In vivo ultrastructure of chorioretinal disease

 描述(由申请人提供)：老年性黄斑变性(AMD)是1000多万美国老年人视力丧失的主要原因。几十年来，AMD的特点是在Bruch膜(BRM)的内表面，视网膜色素上皮(RPE)后面的一个称为RPE下间隙的间隔内，积累了称为玻璃体周围的细胞外病变。玻璃体现在被认为是一个更大的系统中最著名的一半，这个系统被认为是视网膜外部脂质稳态的假设，包括在光感受器和RPE之间的一个称为视网膜下间隙的空间中非常普遍的细胞外病变。视网膜下玻璃体沉积(SDD)聚集在RPE前部，临床上表现为网状假性玻璃体沉积(RPD)。这些在多种成像方式中可见的生物显微镜征象与AMD的两个晚期阶段脉络膜新生血管(CNV)和地理萎缩(GA)的进展高度相关。RPD与经典玻璃斑疹的不同位置意味着对覆盖的光感受器细胞的不同影响，导致晚期AMD的不同过程，以及不同的生物发生机制。RPD对覆盖的光感受器的影响以及为什么RPD是视力丧失的重要危险因素仍然是个谜。我们假设RPD/SDD像玻璃斑疹一样，是脉络膜视网膜变性的生物显微镜迹象，在形成和退化阶段都会影响光感受器的结构和功能。我们预测，RPD/SDD对光感受器的影响将比玻璃体更大，因为它们位于视网膜下空间，因此与光感受器直接接触。我们进一步预测，核棒将受到更大的影响 在这两个病变中，视杆细胞比视锥细胞更容易受到脉络膜供应途径中断的影响。因此，我们建议描述非新生血管性AMD患者RPD的超微结构和自然病史，以及与覆盖的光感受器的结构和功能以及RPE/脉络膜健康的关系。我们的目标有两个：更好地了解RPD在AMD病理生理学中的作用，以及开发基于自适应光学(AO)成像的生物标志物和生物计量学，用于敏感和定量评估AMD的光感受器变性。我们研制了一种集扫描激光检眼镜和光学相干断层成像于一体的新型声光成像仪(AO-SLO-OCT)。该仪器能够以2.5微米×2.5微米×5微米的三维空间分辨率对视网膜成像，从而允许在体内对RPD和单个光感受器的面内和横切面的超微结构进行评估。我们将通过使用AO高分辨率成像和标准的多模式临床成像来实现我们的目标。

 DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is a leading cause of vision loss in more than 10 million older Americans. For decades, AMD has been characterized by accumulation of extracellular lesions called drusen on the inner surface of Bruch's membrane (BrM), posterior to the retinal pigment epithelium (RPE), in a compartment called the sub-RPE space. Drusen are now recognized as the best known half of a larger system postulated for outer retinal lipid homeostasis that includes highly prevalent extracellular lesions in a compartment called the subretinal space, between the photoreceptors and RPE. Subretinal drusenoid deposits (SDD), which accumulate anterior to the RPE, are thought to clinically manifest as reticular pseudodrusen (RPD). These biomicroscopic signs visible in multiple imaging modalities are highly associated with progression to choroidal neovascularization (CNV) and geographic atrophy (GA), AMD's two late stages. The disparate location of RPD compared to that of classical drusen implies different impact on overlaying photoreceptor cells, different processes leading to late stage AMD, and different biogenesis mechanisms. The effect of RPD on overlying photoreceptors and why RPD are significant risk factors for vision loss remains mysterious. We hypothesize that RPD/SDD, like drusen, are biomicroscopic signs of chorioretinal degeneration that impact the structure and function of photoreceptors at both formative and regressing stages. We predict that RPD/SDD will have more impact on photoreceptors than drusen, because they are in the sub-retinal space and therefore in direct contact with photoreceptors. We further predict that rods will more be affected than cones in both lesions, because the rods are more vulnerable to interruption of their supply route from the choroid than are cones. Thus, we propose to characterize the ultrastructure and natural history of RPD, in relation to the structure and function of overlaying photoreceptors and RPE/choroid health in patients with non- neovascular AMD. Our objectives are two-fold: better understanding of RPD's role in the pathophysiology of AMD, and developing adaptive optics (AO) imaging based biomarkers and biometrics for sensitive and quantitative assessment of photoreceptor degeneration in AMD. We have developed a novel AO imaging instrument that integrates scanning laser ophthalmoscopy and optical coherence tomography (AO-SLO-OCT). This instrument can image the retina with 3-D spatial resolution of 2.5 µm X 2.5 µm X 5 µm thereby allowing for in-vivo ultrastructure assessment of RPD and individual photoreceptors in both en face and cross-sectional planes. We will accomplish our goals by use of AO high resolution imaging and standard multimodal clinical imaging.