Structural and functional tests of ganglion cell damage in glaucoma

这个项目将使用结构和功能测量的组合来测试早期- 人类青光眼的阶段性损害首先发生在视网膜的内丛状层(IPL)--尤其是它的外侧 亚板层--如小鼠青光眼模型所示。在第一个目标中，我们将使用一种新型的可见光光学 相干断层扫描(VIS OCT)研究青光眼患者视网膜结构的变化。最新的 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数据中的子层析，这是现有近红外OCT目前无法实现的 乐器。我们将在IPL内和IPL之间，神经节细胞之间进行比较测量 视网膜神经纤维层(RNFL)。因为来自青光眼小鼠模型的数据表明 早期损伤优先发生在IPL的非亚椎板内，我们将单独进行VIS OCT 对IPL的离亚胺和开亚胺的测量有偏差，并使用机器学习方法来 确定是否可以在人类身上演示类似的损伤过程。以测试是否偏离了路径 青光眼患者优先丧失功能，我们将使用一种新的稳态视觉诱发电位(SSVEP) 使用锯齿递增和递减来将测量偏向于开与关路径的范例， 分别是，我们的数据表明，一种范式区分了青光眼和对照组患者。第二个目标是 优化此SSVEP测量以测试视野的局部区域。第三个目标将使 大样本青光眼视野、VIS、OCT和SSVEP丢失模式的比较测量 患者和年龄和性别匹配的对照组。厚度和界面反射率幅度图源自 RNFL、GCL和IPL包括亚板的VIS OCT成像将在地形图上与视觉相关 视野缺陷用于评估我们的结构生物标记物在视野位置及附近的相对敏感性 在常规(汉弗莱)视野上有明显的损失。同样，来自不同国家的SSVEP响应 视野中的位置将在地形上与视野损失图案和VIS OCT损失相关， 特别强调了IPL的Off和On亚板的结构损伤与功能 由区域递减和递增的SSVEP得出的相关性。分开和组合，我们的 结构和功能测量旨在提供对生物学假设的强有力的测试，即 Off通路在人类青光眼中优先受损，并揭示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.