Advancing OCT evaluation to reveal early-stage changes in glaucoma

推进 OCT 评估以揭示青光眼的早期变化

• 批准号: 10457862
• 负责人: BRAD FORTUNE
• 金额: $ 52.95万
• 依托单位: LEGACY EMANUEL HOSPITAL AND HEALTH CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10457862
• 关键词: 3-Dimensional; Acute; Anatomy; Angiography; Area; Atrophic; Axon; Biological Markers; Biomechanics; Blindness; Blood capillaries; Blood flow; Caring; Cells; Chronic; Chronic Disease; Clinical; Cues; Cytoskeleton; Data; Data Analyses; Devices; Diagnosis; Distress; Dropout; Evaluation; Experimental Models; Exposure to; Eye; Functional disorder; Glaucoma; Goals; Homeostasis; Human; Image; Imaging Techniques; Individual; Inner Plexiform Layer; Location; Measurement; Measures; Methods; Optic Disk; Optic Nerve; Optical Coherence Tomography; Pathology; Patients; Physiologic Intraocular Pressure; Physiology; Research Personnel; Retina; Retinal Ganglion Cells; Risk; Scanning; Severities; Structure; System; Techniques; Testing; Texture; Thinness; Time; Tissues; Translating; Transmission Electron Microscopy; Vision; Visual Fields; Visual impairment; cell injury; clinical care; clinical diagnostics; clinical implementation; density; in vivo; instrument; instrumentation; macula; microscopic imaging; next generation; nonhuman primate; novel; novel marker; reconstruction; research clinical testing; retinal damage; retinal nerve fiber layer; serial imaging; success; tool

Currently, diagnosis of glaucoma and patient management decisions are often informed by thinning of the optic nerve head (ONH) neuro-retinal rim, peripapillary retinal nerve fiber layer (RNFL), and macular inner retinal layers, as detected using optical coherence tomography (OCT). These measurements are useful because they are predictive of subsequent visual field decline, and of faster rates of subsequent thinning. However, by the time thinning can be detected with current OCT systems, retinal ganglion cells (RGCs) and their axons have already been lost, and therefore some impairment of visual function is unavoidable. Thus, a key gap in the current approach to glaucoma care is the lack of reliable biomarkers that alert the clinician to early-stage glaucomatous damage of RGCs/axons before they are permanently lost. We propose that such information is present within OCT scans from commercially available instruments, but that additional approaches for testing and analysis are required to reveal this information. Our overarching hypothesis is that cues of eye-specific sensitivity to intraocular pressure (IOP) and early RGC/axon distress and damage are present in OCT scans, and that exploiting them will provide meaningful clinical benefits. We will use a well-established non-human primate (NHP) model of experimental glaucoma to test three independent, but mutually supportive, hypotheses, each with its own strong potential to advance clinical care and patient management. In Aim 1, we will test the hypothesis that larger magnitude deformations within the ONH rim and peripapillary RNFL tissues will predict earlier and more severe loss of RGCs/axons across eyes and locations (sectors). Specifically, in Aim 1.1, we test this prediction using the deformations resulting from acute IOP elevation (i.e., elastic deformations or strains), and in Aim 1.2, using the deformations measured after exposure to chronic IOP elevation (plastic deformations and remodeling). In Aim 2, we will test the hypothesis that autoregulation dysfunction within the ONH and peripapillary RNFL tissues precedes capillary dropout (Aim 2.1) and precedes RGCs/axon loss (Aim 2.2). In Aim 3, we will test the hypothesis that an early stage of RGC pathology, characterized by disruption of axonal cytoskeletal ultrastructure and dendritic atrophy, is detectable by OCT (Aim 3.1); that its onset and location are predicted by the acute and chronic deformations determined by strain mapping (Aim 3.2); and that it represents a sign of imminent loss of RGCs/axons (Aim 3.3). Success of any one Aim would represent an important step forward in the determination of risk for glaucoma progression in individual eyes; success of all three Aims would represent a major step forward in this area as each biomarker could enhance the predictive capacity of the others. Moreover, because we are conducting these studies in a species with anatomy and physiology so similar to human beings and with standard, commercially available clinical instrumentation (OCT/OCT-angiography devices), the results could rapidly translate to clinical testing and provide beneficial analysis tools for use by clinicians and researchers.

目前，青光眼的诊断和患者管理决策通常是根据青光眼的稀疏程度来决定的。 视神经乳头 (ONH) 神经视网膜边缘、视乳头周围视网膜神经纤维层 (RNFL) 和黄斑内层 使用光学相干断层扫描 (OCT) 检测到的视网膜层。这些测量很有用 因为它们可以预测随后的视野下降以及随后更快的变薄速度。 然而，当当前的 OCT 系统、视网膜神经节细胞 (RGC) 和视网膜神经节细胞 (RGC) 可以检测到变薄时， 他们的轴突已经丧失，因此视觉功能的一些损害是不可避免的。因此，一个 当前青光眼护理方法的主要差距是缺乏可靠的生物标志物来提醒临床医生 RGC/轴突在永久丧失之前的早期青光眼损伤。我们建议此类 信息存在于商用仪器的 OCT 扫描中，但额外的 需要测试和分析方法来揭示这些信息。我们的总体假设是 提示眼睛对眼压 (IOP) 和早期 RGC/轴突窘迫的特异性敏感性 OCT 扫描中存在损伤，利用它们将带来有意义的临床益处。 我们将使用成熟的非人类灵长类动物 (NHP) 实验性青光眼模型来测试三个 独立但相互支持的假设，每个假设都有推进临床护理的强大潜力 和患者管理。在目标 1 中，我们将检验以下假设：在 ONH 边缘和视乳头周围的 RNFL 组织将预测眼睛中 RGC/轴突的更早和更严重的损失 和地点（部门）。具体来说，在目标 1.1 中，我们使用以下结果产生的变形来测试这一预测： 急性眼压升高（即弹性变形或应变），并在目标 1.2 中使用测量的变形 暴露于慢性眼压升高（塑性变形和重塑）后。在目标 2 中，我们将测试 假设 ONH 和视乳头周围 RNFL 组织内的自动调节功能障碍先于毛细血管 脱落（目标 2.1）并先于 RGC/轴突损失（目标 2.2）。在目标 3 中，我们将检验以下假设：早期 RGC病理学阶段，其特征是轴突细胞骨架超微结构破坏和树突萎缩， 可通过 OCT 检测（目标 3.1）；它的发生和位置是由急性和慢性变形预测的 通过应变图确定（目标 3.2）；它代表 RGC/轴突即将丧失的迹象（目标 3.3）。任何一个目标的成功都将代表着在确定风险方面向前迈出了重要的一步。 个别眼睛的青光眼进展；所有三个目标的成功将代表着在这方面向前迈出了一大步 因为每个生物标志物都可以增强其他生物标志物的预测能力。而且，因为我们是 在解剖学和生理学与人类非常相似的物种中进行这些研究 标准的市售临床仪器（OCT/OCT 血管造影设备），结果可以 快速转化为临床测试，并为临床医生和研究人员提供有益的分析工具。