Structural and functional tests of ganglion cell damage in glaucoma

该项目将结合使用结构和功能测量来检验早期的假设 人类青光眼的阶段性损伤首先发生在视网膜的内丛状层（IPL）——尤其是其关闭处 亚层——如小鼠青光眼模型所示。在第一个目标中，我们将使用一种新颖的可见光光学器件 相干断层扫描（VIS OCT）用于研究青光眼患者视网膜的结构变化。新的 开发的 VIS OCT 具有足够的图像对比度和分辨率来分割 IPL 边界并定义 体积 OCT 数据中的子层压，目前现有近红外 OCT 无法实现 仪器。我们将在 IPL 内以及 IPL 之间（神经节细胞）进行比较测量 视网膜神经纤维层（GCL）和视网膜神经纤维层（RNFL）。因为青光眼小鼠模型的数据表明 由于早期损伤优先发生在 IPL 的 OFF 子层内，我们将进行单独的 VIS OCT 测量结果偏向 IPL 的 OFF 和 ON 亚层，并使用机器学习方法 确定是否可以在人体中证明类似的损伤过程。测试是否关闭路径 青光眼功能优先丧失，我们将使用一种新颖的稳态视觉诱发电位（SSVEP） 采用锯齿形增量和减量将测量偏向 ON 与 OFF 路径的范式， 分别地，我们的数据表明将青光眼患者与对照患者区分开来的范例。第二个目标将 优化此 SSVEP 测量以测试视野的局部区域。第三个目标将使 青光眼大样本中视野、VIS OCT 和 SSVEP 损失模式的比较测量 患者以及年龄和性别匹配的对照。厚度和界面反射率幅度图源自 RNFL、GCL 和 IPL（包括亚层）的 VIS OCT 成像将在地形上与视觉相关 场缺陷来评估我们的结构生物标志物在视野位置和视野附近的相对敏感性 传统（汉弗莱）视野检查有明显的损失。同样，SSVEP 的响应来自不同的 视野中的位置将在地形上与视野损失模式和 VIS OCT 损失相关， 特别强调将 IPL 的 OFF 与 ON 子层的结构损伤与功能性相关联 来自区域递减和增量 SSVEP 的相关性。单独和组合，我们的 结构和功能测量旨在为以下生物学假设提供强有力的检验： OFF 通路在人类青光眼中优先受损，并揭示了该疾病的新生物标志物。

This project will use a combination of structural and functional measurements to test the hypothesis that early- stage damage in human glaucoma occurs first in the inner plexiform layer (IPL) of the retina – especially its OFF sub-lamina – as suggested by murine glaucoma models. In the first Aim, we will use a novel visible-light optical coherence tomograph (VIS OCT) to study structural changes in the retina of glaucoma patients. The newly developed VIS OCT has sufficient image contrast and resolution to segment the IPL boundaries and to define sub-lamination in volumetric OCT data, something not currently possible with existing near-infrared OCT instruments. We will make comparative measurements within the IPL and between the IPL, the ganglion cell layer (GCL) and the retinal nerve fiber layer (RNFL). Because data from mouse models of glaucoma suggests that early damage occurs preferentially within the OFF sub-lamina of the IPL, we will make separate VIS OCT measurements biased for the OFF- and ON-sublaminae of the IPL and use machine learning approaches to determine whether a similar damage process can be demonstrated in human. To test whether OFF-pathway function is preferentially lost in glaucoma, we will use a novel Steady-State Visual Evoked Potential (SSVEP) paradigm that employs sawtooth increments and decrements to bias the measurement to ON vs OFF pathways, respectively, a paradigm our data suggests discriminates glaucoma from control patients. The second Aim will optimize this SSVEP measurement for testing localized areas of the visual field. The third Aim will make comparative measurements of visual-field, VIS OCT and SSVEP loss patterns in a large sample of glaucoma patients and in age- and sex-matched controls. Thickness and interface reflectivity amplitude maps derived from VIS OCT imaging of the RNFL, GCL and IPL including sublaminae will be correlated topographically with visual field defects to assess the relative sensitivity of our structural biomarkers at and near visual field locations with demonstrable losses on conventional (Humphrey) perimetry. Similarly, SSVEP responses from different locations in the visual field will be correlated topographically with visual field loss patterns and to VIS OCT losses, with special emphasis on correlating structural damage in OFF vs ON sub-laminae of the IPL with the functional correlates derived from regional decremental and incremental SSVEPs. Separately and in combination, our structural and functional measurements are designed to provide strong tests of the biological hypothesis that the OFF pathway is preferentially damaged in human glaucoma, and to reveal new biomarkers for the disease.