Spatial distribution of cuticular drusen and its association with category-specific progression risk in intermediate AMD

Objectives To investigate the spatial distribution pattern of cuticular drusen using en face OCT and determine its relationship with 2-year progression of age-related macular degeneration (AMD). Methods This study included 87 eyes from 57 participants with intermediate AMD and cuticular drusen enroled in the Amish Eye Study who completed two years of follow-up. Multimodal imaging, including volume spectral-domain OCT, was performed. Density of cuticular drusen was quantified on en face OCT across three Early Treatment Diabetic Retinopathy Study (ETDRS) grid zones using ImageJ. K-means clustering analysis was used to categorize distribution patterns. Firth’s penalized logistic regression evaluated association between cuticular drusen distribution categories and progression to late AMD at 2 years. Results Three spatial phenotypes of cuticular drusen were identified: central-dominant (57.5%), outer-macular-dominant (32.2%), and diffuse (10.3%). Over two years, five eyes progressed to late AMD, four of which belonged to the outer-macular-dominant group. In unadjusted Firth regression, the outer-macular-dominant phenotype was associated with higher odds of progression than the other phenotypes (OR 7.16; 95% CI 1.24–74.20, p = 0.027). After adjustment for subretinal drusenoid deposits (SDDs) and large drusen, the association between spatial phenotype and progression remained (OR 11.53; 95% CI 1.62–169.00; p = 0.013), while SDDs were also associated with progression (OR 9.26; 95% CI 1.36–78.65; p = 0.023). Conclusions Clustering of en face OCT–derived spatial features identified distinct cuticular drusen phenotypes within the macula. The outer-macular-dominant phenotype may be associated with an increased likelihood of AMD progression in this exploratory analysis.