Macular Degeneration Research Articles

Imaging-Guided Classification of Neovascularization in Neovascular Age-Related Macular Degeneration: Progress to Date

Purpose: To review the evolution of terminology describing the classification of lesions in neovascular age-related macular degeneration (nAMD) based on retinal imaging technologies. Methods: A review of the current and historical literature on imaging-guided classification of neovascularization in nAMD was performed. Results: Imaging-guided classification of neovascularization in nAMD facilitates understanding of the pathological mechanisms and disease progression. Neovascularization classification has evolved with advances in imaging technologies, from earlier classifications based on neovascularization patterns assessed by fluorescein angiography to multimodal imaging patterns, resulting in varied descriptions of lesions depending on the techniques used. Until recently, there has been a lack of consensus regarding the clinical features of choroidal neovascularization lesion types as a result of the imaging modalities initially used to define them; a recent consensus on classification has the potential to simplify and clarify descriptions of neovascularization in nAMD. The use of multimodal imaging techniques will improve lesion identification and has the potential to individualize treatment plans and improve outcomes. Conclusions: Widespread adoption of a consensus-based, image-guided classification system for neovascular lesions in nAMD and the appropriate imaging techniques used to identify them will aid clinical research and could potentially improve patient outcomes by individualizing treatment plans in the future.

Evaluating the persistence of large choroidal hypertransmission defects using SS-OCT imaging

In age-related macular degeneration (AMD), large choroidal hypertransmission defects (hyperTDs) are identified on en face optical coherence tomography (OCT) images as bright lesions measuring at least 250 μm in greatest linear dimension (GLD). These choroidal hyperTDs arise from focal attenuation or loss of the retinal pigment epithelium (RPE). We previously reported that once large hyperTDs formed, they were likely to persist compared with smaller lesions that were more likely to be transient. Due to their relative persistence, these large persistent choroidal hyperTDs are a point-of-no-return in the progression of intermediate AMD to the late stage of atrophic AMD. Moreover, the onset of these large choroidal hyperTDs can serve as a clinical trial endpoint when studying therapies that might slow disease progression from intermediate AMD to late atrophic AMD. To confirm the persistence of these large choroidal hyperTDs, we studied an independent dataset of AMD eyes enrolled in an ongoing prospective swept-source OCT (SS-OCT) natural history study to determine their overall persistence. We identified a total of 202 eyes with large choroidal hyperTDs containing 1725 hyperTDs followed for an average of 46.6 months. Of the 1725 large hyperTDs, we found that 1718 (99.6%) persisted while only 7 hyperTDs (0.4%) were non-persistent. Of the 7 non-persistent large hyperTDs in 6 eyes, their average GLD at baseline was 385 μm. Of the large hyperTDs ranging in size between 250 and 300 μm when first detected, only one was not persistent with a baseline GLD of 283 μm. In 6 of the non-persistent hyperTDs, the loss of a detectable large hyperTD was due to the accumulation of hyperreflective material along the retinal pigment epithelium (RPE) and in the retina over the area where the hyperTD was located. This hyperreflective material is thought to represent the migration and aggregation of RPE cells into this focal region where the choroidal hyperTD arose due to attenuated or lost RPE.

National Experience of Technology-based Eye Care Services (TECS): A Comprehensive Ophthalmology Telemedicine Initiative

Technology-Based Eye Care Services (TECS) is a tele-ophthalmology program operating in the Veterans' Administration since 2015. This study explores characteristics of the national TECS population, evaluates implementation and sustainability of TECS, and analyzes possible associations and effects of demographic characteristics and social determinants of health (SDOH) on being diagnosed with a vision threatening (VT) disease. Implementation and sustainability of TECS from 2015-2022 was examined along with the sociodemographic characteristics of Veterans served through TECS in 2021. Veteran patients seen in TECS nationwide. Characteristics, disease prevalence and diagnoses, implementation success rate, sustainability rate, preliminary analysis of outcomes and disparity. Per quarter from 2015-2022, TECS sites were classified as implementing, active, or sustained. Standard Query Language (SQL) was used to determine sociodemographic data and logistic regression models were used to identify risk factors associated with VT eye diagnosis. 21,712 Veterans, 52.1% rural or highly rural, were served by TECS in 2021. The average age was 64.7 years, with females comprising 10.9% of the population served. From 2015-2022, of the 67 TECS sites initiated, 6 were implementing with 51 of 61 initiated sites still operational in the first quarter (Q1) of 2022 (83.6% success rate).Macular degeneration (AMD) and cataracts were more prevalent in rural and highly rural populations (7.6% and 11.3%, and 48.8% and 55.0%, respectively) vs. urban populations; glaucoma and diabetic retinopathy (DR) had the opposite association. The prevalence of any type of VT eye disease was lowest in the Mountains/Central region (0.54%) and highest in the Southeast region (3.2%) of the US. Rural and highly rural residents were 1.3 and 2.5 times as likely, respectively, to be diagnosed with a VT eye disease than urban residents. Implementation and sustainability of TECS has been promising. The data provides key information that can be utilized to improve the deployment of TECS and similar programs, along with the possible future direction of TECS services. Moreover, experience from one national ocular telehealth program clearly illustrates that telemedicine can address eye care disparities in the Veteran population and may be utilized for other vulnerable groups as well.

Efficacy and Safety of Intravitreal Faricimab in Neovascular Age-Related Macular Degeneration, Diabetic Macular Edema, and Retinal Vein Occlusion: A Meta-Analysis.

Intravitreal anti-vascular endothelial growth factor (VEGF) therapy has become the mainstay of treatment in many retinal diseases. The comparative efficacy and safety of newer bispecific anti-VEGF/angiopoietin 2 (Ang2) agents in the treatment paradigm versus widely used monospecific anti-VEGF agents remains unclear. A systematic literature search of MEDLINE, Embase, and Cochrane Library was conducted to identify comparative observational studies and randomized controlled trials published from 2015 to Jul 2024. With assessment by three independent reviewers, original English peer-reviewed full-text articles evaluating faricimab versus monospecific anti-VEGF agent(s) in FDA-indicated retinal disease with data on at least one set of efficacy and/or safety outcomes for each treatment arm and a minimum 3-month follow-up period were included. Data were appraised using the Cochrane RoB2 and ROBINS-I tools, PRISMA, and GRADE guidelines. All outcomes were collected at last follow-up. Random effects meta-analyses with 95% confidence intervals (CI) were conducted to calculate weighted mean differences (WMD) and risk ratios (RR). Change in best-corrected visual acuity (BCVA, ETDRS letters), change in central subfield thickness (CSFT, μm), and presence of retinal fluid were primary endpoints; ocular adverse events were secondary endpoints. Across 13 studies, in the context of neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), and retinal vein occlusion (RVO), 2226 eyes received anti-VEGF monotherapy and 3022 received faricimab. Final and change in BCVA were similar between treatment groups. Faricimab was associated with a significantly higher reduction in CSFT in DME and RVO eyes but not in nAMD eyes. The incidence of ocular adverse events were similar between groups. There was no difference in BCVA between faricimab and anti-VEGF monotherapy in nAMD, DME, and RVO. While faricimab offered superior improvement in central subfield thickness at final follow-up for DME and RVO eyes, this effect was not seen in nAMD eyes. Future studies are needed to establish the long-term safety and efficacy of faricimab for retinal vascular disease.

Visual and anatomical outcomes following vitrectomy with subretinal tPA injection in patients with submacular haemorrhages secondary to wet AMD

Purpose: Submacular haemorrhages (SMHs) are most commonly associated with wet age-related macular degeneration (AMD) and their size and duration are strong prognostic factors for visual outcome. The aim of this audit was to evaluate outcomes of direct injection of submacular tissue plasminogen activator (t-PA) into these lesions during pars plana vitrectomy (PPV). Methods: All patients presenting to the Mater Misericordiae Hospital from January 2017 to December 2019 with large SMHs secondary to wet AMD who underwent this treatment were included for review. All ten patients underwent complete PPV, injection of 0.2ml (50µg) subretinal t-PA and air tamponade. Pre-operative and post-operative evaluations included visual acuity testing (VA), optical coherence tomography (OCT) and slit lamp examination. Results: Eight patients (80%) showed improvement of their VA, with 4 patients achieving a VA of ≤0.4 LogMAR (20/50). Six patients had a total clearing of the macular haemorrhage, with a further 2 having sub-total clearance. One patient subsequently developed a retinal detachment requiring oil tamponade. Conclusions: SMH secondary to wet AMD is a sight threatening event with a varied prognosis but in most cases, vitrectomy with subretinal t-PA injection results in improved anatomical and visual outcomes.

A new texture-based labeling framework for hyper-reflective foci identification in retinal optical coherence tomography images

An important abnormality in Optical Coherence Tomography (OCT) images is Hyper-Reflective Foci (HRF). This anomaly can be interpreted as a biomarker of serious retinal diseases such as Age-related Macular Degeneration (AMD) and Diabetic Macular Edema (DME) or the progression of disease from an early stage to a late one. In this paper, a new method is proposed for the identification of HRFs. The new method divides the OCT B-scan into patches and separately verifies each patch to determine whether or not the patch contains an HRF. The procedure of patch verification contains a texture-based framework which assigns appropriate labels according to intensity changes to each column and row. Then, a feature vector is extracted for each patch based on the assigned labels. The feature vectors are utilized in the training step of well-known classifiers like Support Vector Machine (SVM). Then, the classifiers are used to produce the labels for the test OCT images. The new method is evaluated on a public dataset including HRF labels. The experimental results show that the new method is capable of providing outstanding results in terms of speed and accuracy.

Reactivation of stable neovascular age-related macular degeneration following treat-and-extend regimen discontinuation.

To describe the incidence and pattern of reactivation of neovascular age-related macular degeneration (nAMD) following successful treatment with treat-and-extend intravitreal anti-vascular endothelial growth factor therapy. Consecutive patients with treated nAMD who did not require further treatment over a 6-month period and who attended their 3-monthly optical coherence tomography monitoring clinic in Moorfields Eye Hospital from 1 November 2019 to 31 January 2020 were included. Patients with diagnoses of macular neovascularization other than AMD, and patients with incomplete data were excluded. Baseline demographics recorded were age, sex, race, laterality, cause of macular neovascularization, drug, number of injections, and duration of treatment. Date, setting, symptoms, and time to retreatment were collected among patients with disease reactivation. The medical records of 286 patients were included. Most patients were female (64.3%), white (68.18%), and were receiving aflibercept monotherapy (55.2%). Mean number of injections at baseline was 17.79 ± 11.74 (range 3-62) with a mean treatment duration of 39.47 ± 30.68 months (range 2-139). Reactivation of AMD was identified in 32.2% of cases with 87% of recurrences identified via scheduled visit. The most common symptom was blurring of vision in 44.6%, while 39.1% were asymptomatic. Mean time from baseline to retreatment was 29.37 ± 22.40 months (range 5-104), with 20.7%, 73.9% and 88.04% of these patients requiring retreatment within 1, 3, and 5 years, respectively. Despite prior treatment with no reactivation in 6 months, 32.2% reactivate, 73.9% of which within 3 years. A significant proportion, 39.1%, reactivated without symptoms necessitating regular monitoring in the first 5 years.

Mast cells promote choroidal neovascularization in a model of age-related macular degeneration

‘Wet’ age-related macular degeneration (AMD) is characterized by pathologic choroidal neovascularization (CNV) that destroys central vision. Abundant evidence points to inflammation and immune cell dysfunction in the progression of CNV in AMD. Mast cells are resident immune cells that control the inflammatory response. Mast cells accumulate and degranulate in the choroid of patients with AMD, suggesting they play a role in CNV. Activated mast cells secrete various biologically active mediators, including inflammatory cytokines and proteolytic enzymes such as tryptase. We investigated the role of mast cells in AMD using a model of CNV. Conditioned media from activated mast cells exerts proangiogenic effects on choroidal endothelial cells and choroidal explants. Laser-induced CNV in vivo was markedly attenuated in mice genetically depleted of mast cells (KitW−sh/W−sh) and in wild-type mice treated with mast cell stabilizer, ketotifen fumarate. Tryptase was found to elicit pronounced choroidal endothelial cell sprouting, migration and tubulogenesis; while tryptase inhibition diminished CNV. Transcriptomic analysis of laser-treated RPE/choroid complex revealed collagen catabolism and extracellular matrix (ECM) reorganization as significant events correlated in clusters of mast cell activation. Consistent with these analyses, compared to wildtype mice choroids of laser-treated mast cell-deficient mice displayed less ECM remodelling evaluated using collagen hybridizing peptide tissue binding. Findings herein provide strong support for mast cells as key players in the progression of pathologic choroidal angiogenesis and as potential therapeutic targets to prevent pathological neovascularization in ‘wet’ AMD.

Integrative multiomic analysis unveils the molecular nexus of mitochondrial dysfunction in the pathogenesis of age-related macular degeneration

Mitochondrial dysfunction is linked to age-related macular degeneration (AMD), but its mechanisms and related molecular networks remain unclear. We explored the association between mitochondrial-related genes and AMD by integrating multiomic data. We acquired summary-level data on mitochondrial-related protein abundance, gene expression, and gene methylation from quantitative trait locus studies. Genetic associations with AMD were sourced from the International Age-related Macular Degeneration Genomics Consortium (discovery), FinnGen (replication), and UK Biobank (replication) studies. We used summary-data-based Mendelian randomization to assess the correlations between mitochondrial-related gene molecular characteristics and AMD. Furthermore, colocalization analysis was performed to ascertain if the detected signal pairings had a common causative genetic variation. Mitochondrial-relatedl gene NFKB1 demonstrated a protective role in AMD (tier 1 evidence), whereas HSPA1A and HSPA1B genes were also associated with decreased AMD risk (tier 2 evidence). The methylation of cg09390974 and cg15409712 in NFKB1 was associated with increased NFKB1 expression, consistent with the protective effect on AMD risk, whereas inverse associations were observed between gene methylation and gene expression for HSPA1B (cg04835051 and cg16372051), supporting the risk roles of methylation in AMD. At circulating protein level, genetically predicted higher levels of HSPA1A (odds ratio [OR] 0.28, 95% confidence interval [CI] 0.19−0.41, P<0.001), HSPA1B (OR 0.13, 95% CI 0.06−0.27, P<0.001), and NFKB1 (OR 0.43, 95% CI 0.27−0.68, P<0.001) were inversely associated with AMD risk. These associations were corroborated in the colocalization analysis. We identified AMD-linked mitochondrial-related genes, potentially improving the understanding of its pathophysiological mechanisms and aiding the identification of novel pharmaceutical targets.

Aberrant Lipid Metabolism and Complement Activation in Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) stands as a leading cause of severe visual impairment and blindness among the elderly globally. As a multifactorial disease, AMD's pathogenesis is influenced by genetic, environmental, and age-related factors, with lipid metabolism abnormalities and complement system dysregulation playing critical roles. This review delves into recent advancements in understanding the intricate interaction between these two crucial pathways, highlighting their contribution to the disease's progression through chronic inflammation, drusen formation, and retinal pigment epithelium dysfunction. Importantly, emerging evidence points to dysregulated lipid profiles, particularly alterations in high-density lipoprotein levels, oxidized lipid deposits, and intracellular lipofuscin accumulation, as exacerbating factors that enhance complement activation and subsequently amplify tissue damage in AMD. Furthermore, genetic studies have revealed significant associations between AMD and specific genes involved in lipid transport and complement regulation, shedding light on disease susceptibility and underlying mechanisms. The review further explores the clinical implications of these findings, advocating for a novel therapeutic approach that integrates lipid metabolism modulators with complement inhibitors. By concurrently targeting these pathways, the dual-targeted approach holds promise in significantly improving outcomes for AMD patients, heralding a new horizon in AMD management and treatment.

Retinal Pigment Epithelium Curvature Can Predict Late Age-Related Macular Degeneration.

Outer retinal band integrity strongly predicts late age-related macular degeneration (AMD). However, it is often assessed subjectively as "continuity" using inconsistent definitions. Alternatively, "curvature" of the outer retinal bands is a quantitative metric that strongly correlates with AMD biomarkers and can screen for intermediate AMD. We evaluated the prognostic ability of retinal pigment epithelium (RPE) and ellipsoid zone (EZ) curvature for late AMD against outer retinal band continuity, pigmentary abnormalities, reticular pseudodrusen, and drusen volume. Consecutive patients with intermediate AMD who progressed to late AMD (n = 17) or remained stable (n = 42) were recruited. RPE and EZ curvature were quantified as a ratio of their lengths over Bruch's membrane using the sinuosity method of assessing river curvature, where a ratio of ∼1 indicates no outer retinal pathology. RPE, EZ, and Bruch's membrane were manually segmented and their lengths automatically extracted. The primary outcomes were outer retinal sinuosity and the odds ratio of predicting late AMD. Mean follow-up time for progressors and nonprogressors was 4.4 and 3.6 years. RPE sinuosity was strongly associated with pigmentary abnormalities (P = 0.001) and drusen volume (P = 0.004) but not reticular pseudodrusen (P = 0.28). RPE sinuosity >1.03 was the strongest predictor of late AMD developing within 5 years (15 [2.9-75]) and across the study period (25 [2.3-282]). Drusen volume >0.03 mm3 was the strongest predictor of progression within 2 years (33 [2.5-426]), and RPD could not independently predict progression within any time frame. RPE curvature is a promising, quantitative outer retinal biomarker that can prognosticate late AMD and potentially enhance prognostic models.

ACUTE POSTERIOR MULTIFOCAL PLACOID PIGMENT EPITHELIOPATHY AND PLACOID VARIANT DISEASES MASQUERADING AS AGE-RELATED MACULAR DEGENERATION IN THE ELDERLY: A Case Series.

To report eight cases of acute posterior multifocal placoid pigment epitheliopathy (APMPPE) or persistent placoid maculopathy (PPM) initially masquerading as age-related macular degeneration in elderly individuals. APMPPE or PPM eyes in patients above age 55 years with macular retinal pigment epithelium disruption including drusenoid lesions on macular examination and/or with multimodal imaging were included. At least one method of multimodal imaging including fluorescein angiography (FA), indocyanine green angiography, optical coherence tomography (OCT), and OCT angiography (OCTA) was performed in all eyes for diagnosis and to monitor for macular neovascularization. Eight elderly male patients presented with vision loss and were all initially diagnosed with non-neovascular or neovascular age-related macular degeneration. With the aid of multimodal retinal imaging, a final diagnosis of either APMPPE or PPM was rendered. With FA and indocyanine green angiography, choroidal hypoperfusion was detected in all but one eye. With OCT, the angular sign of Henle fiber layer hyperreflectivity was identified in >50% of eyes. With OCTA, inner choroidal flow deficits were detected in all eyes. Macular neovascularization requiring anti-vascular endothelial growth factor injection therapy complicated three of eight cases. Both APMPPE and PPM may develop in elderly individuals and may masquerade as age-related macular degeneration on presentation. Multimodal imaging including FA, indocyanine green angiography, and OCTA are important diagnostic modalities to assess for inner choroidal hypoperfusion to arrive at an accurate diagnosis and to detect macular neovascularization, which frequently complicates APMPPE and PPM. In these patients, serial anti-vascular endothelial growth factor intravitreal injections are essential in treating macular neovascularization and in preventing significant vision loss.

Visual Improvements After Excimer Laser Multiple Light Redirection in Eyes With Central Visual Loss From Macular Degeneration and Geographic Atrophy: First Report of Cases

Purpose To analyze outcomes after multiple light redirection (MLR) by photoablation of a small paracentral portion of Bowman's layer in each corneal quadrant using standard myopic laser in situ keratomileusis (LASIK) software with non-customized fenestrated MLR corneal light shields (Excimer-MLR) without postoperative visual training or magnification in pseudophakic eyes with central visual loss from age-related macular degeneration (AMD) with geographic atrophy (GA). Methods Retrospective analysis of two cases. Results Outcomes after Excimer-MLR in the worse-seeing eyes of an 86-year-old and a 65-year-old pseudophakic man with AMD and GA revealed corrected distance/near visual acuity gains of 6.0/6.0 and 11.8/10.0 lines within 12 days and 5.0/5.0 and 12.2/9.8 lines at 9 months, respectively, with improved Amsler grids, no distance or near glasses change, no complications, and no adverse events related to Excimer-MLR. Contrast sensitivity and stereopsis, measured in case 2, improved postoperatively. Conclusions This first report showed that Excimer-MLR safely produced large improvements in visual function up to 9 months postoperatively in two eyes with central visual loss from AMD. [ Journal of Refractive Surgery Case Reports. 2024;4(4):e29–e35.]

Age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of visual impairment in patients age 50 and older, with an estimated 200 million people affected worldwide and a projected 288 million by 2040. This article provides an overview of the epidemiology, risk factors, pathophysiology, clinical manifestations, diagnosis, management, and nursing considerations for AMD to equip nurses with the knowledge to play a crucial role in the early detection of this disease.

PATHWAYS TO GEOGRAPHIC ATROPHY IN NONNEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

To characterize and quantify the precursor lesions of geographic atrophy in eyes with age-related macular degeneration. A retrospective study of eyes with a minimum of 6-month follow-up before developing geographic atrophy. Evaluations included color and autofluorescence imaging, along with spectral-domain optical coherence tomography, employing definitions from the Consensus of Atrophy Meeting Group and Consensus on Neovascular Age-Related Macular Degeneration Nomenclature Study Group. There were 55 eyes of 44 patients, who had a mean age of 81.3 years at onset of atrophy; 35 (63.6%) were female. The mean duration of follow-up before and after the advent of geographic atrophy was 4.9 years and 1.2 years, respectively. Geographic atrophy was preceded by collapse of a druse in 41 eyes (74.5%). Of these, 29 (70.7%) were drusenoid pigment epithelial detachments. Among the eyes with regressing drusen, there were 9 with overlying vitelliform deposit, and all had concurrent subretinal drusenoid deposit; however, 19 of 30 eyes with no vitelliform deposit overlying the druse had concurrent subretinal drusenoid deposit, a difference that was significant ( P < 0.001). Regression of subretinal drusenoid deposit was found in 4 eyes (7.3%), regression of vitelliform deposit associated with subretinal drusenoid deposit in 5 (9.1%), and regression of vitelliform deposit in eyes concurrently harboring drusen was found in 3 (5.4%) and regression of vitelliform deposit alone in 2 (3.6%) at the site of eventual development of geographic atrophy. Geographic atrophy appears to develop from multiple pathways as manifested by the many precursor lesions, all various forms of extracellular deposit, that upon regression, result in a common end-stage appearance.

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

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

Human iPSC-based disease modeling studies identify a common mechanistic defect and potential therapies for AMD and related macular dystrophies.

Age-related macular degeneration (AMD) and related macular dystrophies (MDs) primarily affect the retinal pigment epithelium (RPE) in the eye. A hallmark of AMD/MDs that drives later-stage pathologies is drusen. Drusen are sub-RPE lipid-protein-rich extracellular deposits, but how drusen forms and accumulates is not known. We utilized human induced pluripotent stem cell (iPSC)-derived RPE from patients with AMD and three distinct MDs to demonstrate that reduced activity of RPE-secreted matrix metalloproteinase 2 (MMP2) contributes to drusen in multiple maculopathies in a genotype-agnostic manner by instigating sterile inflammation and impaired lipid homeostasis via damage-associated molecular pattern molecule (DAMP)-mediated activation of receptor for advanced glycation end-products (RAGE) and increased secretory phospholipase 2-IIA (sPLA2-IIA) levels. Therapeutically, RPE-specific MMP2 supplementation, RAGE-antagonistic peptide, and a small molecule inhibitor of sPLA2-IIA ameliorated drusen accumulation in AMD/MD iPSC-RPE. Ultimately, this study defines a causal role of the MMP2-DAMP-RAGE-sPLA2-IIA axis in AMD/MDs.

ReCLAIM-2: A Randomized Phase 2 Clinical Trial Evaluating Elamipretide in Age-related Macular Degeneration, Geographic Atrophy Growth, Visual Function, and Ellipsoid Zone Preservation

ObjectiveThis study evaluated the safety and efficacy of elamipretide in dry age-related macular degeneration (AMD) with non-central geographic atrophy (GA). DesignReCLAIM-2 was a prospective, phase 2, randomized, placebo-controlled, double-masked, multicenter trial (NCT03891875). SubjectsPatients aged ≥55 years with at least one eye with dry AMD with GA were enrolled. MethodsAdministration of daily subcutaneous elamipretide 40 mg was investigated in subjects for 48 weeks followed by a 4-week follow-up period. Main Outcome MeasuresThe primary efficacy endpoints were the mean change from baseline in low-luminance best-corrected visual acuity (LL BCVA) and the change in square root converted GA area from baseline as measured by optical coherence tomography (OCT). Additional predefined endpoints included ellipsoid zone (EZ) integrity preservation assessment and categorical changes in LL BCVA. The primary safety endpoint was the incidence and severity of adverse events. ResultsOf the 176 patients randomized, there were 117 and 59 patients in the elamipretide and placebo groups, respectively. Although elamipretide did not meet statistical significance for the primary endpoints (mean change in LL BCVA and mean change in square root converted GA area), elamipretide produced a 43% reduction in the mean progression from baseline in the macular percentage of total EZ attenuation/loss (i.e., complete loss of EZ band; nominal P=0.003) and 47% reduction in the mean progression of macular percentage of partial EZ attenuation/degradation (i.e., EZ-RPE thickness of 20 microns or less; nominal P=0.004) versus placebo at week 48. Elamipretide treatment was also associated with significantly more patients experiencing a ≥10 letter gain in LL-BCVA versus placebo (14.6% vs 2.1%; nominal P=0.0404). Adverse events were reported in 86% of those receiving elamipretide and 71% of the placebo group with the most common events being injection site reactions (e.g., pruritus, injection site pain, bruising, erythema). ConclusionsWhile the primary endpoints were not met in this phase 2 study, elamipretide treatment was associated with a slowing of progressive EZ degradation/loss, a surrogate for photoreceptor damage. These findings have important clinical relevance since EZ attenuation/photoreceptor loss precedes and predicts the progressive pathological changes associated with vision loss and AMD. The EZ attenuation/loss endpoint will serve as the regulatory-approved primary endpoint in the elamipretide Phase 3 clinical development program.

Bispectrum Analysis of Thermal Images for the Classification of Retinal Vascular Diseases

In the field of medicine, thermal imaging provides a non-invasive means to diagnose diseases by displaying temperature variations. Specifically, thermal images of the ocular region are proving effective in diagnosing retinal diseases like diabetic retinopathy (DR), diabetic macular edema (DME), age-related macular degeneration (AMD), and wet AMD. This study explores the use of bispectrum analysis on ocular thermal images. The bispectrum, derived from third-order statistics (cumulants), is estimated using parametric (ARMA) and non-parametric methods (direct and indirect). Various entropy measures are extracted as features from these bispectrum images. The effectiveness of these features is evaluated through experiments employing different machine learning algorithms: discriminant analysis (DA), K-nearest neighbour (KNN), decision tree (DT), and Naïve Bayes Classifier (NBC). The results indicate that the KNN classifier achieves the highest accuracy when using features extracted via the indirect method of bispectrum estimation. Meanwhile, the DT classifier performs exceptionally well with bispectrum features extracted through the direct method, outperforming other feature extraction approaches.

Comparison between OCT 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 and outer retinal atrophy (cRORA) and incomplete retinal pigment epithelium 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 OCT angiography (SS-OCTA) en face images. Comparative diagnostic analysis of prospective study data METHODS: Patients with late nonexudative AMD underwent same day 6 × 6 mm macular scans using both SD-OCT (Spectralis® Heidelberg, 512 × 97, ART: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-retinal pigment epithelium slab positioned 64-400 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, while 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 a greatest linear dimensions in the non-horizontal 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 non-horizontal dimension. Even though neighboring B-scans were inspected, 27.5% of iRORA lesions were actually part of larger cRORA lesions when graded using an en face strategy.