Multimodal imaging biomarkers for progression from intermediate to advanced age-related macular degeneration (AMD): a 10-year prospective longitudinal cohort study from the University of Colorado AMD registry

Abstract

Objective: To evaluate multimodal imaging (MMI) biomarkers for predicting progression from intermediate to advanced age-related macular degeneration (AMD).

Methods and analysis: This prospective longitudinal cohort study included patients with intermediate AMD (iAMD) enrolled in the University of Colorado AMD registry between July 2014 and August 2023, with follow-up through February 2024. At enrolment, patients' medical histories and MMI were collected. Baseline and follow-up imaging were reviewed for progression to geographic atrophy (GA) and neovascular AMD (nAMD). Univariate and multivariable Cox proportional hazard modelling with competing risks to determine HRs for progression.

Results: A total of 367 patients (733 eyes) with iAMD were included in the study, with a median follow-up of 27.8 months. During this period, 100 eyes progressed to GA, 58 to nAMD. Adjusted for age, BMI and hypertension, progression to nAMD was significantly associated with soft drusen (HR 5.31, 95% CI 1.95 to 14.4, p=0.001), pigmentary changes (HR 2.74, 95% CI 1.52 to 4.92, p=0.0008) on colour fundus photography (CFP) and subretinal hyper-reflective material (SHRM) (HR 3.36, 95% CI 1.88 to 6.02, p<0.0001) and intraretinal hyper-reflective foci (IHRF) (HR 3.12, 95% CI 1.74 to 5.57, p=0.0001) on optical coherence tomography (OCT). Adjusted for age, progression to GA was predicted by soft drusen (HR 1.90, 95% CI 1.11 to 3.27, p=0.020), drusenoid pigment epithelial detachment (PED) (HR 5.51, 95% CI 2.49 to 12.2, p<0.0001), avascular non-drusenoid PED (HR 6.59, 95% CI 1.54 to 28.1, p=0.011), pigmentary changes (HR 4.44, 95% CI 2.84 to 6.96, p<0.0001) on CFP and nnSRF (HR 6.41, 95% CI 1.39 to 29.6, p=0.017), SHRM (HR 2.55, 95% CI 1.45 to 4.49, p=0.001), drusenoid PED (HR 2.25, 95% CI 1.43 to 3.55, p=0.0005), avascular non-drusenoid PED (HR 4.67, 95% CI 2.45 to 8.92, p<0.0001), IHRF (HR 6.27, 95% CI 3.89 to 10.1, p<0.0001) and incomplete retinal pigment epithelium and outer retinal atrophy (HR 9.42, 95% CI 5.82 to 15.2, p<0.0001) on OCT (table 3).

Conclusions: Key imaging biomarkers associated with the progression were identified, which may offer prognostic information for providers. However, the study is limited by its predominantly Caucasian population and single-centre design, which may affect the generalisability of certain biomarkers.

Keywords: Epidemiology; Imaging; Macula; Macular Degeneration; Retina.

Figure 1. Kaplan-Meier curve of time to progress from intermediate iAMD (iAMD) to either form of advanced AMD. Time in months is on the x-axis. The proportion of patients progressing to the advanced forms of AMD is on the y-axis. Numbers of subjects at risk are listed at the bottom of the graph. AMD, age-related macular degeneration; iAMD, intermediate AMD; GA, Geographic Atrophy; nAMD, neovascular AMD; SAS, Statistical Analysis System. The lifetest procedure is a feature in SAS software that is used to compute nonparametric estimates of survivor functions, compare survival curves, and perform rank tests to assess the association between failure time variables and covariates. It is commonly applied in survival analysis to handle censored data and generate Kaplan-Meier survival plots.

Figure 2. Optical coherence tomography (OCT) illustration of an eye with intermediate AMD (iAMD) at baseline progressing to geographic atrophy (GA) over time. Baseline OCT of the left eye shows a drusenoid pigment epithelial detachment (PED; white arrow), acquired vitelliform lesion (AVL; arrowhead) and non-neovascular subretinal fluid (nnSRF; asterisk) at enrolment in the Age-Related Macular Degeneration Registry. At 18 months, the OCT shows an increase in choroidal hypertransmission in the area of drusenoid PED, indicating loss of retinal pigment epithelium (RPE; white arrow) and an increase in SHRM (arrowhead). By 24 months, there is further progression of RPE loss in the area of the PED (white arrow) and increased thinning of the outer retina. By 30 months, the complete collapse of the drusenoid PED results in complete RPE and outer retina atrophy (white arrow). SHRM, subretinal hyper-reflective material.