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.

ALSTAR2是一项前瞻性研究，旨在确定 从衰老到早期AMD再到中期AMD的进展顺序。因为ALSTAR2被设计成 为了结合目前存款驱动的AMD进展和人类视网膜神经科学的概念，它 还将揭示和完善AMD早期阶段的病理机制。注册时间： 2019年10月和2021年9月导致532名成年人≥60岁。我们将开始为期3年的跟踪调查 2022年10月访问。今天，我们请求补充资金，为后续行动提供一个独特的机会 可能支持一项新的临床试验和饮食建议，以促进AMD的预防。简而言之，我们 希望测量视网膜和血清中叶黄素类胡萝卜素的水平(叶黄素，L；玉米黄质；Z，Meso-Z) 在人类斑疹中发现。补充L和Z可降低脉络膜新生血管的风险 此前在对AREDS2的二次分析中显示了这一点。与最初拨款的资助目标相一致 应用，我们在基线研究中增加了一项对类胡萝卜素的客观成像研究，使用机构 资金。双波长自发荧光是光谱OCT仪器上的一种形式，我们使用它来 我们的其他成像测试。2020年，我们的团队发表了第一批使用这项技术的AMD眼睛的图像。 在ALSTAR2基线中，我们还通过高效液体测定了血清类胡萝卜素 层析法。基线的这个附加组件的目的是探索中心环绕的一个方面 存款驱动型AMD进展模型。这一模式连接了高风险的中心凹紧密集中 软性黄褐斑，与饮食有关的Bruchs膜脂的成分，从 循环到中央凹细胞，以及视杆介导的暗适应不良的副中央窝。令人振奋的发现来自 基线在英国剑桥举行的国际脑和眼营养会议上公布 (2022年7月下旬)。MPOV与血清类胡萝卜素水平呈正相关(r=0.49)，且水平较高 比以前的文学作品都要好。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的转移与软德鲁斯的形成有关。我们的基线结果耐人寻味，但也有交叉- 分段的。在这个大样本中确定随时间的变化对于理解L的角色至关重要 在衰老和AMD中为Z。因此，我们希望在3年的随访中检测血清L和Z，以及 目的双波长自体荧光成像与MPOV。因为我们还假设 AMD Gwas的高密度脂蛋白基因调节从肠道到中心凹的类胡萝卜素生物利用度 ALSTAR2参与者的基因组测序也在从其他来源并行寻找。