Advancing OCT evaluation to reveal early-stage changes in glaucoma

目前，青光眼的诊断和患者的治疗决策通常是通过青光眼的变薄来提供信息的 视神经头(ONH)神经视网膜缘、视乳头周围视网膜神经纤维层(RNFL)和黄斑内侧 视网膜层，使用光学相干断层扫描(OCT)检测。这些测量是有用的 因为它们预示着随后的视野下降，以及随后变薄的更快速度。 然而，到目前的OCT系统可以检测到变薄的时候，视网膜神经节细胞(RGC)和 他们的轴突已经丢失，因此视觉功能的一些损害是不可避免的。因此，一个 目前青光眼治疗方法的主要缺陷是缺乏可靠的生物标志物来提醒临床医生 视网膜神经节细胞/轴突在永久消失之前的早期青光眼损害。我们建议这样做 信息存在于OCT扫描中，来自商业仪器，但额外的 需要测试和分析的方法来揭示这一信息。我们最重要的假设是 眼球对眼压(IOP)和早期RGC/轴突窘迫的敏感性和 OCT扫描中存在损伤，利用这些损伤将提供有意义的临床好处。 我们将使用一个公认的实验性青光眼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说，每个假说都有自己推动临床护理的强大潜力 和病人管理。在目标1中，我们将测试假设，较大的震级变形在 ONH边缘和乳头周围RNFL组织可以预测RGCs/轴突在眼部更早和更严重的丢失 和地点(区段)。具体地说，在目标1.1中，我们使用由以下因素引起的变形来测试这一预测 急性眼压升高(即弹性变形或应变)，在Aim 1.2中，使用测量的变形 暴露在慢性眼压升高(塑料变形和重塑)后。在目标2中，我们将测试 假设ONH和乳头周围RNFL组织内的自动调节功能障碍先于毛细血管 辍学(目标2.1)，在视网膜节细胞/轴突丧失之前(目标2.2)。在目标3中，我们将检验一个假设，即早期的 RGC病理阶段，以轴突细胞骨架超微结构破坏和树突萎缩为特征， 可通过OCT(目标3.1)检测到；根据急性和慢性畸形预测其发病和位置 由应变图确定(AIM 3.2)；它代表RGCs/轴突即将丧失的迹象(AIM 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的重要一步 单眼青光眼进展；这三个目标的成功将代表着在这方面向前迈出了重要的一步 区域作为每个生物标志物都能增强其他生物标志物的预测能力。此外，因为我们是 在一个解剖学和生理学与人类如此相似的物种中进行这些研究 标准的商业化临床仪器(OCT/OCT-血管造影仪)，结果可能 快速转化为临床测试并提供有益的分析工具，供临床医生和研究人员使用。

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.