Delayed Near InfraRed Analysis (DNIRA) identifies novel Imaging Biomarkers (IBs) for “dry” Age Related Macular Degeneration (AMD) in a prospective, natural history study

Abstract

Purpose : Treatments to reduce vision loss are not yet available for patients with dry AMD, but can be accelerated by IBs that inform clinical trial design and insight into disease. To this end, we translated DNIRA from the lab to the clinic. DNIRA is a dye-based, non-angiographic method first described in rodents to enhance visualization of the retinal pigment epithelium (RPE; ARVO MIT award, 2014). We hypothesized that DNIRA provides similar information as blue fundus autofluorescence (FAF), a gold standard to view RPE, in control eyes and in eyes with geographic atrophy (GA) and quantifiable RPE loss. We report the technical validity and biological validity (applicability) of DNIRA imaging and DNIRA-based IBs to dry AMD.

Methods : With consent, study subjects underwent multi-modal imaging including DNIRA, performed using low gain, short acquisition-time, confocal imaging in the ICG ex/em spectrum. Baseline, pre-dye images were acquired, followed by intravenous ICG (25mg). DNIRA images were acquired 2-3 days later without further injection of dye. Regions of GA (hypoFAF) were manually segmented, confirmed by OCT. Later, with MD input, AI/ML algorithms registered, segmented and compared regions of GA and hypoDNIRA. Performance was assessed by Bland-Altman (BA), fixed feature, & ROC analysis.

Results : Of 138 subjects, 114 eyes had early AMD, 51 had GA; 47 were controls/comparators. On a single device, DNIRA was repeatable (93% of data < 2 std devs, BA). In controls, DNIRA and FAF shared features consistent with RPE, with less foveal diminution in DNIRA. In eyes with GA, the area of hypoDNIRA was the same as the area of hypoFAF (< 5%) in 27% of eyes, confirming our hypothesis; however, hypoDNIRA exceeded hypoFAF in 73% (sensitivity for GA 99%, specificity 32%; p<0.003, McNemar’s X2). The area of hypoDNIRA exceeded hypoFAF in 100% of eyes with early AMD. In cross-modal analysis, hypoDNIRA was anatomically associated with atrophy, drusen, RPE detachment, hypolucent drusen, and hyperfluorescent FAF. No anatomical correlation was found for the “weave”, “smudge”, and “profoundly black” patterns, supporting structural change below OCT resolution or a functional defect in dye uptake into diseased RPE.

Conclusions : DNIRA & DNIRA IBs are technically repeatable, and offer new insights into dry AMD. Their clinical utility awaits multi-site study.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.