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Purpose: In aging and early-intermediate age-related macular degeneration (AMD), rod-mediated dark adaptation (RMDA) slows more at 5° superior than at 12°. Using optical coherence tomography angiography (OCTA), we asked whether choriocapillaris flow deficits are related to distance from the fovea., Methods: Persons ≥60 years stratified for AMD via the Age-Related Eye Disease Study's nine-step system underwent RMDA testing. Two adjacent 4.4° × 4.4° choriocapillaris OCTA slabs were centered on the fovea and 12° superior. Flow signal deficits (FD%) in concentric arcs (outer radii in mm, 0.5, 1.5, 2.2, 4.0, and 5.0 superior) were correlated with rod intercept time (RIT) and best-corrected visual acuity (BCVA)., Results: In 366 eyes (170 normal, 111 early AMD, 85 intermediate AMD), FD% was significantly worse with greater AMD severity in all regions (overall P < 0.05) and poorest under the fovea (P < 0.0001). In pairwise comparisons, FD% worsened with greater AMD severity (P < 0.05) at distances <2.2 mm. At greater distances, eyes with intermediate, but not early AMD differed from normal eyes. Foveal FD% was more strongly associated with longer RIT at 5° (r = 0.52) than RIT at 12° (r = 0.39) and BCVA (r = 0.21; all P < 0.0001). Choroidal thickness was weakly associated with longer RIT at 5° and 12° (r = 0.10-0.20, P < 0.05) and not associated with AMD severity., Conclusions: Reduced transport across the choriocapillaris-Bruch's membrane-retinal pigment epithelium complex, which contributes to drusen formation under the macula lutea (and fovea), may also reduce retinoid resupply to rods encircling the high-risk area. FD% has potential as a functionally validated imaging biomarker for AMD emergence.

Purpose: We aimed to identify structural differences in normal eyes, early age-related macular degeneration (AMD), and intermediate AMD eyes using optical coherence tomography (OCT) in a well-characterized, large cross-sectional cohort., Methods: Subjects ≥ 60 years with healthy normal eyes, as well as early or intermediate AMD were enrolled in the Alabama Study on Age-related Macular Degeneration 2 (ALSTAR2; NCT04112667). Using Spectralis HRA + OCT2, we obtained macular volumes for each participant. An auto-segmentation software was used to segment six layers and sublayers: photoreceptor inner and outer segments, subretinal drusenoid deposits (SDDs), retinal pigment epithelium + basal lamina (RPE + BL), drusen, and choroid. After manually refining the segmentations of all B-scans, mean thicknesses in whole, central, inner and outer rings of the ETDRS grid were calculated and compared among groups., Results: This study involved 502 patients, 252 were healthy, 147 had early AMD, and 103 had intermediate AMD eyes (per Age-Related Eye Disease Study [AREDS] 9-step). Intermediate AMD eyes exhibited thicker SDD and drusen, thinner photoreceptor inner segments, and RPE compared to healthy and early AMD eyes. They also had thicker photoreceptor outer segments than early AMD eyes. Early AMD eyes had thinner photoreceptor outer segments than normal eyes but a thicker choroid than intermediate AMD eyes. Using the Beckman scale, 42% of the eyes initially classified as early AMD shifted to intermediate AMD, making thickness differences for photoreceptor outer segments and choroid insignificant., Conclusions: With AMD stages, the most consistent structural differences involve appearance of drusen and SDD, followed by RPE + BL thickness, and then thickness of photoreceptor inner and outer segments. Structural changes in the transition from aging to intermediate AMD include alterations in the outer retinal bands, including the appearance of deposits on either side of the RPE.

Objective: The objective of this study was to determine whether high-resolution OCT (HR-OCT) could enhance the identification and classification of atrophic features in age-related macular degeneration (AMD) compared with standard resolution OCT., Design: Prospective, observational, cross-sectional study., Subjects: The study included 60 eyes from 60 patients > 60 years of age with a diagnosis of AMD., Methods: The participants underwent volume OCT scanning using HR-OCT and standard resolution OCT devices. Trained graders reviewed and graded the scans, identifying specific regions of interest for subsequent analysis., Main Outcome Measures: The study focused on identifying and classifying complete retinal pigment epithelium (RPE) and outer retinal atrophy (cRORA), incomplete RORA (iRORA), and other nonatrophic AMD features. Additionally, qualitative and quantitative features associated with atrophy were assessed., Results: The agreement among readers for classifying atrophic lesions was substantial to perfect for both HR-OCT (0.88) and standard resolution OCT(0.82). However, HR-OCT showed a higher accuracy in identifying iRORA lesions compared with standard OCT. Qualitative assessment of features demonstrated higher agreement for HR-OCT, particularly in identifying external limiting membrane (ELM) (0.95) and ellipsoid zone (EZ) disruption (0.94). Quantitative measurements of features such as hypertransmission defects, RPE attenuation/disruption, EZ disruption width, and ELM disruption width showed excellent interreader agreement with HR-OCT (> 0.90 for all features) but only moderate agreement with standard OCT (0.51-0.60)., Conclusions: The study results suggest that HR-OCT improves the accuracy and reliability of classifying and quantifying atrophic lesions associated with AMD compared with standard resolution OCT. The quantitative findings in particular may have implications for future research and clinical practice, especially with the availability of therapeutic agents for treating geographic atrophy and the development of commercially available HR-OCT devices., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the progression of atrophy as determined by spectral-domain optical coherence tomography (SD-OCT) in patients with molecularly confirmed PROM1-associated retinal degeneration (RD) over a 24-month period., Design: International, multicenter, prospective case series., Methods: A total of 13 eyes (13 patients) affected with PROM1-associated RD were enrolled at 5 sites and SD-OCT images were obtained at baseline and after 24 months. Loss of mean thickness (MT) and intact area were estimated after semi-automated segmentation for the following individual retinal layers in the central subfield (CS), inner ring, and outer ring of the ETDRS grid: retinal pigment epithelium (RPE), outer segments (OS), inner segments (IS), outer nuclear layer (ONL), inner retina (IR), and total retina (TR)., Results: Statistically significant losses of thickness of RPE and TR were detected in the CS and inner ring and of ONL and IS in the outer ring (all P < .05); a statistically significant decrease in the intact area of RPE and IS was observed in the inner ring, and of ONL in the outer ring (all P < .05); the change in MT and the intact area of the other layers showed a trend of decline over an observational period of 24 months., Conclusions: Significant thickness losses could be detected in outer retinal layers by SD-OCT over a 24-month period in patients with PROM1-associated retinal degeneration. Loss of thickness and/or intact area of such layers may serve as potential endpoints for clinical trials that aim to slow down the disease progression of PROM1-associated retinal degeneration., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Lack of valid end points impedes developing therapeutic strategies for early age-related macular degeneration (AMD). Delayed rod-mediated dark adaptation (RMDA) is the first functional biomarker for incident early AMD. The relationship between RMDA and the status of outer retinal bands on optical coherence tomography (OCT) have not been well defined. This study aims to characterize these relationships in early and intermediate AMD., Methods: Baseline data from 476 participants was assessed including eyes with early AMD (n = 138), intermediate AMD (n = 101), and normal aging (n = 237). Participants underwent volume OCT imaging of the macula and rod intercept time (RIT) was measured. The ellipsoid zone (EZ) and interdigitation zone (IZ) on all OCT B-scans of the volumes were segmented. The area of detectable EZ and IZ, and mean thickness of IZ within the Early Treatment Diabetic Retinopathy Study (ETDRS) grid were computed and associations with RIT were assessed by Spearman's correlation coefficient and age adjusted., Results: Delayed RMDA (longer RIT) was most strongly associated with less preserved IZ area (r = -0.591; P < 0.001), followed by decreased IZ thickness (r = -0.434; P < 0.001), and EZ area (r = -0.334; P < 0.001). This correlation between RIT and IZ integrity was not apparent when considering normal eyes alone within 1.5 mm of the fovea., Conclusions: RMDA is correlated with the status of outer retinal bands in early and intermediate AMD eyes, particularly, the status of the IZ. This correlation is consistent with a previous analysis of only foveal B-scans and is biologically plausible given that retinoid availability, involving transfer at the interface attributed to the IZ, is rate-limiting for RMDA.

Purpose: This study aimed to investigate the correspondence between intraretinal hyperreflective foci (IHRF) identified on optical coherence tomography (OCT) B-scans with hyperpigmentation on colour fundus photography (CFP) or hyperreflectivity on infrared reflectance (IR) images in eyes with age-related macular degeneration (AMD)., Methods: Flash CFP, IR images and OCT B-scans obtained at the same visit were evaluated. Individual IHRF identified on OCT B-scans were assessed for the qualitative presence or absence of a hypotransmission tail into the choroid. The corresponding IR image obtained at the time of OCT acquisition was analysed for the presence or absence of hyperreflectivity in this region. The IR images were manually registered to the CFP image, and CFP images were inspected for the presence or absence of hyperpigmentation at the location of IHRF., Results: From 122 eyes, a total of 494 IHRF were evaluated. For the primary analysis of qualitative presence or absence of hyperpigmentation on CFP and hyperreflectivity on IR at the locations corresponding to IHRF on OCT, 301 (61.0%) of the IHRFs demonstrated evidence of hyperpigmentation on CFP, while only 115 (23.3%) showed evidence of hyperreflectivity on IR. The qualitative determination of the presence or absence of an abnormality on CFP or IR were significantly different (p < 0.0001). 327 (66.2%) of the IHRF showed hypotransmission, and 80.4% of these IHRF showed hyperpigmentation on CFP, though only 23.9% (p < 0.0001) demonstrated hyperreflectivity on IR., Conclusions: Less than two-thirds of IHRF evident on OCT manifest as hyperpigmentation on colour photos, though IHRF with posterior shadowing are more likely to be evident as pigment. IR imaging appears to be even more poorly sensitive for visualizing IHRF., (© 2023 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: To investigate the imaging features preceding the occurrence of type 3 (T3) macular neovascularization (MNV) using tracked spectral-domain optical coherence tomography., Method: From a cohort of eyes with T3 MNV and ≥ 12 months of previously tracked spectral-domain optical coherence tomography, T3 lesions that developed above soft drusen were selected for optical coherence tomography analysis. Retinal imaging findings at the location where type T3 MNV occurred were analyzed at each follow-up until the onset of T3 MNV. The following optical coherence tomography parameters were assessed: drusen size (height and width), outer nuclear layer/Henle fiber layer thickness at the drusen apex, and the presence of intraretinal hyperreflective foci, retinal pigment epithelium disruption, incomplete retinal pigment epithelium and outer retina atrophy, and complete retinal pigment epithelium and outer retina atrophy., Results: From a cohort of 31 eyes with T3 MNV, T3 lesions developed above soft drusen in 20 eyes (64.5%). Drusen showed progressive growth ( P < 0.001) associated with outer nuclear layer/Henle fiber ( P < 0.001) thinning before T3 MNV. The following optical coherence tomography features were identified preceding the occurrence of T3 MNV, typically at the apex of the drusenoid lesion: disruption of the external limiting membrane/ellipsoid zone and/or the retinal pigment epithelium, hyperreflective foci, and incomplete retinal pigment epithelium and outer retina atrophy/complete retinal pigment epithelium and outer retina atrophy., Conclusion: The results demonstrate specific anatomic alterations preceding the occurrence of T3 MNV that most commonly originates above soft drusen. Drusen growth, reduced outer nuclear layer/Henle fiber thickness, and retinal pigment epithelium atrophy at the drusen apex precede the development of T3 MNV. Identifying these optical coherence tomography features should warrant close monitoring for identification of T3 MNV, which can benefit from prompt intravitreal anti-vascular endothelial growth factor therapy.

Purpose: To evaluate the impact of pigment epithelial detachment (PED) thickness (i.e., height) and thickness variability on best-corrected visual acuity outcomes in patients with neovascular age-related macular degeneration in the Phase 3 HAWK and HARRIER trials., Methods: Optical coherence tomography images from the pooled brolucizumab 6 mg and aflibercept 2 mg arms were analyzed for the maximum PED thickness across the macula at baseline through to week 96. Best-corrected visual acuity outcomes were compared in patients with different PED thickness and variability cut-off thresholds., Results: Greater PED thickness at baseline or at week 12 was associated with lower mean best-corrected visual acuity gain from baseline to week 96 (baseline PED ≥200 µ m: +4.6 letters; <200 µ m: +7.0 letters; week 12 PED ≥100 µ m: +5.6 letters; <100 µ m: +6.6 letters). Eyes with the largest PED thickness variability from week 12 through week 96 gained fewer letters from baseline at week 96 (≥33 µ m: +3.3 letters; <9 µ m: +6.2 letters). Furthermore, increased PED thickness at week 48 was associated with higher prevalence of intraretinal and subretinal fluid., Conclusion: In this treatment-agnostic analysis, greater PED thickness and PED thickness variability were associated with poorer visual outcomes in patients with neovascular age-related macular degeneration and greater neovascular activity., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

Purpose: To evaluate the optical coherence tomography (OCT) features of hyperpigmented lesions in the absence of intraretinal hyperreflective foci (IHRF) on OCT in eyes with age-related macular degeneration (AMD)., Methods: We retrospectively analyzed OCT images of eyes with intermediate AMD (iAMD) and macular hyperpigmentation (HP) on color fundus photograph (CFP) but without IHRF on OCT in the corresponding location. The most prominent or definite HP was selected for analysis. The infrared reflectance (IR) image registered with the CFP, and the location corresponding to the HP lesion were defined on the IR image. The location of the HP on the corresponding OCT B-scan was assessed for retinal pigment epithelium (RPE) elevation, acquired vitelliform lesion (AVL), abnormal retinal pigment epithelium + basal lamina (RPE + BL) band reflectivity, RPE + BL band thickening, as well as interdigitation zone (IZ), ellipsoid zone (EZ) and external limiting membrane (ELM) disruption., Results: 49 eyes (39 patients) were included in this study. Forty-six (94%) of the hyperpigmented lesions showed a thickened RPE + BL band. RPE + BL band reflectivity was increased in 37 (76%) of the lesions. RPE + BL band thickening, however, was not correlated with RPE + BL band reflectivity (p-value = 0.31). Either thickening or hyperreflectivity of the RPE + BL band was present in all cases. Twenty (41%) lesions had evidence of ELM disruption, 42 (86%) demonstrated EZ disruption and 48 (98%) had IZ disruption. Five (10%) HPs demonstrated AVL. Among cases with RPE elevation (15 cases, 31%), 10 were classified as drusen, 2 as drusenoid PEDs, and 3 as fibrovascular PEDs., Conclusions: Thickening and/or hyperreflectivity of the RPE + BL band commonly correspond to regions of macular hyperpigmentation without IHRF in eyes with iAMD.

Purpose: To determine the prevalence and rate of persistence over 2 years of various-sized hypertransmission defects (hyperTDs) in eyes with intermediate age-related macular degeneration., Methods: Retrospective analysis of optical coherence tomography data from consecutive intermediate age-related macular degeneration patients. Choroidal en face optical coherence tomography images were evaluated for the presence and number of hyperTDs of three different sizes based on greatest linear dimension (small, 63-124 µ m; medium, 125-249 µ m; large, ≥250 µ m) at baseline and at the 2-year follow-up. Interreader agreement was determined by Gwet's agreement coefficient. Disagreements between graders were resolved by the senior investigator to yield a single consensus for all cases., Results: From 273 intermediate age-related macular degeneration eyes (247 patients), 72 and 76 hyperTD lesions were independently identified by two graders at baseline and overall agreement coefficient was 0.89 (95% CI, 0.86-0.93). After adjudication by the senior grader, the final consensus yielded 78 hyperTD lesions from 46 eyes (16.8%) of 42 patients (17.0%) in this study cohort. Among eyes with follow-up optical coherence tomography, 32 of 45 hyperTD lesions (71.1%) persisted. The rates of persistence were 100.0%, 72.7%, and 53.3% in large, medium, and small hyperTD sizes, respectively., Conclusion: HyperTDs were present in a significant proportion of intermediate age-related macular degeneration eyes. Acceptable interreader agreement was demonstrated in identifying hyperTD. Larger hyperTD lesions were more likely to persist over 2 years.

Introduction: The aim of this study was to evaluate the progression of atrophy as determined by spectral-domain optical coherence tomography (SD-OCT) in patients with molecularly confirmed ABCA4-associated Stargardt disease type 1 (STGD1) over a 24-month period in a multicenter prospective cohort study., Methods: SD-OCT images from 428 eyes of 236 patients were analyzed. Change of mean thickness (MT) and intact area were estimated after semiautomated segmentation for the following individual layers in the central subfield (CS), inner ring (IR), and outer ring (OR) of the ETDRS grid: retinal pigment epithelium (RPE), outer segments (OSs), inner segments (IS), outer nuclear layer (ONL) inner retina (IR), and total retina., Results: Statistically significant decreases of all outer retinal layers (RPE, OS, IS, and ONL) could be observed over a 24-month period both in decline of mean retinal thickness and intact area (p &lt; 0.0001, respectively), whereas the IR showed an increase of retinal thickness in the CS and IR and remained unchanged in the OR., Conclusions: Significant loss could be detected in outer retinal layers by SD-OCT over a 24-month period in patients with STGD1. Loss of thickness and/or intact area of such layers may serve as potential endpoints for clinical trials that aim to slow down the disease progression of STGD1., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background/aims: To evaluate efficacy, safety, pharmacokinetics (PK) and immunogenicity of SB15 versus reference aflibercept (AFL), and switching from AFL to SB15 in neovascular age-related macular degeneration (nAMD)., Design: Prospective, double-masked, randomised, phase 3 trial., Methods: Participants with nAMD were randomised 1:1 to receive SB15 (N=224 participants) or AFL (N=225). At week 32, participants either continued on SB15 (SB15/SB15, N=219) or AFL (AFL/AFL, N=108), or switched from AFL to SB15 (AFL/SB15, N=111). This manuscript reports 1-year and switching results of secondary efficacy endpoints such as changes from baseline to week 56 in best-corrected visual acuity (BCVA), central subfield thickness (CST, from internal limiting membrane (ILM) to retinal pigment epithelium), and total retinal thickness (TRT, from ILM to Bruch's membrane). Additional endpoints included safety, PK and immunogenicity., Results: Efficacy results were comparable between groups. The least squares mean (LSmean) change in BCVA from baseline to week 56 was 7.4 letters for SB15/SB15 and 7.0 letters for AFL/AFL (difference (95% CI)=0.4 (-2.5 to 3.2)). The LSmean changes from baseline to week 56 in CST and TRT were -119.2 µm and -132.4 µm for SB15/SB15 and -126.6 µm and -136.3 µm for AFL/AFL, respectively (CST: difference (95% CI)=7.4 µm (-6.11 to 20.96); TRT: difference (95% CI)=3.9 µm (-18.35 to 26.10)). Switched and non-switched participants showed similar LSmean changes in BCVA from baseline to week 56 (AFL/SB15, 7.9 letters vs AFL/AFL, 7.8 letters; difference (95% CI)=0.0 (-2.8 to 2.8)). Safety, PK and immunogenicity were comparable between groups., Conclusions: Efficacy, safety, PK and immunogenicity were comparable between SB15 and AFL and between switched and non-switched participants., Competing Interests: Competing interests: WC, IO and HJ are employed by Samsung Bioepis. Samsung Bioepis funded medical writing support and article processing charges. Additional potential conflicts of interest are listed below. SJW obtained consulting fees from Samsung Bioepis, Janssen, Novartis, Curacle, Novelty Nobility, Sometech, Rznomics and Pharmabcine, grants from Samsung Bioepis, Novelty Nobility, Novartis, Alteogen, Roche, Geneunitech, Bayer, Bio Bank Healing, and Curacle, and payments for lectures from Novartis, Bayer, and Allergan-Abbvie. He serves as equity owner of Retimark and Panolos Bioscience. SRS obtained consulting fees from Apellis, Amgen, Abbvie/Allergan, Samsung Bioepis, Biogen, Boerhinger Ingelheim, Iveric, Novartis, Roche, Bayer, Regeneron, Pfizer, Astellas, Nanoscope, Jannsen, Centervue, Optos and Heidelberg, and honoraria for lectures from Novartis, Roche, Optos, and Heidelberg. He is part of the Data Safety Monitoring/Advisory Board of Regeneron and holds leadership/fiduciary functions in ARVO and Macula Society. MB obtained honoraria for presentations by Novartis and Abbvie. He is part of the advisory board of Novartis and obtained grants for clinical trials from Iveric Bio (former Optotech), Novartis, Roche, Ophthea and Samsung Bioepis. AV obtained consulting fees and honoraria for lectures from Novartis, Roche, Pfizer, Bausch & Lomb, Zeiss, and Alcon. He also obtained support for meeting attendances by Novartis, Pfizer, Bausch & Lomb, Roche, Zeiss, Alcon, Iveric Bio, Amgen, Chengdu, Mylan, Panoptica, Formycon, Thrombogenics, Regeneron and Clearside. He is part of the Data Safety Monitoring/Advisory Board of Zeiss, Bayer, Novartis, Pfizer, and Roche. MS obtained grants from Allergan/Abbvie, Bayer and Novartis, consulting fees from Samsung Bioepis, Bayer, Novartis, Allergan/Abbvie, Roche, Alcon and Curacle, honoraria for lectures from Samsung Bioepis, Bayer, Novartis, Allergan/Abbvie, Roche, Alcon and Johnson & Johnson, and support for meeting attendances from Bayer, Allergan/Abbvie and Novartis. Min Sagong is part of the Data Safety Monitoring/Advisory board of Bayer, Novartis, and Allergan/Abbvie. JS obtained consulting fees from Abbvie and support for meeting attendances from Bayer. MV obtained consulting fees from Abbvie and Roche and support for meeting attendances from Bayer. EW obtained honoraria for lectures from Bayer, Roche, Alfa Sigma, Allergan, Zeiss and Thea, and is part of the advisory board of Allergan. SP obtained grants from Aerie, Aerpio, Allergan, Allgenesis, Apellis, Boehringer Ingelheim, Chengdu Kanghong, Clearside, EyePoint, Genentech-Roche, Ionis Pharmaceuticals, IVERIC Bio, KalVista, Kodiak Sciences, Mylan, Novartis, Oculis, Opthea, Ora, Oxurion, Regeneron, Samsung, SmileBiotek, Stealth Biotherapeutics, ThromboGenics, Xbrane Biopharma, consulting fees from AiViva, Allergan, Allgenesis, Genentech-Roche, Kala, Kodiak Sciences, Oxugenix, and RegenxBio, and support for travel expenses from EyePoint. He is part of the Data Safety Monitoring/Advisory Board of Allergan, Allgenesis Biotherapeutics, Genentech-Roche, Kodiak Sciences, and Iveric Bio and serves as equity owner and chief medical officer for Allgenesis Biotherapeutics. WC received consulting fees from Samsung Bioepis and payments for lectures from Bayer, Novartis and Chong Kun Dang., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To describe the course of non-neovascular fluid in age-related macular degeneration (AMD) after anti-vascular endothelial growth factor (anti-VEGF) therapy or after observation without injections., Design: Retrospective case series., Methods: AMD eyes with macular drusen and (or) drusenoid pigment epithelial detachment associated with non-neovascular fluid were included. Optical coherence tomography (OCT) angiography was performed in all eyes to exclude the presence of macular neovascularization. Subretinal fluid (SRF) was measured to determine the response after anti-VEGF therapy and after observation without injections., Results: Ten eyes of 9 patients with intermediate AMD and SRF were studied over a median period of 59.5 months (range, 7-128 months). Six patients (6 eyes) had a history of anti-VEGF therapy. Median follow-up off injections was 13.5 months (range, 4-44 months). SRF thickness remained stable and unchanged during the follow-up off injections in all eyes (n = 6) with prior injection and in all eyes (n = 4) that had never been injected. Six eyes developed complete retinal pigment epithelial (RPE) and outer retinal atrophy, and 1 eye developed incomplete RPE and outer retinal atrophy. All eyes exhibited at least 2 OCT biomarkers associated with a high risk for progression to atrophy., Conclusion: This study provides preliminary data regarding the progression of non-neovascular fluid in AMD with or without anti-VEGF injections. A possible mechanism for fluid development may be related to RPE pump impairment. Distinguishing neovascular versus non-neovascular fluid using multimodal imaging, including OCT angiography, is essential to avoid unnecessary anti-VEGF therapy. An observe-and-extend regimen may be considered in AMD eyes with non-neovascular fluid., (Published by Elsevier Inc.)

Purpose: To assess the relationship between the distribution of intra-retinal hyper-reflective foci (IHRF) on optical coherence tomography (OCT) and progression of intermediate age-related macular degeneration (iAMD) over 2 years., Methods: Cirrus OCT volumes of the macula of subjects enrolled in the Amish Eye Study with 2 years of follow-up were evaluated for the presence of iAMD and IHRF at baseline. The IHRF were counted in a series of 5 sequential en face slabs from outer to inner retina. The number of IHRF in each slab at baseline and the change in IHRF from baseline to year 2 were correlated with progression to late AMD at 2 years., Results: Among 120 eyes from 71 patients with iAMD, 52 eyes (43.3%) of 42 patients had evidence of both iAMD and IHRF at baseline. Twenty-three eyes (19.0%) showed progression to late AMD after 2 years. The total IHRF count increased from 243 at baseline to 604 at 2 years, with a significant increase in the IHRF number in each slab, except for the innermost slab 5 which had no IHRF at baseline or follow-up. The IHRF count increased from 121 to 340 in eyes that showed progression to late AMD. The presence of IHRF in the outermost retinal slabs 1 and 2 was independently associated with a significant risk of progression to late AMD. A greater increase in IHRF count over 2 years in these same slabs 1 and 2 was also associated with a higher risk of conversion to late AMD., Conclusions: The risk of progression to late AMD appears to be significantly associated with the distribution and extent of IHRF in the outermost retinal layers. This observation may point to significant pathophysiologic differences of IHRF in inner versus outer layers of the retina., (© 2023. The Author(s).)

Background: To evaluate whether the status of vasculature at the top of type 1 macular neovascularisation (MNV) could function as mediator of the observed protective effect against the development of complete retinal pigment epithelial and outer retinal atrophy (cRORA)., Methods: In consecutive treatment-naïve patients, the vasculature at the anterior surface of the MNV was isolated using a slab designed to extract the most superficial vascular portion of the MNV lesion showing a choriocapillaris (CC)-like structure which we termed the 'neo-CC'. The ratio between the neo-CC area (isolated using this custom slab) and the MNV area (isolated using the standard outer retina-CC slab) at baseline and at last follow-up was evaluated., Results: Forty-four eyes from 44 patients were included. 20 showed cRORA by the final follow-up (median 23 months), whereas 24 did not progress to atrophy (median 23.5 months). The proportion of MNV with neo-CC at the anterior surface was significantly lower in eyes which progressed to cRORA compared with those which did not. The multivariate regression showed that a lower proportion of neo-CC coverage over the MNV was associated with an increased odds for cRORA development., Conclusions: More extensive coverage of neo-CC is associated with a lower likelihood of development of macular atrophy in eyes receiving antivascular endothelial growth factor therapy, suggesting the protective effect of a type 1 MNV may be mediated by the development of a neo-CC and may provide insights into the biological significance of MNV as a response mechanism in eyes with age-related macular degeneration., Competing Interests: Competing interests: GS reports personal fees from Heidelberg Engineering; grants, personal fees and others from Zeiss Meditec; grants from Optovue; grants and others from Optos; grants, personal fees and others from Centervue; grants from Nidek; grants, personal fees and others from Novartis; personal fees and others from Bayer; others from Boeheringer, Allergan, Alcon, outside the submitted work. DS reports consulting fees from Amgen, Bayer, Genetech and Optovue and has received grant support from Heidelberg, Regeneron, Topcon. KBF reports consulting fees from Heidelberg Engineering, Zeiss, Allergan, Bayer, Genentech, Regeneron and Novartis; and research support from Genentech/Roche outside the submitted work. SRS reports consulting fees from Amgen, Allergan, Regeneron, Roche/Genentech, Novartis, Merck, 4DMT, Optos, Heidelberg and Centervue; and also receiving research instruments from Topcon, Nidek, Heidelberg, Centervue, Optos and Carl Zeiss Meditec, outside the submitted work., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To compare drusen size metrics (apical height and basal width) on optical coherence tomography (OCT) B-scans with their size assessed on color photos in eyes with age-related macular degeneration (AMD) and normal aging., Methods: A total of 508 drusen were evaluated in this analysis. Flash color fundus photos (CFP), infrared reflectance (IR) images, and OCT B-scans obtained at the same visit were evaluated. Individual drusen were identified on CFPs and the diameters of the drusen were measured in planimetric grading software. CFPs were manually registered to the IR image with their corresponding OCT volume. After confirming correspondence between the CFP and OCT, the apical height and basal width of the same drusen were measured on OCT B-scans., Results: Drusen were divided into small, medium, large, and very large categories based on their diameter on the CFP images (< 63, 63 to 124, 125 to 249, and [Formula: see text] 250 μm, respectively). The OCT apical height of small drusen on CFP ranged from 20 to 31 μm, while medium drusen ranged from 31 to 46 μm, large drusen ranged from 45 μm to 111 µm, and very large drusen ranged from 55 μm to 208 μm. The OCT basal width measured < 99 μm in small drusen, from 99 to 143 μm in medium drusen, from 141 to 407 µm in large drusen, and > 209 µm in very large drusen., Conclusion: Drusen of different size categories on color photographs may also be separated according to their apical height and basal width on OCT. The apical height and basal width ranges defined in this analysis may be of value in the design of an OCT-based grading scale for AMD., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Progress toward treatment and prevention of age-related macular degeneration (AMD) requires imaging end points that relate to vision. We investigated choriocapillaris flow signal deficits (FD%) and visual function in eyes of individuals aged ≥60 years, with and without AMD., Methods: One eye of each participant in the baseline visit of the Alabama Study on Early Age-Related Macular Degeneration 2 (ALSTAR2; NCT04112667) was studied. AMD presence and severity was determined using the Age-Related Eye Disease Study (AREDS) grading system. FD% was quantified using macular spectral domain optical coherence tomography angiography (OCTA) scans. Vision tests included rod-mediated dark adaptation (RMDA), best-corrected visual acuity, and contrast sensitivity (photopic and mesopic), and microperimetric light sensitivity (scotopic, mesopic, and photopic). Presence of subretinal drusenoid deposits (SDD) was determined using multimodal imaging., Results: In 410 study eyes of 410 participants (mean [SD] age = 71.7 years [5.9]), FD% was higher in early AMD (mean [SD] = 54.0% [5.5], N = 122) and intermediate AMD (59.8% [7.4], N = 92), compared to normal (52.1% [5.3], N = 196) eyes. Among visual functions evaluated, RMDA showed the strongest association with FD% (r = 0.35, P < 0.0001), followed by contrast sensitivity (r = -0.22, P < 0.0001). Eyes with SDD had worse FD% (58.3% [7.4], N = 87), compared to eyes without SDD (53.4% [6.0], N = 323, P = < 0.0001)., Conclusions: Choriocapillaris FD% were associated with AMD severity and with impaired vision, especially RMDA. Reduced metabolic transport and exchange across the choriocapillaris-Bruch's membrane retinal pigment epithelium (RPE) complex, a causal factor for high-risk soft drusen formation, also may impair photoreceptor sustenance from the circulation. This includes retinoid resupply, essential to dynamic rod function.

Despite the success of antiangiogenic therapy in controlling exudation in neovascular age-related macular degeneration (nAMD), the involvement of the outer retina in fibrosis results in gradual vision loss over time. The development of drugs that prevent or ameliorate fibrosis in nAMD requires that it is accurately detected and quantified with reliable endpoints and identification of robust biomarkers. Achievement of such an aim is currently challenging due to the lack of a consensus definition of fibrosis in nAMD. As a first step towards the establishment of a clear definition of fibrosis, we provide an extensive overview of the imaging modalities and criteria used to characterize fibrosis in nAMD. We observed variety in the selection of individual and combinations of imaging modalities, and criteria for detection. We also observed heterogeneity in classification systems and severity scales for fibrosis. The most commonly used imaging modalities were color fundus photography, fluorescein angiography and optical coherence tomography (OCT). A multimodal approach was frequently utilized. Our review suggests that OCT offers a more detailed, objective and sensitive characterization than color fundus photography/fluorescein angiography. Thus, we recommend it as a primary modality for fibrosis evaluation. This review provides a basis for future discussions to reach a consensus definition using standardized terms based on a detailed characterization of fibrosis, its presence and evolution, and taking into consideration impact on visual function. Achieving this goal is of paramount importance for the development of antifibrotic therapies., Competing Interests: Declaration of Competing Interest IB: employee of F. Hoffmann La-Roche Ltd. BGA: employee of F. Hoffmann La-Roche Ltd. SY: employee of F. Hoffmann La-Roche Ltd. RJ: employee of F. Hoffmann La-Roche Ltd. AE: former employee of F. Hoffmann La-Roche Ltd. CG: employee of F. Hoffmann La-Roche Ltd. DP: The author reports no proprietary or commercial interest in any product mentioned or concept discussed in this article. SRS: Consultant for Abbvie/Allergan, Amgen, Apellis, CenterVue, Heidelberg Engineering, Iveric Bio, Pfizer, Novartis, Optos, Oxurion, Roche/Genentech, Biogen, Boehringer-Ingelheim, Janssen, Alexion, Alnylam, Astellas, Bayer, Regeneron, Samsung Bioepis; Honoraria/Speaker Fees: Nidek, Topcon, Heidelberg Engineering, Optos, Novartis, Roche; Recipient of research instruments from Carl Zeiss Meditec, Nidek, Optos, Topcon, Heidelberg Engineering, CenterVue; Research Grant: Carl Zeiss Meditec. UC: Consultant to Abbvie, Alimera, Apellis, Amgen, Deepeye, Iveric, Kyowa Kirin, Retina AI, F. Hoffmann-La Roche Ltd., Unity. SF: employee of F. Hoffmann La-Roche Ltd., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: This study evaluated the relationship between statin use and the age of onset of age-related macular degeneration (AMD)., Methods: Electronic Health Records from 52,840 patients evaluated at University of California Los Angeles (UCLA) Ophthalmology Clinics and 9,977 patients evaluated at University of California San Francisco (UCSF) Ophthalmology Clinics were screened. Survival analysis was performed using Cox proportional hazards regression models and visualized using Kaplan Meier survival curves, with the following covariates-sex, ethnicity, smoking history, fluoxetine use, obesity, diabetes mellitus, and hypertension., Results: 5,498 of 52,840 patients at UCLA were diagnosed with AMD. Statin use was associated with a later AMD onset (HR = 0.8823, p < 0.0001), while female sex (HR = 1.0852, p= 00,035), obesity (HR = 1.4555, p < 0.0001), and fluoxetine (HR = 1.3797, p= 0.0003) were associated with an earlier AMD onset. Non-hispanic black (HR = 0.5687, p < 0.0001) and hispanic ethnicities (HR = 0.8269, p= 0.0028) were associated with a later AMD onset. When stratifying for ethnicity, statins, fluoxetine, sex, and obesity were significant only within non-hispanic white subjects. Statin use was significant among patients with dry AMD (HR = 0.8410, p= 0.0001) but not wet AMD (0.9188, p= 0.0351). In the replication cohort, 526 of 9,977 patients at UCSF had AMD. Associations between statins (HR = 0.7643, p= 0.0033), non-hispanic black ethnicity (HR = 0.5043, p= 0.0035), and obesity (HR = 1.9602, p < 0.0001) on AMD onset were confirmed., Conclusions: In both cohorts, statin use and non-hispanic black ethnicity are associated with a later AMD onset, while obesity with an earlier AMD onset., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Importance: Aflibercept biosimilars can expand available treatment options in retinal diseases and have the potential to improve patient access to safe and effective therapy., Objective: To establish equivalence in efficacy and similarity in safety, pharmacokinetics, and immunogenicity of SB15 and reference aflibercept (AFL) in neovascular age-related macular degeneration (nAMD)., Design, Setting, and Participants: This was a randomized double-masked parallel group phase 3 trial conducted at 56 centers in 10 countries from June 2020 to March 2022, including follow-up through 56 weeks. Of 549 screened participants, 449 participants 50 years and older with treatment-naive nAMD were included and randomly assigned to SB15 (n = 224) or AFL (n = 225). Key exclusion criteria included considerable scarring, fibrosis, atrophy, and hemorrhage. This report includes results up to the end of the parallel group period at week 32. Of the 449 randomized participants, 438 (97.6%) completed week 32 follow-up., Intervention: Participants were randomized 1:1 to receive 2 mg of SB15 or AFL every 4 weeks for the first 12 weeks (3 injections), followed by dosing every 8 weeks up to week 48, with final assessments at week 56., Main Outcomes and Measures: The primary end point was the change in best-corrected visual acuity (BCVA) from baseline to week 8 with predefined equivalence margins of -3 letters to 3 letters. Other key end points were changes in BCVA and central subfield thickness up to week 32, safety, pharmacokinetics, and immunogenicity., Results: The mean (SD) age among the 449 included participants was 74.0 (8.1) years, and 250 participants (55.7%) were female. Baseline demographic characteristics and most disease characteristics were comparable between treatment groups. The least squares mean change in BCVA from baseline to week 8 in the SB15 group was equivalent to that in the AFL group (6.7 letters vs 6.6 letters, respectively; difference, 0.1 letters; 95% CI, -1.3 to 1.4). Comparable efficacy between treatment groups was maintained up to week 32 (least squares mean change from baseline in BCVA: SB15, 7.6 letters vs AFL, 6.5 letters; least squares mean change from baseline in central subfield thickness: SB15, -110.4 μm vs AFL, -115.7 μm). No clinically relevant differences were observed in the incidence of treatment-emergent adverse events (TEAEs) (SB15, 107/224 [47.8%] vs AFL, 98/224 [43.8%]) and ocular TEAEs in the study eye (SB15, 41/224 [18.3%] vs AFL, 28/224 [12.5%]). The serum concentration profiles and cumulative incidences of overall antidrug antibody positive participants were comparable., Conclusions and Relevance: In this phase 3 randomized clinical trial, SB15 and AFL showed equivalent efficacy and comparable safety, pharmacokinetics, and immunogenicity in participants with nAMD., Trial Registration: ClinicalTrials.gov Identifier: NCT04450329.

Purpose: To investigate the association of nascent geographic atrophy (GA) preceding the development of exudative type 3 macular neovascularization (MNV) in patients with age-related macular degeneration (AMD)., Design: Retrospective longitudinal study., Participants: Patients with AMD diagnosed with treatment-naive exudative type 3 MNV in 1 or both eyes were evaluated. Inclusion criteria included serial tracked structural OCT examinations for ≥ 2 years before the detection of exudative type 3 MNV., Methods: Clinical characteristics and retinal imaging, including structural OCT at baseline and at each follow-up examination, were analyzed. Eyes showing the presence of nascent GA during the follow-up were selected for analysis of prevalence, and clinical characteristics at the site of subsequent type 3 MNV development., Main Outcome Measures: Description of the prevalence and clinical characteristics of nascent GA at the site of subsequent type 3 MNV development., Results: Overall, 97 eyes affected by type 3 MNV meeting inclusion criteria were analyzed. Of 97 eyes (71 patients), 22 eyes of 21 patients (mean age 82 ± 9 years) showed nascent GA preceding exudative type 3 MNV. The observed prevalence of nascent GA preceding exudative type 3 MNV was 22.7% (95% confidence interval, 14.4%-31.0%). Exudative type 3 MNV developed a mean of 9 ± 6 months after detection of nascent GA. The presence of reticular pseudodrusen in the study eye did not significantly influence the timing of exudative type 3 MNV development after the observation of nascent GA (P > 0.1 in all analyses). Reduced best-corrected visual acuity was recorded at the exudative type 3 stage in comparison with the nascent GA stage (P = 0.003)., Conclusions: As nascent GA may precede the development of exudative type 3 MNV, the detection of nascent GA in eyes with AMD may warrant closer surveillance to identify early exudative type 3 MNV warranting treatment., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

The Henle fiber layer (HFL) is comprised of bundles of unmyelinated photoreceptor axons intermingled with outer Müller cell processes. The photoreceptor axons extend from the cell bodies located in the outer nuclear layer and radially project toward the outer plexiform layer, the inner third of which includes the synaptic junctional complexes and the outer two-thirds of which includes the HFL. The oblique path of the HFL provides unique structural and reflectance properties and this radial anatomy is highlighted in many macular disorders including those with macular star exudation and HFL hemorrhage. Recent investigations using multimodal imaging techniques, especially cross sectional and en face optical coherence tomography (OCT), have provided new perspectives regarding HFL disruption in retinal diseases. The aim of this review is to highlight the pathoanatomy and multimodal imaging, especially OCT, associated with HFL disruption that is present in various macular diseases. After describing the current knowledge of the embryology, anatomy, and physiology of the HFL, we review the existing imaging modalities that allow in vivo visualization of the HFL in the healthy and diseased retina. Finally, we report the clinical and imaging findings of acute HFL alteration in various macular disorders, including degenerative, inflammatory, and vascular conditions. Also, we propose a novel and signature OCT biomarker indicative of acute photoreceptor disruption involving the HFL, termed the "angular sign of HFL hyperreflectivity" (ASHH) of macular disease, to unify the pathoanatomy common to these various macular disorders and to provide clarity regarding the underlying pathogenesis., (Published by Elsevier Ltd.)

Purpose: To estimate the progression rate of atrophic lesions in Stargardt disease derived from fundus autofluorescence (FAF)., Design: International, multicenter, prospective cohort study., Methods: A total of 259 participants aged ≥6 years with disease-causing variants in the ABCA4 gene were enrolled from 9 centers and followed over a 24-month period. FAF images were obtained every 6 months, and areas of definitely decreased autofluorescence (DDAF) and decreased autofluorescence (DAF) were quantified. Progression rates were estimated from linear mixed models with time as the independent variable., Results: A total of 488 study eyes of 259 participants (88.8% with both eyes) were enrolled and images from 432 eyes were followed for 24 months. The overall estimated progression of DDAF was 0.74 mm 2 /y (95% CI 0.64-0.85, P < .0001) and that of DAF was 0.64 mm 2 /y (95% CI 0.57-0.71) over a 24-month period in univariate analysis. Growth rates were strongly dependent on baseline lesion area. After square root transformation, the DDAF growth rate was not dependent on baseline lesion radius (P = .11), whereas the DAF growth rate was dependent (P < .0001). Genotype was not found to significantly impact the growth rate of DDAF or DAF lesions., Conclusions: FAF may serve as a convenient monitoring tool and suitable end point for interventional clinical trials that aim to slow disease progression. DDAF and DAF lesion sizes at baseline are strong predicting factors for lesion area growth and can be partially accounted for by square root transformation., (Copyright © 2023. Published by Elsevier Inc.)

Objective: To use multimodal assessment (fluorescein angiography [FA], color fundus photography [CFP], and spectral-domain-OCT [SD-OCT]) to reevaluate macular atrophy (MA) and macular neovascularization (MNV) type in the HARBOR trial according to the consensus on neovascular age-related macular degeneration (nAMD) Nomenclature criteria; and to determine if there are any associations between baseline demographic factors, ocular characteristics, and treatment for nAMD and the development of MA by month 24., Design: Post hoc analysis of the phase III, randomized, multicenter, double-masked, controlled HARBOR trial (NCT00891735)., Subjects: Nine-hundred and twenty-two study eyes and 919 fellow eyes from the HARBOR trial., Methods: This post hoc analysis included patients with multimodal assessments on FA, CFP, and SD-OCT at baseline. A risk analysis for the development of MA was performed by multimodal assessment and SD-OCT on study eyes without MA at baseline that had completed SD-OCT assessments for MA at month 24., Main Outcome Measures: Development of MA in study eyes at month 24 and a risk analysis for developing MA at month 24 in study eyes that had no MA at baseline, as assessed by multimodal assessment., Results: Of 1097 patients in the HARBOR trial with nAMD and active subfoveal MNV, a total of 922 study eyes and 919 fellow eyes were included in the multimodal analysis of MNV. Macular atrophy assessment was performed on SD-OCT. Of these, 593 had no baseline MA and were included in the risk analysis for developing MA. In eyes with no detectable MA at baseline, a larger proportion of eyes with any MNV type 3 (including mixed type) at baseline developed new MA at month 24 (49.2%) than eyes with MNV type 1 (26.5%), type 2 (29.1%), or mixed type 1 and 2 (34.6%). Macular neovascularization type 3 and fellow eye MA were identified as risk factors for new MA development at month 24., Conclusions: Macular neovascularization type 3 was a strong risk factor for new MA development at month 24, with fellow eye MA also being identified as a predictor. No other variables, including ranibizumab treatment, were identified as risk factors for new MA development., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2023. Published by Elsevier Inc.)

Purpose: To evaluate cone photoreceptor density in clinically unremarkable retinal regions in patients with age-related macular degeneration (AMD) using adaptive optics scanning laser ophthalmoscopy (AOSLO)., Design: Prospective case series with normal comparison group., Methods: Ten eyes of 7 patients with intermediate AMD were studied, including 4 with predominantly subretinal drusenoid deposits (SDD) and 3 without SDD. Macular regions with a clinical absence of AMD-associated lesions were identified by cone packing structure on AOSLO and optical coherence tomography. Cone density was measured in 1174 clinically unremarkable regions within the central subfield (CSF), the inner (IR), and outer rings (OR) of the Early Treatment Diabetic Retinopathy Study grid over 39.6 ± 3.3 months and compared with age-matched normal values obtained in 17 participants., Results: Cone density decreased at 98.3% of the examined locations over time in the eyes with AMD. In the CSF, IR, and OR, cones declined by -255 ± 135, -133 ± 45, and -59 ± 24 cones/degree 2 /year, respectively, in eyes with SDD, and by -212 ± 89, -83 ± 37, and -27 ± 18 cones/degree 2 /year, respectively, in eyes without SDD. The percentage of retinal loci with cone density lower than normal (Z score < -2) increased over the follow-up: from 42% at the baseline to 80% at the last visit in eyes with SDD and from 31% to 70% in eyes without SDD., Conclusions: AOSLO revealed cone photoreceptor loss in regions that appear otherwise unremarkable clinically. These findings may help explain the loss of mesopic sensitivity reported in these areas in eyes with intermediate AMD., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: To identify optical coherence tomography (OCT) biomarkers, including thin and thick double-layer sign (DLS) for the progression from intermediate AMD (iAMD) to exudative macular neovascularization (MNV) over 24 months., Design: Retrospective cohort study., Methods: Setting: Retina consultants of Texas., Patient Population: 458 eyes of 458 subjects with iAMD in at least 1 eye with 24 months of follow-up data., Main Outcomes Measures: The following biomarkers were assessed at baseline: high central drusen volume (≥0.03 mm 3 ), intraretinal hyper-reflective foci (IHRF), subretinal drusenoid deposits, hyporeflective drusen cores, thick DLS, thin DLS, and central choroidal thickness. A binary logistic regression was computed to investigate the association between baseline OCT covariates and the conversion to exudative MNV within 24 months. In addition, fellow eye status was also included in the model., Results: During follow-up, 18.1% (83 of 458) of eyes with iAMD progressed to exudative MNV. Thick DLS, IHRF, and fellow eye exudative MNV were found to be independent predictors for the development of exudative MNV within 2 years. The baseline frequencies, odds ratios, 95% confidence intervals, and P values for these biomarkers were as follows: thick DLS (9.6%, 4.339, 2.178-8.644; P < .001), IHRF (36.0%, 2.340, 1.396-3.922; P = 0.001), and fellow eye exudative MNV (35.8%, 1.694, 1.012-2.837; P = .045)., Conclusions: Thick DLS, IHRF, and fellow eye exudative MNV were associated with an increased risk of progression from iAMD to exudative MNV. These biomarkers, which are readily identified by the review of OCT volume scans, may aid in risk prognostication for patients and for identifying patients for early intervention trials., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Retinal microperimetry (MP) is a procedure that assesses the retinal sensitivity while the fundus is directly observed, and an eye tracker system is active to compensate for involuntary eye movements during testing. With this system, the sensitivity of a small locus can be accurately determined, and it has become an established ophthalmic test for retinal specialists. Macular diseases are characterized by chorioretinal changes; therefore, the condition of the retina and choroid requires careful and detailed evaluations to perform effective therapy. Age-related macular degeneration is a representative retinal disease in which the macular function has been evaluated by the visual acuity throughout the course of the disease process. However, the visual acuity represents the physiological function of only the central fovea, and the function of the surrounding macular area has not been sufficiently evaluated throughout the different stages of the macula disease process. The new technique of MP can compensate for such limitations by being able to test the same sites of the macular area repeatedly. This is especially useful in the recent management of age-related macular degeneration or diabetic macular edema during anti-vascular endothelial growth factor treatments because MP can assess the effectiveness of the treatment. MP examinations are also valuable in diagnosing Stargardt disease as they can detect visual impairments before any abnormalities are found in the retinal images. The visual function needs to be carefully assessed along with morphologic observations by optical coherence tomography. In addition, the assessment of retinal sensitivity is useful in the presurgical or postsurgical evaluations., Competing Interests: SH belongs to Department of Advanced Ophthalmic Imaging at Tokyo Medical and Dental University, which is funded by NIDEK co. There are no other conflict of interest regarding this review article., (Copyright © 2023 Asia-Pacific Academy of Ophthalmology. Published by Wolters Kluwer Health, Inc. on behalf of the Asia-Pacific Academy of Ophthalmology.)

Purpose: To determine the frequency of multiple OCT biomarkers of intermediate age-related macular degeneration (iAMD) and their relationship with the development of complete retinal pigment epithelium and outer retinal atrophy (cRORA) after 2 years., Design: Retrospective cohort study., Participants: This retrospective analysis included 330 eyes of 330 consecutive patients with iAMD in ≥ 1 eye who had 24 months of follow-up data., Methods: Spectralis OCT volume scans (49 B-scans over 6 × 6 mm, automatic real time = 6, fovea-centered) at baseline were evaluated for the previously described iAMD biomarkers, including a high-central drusen volume (DV; ≥ 0.03 mm 3 ), intraretinal hyper-reflective foci (IHRF), subretinal drusenoid deposits (SDDs), hypo-reflective drusen cores (hDCs), and a thin or thick (multilayered) double-layer sign (DLS). The age-related macular degeneration (AMD) status in the fellow eye was also assessed and classified as normal or early AMD, iAMD, exudative macular neovascularization, or cRORA., Main Outcome Measures: Incidence of cRORA, odds ratio for demographics, and OCT features., Results: At month 24, 16.36% (54/330) of the iAMD eyes developed cRORA. Several baseline features, including high-central DV, IHRF, SDD, hDC, thin DLS, and cRORA in the fellow eye, were associated with a significantly greater risk for development of cRORA at 2 years. The odds ratio, 95% confidence interval, P value, and baseline frequencies of these biomarkers were DV (6.510, 2.467-17.176, P < 0.001, 49.1%), IHRF (12.763, 4.763-34.202, P < 0.001, 38.8%), SDD (2.307, 1.003-5.304, P = 0.049, 34.2%), hDC (3.012, 1.152-7.873, P = 0.024, 13.0%), thin DLS (4.517, 1.555-13.126, P = 0.006, 11.8%), and cRORA in the fellow eye (7.184, 1.938-26.623, P = 0.003, 8.2%)., Conclusions: In addition to the 4 previously reported factors that are present in a significant proportion of iAMD (DV, IHRF, hDC, and SDD), a thin DLS and cRORA in the fellow eye were associated with an increased risk of progression to cRORA over 2 years. These biomarkers may aid in prognostication, risk stratification, and selection of patients for clinical trials., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: To assess and validate a deep learning algorithm to automatically detect incomplete retinal pigment epithelial and outer retinal atrophy (iRORA) and complete retinal pigment epithelial and outer retinal atrophy (cRORA) in eyes with age-related macular degeneration., Design: In a retrospective machine learning analysis, a deep learning model was trained to jointly classify the presence of iRORA and cRORA within a given B-scan. The algorithm was evaluated using 2 separate and independent datasets., Participants: OCT B-scan volumes from 71 patients with nonneovascular age-related macular degeneration captured at the Doheny-University of California Los Angeles Eye Centers and the following 2 external OCT B-scans testing datasets: (1) University of Pennsylvania, University of Miami, and Case Western Reserve University and (2) Doheny Image Reading Research Laboratory., Methods: The images were annotated by an experienced grader for the presence of iRORA and cRORA. A Resnet18 model was trained to classify these annotations for each B-scan using OCT volumes collected at the Doheny-University of California Los Angeles Eye Centers. The model was applied to 2 testing datasets to assess out-of-sample model performance., Main Outcomes Measures: Model performance was quantified in terms of area under the receiver operating characteristic curve (AUROC) and area under the precision-recall curve (AUPRC). Sensitivity, specificity, and positive predictive value were also compared against additional clinician annotators., Results: On an independently collected test set, consisting of 1117 volumes from the general population, the model predicted iRORA and cRORA presence within the entire volume with nearly perfect AUROC performance and AUPRC scores (iRORA, 0.61; 95% confidence interval [CI] [0.45, 0.82]: cRORA, 0.83; 95% CI [0.68, 0.95]). On another independently collected set, consisting of 60 OCT B-scans enriched for iRORA and cRORA lesions, the model performed with AUROC (iRORA: 0.68, 95% CI [0.54, 0.81]; cRORA: 0.84, 95% CI [0.75, 0.94]) and AUPRC (iRORA: 0.70, 95% CI [0.55, 0.86]; cRORA: 0.82, 95% CI [0.70, 0.93])., Conclusions: A deep learning model can accurately and precisely identify both iRORA and cRORA lesions within the OCT B-scan volume. The model can achieve similar sensitivity compared with human graders, which potentially obviates a laborious and time-consuming annotation process and could be developed into a diagnostic screening tool., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Retinal imaging has greatly expanded our understanding of various pathological conditions. This article presents a summary of the key points covered during the 2022 Ophthalmologica Lecture held at the Euretina Congress in Hamburg. The first part of the article focuses on the use of optical coherence tomography angiography to examine and comprehend the choroid in age-related macular degeneration (AMD). Subsequently, we delve into the discussion of the "postreceptor neuronal loss" theory in AMD, which was studied using en face structural optical coherence tomography (OCT). Following that, we explore pertinent findings obtained through cross-sectional OCT in retinal and optic nerve diseases, such as AMD, diabetic macular edema, pathologic myopia, central serous chorioretinopathy, and Leber's hereditary optic neuropathy., (© 2023 S. Karger AG, Basel.)

Non-exudative macular and choroidal neovascularization (MNV and CNV) usually refers to the entity of treatment-naïve type 1 neovascularization in the absence of associated signs of exudation. Histopathological studies, dating back in the early 70s, identified the presence of non-exudative MNV, but the first clinical report of this finding was in the late 90s using indocyanine green angiography in eyes with age-related macular degeneration (AMD). With more advanced retinal imaging, there has been an ever increasing appreciation of non-exudative MNV associated with AMD and CNV with other macular disorders. However, consensus regarding the exact definition and the clinical management of this entity is lacking. Furthermore, there may be variation in the imaging features and clinical course suggesting that a spectrum of disease may exist. Herein, we review the large body of published work that has provided a better understanding of non-exudative MNV and CNV in the last decade. The prevalence, multimodal imaging features, clinical course, and response to treatment are discussed to elucidate further key insights about this entity. Based on these observations, this review also proposes a new theory about the origin and course of different sub-types of non-exudative MNV/CNV which can have different etiologies and pathways according to the clinical context of disease., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Age-related macular degeneration (AMD) is the most widespread cause of blindness and the identification of baseline AMD features or biomarkers is critical for early intervention. Optical coherence tomography (OCT) imaging produces a 3D volume consisting of cross sections of retinal tissue while fundus fluorescence (FAF) imaging produces a 2D mapping of retina. FAF has been a good standard for assessing dry AMD late-stage geographic atrophy (GA) while OCT has been used for assessing early AMD biomarkers beyond as well. However, previous approaches in large extent defined AMD features subjectively based on clinicians' observation. Deep learning-an objective artificial intelligence approach, may enable to discover 'true' salient AMD features. We develop a novel reverse engineering approach which bases on the backbone of a fully convolutional neural network to objectively identify and visualize AMD early biomarkers in OCT from baseline exams before significant atrophy occurs. Utilizing manually annotated GA regions on FAF from a follow-up visit as ground truth, we segment GA regions and reconstruct early AMD features in baseline OCT volumes. In this preliminary exploration, compared with ground truth, we achieve baseline GA segmentation accuracy of 0.95 and overlapping ratio of 0.65. The reconstructions consistently highlight that large druse and druse clusters with or without mixed hyper-reflective focus lesion on baseline OCT cause the conversion of GA after 12 months. However, hyper-reflective focus lesions and subretinal drusenoid deposit lesions alone are not seen such conversion after 12 months. Further research with larger dataset would be needed to verify these findings., (© 2022. The Author(s).)

Purpose: To evaluate the relationship between retinal fluid location, amount/severity, and vision with ranibizumab-treated neovascular age-related macular degeneration (nAMD)., Methods: In the phase 3 HARBOR trial (NCT00891735), treatment-naive patients with nAMD received ranibizumab 0.5 or 2.0 mg through month 24. This post hoc analysis included eyes with subretinal fluid (SRF) and/or intraretinal fluid (IRF) at screening, baseline, or week 1, and optical coherence tomography data at months 12 and 24 (n = 917). Outcomes were best-corrected visual acuity (BCVA) change from baseline and proportion of eyes with 20/40 or better vision at months 12 and 24. Eyes were stratified by the location, amount, and/or severity of fluid., Results: At baseline, 86% and 63% of eyes had SRF and IRF, respectively. Among eyes with residual SRF, mean BCVA gains at each time point were greater in eyes with central versus noncentral SRF; location did not affect the odds of having 20/40 or better vision over 24 months. Eyes with 20/40 or better BCVA at month 12 had significantly lower SRF thickness versus eyes with worse vision; however, no difference was apparent at month 24. Vision was comparatively worse in eyes with residual IRF at months 12 and 24; location and severity did not appear to affect this outcome., Conclusion: Residual IRF was associated with worse vision outcomes, regardless of location/severity, whereas, despite continued treatment, residual SRF was not associated with worse vision outcome at 24 months, regardless of location/thickness. These data suggest complex relationships between residual fluid, severity, and vision., (© 2022. The Author(s).)

Purpose: To compare choriocapillaris flow deficit (CC-FD) analysis using optical coherence tomography angiography (OCTA) in eyes of patients treated with high cumulative dosages of pentosan polysulfate sodium (PPS) but no signs of retinal toxicity versus healthy age-matched controls., Design: Retrospective clinical cohort study., Methods: Patients treated with PPS for interstitial cystitis with a cumulative dose of > 1000 g underwent multimodal imaging screening to exclude evidence of PPS maculopathy or other retinal findings. All study patients and age-matched healthy controls completed a 3 × 3 mm macular volume scan OCTA using the SOLIX full-range OCT. En face OCTA images at the level of the CC were exported and CC-FDs were computed and compared between groups., Results: Fifteen patients treated with PPS and 15 age-matched controls were included. The mean PPS cumulative dose was 1974 ± 666 g over a mean of 17.6 ± 6.8 treatment years. All patients registered a visual acuity of 20/25 or better and normal fundus autofluorescence (FAF), OCT, multicolor, near-infrared reflectance (NIR), and ultra-widefield fundus color and autofluorescence images. The CC-FD was 32.7 ± 3.6% in the PPS group compared with 28.6 ± 4.3% in the control group (P = .023)., Conclusions: Patients treated with PPS long enough to accumulate dosages > 1000 g showed significant CC flow impairment before the development of macular toxicity signs with OCT, NIR, and FAF compared with age-matched normal controls. Thus, the choroid may be the earliest manifestation of ocular toxicity, predating the development of clinically evident retinal pigment epithelium (RPE) injury. The subsequent RPE disruption may be the result of choriocapillaris impairment or primary PPS toxicity. Assessment of the CC on OCTA may be a useful tool for early detection of toxicity, although further longitudinal studies are required., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: To evaluate whether processing a color fundus photo (CFP) using an image embossing technique can improve the detection of reticular pseudodrusen (RPD)., Methods: This post-hoc analysis included the eyes of subjects enrolled in the Amish Eye Study with early or intermediate age-related macular degeneration and evidence of RPD. All patients underwent CFP, near-infrared reflectance (NIR), and fundus autofluorescence (FAF) imaging. The ground-truth presence of RPD was established with a combination of NIR and FAF imaging. An embossing processed (EP) image was created by replacing each pixel of the CFP image with a highlight or a shadow representing light and dark boundaries in the original CFP image. The presence of RPD in CFP and EP images was assessed by two graders in a masked fashion and the sensitivity of CFP and EP for detection of RPD was evaluated. Cohen's kappa (k) was used to test inter-grader agreement for CFP and EP., Results: A total of 106 eyes from 62 patients with RPDs were analyzed. The sensitivity for detection of RPD on CFP and EP was 63.2% (95%CI: 52.0%-74.4%) and 91.5% (95%CI: 85.0%-98.0%), respectively. The inter-rater reliabilities of CFP and EP for RPD detection were 0.81 and 0.84, respectively., Conclusions: Embossing of CFP can improve the sensitivity for detection of RPD. The embossing technique can be a useful tool for better assessment of the true frequency of RPD in datasets where only CFP images are available.

Purpose: To determine if increasing drusen height correlates with predictive optical coherence tomography (OCT) biomarkers of atrophy., Methods: Retrospective cross-sectional study that enrolled patients with drusen associated with intermediate AMD. Macular drusen were classified as small, intermediate, large, or very large based on OCT quartile measurement of height. Drusen diameter was also tabulated. The presence and localization of the OCT biomarkers of atrophy were assessed: disruption of the external limiting membrane and ellipsoid zone, intraretinal hyper-reflective foci, RPE disruption, choroidal hypertransmission, and presence of hyporeflective cores. Predictive OCT biomarkers of atrophy were correlated with drusen height., Results: A total of 155 eyes from 104 patients met the inclusion and exclusion criteria. The mean age was 75.7 ± 8.7 years, and patients were predominantly female (74.0%). The mean visual acuity was logMAR 0.2 ± 0.2 (Snellen equivalent 20/32). The average drusen height was 134.6 ± 107.5 µm and the greatest horizontal diameter was 970.7 ± 867.4 µm. Disruption of the external limiting membrane and ellipsoid zone, RPE thickening or thinning, intraretinal hyper-reflective foci, choroidal hypertransmission, and presence of hyporeflective cores (P &lt; 0.05) were more common in eyes with large drusen and very large drusen versus small or intermediate drusen. All biomarkers were positively correlated with drusen height. OCT biomarkers of atrophy were predominantly located at the apex of the drusen., Conclusions: Predictive OCT biomarkers of atrophy, specifically signs of RPE breakdown and disruption, occur more commonly in large or very large drusen, especially in drusen with greater height and separation of the RPE from the underlying choroid.

Purpose: To compare the enlargement rates of geographic atrophy (GA) over 5 years of follow-up with those of macular atrophy (MA) associated with macular neovascularization (MNV)., Design: Retrospective, longitudinal, comparative case series., Participants: Consecutive series of patients with age-related macular degeneration and GA (dry) or with MA and MNV., Methods: Atrophic regions detected on serial registered fundus autofluorescence images were semiautomatically delineated, and the measurements of these areas were recorded every 6 ± 3 months for the first 2 years of follow-up and at yearly intervals for up to 5 years., Main Outcome Measures: Annual raw and square root-transformed rates of atrophy growth., Results: The study included 117 eyes of 95 patients (61 in the GA cohort and 56 in the MA cohort); 100% and 38.5% of the eyes completed 2 and 5 years of follow-up, respectively. The mean size of lesions at baseline was similar between the 2 groups (raw: 1.74 vs. 1.53 mm 2 , P = 0.56; square root-transformed: 1.17 vs. 1.02 mm, P = 0.26). The overall enlargement rates were greater for the GA cohort (raw: 1.72 vs. 1.32 mm 2 /year, P = 0.002; square root-transformed: 0.41 vs. 0.33 mm/year, P = 0.03), and so was the area of atrophy growth at 5 years (raw: +8.06 vs. +4.55 mm 2 , P = 0.001; square root-transformed: +1.93 vs. +1.38 mm, P = 0.02). The estimated square root-transformed area was also significantly greater for the GA cohort at 2 years (1.84 vs. 1.67 mm, P = 0.01)., Conclusions: The presence of MNV was associated with a slower rate of expansion, resulting in overall smaller areas of atrophy over time. These findings support the hypothesis that MNV may protect against the progression of atrophy., (Copyright © 2022. Published by Elsevier Inc.)

Purpose: To evaluate the impact of reducing the density of B-scans in an optical coherence tomography (OCT) volume on the sensitivity for detecting intraretinal hyperreflective foci (IHRF) in eyes with intermediate age-related macular degeneration (AMD)., Methods: A total of 165 eyes with intermediate AMD and IHRF were evaluated in this retrospective analysis. For each case, Cirrus HD-OCT volumes were imported into the reading center 3 D-OCTOR software. The number of IHRF cases was assessed based on all 128 B-scans (spaced 47 μm apart), using a categorical scale (graded as 1-4, 5-9, 10-14, 15-19, and >20). Additionally, the B-scan densities in the volume were lowered to 64 B-scans (spaced 94 μm apart), 43 B-scans (spaced 140 μm apart), and 32 B-scans (spaced 188 μm apart). The number of eyes with any IHRF and the numerical category of IHRF in the eye were used to compare the sensitivity at each reduced B-scan density against the reference 128 B-scan volume., Results: In the primary analysis for the qualitative presence or absence of any IHRF, the sensitivity decreased to 98.2% ( p  = .32) with 64 B-scans, 92.7% ( p  = .001) with 43 B-scans, and 75.2% ( p  = .001) with 32 B-scans, compared with the 128 B-scan reference. With regard to the number of IHRF per eye, there was a significant difference (with a lower level chosen on the scale) when the B-scan density was reduced to 43 or 32 B-scans ( p  = .002 and p  < .001, respectively)., Conclusion: Increasing the inter-B-scan spacing from 47 to 188 microns significantly reduced the ability to accurately determine whether IHRF were present in an eye. An increase in inter-B-scan spacing to 140 microns was associated with a significant misclassification of the IHRF quantity. These findings may be relevant in the design of OCT scanning protocols for studies utilizing these biomarkers for AMD progression.

Purpose: Brolucizumab has high efficacy in retinal fluid resolution and provides the possibility for longer dosing intervals in the treatment of neovascular age-related macular degeneration. However, brolucizumab has been associated with events of retinal vasculitis and retinal vascular occlusion typically in the presence of other signs of intraocular inflammation (IOI). The purpose of this report is to provide guidance on the use of brolucizumab for neovascular age-related macular degeneration to a global audience., Methods: A literature review was conducted on adverse events related to IOI after administration of brolucizumab in eyes with neovascular age-related macular degeneration., Results: Possible risk factors for IOI and retinal vascular occlusion after brolucizumab should be considered before administering brolucizumab. Patients who receive brolucizumab should be educated on the symptoms, signs, and time course of IOI after brolucizumab. Before each injection of brolucizumab, physicians should assess the eye for any signs of inflammation and not treat with brolucizumab if inflammation is detected. Treatment of IOI should be prompt and provided with particular attention to the posterior segment., Conclusion: Careful patient selection, patient education, assessment for inflammation, and intensive treatment of possible inflammation are important when using brolucizumab in patients with neovascular age-related macular degeneration., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

Age-related macular degeneration (AMD) and Stargardt disease are the leading causes of blindness for the elderly and young adults respectively. Geographic atrophy (GA) of AMD and Stargardt atrophy are their end-stage outcomes. Efficient methods for segmentation and quantification of these atrophic lesions are critical for clinical research. In this study, we developed a deep convolutional neural network (CNN) with a trainable self-attended mechanism for accurate GA and Stargardt atrophy segmentation. Compared with traditional post-hoc attention mechanisms which can only visualize CNN features, our self-attended mechanism is embedded in a fully convolutional network and directly involved in training the CNN to actively attend key features for enhanced algorithm performance. We applied the self-attended CNN on the segmentation of AMD and Stargardt atrophic lesions on fundus autofluorescence (FAF) images. Compared with a preexisting regular fully convolutional network (the U-Net), our self-attended CNN achieved 10.6% higher Dice coefficient and 17% higher IoU (intersection over union) for AMD GA segmentation, and a 22% higher Dice coefficient and a 32% higher IoU for Stargardt atrophy segmentation. With longitudinal image data having over a longer time, the developed self-attended mechanism can also be applied on the visual discovery of early AMD and Stargardt features., (© 2022. The Author(s).)

Purpose: To evaluate the correlation between fundus autofluorescence (FAF) and en face spectral-domain OCT (SD-OCT) measurements of geographic atrophy (GA) area associated with age-related macular degeneration., Design: Retrospective, cross-sectional study., Participants: Two hundred seventy eyes from 172 subjects with GA associated with age-related macular degeneration., Methods: Subjects with atrophic age-related macular degeneration who underwent both FAF (Heidelberg HRA + Spectralis) and dense volume (128 B-scans over 6 × 6 mm 2 ) SD-OCT (Cirrus OCT) imaging were included in this retrospective analysis. The borders of all areas of definite decreased autofluorescence (DDAF) corresponding to GA were manually outlined on FAF images by certified graders at Doheny Image Reading Center using validated planimetric grading tools. Geographic atrophy was also automatically delineated using en face OCT (at the level of the choroid) using an instrument software (Cirrus v.6.2), and segmentation errors were manually corrected before the computation of the GA area. The fundus autofluorescence and SD-OCT-derived measurements were correlated., Main Outcome Measures: Correlation between the SD-OCT and FAF measurements of the GA area., Results: The mean GA area measured from the FAF images was 8.1 ± 5.04 mm 2 , compared with an automated, uncorrected GA area of 6.82 ± 3.84 mm 2 measured using SD-OCT. Despite the presence of apparent OCT segmentation errors, there was a significant correlation between the FAF and uncorrected SD-OCT measurements (r = 0.80; P < 0.001). After the manual correction of the SD-OCT GA segmentation errors, the measured GA area increased to 7.29 ± 4.18 mm 2 , and the correlation with the FAF-determined GA area significantly improved (r = 0.98; P < 0.001)., Conclusions: Spectral-domain OCT-derived measurements of GA correlate well with areas of DDAF obtained from FAF images. The manual correction of SD-OCT segmentation errors can further improve this correlation. These observations may support the use of SD-OCT-based measurements of the GA area in clinical research and clinical trials., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the evolution of treatment-naive type 3 macular neovascularization (MNV) undergoing anti-vascular endothelial growth factor (VEGF) treatment through volume rendered three-dimensional (3D) optical coherence tomography angiography (OCTA)., Design: Retrospective observational study., Participants: Patients with type 3 MNV and age-related macular degeneration (AMD)., Methods: Included subjects had three loading injections of an anti-VEGF agent. The OCTA volume data at baseline and follow-up were processed with a previously published algorithm in order to obtain a volume-rendered representation of type 3 MNV. Progressive changes in type 3 lesions were analyzed via 3D OCTA volume rendering., Results: A total of 14 treatment-naive eyes with type 3 MNV from 11 AMD patients (7 females) were included. At both baseline and follow-up visits, a type 3 MNV complex was identifiable. Each complex was composed of a mean number of 2.5 ± 0.7 vascular branches at baseline and 1.4 ± 0.6 at the follow-up visit (p < 0.0001). The mean changes in central macular thickness and visual acuity were significantly correlated with modifications in the number of type 3 MNV branches (ρ = -0.533, p = 0.049, and ρ = -0.581, and p = 0.040, respectively)., Conclusions: This study demonstrated that type 3 lesions do not disappear completely after loading treatment, as indicated previously by histopathologic studies. Importantly, quantitative volume changes in type 3 lesions are directly associated with treatment response., (Copyright © 2021 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to identify genetic risk loci for retinal traits, including drusen, in an Amish study population and compare these risk loci to known risk loci of age-related macular degeneration (AMD)., Methods: Participants were recruited from Amish communities in Ohio, Indiana, and Pennsylvania. Each participant underwent a basic health history, ophthalmologic examination, and genotyping. A genomewide association analysis (GWAS) was conducted for the presence and quantity of each of three retinal traits: geographic atrophy, drusen area, and drusen volume. The findings were compared to results from a prior large GWAS of predominantly European-ancestry individuals. Further, a genetic risk score for AMD was used to predict the presence and quantity of the retinal traits., Results: After quality control, 1074 participants were included in analyses. Six single nucleotide polymorphisms (SNPs) met criteria for genomewide significance and 48 were suggestively associated across three retinal traits. The significant SNPs were not highly correlated with known risk SNPs for AMD. A genetic risk score for AMD provided significant predictive value of the retinal traits., Conclusions: We identified potential novel genetic risk loci for AMD in a midwestern Amish study population. Additionally, we determined that there is a clear link between the genetic risk of AMD and drusen. Further study, including longitudinal data collection, may improve our ability to define this connection and improve understanding of the biological risk factors underlying drusen development.