Visualizing lipid behind the retina in aging and age-related macular degeneration, via indocyanine green angiography (ASHS-LIA)

Age-related macular degeneration (AMD) causes legal blindness in older adults worldwide. Soft drusen are the most extensively documented intraocular risk factor for progression to advanced AMD. A long-standing paradox in AMD pathophysiology has been the vulnerability of Asian populations to polypoidal choroidal vasculopathy (PCV) in the presence of relatively few drusen. Age-related scattered hypofluorescent spots on late phase indocyanine green angiography (ASHS-LIA) was recently proposed as precursors of PCV. Herein, we offer a resolution to the paradox by reviewing evidence that ASHS-LIA indicates the diffuse form of lipoprotein-related lipids accumulating in Bruch’s membrane (BrM) throughout adulthood. Deposition of these lipids leads to soft drusen and basal linear deposit (BLinD), a thin layer of soft drusen material in AMD; Pre-BLinD is the precursor. This evidence includes: 1. Both ASHS-LIA and pre-BLinD/BLinD accumulate in older adults and start under the macula; 2. ASHS-LIA shares hypofluorescence with soft drusen, known to be physically continuous with pre-BLinD/BLinD. 3. Model system studies illuminated a mechanism for indocyanine green uptake by retinal pigment epithelium. 4. Neither ASHS-LIA nor pre-BLinD/ BLinD are visible by multimodal imaging anchored on current optical coherence tomography, as confirmed with direct clinicopathologic correlation. To contextualize ASHS-LIA, we also summarize angiographic characteristics of different drusen subtypes in AMD. As possible precursors for PCV, lipid accumulation in forms beyond soft drusen may contribute to the pathogenesis of this prevalent disease in Asia. ASHS-LIA also might help identify patients at risk for progression, of value to clinical trials for therapies targeting early or intermediate AMD.