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.