Proof of concept, randomized, placebo-controlled study of the effect of simvastatin on the course of age-related macular degeneration

BACKGROUND: HMG Co-A reductase inhibitors are ubiquitous in our community yet their potential role in age-related macular degeneration (AMD) remains to be determined. METHODOLOGY/PRINCIPAL FINDINGS: OBJECTIVES: To evaluate the effect of simvastatin on AMD progression and the effect modification by polymorphism in apolipoprotein E (ApoE) and complement factor H (CFH) genes. DESIGN: A proof of concept double-masked randomized controlled study. PARTICIPANTS: 114 participants aged 53 to 91 years, with either bilateral intermediate AMD or unilateral non-advanced AMD (with advanced AMD in fellow eye), BCVA ≥ 20/60 in at least one eye, and a normal lipid profile. INTERVENTION: Simvastatin 40 mg/day or placebo, allocated 1:1. MAIN OUTCOME MEASURES: Progression of AMD either to advanced AMD or in severity of non-advanced AMD. Results. The cumulative AMD progression rates were 70% in the placebo and 54% in the simvastatin group. Intent to treat multivariable logistic regression analysis, adjusted for age, sex, smoking and baseline AMD severity, showed a significant 2-fold decrease in the risk of progression in the simvastatin group: OR 0.43 (0.18-0.99), p = 0.047. Post-hoc analysis stratified by baseline AMD severity showed no benefit from treatment in those who had advanced AMD in the fellow eye before enrolment: OR 0.97 (0.27-3.52), p = 0.96, after adjusting for age, sex and smoking. However, there was a significant reduction in the risk of progression in the bilateral intermediate AMD group compared to placebo [adjusted OR 0.23 (0.07-0.75), p = 0.015]. The most prominent effect was observed amongst those who had the CC (Y402H) at risk genotype of the CFH gene [OR 0.08 (0.02-0.45), p = 0.004]. No evidence of harm from simvastatin intervention was detected. CONCLUSION/SIGNIFICANCE: Simvastatin may slow progression of non-advanced AMD, especially for those with the at risk CFH genotype CC (Y402H). Further exploration of the potential use of statins for AMD, with emphasis on genetic subgroups, is warranted. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry (ANZCTR) ACTRN1260500032065

Baseline characteristics and age-related macular degeneration in participants of the 'ASPirin in Reducing Events in the Elderly' (ASPREE)-AMD trial

Purpose: To describe the baseline participant characteristics in the ASPREE-AMD study, investigating the effect of aspirin on AMD incidence and progression.Methods: Australian participants from the ASPirin in Reducing Events in the Elderly (ASPREE) trial, randomized to 100 mg aspirin daily or placebo, had non-mydriatic, digital color fundus images graded according to the Beckman AMD classification. Associations with AMD were determined for baseline characteristics and genetic risk variants.Results: ASPREE-AMD sub-study enrolled 4993 participants with gradable macular images. Median age was 73.4 years (IQR, 71.5, 76.6), 52% were female, 10% had diabetes mellitus, 73% had hypertension, and 44% were former/current smokers. Early, intermediate and late AMD (detected in 20.6%, 16.1%, 1.1%, respectively), significantly associated with age, were also associated with increasing HDL levels: OR = 1.52 (95%CI, 1.26, 1.84), OR = 1.43 (1.17, 1.77) and OR = 1.96 (1.02, 3.76), respectively. Female sex was associated with early [OR = 1.37 (1.16, 1.62)], and intermediate [OR = 1.35 (1.12, 1.63)] AMD, as was previous regular use of aspirin, with OR = 1.46 (1.11, 1.92) and OR = 1.37 (1.01, 1.85), respectively. Current smoking had increased odds for late AMD, OR = 4.02 (1.42, 11.36). Genetic risk variant rs3750846 (ARMS2/HTRA1) was associated with each AMD stage (p CFH) with intermediate and late AMD (p C3) with late AMD (p Conclusions: Observed associations are typical of AMD. The ASPREE-AMD clinical trial provides a unique opportunity to determine the risks and benefits of low-dose aspirin for AMD incidence and progression in elderly population

Suppression and Regression of Choroidal Neovascularization in Mice by a Novel CCR2 Antagonist, INCB3344

PURPOSE: To investigate the effect of an intravitreally administered CCR2 antagonist, INCB3344, on a mouse model of choroidal neovascularization (CNV). METHODS: CNV was induced by laser photocoagulation on Day 0 in wild type mice. INCB3344 or vehicle was administered intravitreally immediately after laser application. On Day 14, CNV areas were measured on retinal pigment epithelium (RPE)-choroid flat mounts and histopathologic examination was performed on 7 µm-thick sections. Macrophage infiltration was evaluated by immunohistochemistry on RPE-choroid flat mounts and quantified by flow cytometry on Day 3. Expression of vascular endothelial growth factor (VEGF) protein in RPE-choroid tissue was examined by immunohistochemistry and ELISA, VEGF mRNA in sorted macrophages in RPE-choroid tissue was examine by real-time PCR and expression of phosphorylated extracellular signal-regulated kinase (p-ERK 1/2) in RPE-choroid tissue was measured by Western blot analysis on Day 3. We also evaluated the efficacy of intravitreal INCB3344 to spontaneous CNV detected in Cu, Zn-superoxide dismutase (SOD1) deficient mice. Changes in CNV size were assessed between pre- and 1week post-INCB3344 or vehicle administration in fundus photography and fluorescence angiography (FA). RESULTS: The mean CNV area in INCB3344-treated mice decreased by 42.4% compared with the vehicle-treated control mice (p<0.001). INCB3344 treatment significantly inhibited macrophage infiltration into the laser-irradiated area (p<0.001), and suppressed the expression of VEGF protein (p = 0.012), VEGF mRNA in infiltrating macrophages (p<0.001) and the phosphorylation of ERK1/2 (p<0.001). The area of spontaneous CNV in Sod1⁻/⁻ mice regressed by 70.35% in INCB3344-treated animals while no change was detected in vehicle-treated control mice (p<0.001). CONCLUSIONS: INCB3344 both inhibits newly forming CNV and regresses established CNV. Controlling inflammation by suppressing macrophage infiltration and angiogenic ability via the CCR-2/MCP-1 signal may be a useful therapeutic strategy for treating CNV associated with age-related macular degeneration

Physiological response of the retinal pigmented epithelium to 3-ns pulse laser application, in vitro and in vivo

BACKGROUND: To treat healthy retinal pigmented epithelium (RPE) with the 3-ns retinal rejuvenation therapy (2RT) laser and to investigate the subsequent wound-healing response of these cells. METHODS: Primary rat RPE cells were treated with the 2RT laser at a range of energy settings. Treated cells were fixed up to 7 days post-irradiation and assessed for expression of proteins associated with wound-healing. For in vivo treatments, eyes of Dark Agouti rats were exposed to laser and tissues collected up to 7 days post-irradiation. Isolated wholemount RPE preparations were examined for structural and protein expression changes. RESULTS: Cultured RPE cells were ablated by 2RT laser in an energy-dependent manner. In all cases, the RPE cell layer repopulated completely within 7 days. Replenishment of RPE cells was associated with expression of the heat shock protein, Hsp27, the intermediate filament proteins, vimentin and nestin, and the cell cycle-associated protein, cyclin D1. Cellular tight junctions were lost in lased regions but re-expressed when cell replenishment was complete. In vivo, 2RT treatment gave rise to both an energy-dependent localised denudation of the RPE and the subsequent repopulation of lesion sites. Cell replenishment was associated with the increased expression of cyclin D1, vimentin and the heat shock proteins Hsp27 and αB-crystallin. CONCLUSIONS: The 2RT laser was able to target the RPE both in vitro and in vivo, causing debridement of the cells and the consequent stimulation of a wound-healing response leading to layer reformation.John P. M. Wood, Marzieh Tahmasebi, Robert J. Casson, Malcolm Plunkett, Glyn Chidlo

'Statins in retinal disease'

Statins are known for their blood cholesterol-lowering effect and are widely used in patients with cardiovascular and metabolic diseases. Research over the past three decades shows that statins have diverse effects on different pathophysiological pathways involved in angiogenesis, inflammation, apoptosis, and anti-oxidation, leading to new therapeutic options. Recently, statins have attracted considerable attention for their immunomodulatory effect. Since immune reactivity has been implicated in a number of retinal diseases, such as uveitis, age-related macular degeneration (AMD) and diabetic retinopathy, there is now a growing body of evidence supporting the beneficial effects of statins in these retinopathies. This review evaluates the relationship between statins and the pathophysiological basis of these diseases, focusing on their potential role in treatment. A PubMed database search and literature review was conducted. Among AMD patients, there is inconsistent evidence regarding protection against development of early AMD or delaying disease progression; though they have been found to reduce the risk of developing choroidal neovascular membranes (CNV). In patients with retinal vein occlusion, there was no evidence to support a therapeutic benefit or a protective role with statins. In patients with diabetic retinopathy, statins demonstrate a reduction in disease progression and improved resolution of diabetic macular oedema (DMO). Among patients with uveitis, statins have a protective effect by reducing the likelihood of uveitis development

Relationship Between Rod-Mediated Sensitivity, Low-Luminance Visual Acuity, and Night Vision Questionnaire in Age-Related Macular Degeneration

Purpose: To quantify the association between dark adaptation parameters and other clinical measures of visual function among people with and without early and intermediate age-related macular degeneration (AMD). Methods: In this cross-sectional study, participants underwent multimodal imaging and visual function testing, including best-corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), low-luminance deficit (LLD = BCVA - LLVA) and the 10-item Night Vision Questionnaire (NVQ-10). Dynamic and static dark-adapted chromatic perimetry (DACP) was performed. Sensitivity difference was defined as the difference in sensitivity between the 505-nm and 625-nm stimuli. Rod intercept time (RIT) was estimated as the time required to reach a threshold of -3 log candelas/meter2 with the 505-nm stimulus following bleaching. The magnitude of association between the DACP parameters and other clinical tests was estimated via mixed-effects regression. Results: A total of 51 participants (aged 51-88 years, 65% female, 39% with AMD) were included. RIT was found to be negatively associated with BCVA (P < 0.001), LLVA (P = 0.005), and NVQ-10 score (P = 0.028) but not LLD (P = 0.763). There was no evidence of an association between sensitivity difference and any of the clinical measures (P ≥ 0.081). Conclusions: Reduced rod function, as determined by RIT, was associated with lower NVQ-10 scores (designed to interrogate rod-mediated function) and with worse BCVA and LLVA (measures of cone function). Translational Relevance: Decreasing rod function maybe indicative of more generalized photoreceptor dysfunction involving cones. Further development of questionnaires to target function in scotopic conditions may provide an easier to administer test without the need to perform perimetric tests of rod function

Repeatability of Retinal Sensitivity Measurements Using a Medmont Dark-Adapted Chromatic Perimeter in Healthy and Age-Related Macular Degeneration Cases

Purpose: To determine the intrasession and intersession test-retest repeatability of retinal sensitivity measurements using a dark-adapted chromatic perimeter (DACP). Methods: For intrasession testing, retinal sensitivity within the central 24° for the 505-nm stimulus was measured after 20, 30, and 40 minutes of dark adaptation (DA) and for the 625-nm stimulus was measured after the first and second 505-nm tests. For intersession testing, retinal sensitivity for both stimuli was measured after 30 minutes of DA at baseline and 1 month. The point-wise sensitivity (PWS) difference and coefficient of repeatability (CoR) of each stimulus and group were determined. Results: For intrasession testing, 10 age-related macular degeneration (AMD) and eight control subjects were recruited. The overall CoR for the 505-nm stimulus was 8.4 dB for control subjects and 9.1 dB for AMD cases, and for the 625-nm stimulus was 6.7 dB for control subjects and 9.5 dB for AMD cases. For intersession testing, seven AMD cases and 13 control subjects returned an overall CoR for the 505-nm stimulus of 8.2 dB for the control and 11.7 dB for the AMD group. For the 625-nm stimulus the CoR was 6.2 dB for the control group and 8.4 dB for the AMD group. Approximately 80% of all test points had a PWS difference of ±5 dB between the two intrasession or intersession measurements for both stimuli. Conclusions: The CoR for the DACP is larger than that reported for scotopic perimeters; however, the majority of test points had a PWS difference of ±5 dB between tests. Translational Relevance: The DACP offers an opportunity to measure static and dynamic rod function at multiple locations with an acceptable reproducibility level

Performance of a Defect-Mapping Microperimetry Approach for Characterizing Progressive Changes in Deep Scotomas

Purpose: To examine whether a microperimetry testing strategy based on quantifying the spatial extent of functional abnormalities (termed "defect-mapping" strategy) could improve the detection of progressive changes in deep scotomas compared to the conventional thresholding strategy. Methods: A total of 30 healthy participants underwent two microperimetry examinations, each using the defect-mapping and thresholding strategies at the first visit to examine the test-retest variability of each method. Testing was performed using an isotropic stimulus pattern centered on the optic nerve head (ONH), which acted as a model of a deep scotoma. These tests were repeated at a second visit, except using a smaller stimulus pattern and thereby increasing the proportion of test locations falling within the ONH (to simulate the progressive enlargement of a deep scotoma). The extent of change detected between visits relative to measurement variability was compared between the two strategies. Results: Relative to their effective dynamic ranges, the test-retest variability of the defect-mapping strategy (1.8%) was significantly lower compared to the thresholding strategy (3.3%; P < 0.001). The defect-mapping strategy also captured a significantly greater extent of change between visits relative to variability (-4.70 t-1) compared to the thresholding strategy (2.74 t-1; P < 0.001). Conclusions: A defect-mapping microperimetry testing strategy shows promise for capturing the progressive enlargement of deep scotomas more effectively than the conventional thresholding strategy. Translational Relevance: Microperimetry testing with the defect-mapping strategy could provide a more accurate clinical trial outcome measure for capturing progressive changes in deep scotomas in eyes with atrophic retinal diseases, warranting further investigations

Artificial Intelligence Algorithms for Analysis of Geographic Atrophy: A Review and Evaluation

Purpose: The purpose of this study was to summarize and evaluate artificial intelligence (AI) algorithms used in geographic atrophy (GA) diagnostic processes (e.g. isolating lesions or disease progression). Methods: The search strategy and selection of publications were both conducted in accordance with the Preferred of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed and Web of Science were used to extract literary data. The algorithms were summarized by objective, performance, and scope of coverage of GA diagnosis (e.g. lesion automation and GA progression). Results: Twenty-seven studies were identified for this review. A total of 18 publications focused on lesion segmentation only, 2 were designed to detect and classify GA, 2 were designed to predict future overall GA progression, 3 focused on prediction of future spatial GA progression, and 2 focused on prediction of visual function in GA. GA-related algorithms reported sensitivities from 0.47 to 0.98, specificities from 0.73 to 0.99, accuracies from 0.42 to 0.995, and Dice coefficients from 0.66 to 0.89. Conclusions: Current GA-AI publications have a predominant focus on lesion segmentation and a minor focus on classification and progression analysis. AI could be applied to other facets of GA diagnoses, such as understanding the role of hyperfluorescent areas in GA. Using AI for GA has several advantages, including improved diagnostic accuracy and faster processing speeds. Translational Relevance: AI can be used to quantify GA lesions and therefore allows one to impute visual function and quality-of-life. However, there is a need for the development of reliable and objective models and software to predict the rate of GA progression and to quantify improvements due to interventions