Advancing OCT evaluation to reveal early-stage changes in glaucoma

目前，青光眼的诊断和患者管理决策通常是通过变薄的青光眼来告知的。 视神经乳头（ONH）神经视网膜缘、视乳头周围视网膜神经纤维层（RNFL）和黄斑内 视网膜层，如使用光学相干断层扫描（OCT）检测的。这些测量是有用的 因为它们预示着随后的视野下降和随后变薄的更快速率。 然而，到可以用当前OCT系统检测到变薄的时候，视网膜神经节细胞（RGC）和 他们的轴突已经丧失，因此视觉功能的某些损害是不可避免的。因此 目前青光眼治疗方法中的一个关键差距是缺乏可靠的生物标志物， RGCs/轴突在永久丧失之前的早期昏迷性损伤。我们建议， 信息存在于来自市售仪器的OCT扫描中，但是附加的 需要采用测试和分析方法来揭示这一信息。我们的首要假设是 提示眼睛对眼内压（IOP）和早期RGC/轴突损伤的特异性敏感性， 损伤存在于OCT扫描中，并且利用它们将提供有意义的临床益处。 我们将使用一个完善的非人灵长类动物（NHP）实验性青光眼模型来测试三个 独立但相互支持的假设，每个假设都有自己强大的潜力来推进临床护理 病人管理。在目标1中，我们将检验以下假设： ONH边缘和视乳头周围的RNFL组织将预测更早和更严重的RGC/轴突损失的眼睛 地点（部门）。具体来说，在目标1.1中，我们使用以下变形来测试这个预测： 急性IOP升高（即，在目标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）和之前的RGCs/轴突损失（目标2.2）。在目标3中，我们将检验一个假设， RGC病理学阶段，特征为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）;其发作和位置可通过急性和慢性变形预测 通过应变映射确定（目标3.2）;并且它代表RGC/轴突即将丧失的迹象（目标3.2）。 3.3）。任何一项目标的成功都将是在确定风险方面向前迈出的重要一步， 个别眼睛的青光眼进展;所有三个目标的成功将代表在这方面向前迈出的重要一步。 面积作为生物标志物可以增强其他生物标志物的预测能力。此外，因为我们是 在解剖学和生理学与人类如此相似的物种中进行这些研究， 标准市售临床仪器（OCT/OCT血管造影器械），结果可 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。

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.