Functionally Validated Structural Endpoints for Early AMD

ALSTAR2是一项前瞻性研究，旨在识别功能有效的结构终点

ALSTAR2 is a prospective study designed to identify functionally validated structural endpoints on a progression sequence from aging to early AMD to intermediate AMD. Because ALSTAR2 was designed to incorporate current concepts of deposit-driven AMD progression and human retinal neuroscience, it will also reveal and refine pathologic mechanisms during the earliest stages of AMD. Enrollment between October 2019 and September 2021 resulted in 532 adults ≥ 60 years. We will begin our 3-year follow-up visit in October 2022. Today we request supplemental funds for a unique opportunity at follow-up that may support a new clinical trial and dietary recommendations to facilitate AMD prevention. In brief we wish to measure retinal and serum levels of xanthophyll carotenoids (lutein, L; zeaxanthin; Z, meso-Z) found in human macula. Reduced risk for choroidal neovascularization due to L and Z supplementation was previously shown in a secondary analysis of AREDS2. To the funded aims of the original grant application, we added an objective imaging study of carotenoids to the baseline study, using institutional funds. Two-wavelength autofluorescence is a modality on the Spectralis OCT instrument that we use for our other imaging tests. In 2020 our group published the first images of AMD eyes using this technology. In ALSTAR2 baseline, we also measured serum carotenoids via high-performance liquid chromatography. The purpose of this add-on to baseline was to probe one aspect of a Center-Surround model of deposit-driven AMD progression. This model connects the tight foveal centration of high-risk soft drusen, composition of Bruch’s membrane lipids implicating diet, delivery of xanthophylls from circulation to foveal cells, and poor rod-mediated dark adaptation in parafovea. Exciting findings from baseline were presented at the international Brain and Ocular Nutrition Conference in Cambridge UK (late July 2022). MPOV was positively correlated with serum carotenoid levels (r = 0.49), at levels higher than in previous literature. This correlation was not impacted by L and Z supplement use. We hypothesize that transfer of L and Z is related to soft druse formation. Our baseline results are intriguing yet cross- sectional. Determining change over time in this large sample is critical for understanding the roles of L and Z in aging and AMD. We thus wish to measure serum L and Z at the 3-year follow-up visit, as well as objective two-wavelength autofluorescence imaging and MPOV. Because we also hypothesize that the HDL genes of the AMD GWAS regulate carotenoid bioavailability from gut to fovea, funds for whole genome sequencing of ALSTAR2 participants are also being sought in parallel from other sources.