Cuticular Drusen and the Risk of Progression to Late Age-Related Macular Degeneration: A MACUSTAR Study Report

To analyze the prevalence of cuticular drusen (CD) and their relationship with other structural biomarkers in the progression to late age-related macular degeneration (AMD) within the MACUSTAR study (ClinicalTrials.gov Identifier: NCT03349801).

Longitudinal European multicenter cohort study.

585 study participants at a mean age of 72.1 ± 7.0 years with intermediate age-related macular degeneration (iAMD) at baseline visit.

Using multimodal imaging, study eyes with iAMD were graded at baseline visit for CD and other AMD-associated biomarkers, including retinal pigment epithelium-drusencomplex (RPEDC) volume, reticular pseudodrusen (RPD), hyper-reflective foci (HRF), and pigmentary abnormalities (PA). We analyzed the prevalence of structural biomarkers according to CD status. Multivariable time-discrete hazard models were used to assess the association of CD alongside RPEDC volume, RPD, HRF, and PA on the progression to late-stage AMD within a 4-year follow-up period.

Hazard ratio (HR) of progression from intermediate to late-stage AMD.

At baseline, 15.9% of iAMD eyes (93/585 participants; age 71.0 ± 7.2 years) presented with CD, with the following phenotype distribution: type 1, 45.2%; type 2, 32.2%; and type 3, 22.6%. RPD was less prevalent in eyes with CD (11.8%) compared to eyes without (29.9%), whereas other structural biomarkers were comparably prevalent between individuals with and without CD. Progression to late AMD occurred in 6% of eyes with CD (n = 6) and 16.0% without CD (n = 78). CD alone did not significantly modify the risk of AMD progression (HR = 0.49; 95% confidence interval [CI], 0.21‑1.12; P = 0.09). However, coexisting CD and RPD showed the highest risk (HR, 5.9; 95% CI, 1.1-31.5; P < 0.04), exceeding RPD alone (HR, 3.5; 95% CI, 2.3-5.5; P < 0.0001) or RPEDC volume (HR, 1.3; 95% CI, 1.1-1.5; P = 0.01). The presence of HRF and PA on top of CD did not significantly impact the risk of progression beyond the presence of HRF or PA alone. Over time, CD showed coalescence (37.6%), resorption (19.4%), and pigmentary changes (28.0%).

In iAMD, CD alone does not significantly modify the risk of progression to late AMD in the absence of RPD. However, when CD and RPD coexist, the risk of progression to late AMD is increased. Further investigations, including genetic analyses, are needed to better understand the mechanisms underlying this association.

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