Ultrahigh Resolution OCT Markers of Normal Aging and Early Age-related Macular Degeneration

**Background:** Age-related macular degeneration (AMD) is a leading cause of central vision loss in older populations. Differentiating normal aging from early AMD pathology is critical for developing biomarkers. Histology has identified two basal deposits: basal laminar deposit (BLamD) and basal linear deposit (BLinD). BLamD accumulates internal to the RPE basal lamina and marks the histopathological threshold of early AMD when continuous. Standard clinical OCT lacks resolution to detect these micrometric features. Ultrahigh resolution spectral domain-OCT (UHR SD-OCT) with 2.7 μm axial resolution may enable in vivo visualization of these deposits.

**Methods:** This prospective cross-sectional study enrolled 53 nonexudative (dry) AMD eyes (39 patients, mean age 77.5 years) and 63 normal eyes (39 subjects, mean age 53.6 years, range 23-90). A prototype UHR SD-OCT instrument (128 kHz A-scan rate, 2.7 μm axial resolution) was used with a high-density raster scan protocol (9 mm B-scans, 1800 A-scans, 5 μm spacing, 241 B-scans, 25 μm spacing). Three masked expert readers qualitatively assessed visibility of the RPE-BL-BrM split/hyporeflective band on linear gray scale B-scans. A semi-automatic segmentation algorithm measured band thickness and cross-sectional area. Exemplary histology and transmission electron microscopy (TEM) from donor eyes guided interpretation. Statistical analysis used Wilcoxon rank sum test and linear regression.

**Key Results:** In young normal eyes, UHR SD-OCT consistently resolved a hyporeflective split (band #vi) between two hyperreflective bands (#v and #vii) within the RPE-BL-BrM complex. With normal aging, split visibility and thickness decreased steadily. In normal eyes, median band thickness decreased by −0.041 μm per year (95% CI: −0.050 to −0.032). In early AMD eyes, the split was significantly more visible and thicker compared to age-matched normal eyes (P < 0.001 for thickness; P < 0.001 for area). Qualitative reader assessment showed significantly higher visibility in early AMD vs. age-matched normals (P values ranging from 0.0049 to 0.026 across eccentricities). The hyporeflective band cross-sectional area decreased in normal eyes (−380.3 μm² per year, 95% CI: −449.6 to −311.1) but increased significantly in early AMD (P < 0.001). Intraclass correlation coefficients for readers ranged from 0.81 to 0.84, indicating excellent agreement.

**Clinical Implications:** The RPE-BL-BrM split/hyporeflective band represents different histological origins in young normal eyes (basal RPE with basal infoldings) versus early AMD eyes (accumulation of BLamD). In early AMD, BLamD is continuous and thick, dominating the hyporeflective band signal. This feature can serve as an in vivo imaging marker to differentiate normal aging from early AMD pathology. The ability to quantify BLamD in early disease stages may enable investigation of its role in AMD pathogenesis and progression, facilitate drug discovery, and reduce clinical trial times by providing a measurable endpoint. The study demonstrates that UHR SD-OCT can visualize micrometric outer retinal alterations previously only accessible ex vivo, promising new biomarkers for AMD diagnosis, monitoring, and therapeutic response assessment.