Structural and functional tests of ganglion cell damage in glaucoma

青光眼神经节细胞损伤的结构和功能测试

• 批准号: 10405049
• 负责人: Jeffrey L Goldberg
• 金额: $ 50万
• 依托单位: STANFORD UNIVERSITY
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405049
• 关键词: Address; Affect; Age; Animal Model; Area; Atrophic; Biological Assay; Biological Markers; Biological Testing; Clinical; Complex; Consumption; Data; Disease; Early Diagnosis; Early treatment; Economic Burden; Electrodes; Electrophysiology (science); Elements; Frequencies; Ganglion Cell Layer; Glaucoma; Goals; Gold; Human; Image; Inner Plexiform Layer; Location; Machine Learning; Maps; Measurement; Measures; Methods; Modeling; Modification; Mus; Noise; Optical Coherence Tomography; Optics; Outcome; Pathway interactions; Patients; Pattern; Perimetry; Process; Property; Resolution; Retina; Retinal Ganglion Cells; Rodent Model; Sampling; Scotoma; Severities; Signal Transduction; Site; Specificity; Speed; Structural defect; Structure; Synapses; Techniques; Testing; Thick; Time; Visible Radiation; Vision; Visual; Visual Fields; Visual evoked cortical potential; base; cell injury; comparative; contrast imaging; design; detection method; extrastriate visual cortex; field study; ganglion cell; improved; instrument; mouse model; novel; optic nerve disorder; response; retinal imaging; retinal nerve fiber layer; sex

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.

该项目将使用结构和功能测量的组合来测试早期- 人青光眼的阶段性损伤首先发生在视网膜的内丛状层（IPL）中，特别是其OFF 亚板层-如鼠青光眼模型所示。在第一个目标中，我们将使用一种新的可见光光学 相干断层扫描仪（维斯OCT）研究青光眼患者视网膜的结构变化。新 开发的维斯OCT具有足够的图像对比度和分辨率，可分割IPL边界并定义 体积OCT数据中的子层压，这是现有近红外OCT目前不可能实现的 仪器.我们将在IPL内和IPL之间进行比较测量， 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 早期损伤优先发生在强脉冲光的OFF亚层内，我们将进行单独的维斯OCT 测量值偏向于IPL的关闭和打开亚板层，并使用机器学习方法 确定类似的损伤过程是否可以在人体中得到证实。为了测试关闭通路是否 由于青光眼的视觉功能优先丧失，我们将使用一种新的稳态视觉诱发电位（SSVEP） 采用双稳态增量和减量来将测量偏置到ON与OFF路径的范例， 我们的数据提示的范例分别区分青光眼和对照患者。第二个目标将 优化该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、维斯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。厚度和界面反射率振幅图， RNFL、GCL和IPL（包括椎板下）的维斯OCT成像将在地形图上与视觉 场缺陷，以评估我们的结构生物标志物在视野位置和附近的相对灵敏度， 常规（Humphrey）视野检查可证实的损失。同样，不同的SSVEP反应， 视野中的位置将与视野损失模式和维斯OCT损失地形相关， 特别强调IPL的OFF与ON亚层中的结构损伤与功能 相关性来自区域递减和递增SSVEP。单独和组合，我们的 结构和功能测量旨在为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，并揭示该疾病的新生物标志物。