Functionally Validated Structural Endpoints for Early AMD

项目摘要 视网膜相关性黄斑变性（AMD）是美国不可逆视力损害的主要原因 第三种是涉及视网膜色素的感光支持系统疾病 视网膜上皮细胞（RPE）、布鲁赫膜和脉络膜毛细血管，最终导致光感受器 死亡和最终的视力丧失。我们和其他人的研究清楚地证明了选择性的 视杆细胞感光器的脆弱性和视杆细胞介导的（暗视）视觉，包括延迟视杆细胞介导的 暗适应（RMDA）和受损的杆介导的光敏感性，在老化和早期AMD。RMDA是 与正常黄斑健康的眼睛相比，早期AMD的眼睛不仅更可能较慢， 延迟的RMDA也是功能性生物标志物（即，危险因素）。下一个前沿 目的是建立老年人AMD风险中杆介导的功能障碍的结构基础， 已转换为早期AMD。我们所有目标的统一假设是：早期AMD是一种 微量营养素缺乏和血管功能不全，由于类维生素A的可检测结构变化 从脉络膜毛细血管到光感受器的再供应途径，在功能上表现为延迟的视杆细胞， 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， 反映光感受器支持系统中疾病空间分布的区域。我们 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 视网膜疾病的分析和解释、研究设计和生物统计学。为了实现我们的目标，我们将 在老化-早期AMD转变的表型异常良好的队列中执行3个特定目标， 按AREDS 9步量表进行分期，纵向随访3年：（1）检查 和AMD的特征性沉积物（玻璃疣和新发现的视网膜下玻璃疣样）的程度 通过光学相干断层扫描（OCT）与暗视功能障碍相关;（2） 通过定量眼底检查作为暗视功能障碍的结构相关物的RPE细胞体 （3）通过OCT测量血管密度（黄斑区的覆盖率）， Bruch膜），使用OCT测量外视网膜细胞的交换能力 动脉造影衰老和早期AMD结构-功能关系的准确图谱和时间轴 从我们的研究中获得的信息，特别是从衰老到疾病的关键转变，将有助于确定主要的 可以发展为未来的治疗和预防措施。我们的数据将有助于定义 治疗早期AMD药物临床试验的新终点， 对这种法律的盲目性的普遍原因进行翻译研究。比以往任何时候都更需要端点， 因为由于临床上的原因，针对玻璃疣和BRM中脂质的因果治疗可以向前推进， 和临床前概念验证研究。

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.