Age-related Macular Degeneration

Age-related Macular Degeneration (AMD) Publications

Claessens D, Ichhpujani P, Singh RB. MacuFix® versus Amsler grid for metamorphopsia categorization for macular diseases. Int Ophthalmol 2021;Abstract
PURPOSE: Macular diseases often lead to metamorphopsia, which is traditionally tested using the Amsler grid. This study evaluates a novel method for assessing metamorphopsia, based on the software AMD-A Metamorphopsia Detector, application MacuFix®. METHODS: In this observational study, the usability of a new smartphone-based testing method to assess metamorphopsia was evaluated in 45 patients experiencing metamorphopsia in at least one eye using the questionnaire "System Usability Score (SUS)." Additionally, the diagnostic adherence of self-monitoring with the Amsler grid was compared to self-monitoring with the novel software MacuFix®. RESULTS: The average score of the SUS questionnaire in this study was 76.7 ± 15.5, corresponding to the "good" score on the grading scale. The average interval between two home administered tests was significantly shorter (6 days) when the application was used as compared to using the Amsler grid (19 days). The odds ratio of the frequency of patients using the application to the patients using the home test was 4. CONCLUSION: MacuFix® application can help in effective home monitoring of macular function as high user satisfaction and increased testing frequency was observed in its use in patients with macular diseases.
Ludwig CA, Vail D, Rajeshuni NA, Al-Moujahed A, Rosenblatt T, Callaway NF, Pasricha MV, Ji MH, Moshfeghi DM. Statins and the progression of age-related macular degeneration in the United States. PLoS One 2021;16(8):e0252878.Abstract
PURPOSE: To study the effect of statin exposure on the progression from non-exudative to exudative age-related macular degeneration (AMD). METHODS: Retrospective cohort study of commercially insured patients diagnosed with non-exudative AMD (n = 231,888) from 2007 to 2015. Time-to-event analysis of the association between exposure to lipid-lowering medications and time from non-exudative AMD to exudative AMD diagnosis was conducted. Outcome measures included progression to exudative AMD, indicated by diagnosis codes for exudative AMD or procedural codes for intravitreal injections. RESULTS: In the year before and after first AMD diagnosis, 11,330 patients were continuously prescribed lipid-lowering medications and 31,627 patients did not take any lipid-lowering medication. Of those taking statins, 21 (1.6%) patients were on very-high-dose lipophilic statins, 644 (47.6%) on high-dose lipophilic statins, and 689 (50.9%) on low-dose lipophilic statins. We found no statistically significant relationship between exposure to low (HR 0.89, 95% CI 0.83 to 1.38) or high-dose lipophilic statins (HR 1.12, 95% CI 0.86 to 1.45) and progression to exudative AMD. No patients taking very-high-dose lipophilic statins converted from non-exudative to exudative AMD, though this difference was not statistically significant due to the subgroup size (p = .23, log-rank test). CONCLUSIONS: No statistically significant relationship was found between statin exposure and risk of AMD progression. Interestingly, no patients taking very-high-dose lipophilic statins progressed to exudative AMD, a finding that warrants further exploration.
Saddala MS, Lennikov A, Mukwaya A, Yang X, Tang S, Huang H. Data mining and network analysis reveals C-X-C chemokine receptor type 5 is involved in the pathophysiology of age-related macular degeneration. J Biomol Struct Dyn 2021;:1-10.Abstract
Our previous studies found that the C-X-C motif chemokine receptor 5 (CXCR5) loss leads to retinal pigment epithelium (RPE) dysfunction and AMD pathogenesis. The current study aimed to characterize the G protein-coupled receptor (GPCR) structure of CXCR5 and analyze its interactions with AMD-related risk genes. The sequence alignments, homology model of CXCR5 and structural assessment analysis were performed. Data and text mining were then performed to identify AMD-related risk genes and their interaction with CXCR5 using statistical and mathematical algorithms. Sequence alignment and phylogenetic tree analysis revealed that human CXCR5 was highly similar (85.4839%) to the rabbit. The least similarity (33.871%) was found to be in zebrafish compared to the other species. The CXCR5 model structural assessment and secondary structure analysis exhibited an excellent model. Network analysis revealed that IL10, TNF, ICAM1, CXCL1, CXCL8, APP, TLR4, SELL, C3, IL17A and CCR2 were the most connected genes CXCR5. These findings suggest that CXCR5 signaling may regulate the biological function of RPE and modulate AMD pathophysiology via GPCR signaling and interacting with identified AMD risk genes. In summary, the data presented here provide novel and crucial insights into the molecular mechanisms of CXCR5 involvement in AMD.Communicated by Ramaswamy H. Sarma.
Hibert ML, Chen Y, Ohringer N, Feuer WJ, Waheed NK, Heier JS, Calhoun MW, Rosenfeld PJ, Polimeni JR. Altered Blood Flow in the Ophthalmic and Internal Carotid Arteries in Patients with Age-Related Macular Degeneration Measured Using Noncontrast MR Angiography at 7T. AJNR Am J Neuroradiol 2021;Abstract
BACKGROUND AND PURPOSE: Age-related macular degeneration is associated with reduced perfusion of the eye; however, the role of altered blood flow in the upstream ophthalmic or internal carotid arteries is unclear. We used ultra-high-field MR imaging to investigate whether the diameter of and blood flow in the ophthalmic artery and/or the ICA are altered in age-related macular degeneration and whether any blood flow changes are associated with disease progression. MATERIALS AND METHODS: Twenty-four patients with age-related macular degeneration and 13 similarly-aged healthy controls participated. TOF and high-resolution dynamic 2D phase-contrast MRA (0.26 × 0.26 × 2mm3, 100-ms effective sampling rate) was acquired at 7T. Vessel diameters were calculated from cross-sectional areas in phase-contrast acquisitions. Blood flow time-series were measured across the cardiac cycle. RESULTS: The ophthalmic artery vessel diameter was found to be significantly smaller in patients with age-related macular degeneration than in controls. Volumetric flow through the ophthalmic artery was significantly lower in patients with late age-related macular degeneration, with a significant trend of decreasing volumetric ophthalmic artery flow rates with increasing disease severity. The resistance index was significantly greater in patients with age-related macular degeneration than in controls in the ophthalmic artery. Flow velocity through the ophthalmic artery and ICA was significantly higher in patients with age-related macular degeneration. Ophthalmic artery blood flow as a percentage of ipsilateral ICA blood flow was nearly double in controls than in patients with age-related macular degeneration. CONCLUSIONS: These findings support the hypothesis that vascular changes upstream to the eye are associated with the severity of age-related macular degeneration. Additional investigation into the potential causality of this relationship and whether treatments that improve ocular circulation slow disease progression is warranted.
Pundlik S, Nigalye A, Laíns I, Mendez KM, Katz R, Kim J, Kim IK, Miller JB, Vavvas D, Miller JW, Luo G, Husain D. Area under the dark adaptation curve as a reliable alternate measure of dark adaptation response. Br J Ophthalmol 2021;Abstract
PURPOSE: Quantification of dark adaptation (DA) response using the conventional rod intercept time (RIT) requires very long testing time and may not be measurable in the presence of impairments due to diseases such as age-related macular degeneration (AMD). The goal of this study was to investigate the advantages of using area under the DA curve (AUDAC) as an alternative to the conventional parameters to quantify DA response. METHODS: Data on 136 eyes (AMD: 98, normal controls: 38) from an ongoing longitudinal study on AMD were used. DA was measured using the AdaptDx 20 min protocol. AUDAC was computed from the raw DA characteristic curve at different time points, including 6.5 min and 20 min (default). The presence of AMD in the given eye was predicted using a logistic regression model within the leave-one-out cross-validation framework, with DA response as the predictor while adjusting for age and gender. The DA response variable was either the AUDAC values computed at 6.5 min (AUDAC6.5) or at 20 min (AUDAC20) cut-off, or the conventional RIT. RESULTS: AUDAC6.5 was strongly correlated with AUDAC20 (β=86, p<0.001, R=0.87). The accuracy of predicting the presence of AMD using AUDAC20 was 76%, compared with 79% when using RIT, the current gold standard. In addition, when limiting AUDAC calculation to 6.5 min cut-off, the predictive accuracy of AUDAC6.5 was 80%. CONCLUSIONS: AUDAC can be a valuable measure to quantify the overall DA response and can potentially facilitate shorter testing duration while maintaining diagnostic accuracy.
Ji MH, Callaway NF, Ludwig CA, Vail D, Al-Moujahed A, Rosenblatt TR, Leng T, Sanislo SR, Moshfeghi DM. Visual acuity and progression of macular atrophy in patients receiving intravitreal anti-VEGF for age-related macular degeneration. Eur J Ophthalmol 2021;:11206721211001708.Abstract
PURPOSE: Whether intravitreal anti-vascular endothelial growth factors (VEGFs) cause retinal atrophy is still a subject of debate. We reported 13 eyes that received several injections of anti-VEGF for wet age-related macular degeneration (AMD) with good visual acuity despite geographic atrophy on imaging. METHODS: This is a case series study conducted at Byers Eye Institute at Stanford University. Patients of three retina specialists with wet AMD who received six or more intravitreal injection of anti-VEGFs with visual acuity of 20/60 or better and incomplete RPE and outer retina atrophy (iRORA) or complete RPE and outer retinal atrophy (cRORA) were enrolled in this case series. Different imaging modalities were reviewed by three retina specialists comparing the baseline with the most recent exam. RESULTS: About 13 eyes of 10 patients met the selection criteria. Eleven eyes were classified as iRORA and 2 as cRORA. Despite the development of macular atrophy on imaging after an average of 38.1 injections, eyes maintained stable visual acuity. CONCLUSION: The discrepancy between structural and functional findings in this cohort suggests that patients treated by anti-VEGF drugs exhibit divergent clinical outcomes for currently unknown reasons. The authors propose anti-VEGF may affect melanosomes within RPE without disrupting RPE and photoreceptors function completely. This requires further investigation.
Gnanaguru G, Wagschal A, Oh J, Saez-Torres KL, Li T, Temel RE, Kleinman ME, Näär AM, D'Amore PA. Targeting of miR-33 ameliorates phenotypes linked to age-related macular degeneration. Mol Ther 2021;29(7):2281-2293.Abstract
Abnormal cholesterol/lipid homeostasis is linked to neurodegenerative conditions such as age-related macular degeneration (AMD), which is a leading cause of blindness in the elderly. The most prevalent form, termed "dry" AMD, is characterized by pathological cholesterol accumulation beneath the retinal pigment epithelial (RPE) cell layer and inflammation-linked degeneration in the retina. We show here that the cholesterol-regulating microRNA miR-33 was elevated in the RPE of aging mice. Expression of the miR-33 target ATP-binding cassette transporter (ABCA1), a cholesterol efflux pump genetically linked to AMD, declined reciprocally in the RPE with age. In accord, miR-33 modulated ABCA1 expression and cholesterol efflux in human RPE cells. Subcutaneous delivery of miR-33 antisense oligonucleotides (ASO) to aging mice and non-human primates fed a Western-type high fat/cholesterol diet resulted in increased ABCA1 expression, decreased cholesterol accumulation, and reduced immune cell infiltration in the RPE cell layer, accompanied by decreased pathological changes to RPE morphology. These findings suggest that miR-33 targeting may decrease cholesterol deposition and ameliorate AMD initiation and progression.
Perepelkina T, Fulton AB. Artificial Intelligence (AI) Applications for Age-Related Macular Degeneration (AMD) and Other Retinal Dystrophies. Semin Ophthalmol 2021;36(4):304-309.Abstract
Artificial intelligence (AI), with its subdivisions (machine and deep learning), is a new branch of computer science that has shown impressive results across a variety of domains. The applications of AI to medicine and biology are being widely investigated. Medical specialties that rely heavily on images, including radiology, dermatology, oncology and ophthalmology, were the first to explore AI approaches in analysis and diagnosis. Applications of AI in ophthalmology have concentrated on diseases with high prevalence, such as diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration (AMD), and glaucoma. Here we provide an overview of AI applications for diagnosis, classification, and clinical management of AMD and other macular dystrophies.
Gong D, Kras A, Miller JB. Application of Deep Learning for Diagnosing, Classifying, and Treating Age-Related Macular Degeneration. Semin Ophthalmol 2021;36(4):198-204.Abstract
Age-related macular degeneration (AMD) affects nearly 200 million people and is the third leading cause of irreversible vision loss worldwide. Deep learning, a branch of artificial intelligence that can learn image recognition based on pre-existing datasets, creates an opportunity for more accurate and efficient diagnosis, classification, and treatment of AMD on both individual and population levels. Current algorithms based on fundus photography and optical coherence tomography imaging have already achieved diagnostic accuracy levels comparable to human graders. This accuracy can be further increased when deep learning algorithms are simultaneously applied to multiple diagnostic imaging modalities. Combined with advances in telemedicine and imaging technology, deep learning can enable large populations of patients to be screened than would otherwise be possible and allow ophthalmologists to focus on seeing those patients who are in need of treatment, thus reducing the number of patients with significant visual impairment from AMD.
Wai KM, Vingopoulos F, Garg I, Kasetty M, Silverman RF, Katz R, Laíns I, Miller JW, Husain D, Vavvas DG, Kim LA, Miller JB. Contrast sensitivity function in patients with macular disease and good visual acuity. Br J Ophthalmol 2021;Abstract
INTRODUCTION: Contrast sensitivity function (CSF) may better estimate a patient's visual function compared with visual acuity (VA). Our study evaluates the quick CSF (qCSF) method to measure visual function in eyes with macular disease and good letter acuity. METHODS: Patients with maculopathies (retinal vein occlusion, macula-off retinal detachment, dry age-related macular degeneration and wet age-related macular degeneration) and good letter acuity (VA ≥20/30) were included. The qCSF method uses an intelligent algorithm to measure CSF across multiple spatial frequencies. All maculopathy eyes combined and individual macular disease groups were compared with healthy control eyes. Main outcomes included area under the log CSF (AULCSF) and six CS thresholds ranging from 1 cycle per degree (cpd) to 18 cpd. RESULTS: 151 eyes with maculopathy and 93 control eyes with VA ≥20/30 were included. The presence of a maculopathy was associated with significant reduction in AULCSF (β: -0.174; p<0.001) and CS thresholds at all spatial frequencies except for 18 cpd (β: -0.094 to -0.200 log CS, all p<0.01) compared with controls. Reductions in CS thresholds were most notable at low and intermediate spatial frequencies (1.5 cpd, 3 cpd and 6 cpd). CONCLUSION: CSF measured with the qCSF active learning method was found to be significantly reduced in eyes affected by macular disease despite good VA compared with healthy control eyes. The qCSF method is a promising clinical tool to quantify subtle visual deficits that may otherwise go unrecognised by current testing methods.
Lains I, Pundlik SJ, Nigalye A, Katz R, Luo G, Kim IK, Vavvas DG, Miller JW, Miller JB, Husain D. Baseline Predictors Associated with Three-Year Changes in Dark Adaptation in Age-related Macular Degeneration. Retina 2021;Abstract
PURPOSE: To assess the relationship between baseline age-related macular degeneration (AMD) and disease stage, as well as optical coherence tomography (OCT) features seen in AMD, with three-year changes in dark adaptation (DA). METHODS: Prospective longitudinal study including patients with AMD and a comparison group (n=42 eyes, 27 patients). At baseline and three years, we obtained color fundus photographs, spectral-domain OCT and rod-mediated dark adaptation (20 minutes protocol). Multilevel mixed effect models were used for analyses, with changes in rod intercept time (RIT) at three years as the primary outcome. As some eyes (n=11) reached the DA testing ceiling value at baseline, we used three-year changes in area under the DA curve (AUDAC) as an additional outcome. RESULTS: Baseline AMD, AMD stage and hyperreflective foci on OCT were associated with larger changes in RIT at three years. When change in AUDAC was used as an outcome in addition to these features, the presence of retinal atrophy and drusenoid pigment epithelial detachment (PED) had significant associations. New subretinal drusenoid deposits at three years was also associated with more pronounced changes in RIT and AUDAC. CONCLUSIONS: Specific OCT features are associated with DA impairments over time, which supports that structural changes predict functional loss over three years.
Gonzalez-Buendia L, Delgado-Tirado S, An M, O'Hare M, Amarnani D, Whitmore HAB, Zhao G, Ruiz-Moreno JM, Arboleda-Velasquez JF, Kim LA. Treatment of Experimental Choroidal Neovascularization via RUNX1 Inhibition. Am J Pathol 2021;191(3):418-424.Abstract
Choroidal neovascularization (CNV) is a prevalent cause of vision loss in patients with age-related macular degeneration. Runt-related transcription factor 1 (RUNX1) has been identified as an important mediator of aberrant retinal angiogenesis in proliferative diabetic retinopathy and its modulation has proven to be effective in curbing pathologic angiogenesis in experimental oxygen-induced retinopathy. However, its role in CNV remains to be elucidated. This study demonstrates RUNX1 expression in critical cell types involved in a laser-induced model of CNV in mice. Furthermore, the preclinical efficacy of Ro5-3335, a small molecule inhibitor of RUNX1, in experimental CNV is reported. RUNX1 inhibitor Ro5-3335, aflibercept-an FDA-approved vascular endothelial growth factor (VEGF) inhibitor, or a combination of both, were administered by intravitreal injection immediately after laser injury. The CNV area of choroidal flatmounts was evaluated by immunostaining with isolectin B4, and vascular permeability was analyzed by fluorescein angiography. A single intravitreal injection of Ro5-3335 significantly decreased the CNV area 7 days after laser injury, and when combined with aflibercept, reduced vascular leakage more effectively than aflibercept alone. These data suggest that RUNX1 inhibition alone or in combination with anti-VEGF drugs may be a new therapy upon further clinical validation for patients with neovascular age-related macular degeneration.
Bontzos G, Bagheri S, Ioanidi L, Kim I, Datseris I, Gragoudas E, Kabanarou S, Miller J, Tsilimbaris M, Vavvas DG. Nonresponders to Ranibizumab Anti-VEGF Treatment Are Actually Short-term Responders: A Prospective Spectral-Domain OCT Study. Ophthalmol Retina 2020;4(12):1138-1145.Abstract
PURPOSE: To investigate the inter-individual variability in duration of anti-vascular endothelial growth factor (VEGF) treatment effect in neovascular age-related macular degeneration (nvAMD). DESIGN: Prospective observational multi-centered study. PARTICIPANTS: Forty-eight patients with nvAMD treated with anti-VEGF injections were included. Both treatment naive (n=25) as well as patients who had previously received treatment with ranibizumab (n=23) more than one month prior to their enrollment were recruited. METHODS: Patients received injection with ranibizumab (0.5 mg/0.05 ml) and were followed weekly for 4 weeks with spectral-domain OCT (SD-OCT) assessing the time to maximal reduction of central retinal thickness (CRT) and the presence of intraretinal and subretinal fluid. Other data collected included age, gender, visual acuity, axial length, lens status, and previous injections. The Shapiro-Wilk test was used to examine normal distributions for all variables. Correlations were examined by calculating Spearman's correlation coeficient. Distributions of quantitative variables are described as means (±SD). Qualitative variables are summarized by counts and percentage. MAIN OUTCOME MEASURES: Time to maximal reduction of CRT and intra- and subretinal fluid after ranibizumab injection. RESULTS: A total of 48 eyes of 48 patients (age 74.8±8.3 years, 62.5% female, 52% treatment naive, 35.4% pseudophakic) were assessed. Two-thirds (64.6%) reached maximal CRT reduction earlier than the standard 4-week interval: 6.3% at 1 week postinjection, 22.9% at 2 weeks postinjection, and 35.4% at 3 weeks postinjection. Only 35.4% of patients had maximal CRT reduction at 4 weeks. Twenty percent of treatment-naive and 34.8% of non-naive patients had a week-4 CRT that was >35 μm thicker than the earlier occuring lowest CRT value (nadir). The time to maximal CRT reduction was not related to axial length, age, lens status, or history of injections. CONCLUSIONS: Optimal dosing interval for maximal CRT reduction may be less than 4 weeks for a significant proportion of patients. Most patients will be classified as complete responders if intervals less than 4 weeks are used to assess anti-VEGF treatment response. Disease load rather than eye size appears to be the driver of anti-VEGF treatment duration and therefore, dosing interval needs to be optimized in the cohort of short-term responders.
Narayanan D, Rodriguez J, Wallstrom G, Welch D, Chapin M, Arrigg P, Abelson M. An exploratory study to evaluate visual function endpoints in non-advanced age-related macular degeneration. BMC Ophthalmol 2020;20(1):424.Abstract
BACKGROUND: To prevent irreversible vision loss in age-related macular degeneration (AMD), it is critical to detect retinal dysfunction before permanent structural loss occurs. In the current study we evaluated a series of visual function tests to identify potential endpoints to detect visual dysfunction in non-advanced AMD. METHODS: A series of visual function tests were performed on 23 non-advanced AMD subjects (AREDS grade 1-4 on simplified scale) and 34 age-matched normals (AREDS grade 0). Tests included some commonly used endpoints such as ETDRS visual acuity (VA), low luminance (LL) 2.0ND ETDRS VA, MNREAD as well as newly developed tests such as the Ora-VCF™ test, Ora-tablet reading test, color sensitivity etc. Differences between the two groups were compared for each test. Test-retest repeatability and reproducibility was assessed on a subset of subjects and percent agreement was calculated. RESULTS: There was no difference in standard ETDRS VA between non-advanced AMD (0.06 ± 0.02 logMAR) and normal groups (0.04 ± 0.02 logMAR) (p = 0.57). LL 2.0 ETDRS VA and MNREAD showed no difference between the groups (p > 0.05). Ora-VCF™ test was significantly worse in the non-advanced AMD group compared to normals (0.67 ± 0.07 in AMD; 0.45 ± 0.04 in normals, p = 0.005). Non-advanced AMD subjects also had significantly worse reading performance using the Ora-tablet with LL 2.0ND (114.55 ± 11.22 wpm in AMD; 145.17 ± 9.55 wpm in normals p = 0.049). No significant difference between the groups was noted using other tests. Repeatability was 82% for Ora-VCF™ test and 92% for Ora-tablet LL 2.0ND reading. Reproducibility was 89% for both Ora-VCF™ test and Ora-tablet LL 2.0ND reading. CONCLUSION: While there was no significant difference between non-advanced AMD and normal groups using some current common endpoints such as ETDRS VA, LL 2.0 ETDRS VA or MNREAD, Ora-VCF™ test and Ora-tablet LL 2.0ND reading tests were able to identify significant visual dysfunction in non-advanced AMD subjects. These tests show promise as endpoints for AMD studies.
Roh M, Miller JW, Jeng-Miller KW, Wang JC, Laíns I, Silverman RF, Loewenstein JI, Husain D, Vavvas DG, Miller JB. Subthreshold Exudative Choroidal Neovascularization Associated With Age-Related Macular Degeneration Identified by Optical Coherence Tomography Angiography. J Vitreoretin Dis 2020;4(5):377-385.Abstract
Purpose: This article describes the clinical and multimodal imaging characteristics of subthreshold exudative choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD). Methods: Among 3773 patients with AMD, 8 eyes (6 patients) were identified with the clinical phenotype of interest. Dilated fundus examinations, color fundus photography, fluorescein angiography (FA), indocyanine green angiography (ICGA), optical coherence tomography (OCT), and OCT angiography (OCTA) were performed. Results: OCT typically showed a moderately reflective irregular pigment epithelial detachment with overlying subretinal fluid (SRF). Traditional FA did not show leakage and ICGA showed no definitive neovascular network or hot spots. However, OCTA clearly demonstrated a CNV within the pigment epithelial detachment. The majority of our cases (7 of 8) did not receive antivascular endothelial growth factor (anti-VEGF) injections, and visual acuity remained stable over the available follow-up period of I to 10 years. Conclusions: CNV is often associated with SRF and vision loss in AMD, usually requiring frequent anti-VEGF injections. OCTA allowed us to better identify CNV not readily detected on FA and ICGA. Although some have suggested early clinical intervention with anti-VEGF injections in any case with fluid and confirmed CNV on OCTA, we describe a subset of AMD patients with SRF who may be better managed by observation. These cases may represent a more indolent, mature, and stable vascular network.

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