Functionally Validated Structural Endpoints for Early AMD

早期 AMD 的功能验证结构端点

• 批准号: 10691011
• 负责人: Christine A Curcio
• 金额: $ 6.83万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10691011
• 关键词: Adult; Aging; Applications Grants; Biological Availability; Blood Circulation; Brain; Bruch' s basal membrane structure; Budgets; Carotenoids; Cells; Choroidal Neovascularization; Clinical Trials; Dark Adaptation; Data; Deposition; Diet; Drusen; Enrollment; Eye; Funding; Genes; High Density Lipoproteins; High Pressure Liquid Chromatography; Human; Image; International; Literature; Lutein; Measures; Mediating; Membrane Lipids; Modality; Modeling; Neurosciences; Participant; Pathologic; Prevention; Prospective Studies; Publishing; Recommendation; Research Design; Retina; Risk; Rod; Role; Sampling; Serum; Source; Supplementation; Technology; Testing; Time; Visit; Xanthophylls; design; dietary; follow-up; fovea centralis; genome sequencing; genome wide association study; high risk; imaging study; instrument; macula; normal aging; nutrition; retinal imaging; secondary analysis; symposium; whole genome; zeaxanthin

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.

ALSTAR 2是一项前瞻性研究，旨在确定一项 从衰老到早期AMD再到中期AMD的进展顺序。因为ALSTAR 2的设计 为了结合目前的沉积物驱动的AMD进展和人类视网膜神经科学的概念， 还将揭示和细化AMD早期阶段的病理机制。入组时间 2019年10月和2021年9月，532例成人≥ 60岁。我们将开始3年随访 2022年10月访问。今天，我们请求追加资金，以获得一个独特的后续机会， 可能支持新的临床试验和饮食建议，以促进AMD的预防。简言之， 我希望测量视网膜和血清中叶黄素类胡萝卜素（叶黄素，L;玉米黄质; Z，meso-Z）的水平 发现于人类黄斑。补充L和Z可降低脉络膜新生血管形成的风险 先前在AREDS 2的二次分析中显示。原拨款的资助目标 应用，我们增加了一个客观的成像研究类胡萝卜素的基线研究，使用机构 资金双波长自体荧光是Spectralis OCT仪器上的一种模式， 我们的其他成像测试2020年，我们的团队发布了使用该技术的AMD眼睛的第一张图像。 在ALSTAR 2基线中，我们还通过高效液相色谱法测定了血清类胡萝卜素。 层析这个附加到基线的目的是为了探测中央环绕的一个方面 沉积物驱动的AMD进展模型。该模型将高风险患者的紧密中心凹中心定位 软性玻璃疣，涉及饮食的Bruch膜脂质组成， 中央凹细胞的循环，以及旁视杆细胞介导的暗适应差。令人兴奋的发现来自 在英国剑桥举行的国际脑和眼营养会议上提出了基线 (late 2022年7月）。MPOV与血清类胡萝卜素水平呈正相关（r = 0.49）， 比以前的文学。这种相关性不受L和Z补充剂使用的影响。我们假设 L和Z的转移与软晶簇的形成有关。我们的基线结果很有趣，但交叉- 分段的在这个大样本中确定随时间的变化对于理解L的作用至关重要 而Z代表衰老和老年性黄斑变性因此，我们希望在3年随访时测量血清L和Z，以及 客观双波长自体荧光成像和MPOV。因为我们还假设 AMD GWAS的HDL基因调节从肠道到中央凹的类胡萝卜素生物利用度， ALSTAR 2参与者的基因组测序也正在从其他来源平行寻求。