggest that DHA oxidation is central to the pathogenesis of iron-induced retinal degeneration. They also provide preclinical evidence that dosing with D-DHA could be a viable therapeutic strategy for retinal diseases involving oxidative stress.

Fibroblast growth factor-21 alleviates phenotypic characteristics of dry age-related macular degeneration in mice.

Age-related macular degeneration (AMD) is the main cause of blindness in elderly individuals. As a metabolic regulator, fibroblast growth factor 21 (FGF-21) has been proven indicated to have an effect on wet AMD, but whether this cytokine has a therapeutic effect on dry AMD is unclear. The current study aimed to evaluate the preventive effects of FGF-21 against retinal degeneration in mice and provide mechanistic insights. FGF-21-/- mice were raised to 10 months of age. Then, the morphological changes in the retinal pigment epithelium (RPE)/choroid of the mice were observed by transmission electron microscopy (TEM), and iTRAQ was used to detect the variations in the protein profile. Next, FGF-21-/- and wild-type mice of the same age were fed hydroquinone to generate a dry AMD mouse model to examine whether exogenous FGF-21 can interfere with the occurrence and development of dry AMD. In vivo studies revealed that following FGF-21 knockout, there was an increase in the expression of complement in the RPE/choroid concomitant with the occurrence of dry AMD-like pathological changes. Furthermore, exogenous FGF-21 administration effectively reversed this phenomenon. FGF-21 also demonstrated strong anti-inflammatory effects in the RPE/choroid by inhibiting the NF-κB pathway. In conclusion, the present study demonstrates that FGF-21 treatment presents a novel therapeutic approach for the prevention and development of dry AMD by reducing complement.

Progression of cRORA (Complete RPE and Outer Retinal Atrophy) in Dry Age-Related Macular Degeneration Measured Using SD-OCT.

Purpose: The purpose of this study was to evaluate the long-term rate of progression and baseline predictors of geographic atrophy (GA) using complete retinal pigment epithelium and outer retinal atrophy (cRORA) annotation criteria. Methods: This is a retrospective study. Columns of GA were manually annotated by two graders using a self-developed software on optical coherence tomography (OCT) B-scans and projected onto the infrared images. The primary outcomes were: (1) rate of area progression, (2) rate of square root area progression, and (3) rate of radial progression towards the fovea. The effects of 11 additional baseline predictors on the primary outcomes were analyzed: total area, focality (defined as the number of lesions whose area is >0.05 mm2), circularity, total lesion perimeter, minimum diameter, maximum diameter, minimum distance from the center, sex, age, presence/absence of hypertension, and lens status. Results: GA was annotated in 33 pairs of baseline and follow-up OCT scans from 33 eyes of 18 patients with dry age-related macular degeneration (AMD) followed for at least 6 months. The mean rate of area progression was 1.49 ± 0.86 mm2/year (P < 0.0001 vs. baseline), and the mean rate of square root area progression was 0.33 ± 0.15 mm/year (P < 0.0001 vs. baseline). The mean rate of radial progression toward the fovea was 0.07 ± 0.11 mm/year. A multiple variable linear regression model (adjusted r2 = 0.522) revealed that baseline focality and female sex were significantly correlated with the rate of GA area progression. Conclusions: GA area progression was quantified using OCT as an alternative to conventional measurements performed on fundus autofluorescence images. Baseline focality correlated with GA area progression rate and lesion's minimal distance from the center correlated with GA radial progression rate toward the center. These may be important markers for the assessment of GA activity. Translational Relevance: Advanced method linking specific retinal micro-anatomy to GA area progression analysis.

Diagnosing Persistent Hypertransmission Defects on En Face OCT Imaging of Age-Related Macular Degeneration.

PURPOSE: A training exercise was performed to study the ability of graders to reliably identify precursor lesions to geographic atrophy (GA), known as persistent choroidal hypertransmission defects (hyperTDs), using en face OCT images from eyes with nonexudative age-related macular degeneration (AMD). DESIGN: Intergrader agreement study. PARTICIPANTS: Eleven graders participated in this exercise. METHODS: Formal training on how to identify persistent hyperTDs on en face OCT images was provided to the graders. A persistent hyperTD was defined as a bright lesion having a greatest linear dimension (GLD) of at least 250 µm. Training consisted of a tutorial session followed by the grading of 3 pretest exercises, each consisting of 3 cases. After all graders scored 100% on the pretest exercises, they performed a final exercise consisting of 30 en face OCT images from 29 eyes with nonexudative AMD containing 107 hyperTDs that each grader needed to evaluate. The cases contained a variety of AMD-related atrophic lesions. MAIN OUTCOME MEASURES: The sensitivity, positive predictive value (PPV), and modified accuracy were assessed for each grader. RESULTS: A total of 1177 hyperTDs from 30 en face OCT images were reviewed by the graders. The mean sensitivity, PPV, and modified accuracy for all the graders were calculated to be 99.0%, 99.2%, and 98.2%, respectively. There was a 97% agreement observed between all the graders (first-order agreement coefficient [AC1] = 0.97). Internal graders from the Bascom Palmer Eye Institute had a slightly higher agreement compared with the external graders (AC1 = 0.98 vs. AC1 = 0.96). The hyperTDs most often incorrectly identified included the following features: (1) hyperTDs containing hypotransmission defect cores, (2) single hyperTDs that were incorrectly graded as 2 separate lesions, and (3) hyperTDs with borderline GLDs that were close to 250 µm. CONCLUSIONS: The accurate detection of persistent hyperTDs on en face OCT images by graders demonstrates the feasibility of using this OCT biomarker to identify disease progression in eyes with nonexudative AMD, especially when used as a clinical trial end point in studies designed to test new therapies that may slow disease progression from intermediate AMD to GA.

Examination of Inner Retinal Layers in Unilateral Wet Age-Related Macular Degeneration Treated with Anti-VEGF, Compared to Fellow Untreated Eyes.

The main aim of this study was to characterize the retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) thickness in the macular area eyes affected by wet age-related macular degeneration (wAMD) treated with anti-VEGF and compare the results with the control of fellow untreated eyes affected by early stages of dry age-related macular degeneration (dAMD). Additionally, we aimed to estimate if the number of injections received and other factors, including age, best-corrected visual acuity (BCVA), or sex, may affect the differences in the obtained measurements of retinal nerve fiber layer thickness. We prospectively included 106 eyes of 53 patients with unilateral wet age-related macular degeneration. The fellow eyes with non-advanced dry age-related macular degeneration served as a control group in a cross-sectional study. RNFL and GCL in the macular region were evaluated using optical coherence tomography, with outcomes expressed as differences in the thickness of both examined layers between the study and control groups. We found thinner GCL in wAMD vs. dAMD (p < 0.001). In turn, the RNFL layer did not show any statistically significant differences between the two groups (p = 0.409). Similarly, we found a statistically significant correlation between the number of injections and the layer thickness (p = 0.106). Among all assessed parameters, age over 73 was the only factor significantly affecting the thickness of the retinal nerve fiber layer in both groups (p = 0.042). The morphology of the inner layers of the retina in dry and wet AMD seems to differ, possibly due to differences in the etiopathogenesis of these two forms of the disease. In our study, the retinal ganglion cell layer was thinner in the treated vs. fellow eye (with dry AMD), while the nerve fiber layer was not significantly different between the groups. The number of anti-VEGF injections had no effect on the thickness of the macular nerve fiber layer.

Inter-rater reliability for diagnosis of geographic atrophy using spectral domain OCT in age-related macular degeneration.

PURPOSE: To evaluate the inter-rater reliability for identification of complete retinal pigment epithelium and outer retinal atrophy (cRORA) on SD-OCT images as defined by the Classification of Atrophy Meetings (CAM) group. METHODS: Fifty images of anonymized SD-OCT line scans of eyes with cRORA due to AMD were selected. Each .tiff image was saved in both black-on-white (BW) and white-on-black (WB) format. Five retina-trained clinicians graded both sets of images twice for the diagnosis of cRORA based on the CAM group definition. Fleiss kappa statistic was calculated for inter-rater reliability and Cohen's kappa statistic for intra-grader and inter-grader reliability between any two graders. RESULTS: The inter-grader reliability varied from as low as 0.28 to 0.92 for WB images and 0.34 to 0.86 for BW images. However, the inter-grader and intra-grader agreement was ĸ WB 0.92; ĸ BW 0.86 and ĸ 0.92 respectively, for graders accustomed to the CAM criteria. Fleiss kappa was ĸ 0.49 (p value < 0.0001) for WB images and ĸ 0.34 (p value < 0.0001 for BW images. Overall, the agreement was better using WB images for all parameters except RPE attenuation/loss. CONCLUSION: There is significant variability in diagnosis of cRORA on SD-OCT by retina-trained ophthalmologists in the real world. The study highlights the need for training to recognise the different features of cRORA prior to its implementation in clinical practice.

Unravelling the therapeutic potential of IL-33 for atrophic AMD.

Age-related macular degeneration (AMD), a degenerative disease affecting the retinal pigment epithelium (RPE) and photoreceptors in the macula, is the leading cause of central blindness in the elderly. AMD progresses to advanced stages of the disease, atrophic AMD (aAMD), or in 15% of cases "wet" or neovascular AMD (nAMD), associated with substantial vision loss. Whilst there has been advancement in therapies treating nAMD, to date, there are no licenced effective treatments for the 85% affected by aAMD, with disease managed by changes to diet, vitamin supplements, and regular monitoring. AMD has a complex pathogenesis, involving highly integrated and common age-related disease pathways, including dysregulated complement/inflammation, impaired autophagy, and oxidative stress. The intricacy of AMD pathogenesis makes therapeutic development challenging and identifying a target that combats the converging disease pathways is essential to provide a globally effective treatment. Interleukin-33 is a cytokine, classically known for the proinflammatory role it plays in allergic disease. Recent evidence across degenerative and inflammatory disease conditions reveals a diverse immune-modulatory role for IL-33, with promising therapeutic potential. Here, we will review IL-33 function in disease and discuss the future potential for this homeostatic cytokine in treating AMD.

Fundus autofluorescence and optical coherence tomography biomarkers associated with the progression of geographic atrophy secondary to age-related macular degeneration.

OBJECTIVES: To investigate the impact of qualitatively graded and deep learning quantified imaging biomarkers on growth of geographic atrophy (GA) secondary to age-related macular degeneration. METHODS: This prospective study included 1062 visits of 181 eyes of 100 patients with GA. Spectral-domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) images were acquired at each visit. Hyperreflective foci (HRF) were quantitatively assessed in SD-OCT volumes using a validated deep learning algorithm. FAF images were graded for FAF patterns, subretinal drusenoid deposits (SDD), GA lesion configuration and atrophy enlargement. Linear mixed models were calculated to investigate associations between all parameters and GA progression. RESULTS: FAF patterns were significantly associated with GA progression (p < 0.001). SDD was associated with faster GA growth (p = 0.005). Eyes with higher HRF concentrations showed a trend towards faster GA progression (p = 0.072) and revealed a significant impact on GA enlargement in interaction with FAF patterns (p = 0.01). The fellow eye status had no significant effect on lesion enlargement (p > 0.05). The diffuse-trickling FAF pattern exhibited significantly higher HRF concentrations than any other pattern (p < 0.001). CONCLUSION: Among a wide range of investigated biomarkers, SDD and FAF patterns, particularly in interaction with HRF, significantly impact GA progression. Fully automated quantification of retinal imaging biomarkers such as HRF is both reliable and merited as HRF are indicators of retinal pigment epithelium dysmorphia, a central pathogenetic mechanism in GA. Identifying disease markers using the combination of FAF and SD-OCT is of high prognostic value and facilitates individualized patient management in a clinical setting.