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.

项目摘要 与年龄相关的黄斑变性（AMD），这是美国不可逆转视力障碍的主要原因 在全球第三，是涉及视网膜色素的光感受器支持系统的疾病 上皮（RPE），BRUCH的膜和绒毛膜，最终导致光感受器 灭亡和最终视力丧失。我们与他人的研究清楚地记录了选择性 杆感光体和杆介导的（Scotopic）视觉的脆弱性，包括延迟的杆介导 在衰老和早期AMD中，黑暗适应性（RMDA）和杆介导的光敏感性受损。 rmda是 与正常的黄斑健康相比，与眼睛相比，早期AMD的眼睛的可能性慢，而且更有可能 延迟的RMDA也是事件早期AMD的功能性生物标志物（即风险因素）。下一个边界 是在AMD的老年人中建立杆介导的功能障碍的结构基础， 已经转换为早期AMD。我们在所有目标中的统一假设是：早期AMD是一种疾病 由于类维生素的可检测结构变化，微量营养素缺乏症和血管不足 从脉络膜毛细血管到光感受器的重新供应途径，在功能上表现为延迟的杆 - 介导的黑暗适应。这些结构性干扰将发生在特定的脉络化层中，并且 反映感光器支持系统中疾病空间分布的区域。我们的 多学科团队在视觉心理物理学，流行病学，组织病理学，数字图像方面具有专业知识 视网膜疾病，研究设计和生物统计学的分析和解释。朝着我们的目标，我们将 执行3个特定目标，以异常表现出的同类队列，在年龄的AMD转换时， 由AREDS 9步量表上演，并进行了3年的纵向随访：（1）检查丰度 AMD病原体沉积物的范围（drusen和新认识的视网膜下drusenoid 通过光学相干断层扫描（OCT）与SCOTOPIC功能障碍的关系）； （2）至 通过定量基础，检查RPE细胞体作为Scotopic功能障碍的结构相关性 通过OCT自动荧光和层厚度； （3）测量血管密度（黄斑的覆盖率 BRUCH的膜毛毛皮膜），一种使用OCT的视网膜外细胞交换能力的度量 血管造影。衰老和早期AMD中结构功能关系的准确地图和时间表 从我们的研究中获得的收益，尤其是从衰老到疾病的关键过渡，将有助于定义主要 可以发展为未来治疗和预防措施的影响。我们的数据将有助于定义 用于治疗早期AMD的药物临床试验的新终点 关于这一普遍造成法律失明原因的翻译研究。终点比以往任何时候都需要 因为临床 和临床前证明研究。