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

Abstract

Importance: 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 participants: This 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 measures: To 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.

Results: Of 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 relevance: In 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 factors may help to develop reliable methods of predicting future disease progression.

Figure 1.. Spatial Distribution of Drusen and Hyperreflective Foci (HRF)

A and B, Eyes progressing to macular neovascularization (MNV) had a peak of drusen accumulation in the foveal center, whereas eyes developing macular atrophy (MA) had the highest drusen volume at 0.5-mm eccentricity from the fovea. C and D, HRF occurred predominantly in the 0.5- to 1.0-mm eccentricity zone, whereas fewer HRF were found at the foveal center. Eyes developing MA had the highest mean HRF thickness, with a preponderance temporal to the fovea. In the distribution profiles, the statistical significance of the difference between the curves at each point of distance to the fovea is color coded in the bars below the graph. Red denotes lower P values, whereas blue represents P > .05. P values are adjusted for multiple testing.

Figure 2.. Longitudinal Analysis of Drusen and Hyperreflective Foci (HRF) Volume

A, Eyes progressing to macular neovascularization (MNV) had a faster increase in drusen volume than eyes in the other patients. B, In contrast, a continuous increase in HRF volume was observed in eyes developing MNV, whereas the HRF volume was fluctuating in patients developing MA. Dashed lines represent 95% CIs.

Figure 3.. Topographic Analysis of Hyperreflective Foci (HRF)

A, HRF overlying drusen. B, HRF not overlying drusen. Most HRF were detected in the direct neighborhood of drusen; however, eyes progressing to macular atrophy (MA) also had HRF not associated with drusen. The statistical significance of the difference between the curves at each point of distance to the fovea is color coded in the bars below the graphs. Red denotes lower P values, whereas blue represents P > .05. P values are adjusted for multiple testing. MNV, macular neovascularization.