Non-neovascular Age-related Macular Degeneration Research Articles

Levodopa is associated with reduced development of new-onset geographic atrophy in patients with age-related macular degeneration.

Geographic atrophy (GA) is a significant cause of vision loss in patients with age-related macular degeneration (AMD). Current treatments are limited to anti-complement drugs, which have limited efficacy to delay progression with significant risk of complications. Levodopa (L-DOPA) is a byproduct of melanin synthesis that is associated with reduced development of neovascular AMD. In this study, we determined if L-DOPA was associated with a reduced likelihood of new-onset GA. We performed a retrospective analysis in the Vestrum Health Retina Database. We included eyes with non-neovascular AMD without GA and 1-5years of follow-up. Eyes were divided into two groups. Exposed to L-DOPA before or on the date of non-neovascular AMD without GA diagnosis, and eyes not exposed to L-DOPA. We extracted age, sex, AREDS2 status, dry AMD stage, smoking history, and conversion rate to GA at years 1 through 5. Propensity score matching was used to match L-DOPA and control groups. Cox proportional hazard regression, adjusting for age, sex, AMD severity, AREDS2 use, smoking status, and L-DOPA use was employed to calculate hazard ratios for new-onset GA detection. We identified 112,089 control and 844 L-DOPA exposed eyes with non-neovascular AMD without GA. After propensity score matching, 2532 control and 844 L-DOPA exposed eyes remained that were well-matched for age, sex, AMD severity, AREDS2 use, and smoking status. We found that L-DOPA exposure was associated with a significantly reduced likelihood (HR = 0.68, 95% CI: 0.48-0.95, P = 0.025) of new-onset GA detection. L-DOPA use was associated with reduced detection of new-onset GA.

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.

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.

Assessment of optical coherence tomography biomarkers in patients with non-neovascular age-related macular degeneration (AMD) converting to exudative AMD according to the status of the fellow eye

Assessment of optical coherence tomography biomarkers in patients with non-neovascular age-related macular degeneration (AMD) converting to exudative AMD according to the status of the fellow eye

Association Between Systemic Levels of Vascular Endothelial Growth Factor and Optical Coherence Tomography Biomarkers in a Non-Neovascular Age-Related Macular Degeneration Cohort.

Investigate associations between systemic vascular endothelial growth factor (VEGF) and optical coherence tomography (OCT) biomarkers in eyes with complete retinal pigment epithelium and outer retina atrophy (cRORA) secondary to non-neovascular age-related macular degeneration. Cross-sectional study of patients with cRORA. OCT images and blood samples were collected at study enrollment. OCT images were evaluated for biomarkers. Systemic VEGF levels were measured using a standard multiplex assay. Study included 187 eyes from 96 patients. Lower levels of systemic VEGF were significantly associated with retinal pseudocysts (RPs) and subretinal hyper-reflective material (SHRM), a median of 7.7 pg/mL and 6.1 pg/mL for patients with the imaging biomarkers compared to those without (10.3 pg/mL [P = 0.004] and 9.3 pg/mL [P = 0.02], respectively). This novel study shows that lower systemic VEGF levels were associated with SHRM and RP, which was shown to correspond to an intermediate stage of the atrophic process in age-related macular degeneration. Systemic VEGF could be a useful biomarker and therapeutic target for eyes with cRORA. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Ocular Neovascular Conversion and Systemic Bleeding Complications in Patients with Age-Related Macular Degeneration on Anticoagulants

PurposeConversion to neovascular disease in patients with non-neovascular age-related macular degeneration (AMD) initiated on direct oral anticoagulants (DOAC) compared to matched patients treated with warfarin. DesignRetrospective cohort study. Subjects, Participants, and/or ControlsThe study included 20,300 patients and 13,387 patients with non-neovascular AMD initiated on DOACs or warfarin, respectively, before propensity score matching (PSM). Methods, Intervention, or TestingTriNetX (Cambridge, MA, USA), was used to identify patients diagnosed with non-neovascular AMD stratified by treatment with DOACs or warfarin with at least six months of follow-up. Propensity score matching was performed to control for baseline demographics and medical comorbidities. Main Outcome MeasuresRelative risk (RR) of developing neovascular AMD, macular hemorrhage (MH), vitreous hemorrhage (VH), and requiring an ocular intervention (intravitreal anti-vascular endothelial growth factor (VEGF) therapy or pars plana vitrectomy (PPV)) within six months and one year. Patients with chronic atrial fibrillation (AF) on anticoagulation were separately evaluated for the same measures within 5 years after initiating therapy. ResultsTreatment with warfarin was associated with higher risk of developing neovascular AMD at six months (RR,1.24, 95% CI, 1.12 – 1.39; P<.001) and one year (RR, 1.26, 95% CI, 1.14 – 1.40; P<.001) when compared to matched patients treated with DOACs. There was an increased risk of requiring intravitreal anti-VEGF therapy (6 months: RR, 1.30; 95% CI, 1.13-1.49; P<.001; 1 year: RR, 1.31, 95% CI, 0.72 – 2.05; P<.001) and PPV (6 months: RR, 1.16; 95% CI, 1.16-3.94; P = .01; 1 year: RR, 2.29, 95% CI, 1.30 – 4.05; P=.003). Among patients with AMD and AF treated with warfarin, there was an increased risk of ocular complications (neovascular AMD: RR, 1.25; 95% CI, 1.14-1.38; P<.001; MH: RR, 1.86; 95% CI, 1.47-2.35; P<.001; VH: RR, 2.22; 95% CI, 1.51-3.26; P<.001) and need for intravitreal anti-VEGF therapy (RR, 1.34; 95% CI, 1.18-1.52; P<.001) over an extended 5-year period. There was no significant difference in the development of major systemic hemorrhagic events between the two cohorts over five years. ConclusionsPatients with non-neovascular AMD treated with warfarin were more likely to develop neovascular disease and require ocular intervention for hemorrhagic complications when compared to matched patients initiated on DOACs.

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.

The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in non-neovascular AMD

Non-neovascular or dry age-related macular degeneration (AMD) is a multi-factorial disease with degeneration of the aging retinal-pigmented epithelium (RPE). Lysosomes play a crucial role in RPE health via phagocytosis and autophagy, which are regulated by transcription factor EB/E3 (TFEB/E3). Here, we find that increased AKT2 inhibits PGC-1α to downregulate SIRT5, which we identify as an AKT2 binding partner. Crosstalk between SIRT5 and AKT2 facilitates TFEB-dependent lysosomal function in the RPE. AKT2/SIRT5/TFEB pathway inhibition in the RPE induced lysosome/autophagy signaling abnormalities, disrupted mitochondrial function and induced release of debris contributing to drusen. Accordingly, AKT2 overexpression in the RPE caused a dry AMD-like phenotype in aging Akt2 KI mice, as evident from decline in retinal function. Importantly, we show that induced pluripotent stem cell-derived RPE encoding the major risk variant associated with AMD (complement factor H; CFH Y402H) express increased AKT2, impairing TFEB/TFE3-dependent lysosomal function. Collectively, these findings suggest that targeting the AKT2/SIRT5/TFEB pathway may be an effective therapy to delay the progression of dry AMD.

LONG-TERM PRESERVATION OF VISUAL ACUITY AFTER RESORPTION OF ACQUIRED VITELLIFORM LESIONS IN AGE-RELATED MACULAR DEGENERATION.

To report the long-term (23 years) clinical and multimodal imaging features of acquired vitelliform lesions (AVLs) associated with nonneovascular age-related macular degeneration. Retrospective case report. Color and red-free fundus photographs, high-resolution optical coherence tomography, fluorescein and indocyanine green angiography, and optical coherence tomography-angiography were performed. A 58-year-old man presented with bilateral AVLs in the setting of nonneovascular age-related macular degeneration. At baseline, his best-corrected visual acuity was 20/30 in his right eye and 20/20 in his left eye. Red-free fundus photographs showed AVLs with cuticular drusen in both eyes corresponding to a "stars-in-the-sky" pattern on fluorescein. Indocyanine green angiography showed no evidence of macular neovascularization. Throughout the 23-year follow-up, the patient reported consuming 20 mg/day of lutein supplement. At the end of follow-up, his best-corrected visual acuity was 20/20 in both eyes. Color fundus photographs showed resorption of the AVLs in both eyes and High-Res optical coherence tomography showed relative preservation of the outer retinal bands in the fovea. Optical coherence tomography-angiography confirmed the absence of macular neovascularization. In nonneovascular age-related macular degeneration, spontaneous resorption of AVLs may be associated with long-term maintenance of visual acuity and relative preservation of the outer retinal morphology.

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

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

Non-Neovascular Age-Related Macular Degeneration Assessment: Focus on Optical Coherence Tomography Biomarkers.

The imagistic evaluation of non-neovascular age-related macular degeneration (AMD) is crucial for diagnosis, monitoring progression, and guiding management of the disease. Dry AMD, characterized primarily by the presence of drusen and retinal pigment epithelium atrophy, requires detailed visualization of the retinal structure to assess its severity and progression. Several imaging modalities are pivotal in the evaluation of non-neovascular AMD, including optical coherence tomography, fundus autofluorescence, or color fundus photography. In the context of emerging therapies for geographic atrophy, like pegcetacoplan, it is critical to establish the baseline status of the disease, monitor the development and expansion of geographic atrophy, and to evaluate the retina's response to potential treatments in clinical trials. The present review, while initially providing a comprehensive description of the pathophysiology involved in AMD, aims to offer an overview of the imaging modalities employed in the evaluation of non-neovascular AMD. Special emphasis is placed on the assessment of progression biomarkers as discerned through optical coherence tomography. As the landscape of AMD treatment continues to evolve, advanced imaging techniques will remain at the forefront, enabling clinicians to offer the most effective and tailored treatments to their patients.

Association Between Quantitative and Qualitative Imaging Biomarkers and Geographic Atrophy Growth Rate

Investigate associations between geographic atrophy (GA) growth rate and multimodal imaging biomarkers and patient demographics in patients with advanced non-neovascular age-related macular degeneration (nnAMD). Prospective cohort study. One hundred twenty-one eyes of 66 patients with advanced nnAMD with GA enrolled in the University of Colorado AMD Registry from August 2014 to June 2021, with follow-up through June 2023. Multimodal images were reviewed by two graders for imaging biomarkers at enrollment. GA growth rate and square-root transformed (SQRT) GA growth rate were measured between enrollment and final visit. Associations between the outcome SQRT GA growth rate and imaging biomarkers, baseline GA lesions characteristics, and patient demographics were evaluated. Average GA growth rate was 1.430 mm2/year and SQRT GA growth rate was 0.268 mm/year over a mean of 3.7 years. SQRT GA growth rate was positively associated with patient age (P = .010) and female sex (0.035), and negatively associated with body mass index (0.041). After adjustment for these demographic factors, SQRT GA growth rate was positively associated with presence of non-exudative subretinal fluid (P < .001), non-exudative subretinal hyperreflective material (P = .037), and incomplete retinal pigment epithelium and outer retina atrophy (P = .022), and negatively associated with subfoveal choroidal thickness (P = .031) and presence of retinal pseudocysts (P = .030). Larger baseline GA size at enrollment was associated with faster GA growth rate (P = .002) but not SQRT GA growth rate. Select patient demographic factors and basic clinically-relevant imaging biomarkers were associated with GA growth rate. These biomarkers may guide patient selection when considering treating GA patients with novel therapeutics.

Short term effects of extremely low irradiance photobiomodulation on retinal function, in age related macular degeneration.

recently much studies evidenced the potential role of photo-biomodulation (PBM) in patients affected by Age-related Macular Degeneration (AMD). We designed a new wearable device for self-medication that employs the same broadband red light described in literature, but with extremely low irradiance. to demonstrate the safety and effectiveness of low-fluence light stimulations emitted by a LED source with appropriate wavelengths through our new device in improving short-term visual function in patients affected by severe non neovascular AMD. we prospectively enrolled patients affected by severe non-neovascular AMD with a relative sparing of the foveal region. All the patients were randomly assigned in placebo or in treatment group. The treatment consisted of 10 sessions of 10-min each, using the new device comprised of micro-LEDs that emitted light onto an amorphous support assembled within Metallic eyeglasses. The placebo group blindly underwent the same number of PBM sessions with the micro-LED turned off. Before and after each placebo/treatment sessions all the patients received: optical coherence tomography (OCT), Best-Corrected Visual Acuity (BCVA) and Microperimetry (MP). no significant differences in the anatomical parameters were observed in the two groups. The MP mean sensitivity and the central visual function both far and near significantly improved in the treated group (respectively p < 0.001, p < 0.001). our pivotal demonstrated that the LED PBM delivered through our new device is a safe and effective tool for improving short-term visual function in patients affected by severe non-neovascular AMD.

Serous maculopathy with absence of retinal pigment epithelium (SMARPE) associated with large drusen

PurposeTo describe the association of serous maculopathy with absence of retinal pigment epithelium (SMARPE) and large drusen in patients with non-neovascular age-related macular degeneration (AMD).MethodsA retrospective study of ophthalmic examination and multimodal imaging data of individuals with SMARPE and large drusen observed over a period of 12-month was accomplished. SMARPE was defined as subretinal accumulation of fluid within the macular area due to retinal pigment epithelium (RPE) aperture. Large drusen were identified by the presence of sub-RPE deposits using multimodal imaging analysis (color fundus photography, fundus autofluorescence, and spectral-domain optical coherence tomography).ResultsTwelve eyes of 7 white patients with a mean age of 77 years were observed to have SMARPE associated with large drusen. The median visual acuity was 20/100. Bilateral SMARPE lesions were observed in 71% of study patients. All SMARPE lesions were hypoautofluorescent, located in the subretinal space between the RPE and the ellipsoid zone, and presented as complete or incomplete RPE apertures associated with subretinal fluid. The SMARPE in this study had coincident multimodal imaging features as the SMARPE described in other reports in the literature.ConclusionsBilateral SMARPE can occur in association with typical AMD large drusen. Anomalisms resulting in drusen biogenesis or mechanisms that act alongside to these may be related to SMARPE development.

Telehealth improves follow-up and monitoring of age-related macular degeneration during the COVID-19 pandemic.

To prevent vision loss, it is important to monitor patients with age-related macular degeneration (AMD) for the development of choroidal neovascularization. The coronavirus disease 2019 (COVID-19) pandemic caused many patients to miss or delay visits. To offset those gaps in care, providers utilized telehealth (TH) to evaluate patients for symptoms of disease progression and provide health education on the importance of continuous monitoring. This study evaluates the impact of TH encounters on the rate of return for recommended in-person examinations for 1103 patients with non-neovascular (dry) AMD seen in an outpatient ophthalmology clinic in 2019 and due for return evaluation after the outbreak of COVID-19 in 2020. Logistic regression analysis was used to identify demographic, clinical, and sociomedical factors associated with TH utilization and in-person return. 422 patients (38%) utilized TH during the study period. Patients who completed a TH encounter were more likely to return for an in-person examination as compared with those who did not receive TH (OR: 1.8, CI 95%: 1.4-2.3, P < 0.001). Completing a TH visit was associated with the detection of new wet AMD (OR: 3.3, 95% CI 1.04-10.6, P = 0.043), as well as with an earlier return for those patients who were found to have disease progression (62 ± 54days vs. 100 ± 57days, P = 0.049). Completing a TH visit increased the rate at which patients with dry AMD returned for recommended in-person eye examinations. In many cases, this permitted the earlier detection of wet AMD, which is linked with achieving better outcomes.

Targeted High-Density Microperimetry Testing of Nascent Geographic Atrophy in Age-Related Macular Degeneration

To examine the effectiveness of a targeted high-density microperimetry testing strategy for detecting visual sensitivity abnormalities in eyes with nascent geographic atrophy (nGA) when compared with standard central microperimetry testing. Observational study. Three-hundred and twenty-one eyes from 176 individuals with nonneovascular age-related macular degeneration (AMD). Thirty-five eyes from 33 participants underwent targeted high-density microperimetry testing of atrophic lesions (either nGA or geographic atrophy [GA]) within a 1.75° radius (or approximately 1000 μm diameter) region. Another cohort of 286 eyes from 143 participants with bilateral large drusen at baseline underwent standard microperimetry testing of the central 6° radius region at 6-monthly intervals for up to 36 months and thus included eyes that developed nGA and GA over the follow-up. All eyes underwent 2 tests at each visit to evaluate intrasession measurement repeatability. Magnitude of visual sensitivity abnormalities based on mean sensitivity (MS), pointwise sensitivity standard deviation (PSD), and the number of test locations with a threshold of ≤ 10 decibels (dB; or deep defects) in eyes with nGA, compared between eyes that underwent targeted high-density microperimetry testing and standard central microperimetry testing. The magnitude of visual sensitivity abnormalities based on MS, PSD and the number of deep defects were all significantly greater in eyes with nGA using targeted, high-density microperimetry testing compared with eyes with nGA using standard central microperimetry testing (all P < 0.001) and were all significantly less than eyes with GA using targeted, high-density microperimetry testing (all P ≤ 0.004). The intrasession coefficient of repeatability, where 95% of the test-retest differences are expected to occur, for MS in eyes with atrophic changes was 0.9 dB with the targeted, high-density microperimetry testing, and 1.8 dB with standard central microperimetry testing. Targeted, high-density microperimetry testing enabled the detection of a significantly greater magnitude of visual sensitivity abnormalities in eyes with nGA than standard microperimetry testing. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Association of Metformin and Other Diabetes Medication Use and the Development of New-Onset Dry Age-Related Macular Degeneration: A Case-Control Study.

To investigate if metformin use is associated with decreased odds of developing new non-neovascular ("dry") age-related macular degeneration (AMD). Case-control study examining 194,135 cases with diagnoses of new-onset AMD between 2008 and 2017 and 193,990 matched controls in the Merative MarketScan Research Databases. The diabetic subgroup included 49,988 cases and 49,460 controls. Multivariable conditional logistic regressions identified the risks of exposures on the development of dry AMD. Main outcome measures were odds ratios (ORs) of developing dry AMD with metformin use. In multivariable conditional logistic regression, any metformin use was associated with decreased odds of developing dry AMD (OR = 0.97; 95% confidence interval [CI], 0.95-0.99). This protective effect was noted for cumulative 2-year doses of metformin of 1 to 270 g (OR = 0.93; 95% CI, 0.90-0.97) and 271 to 600 g (OR = 0.92; 95% CI, 0.89-0.96). In a diabetic subgroup, metformin use below 601 g per 2 years decreased the odds of developing dry AMD (1-270 g: OR = 0.95; 95% CI, 0.91-0.99; 271-600 g: OR = 0.92; 95% CI, 0.89-0.96). Unlike in diabetic patients with diabetic retinopathy, diabetic patients without diabetic retinopathy had decreased odds of developing dry AMD with any metformin use (OR = 0.97; 95% CI, 0.94-0.998) and cumulative two-year doses of 1 to 270 g (OR 0.96; 95% CI, 0.91-0.998) and 271 to 600 g (OR = 0.92; 95% CI, 0.88-0.96). Metformin use was associated with decreased odds of developing dry AMD. The protective effect was observed for cumulative 2-year doses below 601 g. In diabetics, this association persisted, specifically in those without diabetic retinopathy. Therefore, metformin may be a strategy to prevent development of dry AMD.

Investigation of the choroidal structure in non-neovascular age-related macular degeneration patients with reticular pseudodrusen

BackgroundThis study aimed to compare choroidal thickness, total choroidal area (TCA), luminal area (LA), stromal area (SA) and choroidal vascularity index (CVI) in patients with reticular pseudodrusen (RPD) and drusen. MethodsA total of 100 eyes of 100 patients with non-neovascular age related macular degeneration (AMD) with five or more medium drusen (63–125 µm) and RPD in two or more quadrants were recruited to the study. 48 eyes of 48 patients with RPD were assigned as Group 1 and 52 eyes of 52 patients with drusen were assigned as Group 2. 40 right eyes of 40 healthy subjects were included as controls. Patients with neovascular AMD or advanced non-neovascular AMD were excluded from the study. After a detailed ophthalmic examination, infrared reflectance images and OCT with enhanced depth imaging mode was obtained from all patients. TCA, SA, LA and CVI were calculated using the Image J program. The data were analyzed for statistics using SPSS software. ResultsThe female/male ratio was 56/44 in the patient groups and 20/20 in the control group. The mean age was 73.63±6.14 (61–91) years for Group 1 and 69.43± 6.97 (59–87) years for Group 2 (p=0.005). The mean age of Group 3 patients was 71.14±8.17 (60–79) years and was statistically similar to Groups 1 and 2 (p=0.09 and p=0.12, respectively). Choroidal thickness, TCA, SA and LA were significantly lower in Group 1 (p<0.001). CVI and foveal thicknesses were not significantly different between Group 1 and 2 (p=0.214 and p=0.384 respectively). CVI was significantly lower in Group 3 (p<0.01). RPD was most commonly seen in the superior quadrant followed by temporal, nasal, and inferior quadrants. ConclusionsTCA, SA and LA, which reflect choroidal vasculature, were decreased in patients with RPD. These parameters can help evaluate the pathophysiology of the disease.

Analysis of Retinol Binding Protein 4 and ABCA4 Gene Variation in Non-Neovascular Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) may be associated with ABCA4 variants and is characterized by the accumulation of visual cycle-byproduct lipofuscin. Reducing retinol-binding protein 4 (RBP4), a retinol transporter protein, may reduce lipofuscin production. This study aims to assess the associations between plasma RBP4, the ABCA4 variation, and AMD severity. Sixty-seven participants were grouped into healthy/mild AMD (n = 32) and severe AMD (n = 35) groups. The latter group was older than the former group and had higher levels of RBP4 (36.8 ± 8.3 vs. 30.4 ± 7.0 μg/mL, p = 0.0012). The ten participants with six ABCA4 linked-variants had higher RBP4 than those without (37.8 ± 7.7 vs. 32.4 ± 7.9 μg/mL; p = 0.026), and eight of them had severe AMD. Univariate analyses showed that severe AMD was related to older age (OR, 1.26; 95% CI, 1.13-1.40; p < 0.0001) and to higher RBP4 levels (OR, 1.12; 95% CI, 1.04-1.20; p = 0.003), whereas the linked ABCA4 variants had no associations. After adjustment, however, only age remained significantly associated with severe AMD. This pilot study shows a trend of higher plasma RBP4 levels in severe AMD or the ABCA4-linked variants, and further age-matched studies are warranted.

Genetic variants in the adenosine triphosphate-binding cassette transporter A1 and risk of age-related macular degeneration

Genetic variants in ABCA1 are associated with higher concentrations of high-density lipoprotein (HDL) cholesterol. Higher HDL cholesterol concentrations are observationally and genetically associated with higher risk of age-related macular degeneration (AMD). However, whether amino acid-changing genetic variants in ABCA1 associated with high HDL cholesterol concentrations confer a higher risk of AMD in the general population is currently unknown. We tested this hypothesis. The study included 80,972 individuals (1,370 AMD cases) from the Copenhagen General Population Study (CGPS) and 9,584 individuals (142 AMD cases) from the Copenhagen City Heart Study (CCHS) with 10 to 18 years of follow-up. We created an HDL cholesterol weighted allele score based on amino acid-changing ABCA1 variants with a minor allele frequency above 0.001 and divided it into tertiles. The study included 55% women. Mean age was 58 years. The ABCA1 allele score for the third versus the first tertile was associated with HRs (95% confidence intervals (CIs)) of 1.30 (1.14–1.49) for all-cause AMD, 1.26 (1.06–1.50) for nonneovascular AMD, and 1.31 (1.12–1.53) for neovascular AMD in a multivariable adjusted model. On a continuous scale, higher concentrations of genetically determined HDL cholesterol were associated with higher risk of all-cause AMD, nonneovascular AMD, and neovascular AMD in an age- and sex adjusted model and in a multivariable adjusted model. In conclusion, amino acid-changing genetic variants in ABCA1 associated with higher HDL cholesterol concentrations were also associated with higher risk of AMD, suggesting a role for ABCA1 in AMD pathogenesis.