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: 9803604
• 负责人: BRAD FORTUNE
• 金额: $ 56.89万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9803604
• 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; Retinal; 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，诊断青光眼和患者管理决策通常是通过稀疏来告知的 视神经头（ONH）神经视网膜轮辋，乳头状视网膜神经纤维层（RNFL）和黄斑内部 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，并且随后变薄的速度更快。 但是，到当前的OCT系统，视网膜神经节细胞（RGC）和 他们的轴突已经丢失，因此不可避免地会损害视觉功能。因此， 当前的青光眼护理方法中的关键差距是缺乏可靠的生物标志物，这些生物标志物会提醒临床医生 RGC/轴突永久丢失之前，RGC/轴突的早期青光眼损伤。我们建议这样 信息在OCT扫描中存在于市售仪器中，但此额外 需要进行测试和分析的方法来揭示此信息。我们的总体假设是 对眼内压（IOP）和早期RGC/轴突遇险的眼睛特异性敏感性以及 OCT扫描中存在损坏，而利用它们将提供有意义的临床益处。 我们将使用实验性青光眼建立良好的非人类灵长类动物（NHP）模型来测试三个 独立但相互支持的假设，每个假设都有其自身的强大潜力来提高临床护理 和患者管理。在AIM 1中，我们将测试以下假设 ONH轮辋和围绕乳腺癌的RNFL组织将较早地预测RGC/轴突的较早损失 和位置（部门）。具体而言，在AIM 1.1中，我们使用由 急性IOP升高（即弹性变形或应变），在AIM 1.2中使用测量的变形 暴露于慢性IOP升高后（塑性变形和重塑）。在AIM 2中，我们将测试 假设ONH和周围RNFL组织内的自动调节功能障碍先于毛细管 辍学（AIM 2.1），并在RGC/轴突丢失（AIM 2.2）之前。在AIM 3中，我们将检验以下假设 RGC病理的阶段，其特征是轴突细胞骨骼超微结构和树突状萎缩的破坏， 可以通过OCT检测到（AIM 3.1）；急性和慢性变形可以预测其发作和位置 通过应变映射确定（AIM 3.2）；它代表了RGC/轴突即将丧失的迹象（AIM 3.3）。任何一个目标的成功将代表确定风险的重要一步 单个眼睛的青光眼进展；这三个目标的成功将代表这方面的重要一步 每个生物标志物都可以提高其他人的预测能力。而且，因为我们是 在具有解剖学和生理学的物种中进行这些研究，与人类非常相似 标准，市售的临床仪器（OCT/OCT-Angiography设备），结果可以 迅速转化为临床测试，并提供有益的分析工具，以供临床医生和研究人员使用。