James G. Fujimoto

Purpose: To demonstrate high-resolution, motion-corrected, volume-fused optical coherence tomography (OCT) for assessing longitudinal changes in macular dot form subretinal drusenoid deposits (SDDs). Methods: Six consecutive isotropic volume raster scans over 6 × 6 mm (500 × 500 A-scans) were acquired using a high-resolution (2.7 µm axial resolution) spectral domain OCT prototype instrument. OCT volumes were computationally motion-corrected and fused. The distribution and longitudinal changes in dot SDDs were evaluated using en face OCT in a 50-µm-thick slab, from 27 µm above Bruch's membrane. Results: Computational motion correction and volume fusion methods improve visibility of small en face features and compensate for motion artifacts to facilitate longitudinal assessment. In total, 326 SDDs were identified in a representative series of four eyes from four patients with intermediate age-related macular degeneration (AMD) and assessed with a 3- to 12-month follow-up. Of the SDDs, 85.3% remained stable over the follow-up, while 9.8% regressed, 3.4% fused, and 1.5% new SDDs appeared. Conclusions: Computational motion correction and volume fusion combined with high-resolution OCT B-scans and en face slabs facilitate visualization and longitudinal tracking of focal pathologies, such as SDDs. Translational Relevance: The methods presented have the potential to improve OCT analysis of focal features, such as quantification of SDDs and other AMD biomarkers.

Purpose: To evaluate visibility of a sub-band posterior to the external limiting membrane (ELM) and assess its age-associated variation. Methods: In a retrospective cross-sectional study, normal eyes were imaged using a high-resolution spectral-domain optical coherence tomography (SD-OCT) prototype (2.7-µm axial resolution). Volume fusion of six sequential scans (each 500 × 500 A-scans over 6 mm × 6 mm) was performed in the motion correction and volume reconstruction in OCT (MoReOCT) framework to enhance feature visibility in OCT. The subjects were divided into three groups: young (21-40 years old), middle (41-60 years old), and older (>60 years old). Three expert graders assessed the visibility of the sub-band on B-scans, and its A-scan intensity relative to ELM intensity (peak intensity ratio) was measured. Results: Forty-four eyes of 44 subjects were imaged. The sub-band, tentatively attributed to the photoreceptor myoid, can be visualized under high-resolution OCT. The B-scan gradings showed that sub-band visibility increased with age (visible in 16.7%, 47.2%, and 66.7% of the young, middle, and older age groups, respectively). The gradings were statistically different among age groups at 1 mm and 2 mm nasal and 1 mm and 2 mm temporal (P < 0.04) from the foveal center. Similarly, the mean peak intensity ratios of the sub-band to the ELM were 71.6%, 77.5%, and 85.2% in the young, middle, and older age groups, respectively, and were positively correlated with age at 1 mm temporal (P = 0.012) and 2 mm temporal (P < 0.001). Conclusions: High-resolution OCT, combined with advanced volume fusion, enables visualization of the photoreceptor myoid and investigation of its age-associated variations. Translational Relevance: Investigating the sub-band can advance our understanding of photoreceptors and their association with aging and disease pathogenesis.

PURPOSE: To assess the repeatability of a microperimetry methodology for quantifying visual function changes in the junctional zone of eyes with geographic atrophy (GA) in the clinical trial context. METHODS: A post hoc analysis of the OAKS phase III trial was conducted, which enrolled patients with GA secondary to age-related macular degeneration. Microperimetry using a standard 10 - 2 fovea centered grid was performed at baseline and follow-up visits. GA regions were traced on fundus autofluorescence (FAF) images. Two graders independently registered baseline microperimetry images with baseline FAF images in a sampling of 30 eyes from the OAKS study. Agreement between the two graders' assessments of mean sensitivity and the number of scotomatous points within a ± 250 𝜇m GA junctional zone was assessed. RESULTS: The intraclass correlation (ICC) and coefficient of repeatability (CoR) for the mean junctional zone sensitivity were 0.987 and 0.214 dB, respectively. The ICC and CoR for the total number of scotomatous points within the junctional zone were 0.991 and 1.42, respectively. CONCLUSIONS: The repeatability of the methodology and its compatibility with standard MP acquisitions appear to make it well-suited for identifying and analyzing retinal sensitivity within high-risk areas of the retina. We present a microperimetry-based methodology for assessing visual function changes in the junctional zone of geographic atrophy lesions using a standard 10 - 2 fovea centered grid in a clinical trial context. The approach's repeatability and compatibility with standard microperimetry grids may make it useful for assessing the effects of GA therapeutics.

Purpose To assess the repeatability of a microperimetry methodology for quantifying visual function changes in the junctional zone of eyes with geographic atrophy (GA) in the clinical trial context. Methods A post hoc analysis of the OAKS phase III trial was conducted, which enrolled patients with GA secondary to age-related macular degeneration. Microperimetry using a standard 10–2 fovea centered grid was performed at baseline and follow-up visits. GA regions were traced on fundus autofluorescence (FAF) images. Two graders independently registered baseline microperimetry images with baseline FAF images in a sampling of 30 eyes from the OAKS study. Agreement between the two graders’ assessments of mean sensitivity and the number of scotomatous points within a ±250 μm GA junctional zone was assessed. Results The intraclass correlation (ICC) and coefficient of repeatability (CoR) for the mean junctional zone sensitivity were 0.994 and 0.349 dB, respectively. The ICC and CoR for the total number of scotomatous points within the junctional zone were 0.997 and 0.218, respectively. Conclusions The repeatability of the methodology and its compatibility with standard MP acquisitions appear to make it well-suited for identifying and analyzing retinal sensitivity within high-risk areas of the retina.

PURPOSE: To investigate retinal capillary plexus capillary flow speed and vessel density in diabetic retinopathy and normal subjects using variable interscan time analysis optical coherence tomography angiography (OCTA). METHODS: High speed swept source OCTA imaging using multiple interscan times was performed over a 5 mm × 5 mm field-of-view with 600 kHz A-scan rate. Second-generation variable interscan time analysis OCTA was used to measure a surrogate marker for capillary blood flow speed, variable interscan time analysis flow speed (VFS), in the superficial and intermediate capillary plexuses VFS , and deep capillary plexus VFS . Vessel density was measured using OCTA. RESULTS: Fifty-seven eyes with different diabetic retinopathy severity and 37 normal eyes were analyzed. Variable interscan time analysis OCTA provided diverse blood flow speed information, including pseudo-color OCTA and mean flow speed in different regions. Both deep capillary plexus VFS and deep capillary plexus VFS /(superficial and intermediate capillary plexuses) VFS were higher in diabetic retinopathy compared with normal eyes. Elevated deep capillary plexus VFS correlated with decreased deep capillary plexus vessel density in nonproliferative diabetic retinopathy. CONCLUSION: Variable interscan time analysis OCTA can measure a quantitative biomarker for blood flow speed alterations in diabetic retinopathy and normal eyes as well as the association with vessel density in different capillary plexuses. Variable interscan time analysis OCTA is promising for studies of pathogenesis and early flow alterations, which may precede nonperfusion.

Purpose: A micrometer scale hyporeflective band within the retinal pigment epithelium basal lamina - Bruch's membrane complex (RPE-BL-BrM) was topographically measured in aging and age-related macular degeneration (AMD). Methods: In a prospective cross-sectional study, 90 normal eyes from 76 subjects (range = 23-90 years) and 53 dry AMD eyes from 47 subjects (range = 62-91 years) were enrolled. Isotropic volume raster scans over 6 mm × 6 mm (500 × 500 A-scans) were acquired using a high-resolution (2.7 µm axial resolution) spectral-domain optical coherence tomography (SD-OCT) prototype instrument. Six consecutive optical coherence tomography (OCT) volumes were computationally motion-corrected and fused to improve feature visibility. A boundary regression neural network was developed to measure hyporeflective band thickness. Topographic dependence was evaluated over a 6-mm-diameter Early Treatment Diabetic Retinopathy Study (ETDRS) grid. Results: The hyporeflective band thickness map (median of 4.3 µm and 7.8 µm in normal and AMD eyes, respectively) is thicker below and radially symmetric around the fovea. In normal eyes, age-associated differences occur within 0.7 to 2.3 mm from the foveal center (P < 0.05). In AMD eyes, the hyporeflective band is hypothesized to be basal laminar deposits (BLamDs) and is thicker within the 3-mm ETDRS circle (P < 0.0002) compared with normal eyes. The inner ring is the most sensitive location to detect age versus AMD-associated changes within the RPE-BL-BrM. AMD eyes with subretinal drusenoid deposits (SDDs) have a significantly thicker hyporeflective band (P < 0.001) than those without SDDs. Conclusions: The hyporeflective band is a quantifiable biomarker which differentiates AMD from aging. Longitudinal studies are warranted. The hyporeflective band may be a useful biomarker for risk stratification and disease progression.