Microstructural determinants of dark adaptation and effects of retinoid administration in age-related macular degeneration

暗适应的微观结构决定因素以及类维生素A给药对年龄相关性黄斑变性的影响

• 批准号: 456558031
• 负责人: Privatdozentin Dr. Kristina Pfau
• 金额: --
• 依托单位: Universitäts-Augenklinik Bonn
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/456558031?language=en
• 关键词: Microstructural; determinants; dark; adaptation; effects

Age-related macular degeneration (AMD) is the most common cause for blindness in industrialised countries. A key role in pathology is attributed to the complex of Bruch Membrane (BrM) and Choriocapillaris (CC). Impairments of this complex include both, barrier effects of diffuse and focal extracellular deposits and vascular limitations. Based on these observations, various therapeutic innovations aimed towards the BrM-CC-complex interchange barrier have been proposed. However, since BrM is not represented on state-of-the-art retinal imaging and visual acuity is often preserved in early stages, a surrogate marker for early alterations in AMD is needed. Dark adaptation (DA) is a measure for recovery of photoreceptors after bleaching and its impairment has in the past been shown to be associated with early disease stages in AMD.The overall objective of the project is to identify functionally validated structural endpoints to detect and monitor early disease stages and their progression, to optimize these for potential applications in clinical interventional trials and to employ these in a clinical trial of Vitamin A substitution in AMD.First, functional alterations assessed by DA and structural alterations assessed with multimodal imaging will be correlated and a model based on structure-derived variables will be developed to predict retinal function (DA). It is yet unknown, if dark adaptation impairment is fully paralleled by concurrent changes in retinal microstructure at the specific location of the DA stimulus visible on state-of-the-art multimodal imaging. Of specific interest is a possible structure-function dissociation, as a means of additional contributors to retinal dysfunction supervening explainable dysfunction by structural data. Furthermor, environmental and non-eye specific factors will be included in the multidimensional model to predict retinal dysfunction and its progression over 5 years. Specifically, patient specific data such as age, behavioral factors (e.g. history of smoking) and genetic risk factors (e.g. SNPs in the ARMS2/HTRA1 gene as well as others) will be included. A specific focus will be to elucidate if these factors have an impact on the retinal structure and subsequently on function (i.e. by choroidal alterations in patients with history of smoking) or if they imply structure-independent impairment of dark adaptation.Next, the optimization of DA test protocols for rod function (test location and device choice) will be addressed. This will consider repeatability and the spatial pattern of dysfunction of the two most relevant DA devices, the AdaptDx and Medmont Dark-Adapted Chromatic Perimeter.The final step will be the application of the previously obtained results in a Vitamin A substitution trial to clarify, if locations with a structure-function dissociation exhibit a pronounced improvement of DA. This would indicate a pathologic process on the level of BrM not represented on multimodal imaging.

老年性黄斑变性(AMD)是工业化国家最常见的致盲原因。Bruch膜(BRM)和脉络膜毛细血管(CC)的复合体在病理中起着关键作用。这种复合体的损害包括弥漫性和局灶性细胞外沉积的屏障效应和血管限制。基于这些观察，针对BRM-CC-复合体交换屏障的各种治疗创新已经被提出。然而，由于BRM在最先进的视网膜成像中没有表现出来，而且视力通常在早期阶段得到保护，因此需要一种替代标记物来反映AMD的早期变化。暗适应(DA)是一种衡量光感受器漂白后恢复的指标，过去它的损害被证明与AMD的早期疾病阶段有关。该项目的总体目标是识别经过功能验证的结构终点，以检测和监测疾病的早期阶段及其进展，优化这些终点，以便在临床干预试验中潜在应用，并将其用于AMD的维生素A替代临床试验。首先，将DA评估的功能变化与多模式成像评估的结构变化相关联，并开发基于结构衍生变量的模型来预测视网膜功能(DA)。目前尚不清楚，暗适应损害是否与在最先进的多模式成像中可见的DA刺激的特定位置的视网膜微结构的同时变化完全平行。特别令人感兴趣的是可能的结构-功能分离，作为视网膜功能障碍的另一种贡献因素，取代了结构数据可解释的功能障碍。此外，环境和非眼睛特定因素将被包括在多维模型中，以预测视网膜功能障碍及其在5年内的进展。具体地说，患者特定的数据，如年龄、行为因素(如吸烟史)和遗传风险因素(如ARMS2/HTRA1基因的SNPs以及其他)将被包括在内。一个具体的焦点将是阐明这些因素是否对视网膜结构和随后的功能产生影响(例如，有吸烟史的患者的脉络膜改变)，或者它们是否意味着结构独立的暗适应损害。接下来，将讨论视杆功能DA测试方案的优化(测试位置和设备选择)。这将考虑两种最相关的DA设备--AdaptDx和Medmont Dark-Adapted Chromal Perimeter的可重复性和功能障碍的空间模式。最后一步将是将先前获得的结果应用于维生素A替代试验，以澄清结构-功能分离的位置是否表现出显著的DA改善。这将表明BRM水平上的病理过程在多模式成像中没有表现出来。