Identifying Imaging Predictors of Intermediate Age-Related Macular Degeneration Progression.

Purpose: Intermediate age-related macular degeneration (iAMD) is a risk factor for progression to advanced stages, but rates of progression vary between individuals. Predicting individual risk is advantageous for programing timely and effective treatment and for patient stratification into future clinical trials. Methods: We conducted a prospective and noninterventional study following patients with iAMD for 24 months. Optical coherence tomography parameters related with drusen, hyper-reflective foci (HRF), presence of incomplete retinal pigment epithelial and outer retinal atrophy (iRORA) and ellipsoid zone (EZ) status were explored at the baseline. Patients were reclassified at the end of the follow-up period and divided according to their progression. A risk prediction model for progression to late AMD was developed. Results: A total of 135 patients were enrolled in the study and 30.4% developed late disease. A multivariate logistic regression model was created using those optical coherence tomography parameters, further optimized by backward feature elimination. Parameters offering the best fit in prediction progression were presence of iRORA, EZ status, drusen area and presence of HRF. iRORA is the feature that provides a higher probability of developing late AMD (odds ratio, 12.91; P = 0.000), followed by EZ disruption status (odds ratio, 3.54; P = 0.0018). The area under the receiver operating characteristic curve calculated for the testing set was 0.77 (95% confidence interval, 0.56-0.98). Conclusions: The combination of iRORA and EZ disruption constitute a high risk of progression to complete RORA within 2 years. Translational Relevance: We propose a practical and useful model to help clinicians in their daily practice in predicting individual progression to advanced AMD.

Quantitative assessment of choriocapillaris flow deficits and type 1 macular neovascularization growth in age-related macular degeneration.

During the past 15 years, new treatment paradigms for neovascular age-related macular degeneration (nvAMD) have evolved due to the advent of intravitreal anti-vascular endothelial growth factor (VEGF) therapy and rapid advances in retinal imaging. Recent publications describe eyes with type 1 macular neovascularization (MNV) as showing more resistance to macular atrophy than eyes with other lesion types. We sought to explore whether the perfusion status of the native choriocapillaris (CC) surrounding type 1 MNV influences its pattern of growth. To evaluate this effect, we analyzed a case series of 22 eyes from 19 nvAMD patients with type 1 MNV exhibiting growth on swept-source optical coherence tomography angiography (SS-OCTA) over a minimum follow-up of 12 months. We observed an overall weak correlation between type 1 MNV growth and CC flow deficits (FDs) average size (τ = 0.17, 95% CI [- 0.20, 0.62]) and a moderate correlation with CC FD % (τ = 0.21, 95% CI [- 0.16, 0.68]). Type 1 MNV was located beneath the fovea in most of the eyes (86%) and median visual acuity was 20/35 Snellen equivalent. Our results support that type 1 MNV recapitulates areas of CC blood flow impairment while serving to preserve foveal function.

Volume Rendering of Deep Retinal Age-Related Microvascular Anomalies.

PURPOSE: To characterize and distinguish non-neovascular deep retinal age-related microvascular anomalies (DRAMA) from type 3 macular neovascularization (MNV) using volume rendering of OCT and OCT angiography (OCTA). DESIGN: Retrospective, consecutive case series. SUBJECTS: Consecutive patients with age-related macular degeneration (AMD) exhibiting de novo non-neovascular abnormalities within the deep vascular plexus (DCP), as detected using high-resolution (High-Res) spectral-domain (SD) and swept-source (SS) OCT or OCTA. Patients with retinal vascular alterations attributable to other disease entities were excluded. METHODS: Complete ophthalmic examination and multimodal imaging, including confocal fundus photography (CFP), SD-OCT, High-Res SD-OCT and OCTA, and volume-averaged SS-OCTA. The volume renderings of High-Res OCTA and averaged SS-OCTA were used to analyze capillary abnormalities and inflow or outflow connectivity pathways. MAIN OUTCOME MEASURES: The primary outcomes were the characteristics of capillary abnormalities (number, size, shape, reflectivity, and location) and inflow or outflow connectivity pathways. The secondary outcomes were nearby changes in CFP and structural OCT (hyperreflective foci [HRF], outer retinal atrophy, and retinal pigment epithelium [RPE] atrophy). RESULTS: From 8 eyes of 8 patients, 2 subtypes of DRAMA were identified: small-diameter perifoveal capillary dilations with hyperreflective walls within the inner nuclear layer (type 1, n = 4) and vascular outpouchings, typically multiple, extending posteriorly into the Henle fiber layer, with reflectivity similar to adjacent normal retinal capillaries (type 2, n = 10). Four eyes had both subtypes of DRAMA. The 3-dimensional visualization of OCTA data demonstrated DRAMA corresponding to the dilations of DCP capillaries without direct inflow or outflow connections to the superficial plexus. Fundus photographs showed circular red dots in 3 eyes, all corresponding to type 1 DRAMA. In all the cases, DRAMA colocalized with HRF. No lesions were found anterior to the areas of the RPE or outer retina atrophy. Asymptomatic intraretinal exudation varied through a follow-up duration of up to 6 years, with no lesions progressing to type 3 MNV. CONCLUSIONS: In eyes with non-neovascular AMD, DRAMA include 2 types of capillary dilations occurring without the remodeling of the surrounding vascular network. Deep retinal age-related microvascular anomalies can resemble microvascular changes due to other causes and can masquerade as type 3 MNV. Mild intraretinal exudation can vary during follow-up, without progression to type 3 MNV.

Macular Vascular Imaging and Connectivity Analysis Using High-Resolution Optical Coherence Tomography.

Purpose: To characterize macular blood flow connectivity in vivo using high-resolution optical coherence tomography (HighRes OCT). Methods: Cross-sectional, observational study. Dense (6-µm interscan distance) perifoveal HighRes OCT raster scans were performed on healthy participants. To mitigate the limitations of projection-resolved OCT-angiography, flow and structural data were used to observe the vascular structures of the superficial vascular complex (SVC) and the deep vascular complex. Vascular segmentation and rendering were performed using Imaris 9.5 software. Inflow and outflow patterns were classified according to vascular diameter and branching order from superficial arteries and veins, respectively. Results: Eight eyes from eight participants were included in this analysis, from which 422 inflow and 459 outflow connections were characterized. Arteries had direct arteriolar connections to the SVC (78%) and to the intermediate capillary plexus (ICP, 22%). Deep capillary plexus (DCP) inflow derived from small-diameter vessels succeeding ICP arterioles. The most prevalent outflow pathways coursed through superficial draining venules (74%). DCP draining venules ordinarily merged with ICP draining venules and drained independently of superficial venules in 21% of cases. The morphology of DCP draining venules in structural HighRes OCT is distinct from other vessels crossing the inner nuclear layer and can be used to identify superficial veins. Conclusions: Vascular connectivity analysis supports a hybrid circuitry of blood flow within the human parafoveal macula. Translational Relevance: Characterization of parafoveal macular blood flow connectivity in vivo using a precise segmentation of HighRes OCT is consistent with ground-truth microscopy studies and shows a hybrid circuitry.

Choroidal Vascular Impairment in Intermediate Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a multifactorial disease, whose complete pathogenesis is still unclear. Local hemodynamics may play a crucial role in its manifestation and progression. To evaluate choroidal and retinal vascular parameters, a total of 134 eyes were analyzed, 100 with intermediate AMD and 34 age matched healthy controls. 131 eyes of 104 patients were eligible for complete image assessment and 3 eyes were excluded for insufficient image quality: Group 1: intermediate AMD (n = 97) and Group 2: healthy controls (n = 34). Spectral domain optic coherence tomography (SD-OCT) with enhanced depth imaging (EDI) and optic coherence tomography angiography (OCT-A) were acquired using Spectralis (Heidelberg Engineering). Choroid and retinal capillary plexus were evaluated and image binarization was used to obtain quantitative data. Mean age was 77.67 years old (YO) and 67.2% were women. Total subfoveal choroidal area and luminal area were significantly reduced in Group 1 compared with Group 2 (0.88 mm2 and 0.40 mm2 vs. 1.24 mm2 and 0.55 mm2, respectively) (p < 0.05). Regarding choriocapillary flow density, AMD eyes recorded reduced values (34.83%) compared with controls (36.25%) (p < 0.05). Chorioretinal vasculature is impaired in intermediate AMD patients and vascular parameters could be attractive new prognostic biomarkers. Future therapeutic approaches may target this vascular dysfunction and delay disease progression.

Formation of Lipofuscin-Like Autofluorescent Granules in the Retinal Pigment Epithelium Requires Lysosome Dysfunction.

Purpose: We aim to characterize the pathways required for autofluorescent granule (AFG) formation by RPE cells using cultured monolayers. Methods: We fed RPE monolayers in culture with a single pulse of photoreceptor outer segments (POS). After 24 hours the cells started accumulating AFGs that were comparable to lipofuscin in vivo. Using this model, we used a variety of light and electron microscopical techniques, flow cytometry and Western blot to analyze the formation of AFGs. We also generated a mutant RPE line lacking cathepsin D by gene editing. Results: AFGs seem to derive from incompletely digested POS-containing phagosomes and after 3 days are surrounded by a single membrane positive for lysosome markers. We show by various methods that lysosome-phagosome fusion is required for AFG formation, and that impairment of lysosomal pH or catalytic activity, particularly cathepsin D activity, enhances AF accumulation. Conclusions: We conclude that lysosomal dysfunction results in incomplete POS degradation and enhanced AFG accumulation.