Characterization of Drusen and Hyperreflective Foci as Biomarkers for Disease Progression in Age-Related Macular Degeneration Using Artificial Intelligence in Optical Coherence Tomography

Abstract

The morphologic changes and their pathognomonic distribution in progressing age-related macular degeneration (AMD) are not well understood.OBJECTIVES To characterize the pathognomonic distribution and time course of morphologic patterns in AMD and to quantify changes distinctive for progression to macular neovascularization (MNV) and macular atrophy (MA). DESIGN, SETTING, AND PARTICIPANTSThis cohort study included optical coherence tomography (OCT) volumes from study participants with early or intermediate AMD in the fellow eye in the HARBOR (A Study of Ranibizumab Administered Monthly or on an As-needed Basis in Patients With Subfoveal Neovascular Age-Related Macular Degeneration) trial. Patients underwent imaging monthly for 2 years (July 1, 2009, to August 31, 2012) following a standardized protocol. Data analysis was performed from June 1, 2018, to January 21, 2020. MAIN OUTCOMES AND MEASURESTo obtain topographic correspondence between patients and over time, all scans were mapped into a joint reference frame. The time of progression to MNV and MA was established, and drusen volumes and hyperreflective foci (HRF) volumes were automatically segmented in 3 dimensions using validated artificial intelligence algorithms. Topographically resolved population means of these markers were constructed by averaging quantified drusen and HRF maps in the patient subgroups. RESULTSOf 1097 patients enrolled in HARBOR, 518 (mean [SD] age, 78.1 [8.2] years; 309 [59.7%] female) had early or intermediate AMD in the fellow eye at baseline. During the 24-month follow-up period, 135 (26%) eyes developed MNV, 50 eyes (10%) developed MA, and 333 (64%) eyes did not progress to advanced AMD. Drusen and HRF had distinct topographic patterns. Mean drusen thickness at the fovea was 29.6 μm (95% CI, 20.2-39.0 μm) for eyes progressing to MNV, 17.2 μm (95% CI, 9.8-24.6 μm) for eyes progressing to MA, and 17.1 μm (95% CI, 12.5-21.7 μm) for eyes without disease progression. At 0.5-mm eccentricity, mean drusen thickness was 25.8 μm (95% CI, 19.1-32.5 μm) for eyes progressing to MNV, 21.7 μm (95% CI, 14.6-28.8 μm) for eyes progressing to MA, and 14.4 μm (95% CI, 11.2-17.6 μm) for eyes without disease progression. The mean HRF thickness at the foveal center was 0.072 μm (95% CI, 0-0.152 μm) for eyes progressing to MNV, 0.059 μm (95% CI, 0-0.126 μm) for eyes progressing to MA, and 0.044 μm (95% CI, 0.007-0.081) for eyes without disease progression. At 0.5-mm eccentricity, the largest mean HRF thickness was seen in eyes progressing to MA (0.227 μm; 95% CI, 0.104-0.349 μm) followed by eyes progressing to MNV (0.161 μm; 95% CI, 0.101-0.221 μm) and eyes without disease progression (0.085 μm; 95% CI, 0.058-0.112 μm). CONCLUSIONS AND RELEVANCEIn this study, drusen and HRF represented imaging biomarkers of disease progression in AMD, demonstrating distinct topographic patterns over time that differed between eyes progressing to MNV, eyes progressing to MA, or eyes without disease progression. Automated localization and precise quantification of these fac...

Topographic Distribution and Progression of Soft Drusen Volume in Age-Related Macular Degeneration Implicate Neurobiology of Fovea

“…In the BMES 15-year follow-up the peak odds ratio (18.5) was lower than at 10 years, which the BMES authors attributed due to disease progression and drop-out of study participants. A similar spatial pattern is visible for drusen volumes recently reported for a clinical trial dataset 55 and normalized for ETDRS subfield area by us in Table 3 . Waldstein et al, also using the Iowa Reference Algorithm, determined the volume of all drusen in OCT scans of eyes that stayed stable, progressed to macular atrophy, or progressed to macular neovascularization.…”

“…Waldstein et al, also using the Iowa Reference Algorithm, determined the volume of all drusen in OCT scans of eyes that stayed stable, progressed to macular atrophy, or progressed to macular neovascularization. 55 For these eyes, drusen volume is maximal in the central subfield; the central-inner-outer gradient (5–7) is markedly shallower than in our study.…”

Measuring the Contributions of Basal Laminar Deposit and Bruch's Membrane in Age-Related Macular Degeneration

“…Hypothesizing that deposit formation has a cellular basis in neurosensory retina, we used a coordinate system anchored on the rod-free zone to study lesion topography. 56,57 High-risk drusen and BLinD concentrate in the central subfield of the Early Treatment Diabetic Retinopathy Study (ETDRS) grid and fall off sharply within 1.5 mm eccentricity. 25,26,58,59 The subfoveal predilection of BMounds in normal eyes supports Sarks' hypothesis that BLamD is a major contributor to drusen accumulation, 15,17 as follows.…”

Properdin Modulates Complement Component Production in Stressed Human Primary Retinal Pigment Epithelium Cells

“…In contrast to inherited eye diseases, where often both eyes are affected to a similar extent, acquired vision loss can occur in different degrees in the left and right eye. For AMD it is known that the disease progression can be dissimilar between both eyes [ 55 , 56 ]. Our data support this monocular specific disease progression also on the level of hpRPE cell-dependent complement secretion.…”