Progressive Choriocapillaris Changes on Optical Coherence Tomography Angiography Correlate With Stage Progression in AMD.

Purpose: We investigated the association between inner choroid flow deficit percentage (IC-FD%) using swept-source optical coherence tomography angiography (SS-OCTA) and progression of AMD. Methods: Retrospective, observational study including 64 eyes (42 participants) with early or intermediate AMD at baseline. Participants had two or more consecutive swept-source optical coherence tomography angiography covering a period of at least 18 months. Demographics, visual acuity, and AMD staging based on Beckman classification were reviewed. OCT was analyzed for hyperreflective foci, subretinal drusenoid deposits, hyporeflective drusen cores, and subfoveal choroidal thickness. IC-FD% was measured within the central 3- and 6-mm using a 16-µm slab, after compensation and binarization (Phansalkar method). Mixed-effects Cox regression models assessed the association between imaging biomarkers and AMD progression. Results: During follow-up (37 ± 9 months), 4 eyes with early AMD (31%) progressed to intermediate AMD and 30 (59%) eyes with intermediate AMD developed late AMD (19 geographic atrophy; 11 wet AMD). Baseline hyporeflective drusen core was associated with geographic atrophy development (P < 0.01), whereas greater IC-FD% (3-mm) was associated with wet AMD (P = 0.03). Time-varying analysis showed that faster subfoveal choroidal thickness reduction and IC-FD% (6-mm) increase were associated with geographic atrophy onset (P < 0.05), whereas IC-FD% (3-mm) increase was associated with wet AMD (P = 0.03). Notably, greater IC-FD% increases in the 3 mm (area under the curve = 0.72) and 6 mm (area under the curve = 0.89) were better predictive of wet AMD and geographic atrophy development, respectively. Conclusions: Our longitudinal IC-FD% assessment emphasizes the role of progressive choriocapillaris changes as a biomarker for AMD progression. Our findings support that widespread choriocapillaris alterations (6 mm) may precede progression to geographic atrophy, whereas more central choriocapillaris loss (3 mm) may provide an ischemic stimulus for wet AMD.

ADVANCES IN PHOTORECEPTOR AND RETINAL PIGMENT EPITHELIUM QUANTIFICATIONS IN INTERMEDIATE AGE-RELATED MACULAR DEGENERATION: High-Res Versus Standard SPECTRALIS Optical Coherence Tomography.

PURPOSE: In this study, differences in retinal feature visualization of high-resolution optical coherence tomography (OCT) devices were investigated with different axial resolutions in quantifications of retinal pigment epithelium and photoreceptors (PRs) in intermediate age-related macular degeneration. METHODS: Patients were imaged with standard SPECTRALIS HRA + OCT and the investigational High-Res OCT device (both by Heidelberg Engineering, Heidelberg, Germany). Drusen, retinal pigment epithelium, and PR layers were segmented using validated artificial intelligence-based algorithms followed by manual corrections. Thickness and drusen maps were computed for all patients. Loss and thickness measurements were compared between devices, drusen versus nondrusen areas, and early treatment diabetic retinopathy study subfields using mixed-effects models. RESULTS: Thirty-three eyes from 28 patients with intermediate age-related macular degeneration were included. Normalized PR integrity loss was significantly higher with 4.6% for standard OCT compared with 2.5% for High-Res OCT. The central and parafoveal PR integrity loss was larger than the perifoveal loss (P < 0.05). Photoreceptor thickness was increased on High-Res OCT and in nondrusen regions (P < 0.001). Retinal pigment epithelium appeared thicker on standard OCT and above drusen (P < 0.01). CONCLUSION: Our study shows that High-Res OCT is able to identify the condition of investigated layers in intermediate age-related macular degeneration with higher precision. This improved in vivo imaging technology might promote our understanding of the pathophysiology and progression of age-related macular degeneration.

Calcified Drusen Prevent the Detection of Underlying Choriocapillaris Using Swept-Source Optical Coherence Tomography Angiography.

Purpose: In age-related macular degeneration (AMD), choriocapillaris flow deficits (CCFDs) under soft drusen can be measured using established compensation strategies. This study investigated whether CCFDs can be quantified under calcified drusen (CaD). Methods: CCFDs were measured in normal eyes (n = 30) and AMD eyes with soft drusen (n = 30) or CaD (n = 30). CCFD density masks were generated to highlight regions with higher CCFDs. Masks were also generated for soft drusen and CaD based on both structural en face OCT images and corresponding B-scans. Dice similarity coefficients were calculated between the CCFD density masks and both the soft drusen and CaD masks. A phantom experiment was conducted to simulate the impact of light scattering that arises from CaD. Results: Area measurements of CCFDs were highly correlated with those of CaD but not soft drusen, suggesting an association between CaD and underlying CCFDs. However, unlike soft drusen, the detected optical coherence tomography (OCT) signals underlying CaD did not arise from the defined CC layer but were artifacts caused by the multiple scattering property of CaD. Phantom experiments showed that the presence of highly scattering material similar to the contents of CaD caused an artifactual scattering tail that falsely generated a signal in the CC structural layer but the underlying flow could not be detected. Similarly, CaD also caused an artifactual scattering tail and prevented the penetration of light into the choroid, resulting in en face hypotransmission defects and an inability to detect blood flow within the choriocapillaris. Upon resolution of the CaD, the CC perfusion became detectable. Conclusions: The high scattering property of CaD leads to a scattering tail under these drusen that gives the illusion of a quantifiable optical coherence tomography angiography signal, but this signal does not contain the angiographic information required to assess CCFDs. For this reason, CCFDs cannot be reliably measured under CaD, and CaD must be identified and excluded from macular CCFD measurements.

Automated classification of choroidal neovascularization, diabetic macular edema, and drusen from retinal OCT images using vision transformers: a comparative study.

Classifying retinal diseases is a complex problem because the early problematic areas of retinal disorders are quite small and conservative. In recent years, Transformer architectures have been successfully applied to solve various retinal related health problems. Age-related macular degeneration (AMD) and diabetic macular edema (DME), two prevalent retinal diseases, can cause partial or total blindness. Diseases therefore require an early and accurate detection. In this study, we proposed Vision Transformer (ViT), Tokens-To-Token Vision Transformer (T2T-ViT) and Mobile Vision Transformer (Mobile-ViT) algorithms to detect choroidal neovascularization (CNV), drusen, and diabetic macular edema (DME), and normal using optical coherence tomography (OCT) images. The predictive accuracies of ViT, T2T-ViT and Mobile-ViT achieved on the dataset for the classification of OCT images are 95.14%, 96.07% and 99.17% respectively. Experimental results obtained from ViT approaches showed that Mobile-ViT have superior performance with regard to classification accuracy in comparison with the others. Overall, it has been observed that ViT architectures have the capacity to classify with high accuracy in the diagnosis of retinal diseases.

Correlation between ellipsoid zone thickness and the presence of subretinal drusenoid deposits in age-related macular degeneration.

PURPOSE: Subretinal drusenoid deposits (SDDs) in age-related macular degeneration (AMD) are associated with systemic vascular diseases that compromise ocular perfusion. We demonstrate that SDDs are associated with decreased ellipsoid zone (EZ) thickness, further evidence of hypoxic damage. METHODS: Post hoc analysis of a cross-sectional study. 165 AMD subjects (aged 51-100; 61% women). Spectral-domain optical coherence tomography was obtained in both eyes. Masked readers assigned subjects to three groups: drusen only, SDD+drusen (SDD+D) and SDD only. EZ thickness was measured subfoveally and 2000 µm nasally, temporally, superiorly and inferiorly from the fovea. Univariate testing was performed using two-tailed t-tests with Bonferroni correction. RESULTS: The mean EZ thickness differences between the SDD+D and drusen-only groups were (in µm) 1.10, 0.67, 1.21, 1.10 and 0.50 at the foveal, nasal, temporal, superior and inferior locations, respectively (p=0.08 inferiorly, otherwise p≤0.01); between the SDD-only and drusen-only groups, the differences were 3.48, 2.48, 2.42, 2.08 and 1.42 (p≤0.0002). Differences in EZ thicknesses across all subjects and between groups were not significantly different based on gender, race or age. CONCLUSION: Subjects with SDDs (±drusen) had thinner EZs than those with drusen only, and the inferior EZ was least affected. EZs were thinnest in SDD-only subjects. This thinning gradation is consistent with progressive destruction of highly oxygen-sensitive mitochondria in the EZ from hypoxia. These findings support the reduced ophthalmic perfusion hypothesis for the formation of SDDs secondary to high-risk systemic vasculopathy.

En Face Optical Coherence Tomography Illustrates the Trizonal Distribution of Drusen and Subretinal Drusenoid Deposits in the Macula.

PURPOSE: To analyze the topographic distribution of macular drusen and subretinal drusenoid deposits (SDDs) using single-capture en face spectral domain optical coherence tomography (SD-OCT) imaging. DESIGN: Retrospective case series. METHODS: Analysis of 33 eyes of 20 patients with evidence of SDDs. Structural en face OCT images were reconstructed using a 40-µm-thick slab positioned from 48 to 88 µm above the Bruch membrane. The Early Treatment of Diabetic Retinopathy Study (ETDRS) grid and a rod/cone density map were overlaid on the en face OCT images, and the distribution of different subtypes of SDDs and macular drusen were assessed. RESULTS: A total of 31 eyes (94%) showed a trizonal distribution pattern of drusen and SDDs. Whereas small to large drusen tended to aggregate in the central circle, dot SDDs predominated in the inner ring and the inner portion of the outer ring of the ETDRS grid and ribbon SDDs localized to the outer ring and outside the ETDRS grid. Of note, drusen colocalized to the region of greatest cone density, whereas ribbon SDDs colocalized to the area of greatest rod density. The dot SDDs mapped to the intermediate region with mixed rod and cone representation. CONCLUSION: Dot and ribbon subtypes of SDDs and macular drusen show a characteristic trizonal distribution. The locations of these lesions colocalize according to the different densities of the cones and rods in the retina and may reflect varying pathophysiological activities of these photoreceptor subtypes.

Retro-mode: a newer insight into dry age-related macular degeneration (AMD).

The purpose of this study is to study the role of retro-mode (RM) in early detection and to compare it with other preexisting available modalities on multimodal imaging system in dry AMD. A prospective observational cross-sectional study was done between November 2020 and October 2021 which included 409 eyes of 207 patients. For study purpose, eyes were divided into 3 groups according to the size and number of the drusen, viz, group 1: No AMD, group 2: early AMD and group 3: intermediate AMD which was further divided into 2 subgroups, viz, subgroup A: eyes with drusen size 63-125 µm and subgroup B: eyes with drusen size 125-250 µm. Patients with active or treated wet AMD, scarred choroidal neovascular membrane (CNVM), other maculopathies, other retinopathies, high myopia, trauma and glaucoma were excluded from the study. In cases of No AMD and early AMD, a number of drusens detected on RM were statistically not significant compared to fundus autofluorescence (FAF) and color photo (CF), but in intermediate AMD cases, it was statistically significant. While the area involved by drusens calculated by RM was statistically significant compared to both other modalities. When all modalities were compared with enhanced depth imaging-optical coherence tomography (EDI-OCT) at the choroid and chorio-capillary (CC) level and vessel density (VD) on optical coherence tomography angiography (OCTA) at the choroid, capillaries, deep retinal and superficial retinal plexus level; it was only RM which was found to be in sync with these proven modalities in terms of pattern and trend. In the present scenario, RM is found to be a better diagnostic modality in detecting early and a greater number of drusens with area of involvement than other existing modalities. Though superior, as found in this study, this mode cannot replace other modalities at present but only acts as a complementary investigation in early detection of this disease.

Accurate drusen segmentation in optical coherence tomography via order-constrained regression of retinal layer heights.

Drusen are an important biomarker for age-related macular degeneration (AMD). Their accurate segmentation based on optical coherence tomography (OCT) is therefore relevant to the detection, staging, and treatment of disease. Since manual OCT segmentation is resource-consuming and has low reproducibility, automatic techniques are required. In this work, we introduce a novel deep learning based architecture that directly predicts the position of layers in OCT and guarantees their correct order, achieving state-of-the-art results for retinal layer segmentation. In particular, the average absolute distance between our model's prediction and the ground truth layer segmentation in an AMD dataset is 0.63, 0.85, and 0.44 pixel for Bruch's membrane (BM), retinal pigment epithelium (RPE) and ellipsoid zone (EZ), respectively. Based on layer positions, we further quantify drusen load with excellent accuracy, achieving 0.994 and 0.988 Pearson correlation between drusen volumes estimated by our method and two human readers, and increasing the Dice score to 0.71 ± 0.16 (from 0.60 ± 0.23) and 0.62 ± 0.23 (from 0.53 ± 0.25), respectively, compared to a previous state-of-the-art method. Given its reproducible, accurate, and scalable results, our method can be used for the large-scale analysis of OCT data.

Six-year incidence of age-related macular degeneration and correlation to OCT-derived drusen volume measurements in a Chinese population.

AIMS: To report the 6-year incidence of optical coherence tomography (OCT)-derived age-related changes in drusen volume and related systemic and ocular associations. METHODS: Chinese adults aged 40 years and older were assessed at baseline and 6 years with colour fundus photography (CFP) and spectral domain (SD) OCT. CFPs were graded for age-related macular degeneration (AMD) features and drusen volume was generated using commercially available automated software. RESULTS: A total of 4172 eyes of 2580 participants (mean age 58.12±9.03 years; 51.12% women) had baseline and 6-year follow-up CFP for grading, of these, 2130 eyes of 1305 participants had gradable SD-OCT images, available for analysis. Based on CFP grading, 136 (3.39%) participants developed incident early AMD and 10 (0.25%) late AMD. Concurrently, retinal pigment epithelial-Bruch's membrane (RPE-BrC) volumes decreased, remained stable and increased in 6.8%, 78.5% and 14.7%, respectively, over 6 years. In eyes where RPE-BrC volumes were >0 mm3 at baseline, this was associated with two-fold higher prevalence rate of any AMD at baseline (p<0.001). Multivariable analysis showed that when compared with eyes where RPE-BrC volume was unchanged, volume decrease was significantly associated with older age (OR=1.30; p<0.001), smoking (OR=2.21; p=0.001) and chronic kidney disease (OR=3.4, p=0.008), while increase was associated with older age (OR=1.36; p<0.001) and hypertension (OR=1.43; p=0.016). CONCLUSION: AMD incidence detected at 6 years on CFP and correlated OCT-derived drusen volume measurement change is low. Older age and some systemic risk factors are associated with drusen volume change, and our data provide new insights into relationship between systemic risk factors and outer retinal morphology in Asian eyes.

Prevalence and risk factors for age-related macular degeneration in a population-based cohort study of older adults in Northern Ireland using multimodal imaging: NICOLA Study.

PURPOSE: To report prevalence and risk factor associations for age-related macular degeneration (AMD) and AMD features from multimodal retinal grading in a multidisciplinary longitudinal population-based study of aging in Northern Ireland. STUDY DESIGN: Population-based longitudinal cohort study. METHODS: Retinal imaging at the Norther Ireland Cohort for the Longitudinal Aging Study health assessment included stereo Colour Fundus Photography (CFP) (Canon CX-1, Tokyo, Japan) and Spectral-Domain Optical Coherence Tomography (SD-OCT) ((Heidelberg Retinal Angopgraph (HRA)+OCT; Heidelberg Engineering, Heidelberg, Germany). Medical history and demographic information was obtained during a home interview. Descriptive statistics were used to describe the prevalence of AMD and individual AMD features. Multiple imputation followed by multiple regression modelling was used to explore risk factor associations including relationships with AMD genetic risk score. RESULTS: Retinal images from 3386 participants were available for analysis. Mean age of the sample was 63.4 (SD 9.01, range: 36-99). Population weighted prevalence of AMD using colour grading in those over 55 years was: no drusen: 6 0.4%; drusen <63 µm: 15.9%; drusen 63-125 µm: 13.7%; drusen >125 µm or pigmentary changes: 8.3%; late AMD: 1.6%. Prevalence of AMD features in those over 55 years was: OCT drusen 27.5%, complete outer retinal pigment epithelium and outer retinal atrophy (cRORA) on OCT was 4.3%, reticular drusen 3.2% and subretinal drusenoid deposits 25.7%. The genetic risk score was significantly associated with drusen and cRORA but less so for SDD alone and non-significant for hyperpigmentation or vitelliform lesions. CONCLUSIONS: Multimodal imaging-based classification has provided evidence of some divergence of genetic risk associations between classical drusen and SDD. Our findings support an urgent review of current AMD severity classification systems.

A Deep Learning Framework for the Detection and Quantification of Reticular Pseudodrusen and Drusen on Optical Coherence Tomography.

Purpose: The purpose of this study was to develop and validate a deep learning (DL) framework for the detection and quantification of reticular pseudodrusen (RPD) and drusen on optical coherence tomography (OCT) scans. Methods: A DL framework was developed consisting of a classification model and an out-of-distribution (OOD) detection model for the identification of ungradable scans; a classification model to identify scans with drusen or RPD; and an image segmentation model to independently segment lesions as RPD or drusen. Data were obtained from 1284 participants in the UK Biobank (UKBB) with a self-reported diagnosis of age-related macular degeneration (AMD) and 250 UKBB controls. Drusen and RPD were manually delineated by five retina specialists. The main outcome measures were sensitivity, specificity, area under the receiver operating characteristic (ROC) curve (AUC), kappa, accuracy, intraclass correlation coefficient (ICC), and free-response receiver operating characteristic (FROC) curves. Results: The classification models performed strongly at their respective tasks (0.95, 0.93, and 0.99 AUC, respectively, for the ungradable scans classifier, the OOD model, and the drusen and RPD classification models). The mean ICC for the drusen and RPD area versus graders was 0.74 and 0.61, respectively, compared with 0.69 and 0.68 for intergrader agreement. FROC curves showed that the model's sensitivity was close to human performance. Conclusions: The models achieved high classification and segmentation performance, similar to human performance. Translational Relevance: Application of this robust framework will further our understanding of RPD as a separate entity from drusen in both research and clinical settings.

Small hard drusen and associated factors in early seniority.

PURPOSE: The purpose of this study was to examine the ocular and systemic risk profile of the fundus phenotype ≥ 20 small hard (macular) drusen (< 63 µm in diameter). METHODS: This single-center, cross-sectional study of 176 same-sex twin pairs aged 30 to 80 (median 60) years was a component of a framework study of the transition from not having age-related macular degeneration to having early AMD. Drusen categories assessed using fundus photography and optical coherence tomography included small hard drusen (diameter < 63 µm), intermediate soft drusen (63-125 µm), and large soft drusen (> 125 µm), of which the soft drusen are compatible with a diagnosis of AMD. RESULTS: Having ≥ 20 small hard drusen within or outside the macula was associated with increasing age, lower body mass index, shorter axial length, hyperopia, female sex, increasing high-density lipoprotein (HDL), high alcohol consumption, and with the presence of soft drusen. CONCLUSIONS: Having ≥ 20 small hard drusen was associated with some AMD-related risk factors, but not with smoking, increasing body mass index, and higher blood pressure. Having ≥ 20 small hard drusen was also associated with soft drusen, in agreement with previous studies. These findings suggest that small hard drusen are not an early manifestation of AMD but the product of a distinct process of tissue alteration that promotes the development of AMD or some subtype thereof.

Longitudinal change of reticular pseudodrusen area in ultrawide-field imaging.

This study aimed to investigate the longitudinal change in the reticular pseudodrusen (RPD) area in the fundus and its association with late age-related macular degeneration (AMD). 91 RPD eyes (55 patients; age 67.9 ± 7.3 years) with > 5 years' follow-up (6.8 ± 0.9 years) from a single medical center were enrolled. Ultrawide-field photography images were analyzed using the concentric rings method, and the RPD area was semi-quantitatively classified according to the affected segment number into central, intermediate, and extensive types. Correlations of longitudinal changes in the RPD area and late AMD risk were investigated. RPD area increased significantly during the follow-up (p < 0.001). The increase rate correlated with age (r = 0.207; p = 0.048), RPD area at first visit (r = - 0.222; p = 0.035), and the decrease rate of subfoveal choroidal thickness (SFCT) (r = 0.217; p = 0.039). Many central (18/49, 36.7%) and intermediate (15/23, 65.2%) types switched to the more advanced type during the follow-up. Macular neovascularization and geographic atrophy developed in 12.3% and 18.7% of patients by 7 years. Late AMD incidence was significantly higher in eyes with large than in those with small RPD areas (p = 0.002). Larger RPD area at baseline, faster increase in RPD area, thinner SFCT, rapid decrease in SFCT, and the presence of late AMD on fellow eye were associated with late AMD. All RPD areas progressively increase over time. The regular assessment of RPD area may help to predict late AMD risk in RPD eyes.

Evaluation of the microperimetry in eyes with cuticular drusen.

Retinal sensitivity may vary by subtypes of cuticular drusen. This retrospective study included 52 eyes of 32 patients with cuticular drusen. All the patients underwent assessment of best-corrected visual acuity (BCVA), spectral-domain optical coherence tomography (SD-OCT), color fundus photography, fluorescein angiography, fundus autofluorescence, and microperimetry. The area occupied by drusen was counted using microperimetry. The cuticular drusen subtype was classified into 3 groups based on the SD-OCT findings. Age, BCVA, pattern standard deviation, area occupied by drusen, pupil size, and the false-positive rate were not significantly different (p > 0.05) according to the cuticular drusen type. The mean retinal sensitivity (MRS) (p = 0.063) and mean deviation (MD) (p = 0.098) showed marginally significant differences among the groups. In the subgroup analyses, type 1 and type 3 cuticular drusen showed significant differences in the MD (- 1.8 ± 2.1 vs - 5.1 ± 5.3; p = 0.011) and MRS (25.1 ± 2.2 vs 21.3 ± 5.7; p = 0.016) without differences in age, BCVA, or the area occupied by drusen (p > 0.05). The results indicate that depending on the subtypes of cuticular drusen type, the deterioration of retinal sensitivity is more likely to occur than decreased vision.

Multispectral pattern recognition measures change in drusen area in age-related macular degeneration with high congruency to expert graders.

Drusen are a hallmark lesion of age-related macular degeneration (AMD) and changes in their area and/or volume are strongly associated with disease progression. Assessment of longitudinal change in drusen size in clinical practice however is limited to a single commercial tool or manual inspection by clinicians. In this study we analysed change in drusen area in 33 eyes with intermediate AMD across two separate visits using a novel technique known as multispectral pattern recognition for en face retinal images from various imaging modalities (infrared (815 nm), fundus autofluorescence (488 nm) and green (532 nm) scanning laser ophthalmoscopy). We found 91% (30/33 eyes) agreement in the direction of drusen change for multispectral pattern recognition relative to expert graders who graded eyes as having drusen progression, regression or being stable. Multispectral pattern recognition showed 100% sensitivity (22/22 eyes) and 73% specificity (8/11 eyes). In comparison, we found only 70% (23/33 eyes) agreement in the direction of drusen change with a commercially available change analysis software, the Cirrus Advanced RPE Analysis relative to expert graders, with a sensitivity 64% (14/22 eyes) and specificity of 82% (9/11 eyes). Total drusen area or amount of change between visits had no significant effect on agreement. This suggests multispectral pattern recognition can quantify longitudinal change in drusen area from multimodal imaging with greater congruency to expert graders than a commercially available platform based on a single imaging modality. Considering the association of drusen area and disease progression, this method could aid clinical assessment and monitoring of AMD.

Age-related macular degeneration eyes presenting with cuticular drusen and reticular pseudodrusen.

This study aimed to describe the clinical characteristics of age-related macular degeneration (AMD) eyes with both cuticular drusen (CD) and reticular pseudodrusen (RPD). Clinical records of patients diagnosed with CD or RPD with multimodal imaging was reviewed for patients diagnosed with both CD and RPD. The distribution patterns of CD (macular and diffuse type) and RPD (localized, intermediate, and diffuse type), presence of soft drusen, large drusen (> 200 µm), variant subretinal drusenoid deposits, and macular complications were investigated. Of the 220 eyes of 110 patients diagnosed with CD and 926 eyes of 463 patients diagnosed with RPD, 13 eyes of seven patients met the diagnostic criteria for both CD and RPD. The mean age at initial presentation was 71.4 ± 8.8 years and six patients were female. The mean subfoveal choroidal thickness was 143.8 ± 25.1 µm. The distribution of CD was of the macular type in all eyes. Distribution of RPD was localized in 11 eyes (84.6%) and intermediate in two eyes (15.4%). Soft drusen, large drusen, and variant subretinal drusenoid deposits were present in 13 (100%), 12 (92.3%) and, seven (53.8%) eyes, respectively. Macular neovascularization was observed in two eyes (15.4%). CD and RPD can coexist in eyes with AMD. Multimodal imaging should be used for AMD eyes with features suggestive of CD and RPD, considering the high likelihood of developing late AMD.

Intersession Repeatability of Structural Biomarkers in Early and Intermediate Age-Related Macular Degeneration: A MACUSTAR Study Report.

Purpose: To analyze the intersession repeatability of structural biomarkers in eyes with early and intermediate age-related macular degeneration (iAMD) within the cross-sectional part of the observational multicenter MACUSTAR study. Methods: Certified site personnel obtained multimodal imaging data at two visits (38 ± 20 [mean ± standard deviation] days apart), including spectral-domain optical coherence tomography (SD-OCT). One junior reader performed systematic and blinded grading at the central reading center, followed by senior reader review. Structural biomarkers included maximum drusen size classification (>63 to ≤125 µm vs. >125 µm), presence of large pigment epithelium detachments (PEDs), reticular pseudodrusen (RPD), vitelliform lesions, and refractile deposits. Intrasession variability was assessed using Cohen's κ statistics. Results: At the first visit, 202 study eyes of 202 participants were graded as manifesting with either early (n = 34) or intermediate (n = 168) AMD. Grading of imaging data between visits revealed perfect agreement for the maximum drusen size classification (κ = 0.817; 95% confidence interval, 0.70-0.94). In iAMD eyes, perfect to substantial agreement was determined for the presence of large PEDs (0.87; 0.69-1.00) and RPD (0.752; 0.63-0.87), while intersession agreement was lower for the presence of vitelliform lesions (0.649; 0.39-0.65) and refractile deposits (0.342; -0.029-0.713), respectively. Conclusions: Multimodal retinal imaging analysis between sessions showed a higher repeatability for structural biomarkers with predefined cutoff values than purely qualitative defined parameters. Translational Relevance: A high repeatability of retinal imaging biomarkers will be important to implement automatic grading approaches and to establish robust and meaningful structural clinical endpoints for future interventional clinical trials in patients with iAMD.

Retinal pigment epithelium-specific CLIC4 mutant is a mouse model of dry age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly. Dry AMD has unclear etiology and no treatment. Lipid-rich drusen are the hallmark of dry AMD. An AMD mouse model and insights into drusenogenesis are keys to better understanding of this disease. Chloride intracellular channel 4 (CLIC4) is a pleomorphic protein regulating diverse biological functions. Here we show that retinal pigment epithelium (RPE)-specific Clic4 knockout mice exhibit a full spectrum of functional and pathological hallmarks of dry AMD. Multidisciplinary longitudinal studies of disease progression in these mice support a mechanistic model that links RPE cell-autonomous aberrant lipid metabolism and transport to drusen formation.

Choroidal structural changes in different intermediate AMD patterns.

PURPOSE: To report variation of choroidal thickness (CT) and choroidal vascularity index (CVI) in subjects with drusen and subjects with reticular pseudodrusen (RPD) compared with healthy individuals using the Spectral-domain (SD)-Optical Coherence Tomography with enhanced depth imaging (EDI) system. DESIGN: A prospective, observational, cross-sectional study. SUBJECTS: Eighty-four participants. METHODS: The patients were imaged using the Heidelberg Spectralis device (Heidelberg Engineering, Heidelberg, Germany) with EDI mode. EDI-OCT images were exported and then imported into image analysis ImageJ software (National Institutes of Health, Bethesda) and a semiautomated algorithm was used for subsequent quantitative analysis. MAIN OUTCOME MEASURES: This study evaluated two choroidal parameters: (i) choroidal thickness (CT); (ii) choroidal vascularity index (CVI). RESULTS: CT analysis was performed in three different regions: (i) foveal region, (ii) parafoveal region; (iii) perifoveal region. All the analyzed regions were significantly decreased in RPD pattern, as compared with both the drusen group (p < .005) and healthy eyes (p < .005). CVI was significantly decreased in the RPD pattern, as compared with healthy eyes (p < 0.001). However, the drusenoid pattern did not have statistical significance in comparison with the control group suggesting the lower incidence of this pattern on choroidal vasculopathy. CONCLUSIONS: We report CT and CVI difference in RPD and drusen eyes. The RPD pattern seems to be a consequence of an alteration in the choroidal vascularity resulting in severe ischemia and excessive hypoxia inducing an increased risk of late AMD compared to the drusenoid pattern.

Quantification of Early and Intermediate Age-related Macular Degeneration Using OCT "en face" Presentation. / Quantifizierung der frühen und intermediären altersabhängigen Makuladegeneration mittels OCT-"en-face"-Darstellung.

BACKGROUND: Early and intermediate age-related macular degeneration (AMD) results in drusen deposits under the retinal pigment epithelium (RPE). These early stages of AMD exhibit different risks of progressing to late AMD. To date, early AMD has been classified and quantified by fundus photography. This does not appear to be sensitive enough for clinical trials studying the impact on drusen. SD-OCT with two-dimensional rendering of the segmented slices analysed allows for en face imaging of the drusen. The present trial studied the potential of quantifying early and intermediate AMD by en-face optical coherence tomography (OCT). MATERIAL AND METHODS: Thirty-one eyes of 29 patients in different stages of early and intermediate AMD were studied. To this end, fundus photographs (Kowa VX-10i, Kowa, Tokyo, Japan) and en-face OCT images (RTVue XR Avanti, Optovue, Inc., Fremont, CA, USA) were taken. First, different segmentation levels (6 µm underneath the RPE, on the RPE, 6 µm and 9 µm above the RPE) and different layer thicknesses (5 µm, 10 µm, 20 µm and 30 µm) were analysed to determine the best segmentation for visualising drusen. Drusen were marked manually and their number and surface area calculated. This analysis was then compared with the standardised drusen analyses on fundus photography. Additional changes in early and intermediate AMD such as pigment epithelial detachments (PEDs) and subretinal drusenoid deposits (SDD) as well as small atrophies were also documented and compared. OUTCOMES: The best segmentation for delineating the drusen on the en-face OCT images was found to be a segmentation 6 µm underneath the RPE with a slice thickness of 20 µm. Comparison of drusen quantification on en-face OCT images with the standardised drusen analysis on fundus photography revealed particularly good similarity. Other changes in early and intermediate AMD, such as PEDs, SDD and small atrophies, were easier to assess on the en-face OCT images. CONCLUSIONS: The analysis and quantification of drusen from en-face OCT images with 20 µm segmentation at 6 µm underneath the RPE allows differentiated quantification of various drusen characteristics. Moreover, other changes in early and intermediate AMD can also be analysed. In future observational and clinical trials, this could help quantify drusen.