Functionally Validated Structural Endpoints for Early AMD

早期 AMD 的功能验证结构端点

• 批准号: 10357762
• 负责人: Christine A Curcio
• 金额: $ 71.56万
• 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 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10357762
• 关键词: Address; Affect; Age related macular degeneration; Aging; Anatomy; Angiography; Anterior; Apoptosis; Attention; Biological; Biological Markers; Biometry; Blindness; Blood Vessels; Bruch' s basal membrane structure; Cells; Characteristics; Choroid; Clinical; Clinical Trials; Communities; Dark Adaptation; Data; Deposition; Development; Disease; Drusen; Elderly; Environment; Epidemiology; Exposure to; Eye; Functional disorder; Fundus; Future; Genotype; Goals; Health; Histopathology; Image Analysis; Impairment; Legal Blindness; Light; Lipids; Maps; Measures; Mediating; Metabolic; Modeling; Morphology; Onset of illness; Optical Coherence Tomography; Organelles; Outcome Measure; Pathogenesis; Patients; Persons; Pharmaceutical Preparations; Phenotype; Photophobia; Photoreceptors; Prevention strategy; Preventive measure; Prospective Studies; Recovery; Research; Research Design; Retina; Retinal Diseases; Retinoids; Risk; Risk Factors; Rod; Route; Signal Transduction; Spatial Distribution; Structure; Structure of retinal pigment epithelium; Structure-Activity Relationship; Support System; Testing; Thick; TimeLine; Tissues; Translational Research; United States Food and Drug Administration; Vision; Visual; Visual Psychophysics; Visual impairment; cohort; density; design; digital imaging; early detection biomarkers; end stage disease; extracellular; follow-up; frontier; geographic atrophy; high risk; innovation; macula; micronutrient deficiency; migration; multidisciplinary; normal aging; novel; pre-clinical; prevent; primary outcome; programs; prospective; public health relevance; retinal imaging; retinal rods; theories; treatment strategy

Project Summary Age-related macular degeneration (AMD), the leading cause of irreversible vision impairment in the US and third globally, is a disease of the photoreceptor support system involving the retinal pigment epithelium (RPE), Bruch's membrane, and the choriocapillaris, ultimately leading to photoreceptor demise and eventual vision loss. Our research with that of others has clearly documented the selective vulnerability of rod photoreceptors and rod-mediated (scotopic) vision, including delayed rod-mediated dark adaptation (RMDA) and impaired rod-mediated light sensitivity, in aging and early AMD. RMDA is not only more likely to be slower in eyes with early AMD compared to eyes in normal macular health, but also delayed RMDA is a functional biomarker (i.e., risk factor) for incident early AMD. The next frontier is to establish the structural basis of rod-mediated dysfunction in older adults at-risk for AMD and those already converted to early AMD. Our unifying hypothesis across all aims is: Early AMD is a disease of micronutrient deficiency and vascular insufficiency, due to detectable structural changes in the retinoid re-supply route from the choriocapillaris to the photoreceptors, manifest functionally as delayed rod- mediated dark adaptation. These structural disturbances will occur in specific chorioretinal layers and regions reflecting the spatial distribution of disease in the photoreceptor support system. Our multidisciplinary team has expertise in visual psychophysics, epidemiology, histopathology, digital image analysis and interpretation for retinal disease, study design, and biostatistics. Toward our goals, we will execute the 3 specific aims in an exceptionally well phenotyped cohort at aging-early AMD transition, staged by the AREDS 9-step scale, with 3 years of longitudinal follow-up: (1) To examine the abundance and extent of AMD's pathognomonic deposits (drusen and newly recognized subretinal drusenoid deposits) in relationship to scotopic dysfunction via optical coherence tomography (OCT); (2) To examine RPE cell bodies as structural correlates of scotopic dysfunction via quantitative fundus autofluorescence and layer thicknesses via OCT; (3) To measure vascular density (coverage of macular Bruch's membrane by choriocapillaris), a measure of exchange capacity for outer retinal cells, using OCT angiography. An accurate map and timeline of structure-function relationships in aging and early AMD gained from our research, especially the critical transition from aging to disease, will help define major effects that can be developed into future treatments and preventative measures. Our data will help define new endpoints for clinical trials for drugs to treat early AMD, the absence of which has impeded translational research on this prevalent cause of legal blindness. Endpoints are needed more than ever, because causal treatments targeting lipids in drusen and BrM can be pressed forward, thanks to clinical and pre-clinical proof- of-concept studies.

项目概要 年龄相关性黄斑变性（AMD）是美国不可逆视力损害的主要原因 全球排名第三的是涉及视网膜色素的感光支持系统疾病 上皮 (RPE)、布鲁赫膜和脉络膜毛细血管，最终形成光感受器 死亡和最终视力丧失。我们与其他人的研究清楚地记录了选择性 视杆细胞感光器和视杆细胞介导的（暗视）视觉的脆弱性，包括视杆细胞介导的延迟视觉 在衰老和早期 AMD 中，暗适应（RMDA）和视杆细胞介导的光敏感性受损。 RMDA 是 与正常黄斑健康的眼睛相比，患有早期 AMD 的眼睛不仅更可能变慢，而且 RMDA 延迟也是早期 AMD 事件的功能性生物标志物（即风险因素）。下一个前沿 旨在为有AMD风险的老年人和那些患有视杆细胞介导的功能障碍的老年人建立结构基础 已经转换为早期AMD。我们所有目标的统一假设是：早期 AMD 是一种疾病 由于类维生素A可检测到的结构变化，导致微量营养素缺乏和血管功能不全 从脉络膜毛细血管到光感受器的再供应路线，在功能上表现为延迟杆- 介导的暗适应。这些结构紊乱将发生在特定的脉络膜视网膜层和 反映光感受器支持系统中疾病的空间分布的区域。我们的 多学科团队拥有视觉心理物理学、流行病学、组织病理学、数字图像方面的专业知识 视网膜疾病的分析和解释、研究设计和生物统计学。为了我们的目标，我们将 在衰老早期 AMD 过渡的表型异常良好的队列中执行 3 个具体目标， 按照 AREDS 9 步量表进行，并进行 3 年的纵向随访： (1) 检查丰度 AMD 特有沉积物的范围（玻璃疣和新认识的视网膜下玻璃膜疣 通过光学相干断层扫描（OCT）与暗视功能障碍相关的沉积物）； (2) 至 通过定量眼底检查 RPE 细胞体作为暗视功能障碍的结构相关性 通过 OCT 测量自发荧光和层厚度； (3) 测量血管密度（黄斑部的覆盖范围） 脉络膜毛细血管的布鲁赫膜），使用 OCT 测量外层视网膜细胞的交换能力 血管造影。衰老和早期 AMD 结构与功能关系的准确图谱和时间线 从我们的研究中获得的成果，特别是从衰老到疾病的关键转变，将有助于定义主要的 可以开发成未来治疗和预防措施的效果。我们的数据将帮助定义 治疗早期 AMD 药物临床试验的新终点，缺乏这些终点阻碍了 对这种法律失明的普遍原因的转化研究。比以往任何时候都更需要端点， 因为针对玻璃疣和 BrM 中脂质的因果治疗可以得到推进，这要归功于临床 和临床前概念验证研究。