IOP and Cerebrospinal Fluid Pressure-related Risk Factors for Glaucoma

摘要 青光眼是世界范围内导致永久性视力丧失的主要原因，但其损害机制尚不完全清楚。 明白视网膜神经节细胞（RGC）及其轴突将视觉信息从视网膜传递到视网膜。 这些轴突通过视神经头（ONH）处的巩膜管穿出眼睛， 由称为筛板（LC）的有孔结缔组织结构跨越。的优势 有证据表明，在青光眼中，ONH的层状区域中的RGC轴突受损。之一 最一致的青光眼危险因素是眼内压（IOP）升高，尽管"安全" IOP 门槛因人而异。虽然有一些证据表明IOP波动有助于 对于青光眼，先前的研究由于缺乏连续的IOP测量而受到阻碍。球后 视神经周围的脑脊液压力（CSFP）通过以下方式部分抵消LC处的IOP 跨层流压（TLP = IOP-CSFP）。回顾性临床研究表明，较高的CSFP (and低TLP）对青光眼有保护作用，低CSFP（和高TLP）增加青光眼风险， 考虑到IOP的影响。此外，由于LC承受ONH中的大部分压力负荷， 由于其相对于周围神经组织的高刚度，LC厚度在神经组织的生长中起着关键作用。 通过跨层压力梯度（TLPG = TLP/LC厚度）在ONH中分布TLP，添加a 形态学成分到TLP。因此，本项目的目标是测试IOP、TLP和 TLPG波动独立地导致眼睛对青光眼发作和进展的特异性易感性 在考虑了对侧眼的平均IOP差异后，并证实了最近的发现，即CSFP和IOP是 通过神经通路连接。在这个项目中，我们将进行机械符合性测试，以量化LC 在单侧青光眼动物模型中，响应于受控急性TLP激发的体内变形 使用连续IOP、CSFP、TLP和TLPG遥测进行仪器化。然后我们将确定 对侧眼中每单位平均IOP差异的轴突和视功能丧失之间的差异，以及1）短暂性和 昼夜IOP波动，2）TLP和TLPG（平均值和波动）和3）LC变形 TLP激发，在眼睛正常时和青光眼发作和进展后测量。影响：如果结果 显示IOP波动、TLP和/或TLPG有助于青光眼发病机制和进展 为了平均IOP，可以开发新的治疗方法来调节这些因素以治疗青光眼。

ABSTRACT Glaucoma is a leading cause of permanent vision loss worldwide, but the mechanisms of damage are not fully understood. The retinal ganglion cells (RGC) and their axons transmit visual information from the retina to the brain, and these axons pass out of the eye through the scleral canal at the optic nerve head (ONH), which is spanned by a fenestrated connective tissue structure known as the lamina cribrosa (LC). The preponderance of evidence suggests that the RGC axons are damaged in the laminar region of the ONH in glaucoma. One of the most consistent glaucoma risk factors is elevated intraocular pressure (IOP), although the “safe” IOP threshold varies widely among individuals. While there is some evidence that IOP fluctuations contribute to glaucoma, prior studies have been hampered by the absence of continuous IOP measurement. Retrobulbar cerebrospinal fluid pressure (CSFP) surrounding the optic nerve partially counteracts IOP at the LC through the translaminar pressure (TLP=IOP-CSFP). Retrospective clinical studies have suggested that higher CSFP (and low TLP) is protective for glaucoma and low CSFP (and high TLP) increases glaucoma risk, after accounting for the effects of IOP. In addition, since the LC bears the bulk of the pressure load in the ONH due to its high stiffness relative to the surrounding neural tissues, LC thickness plays a critical role in the distribution of TLP in the ONH via the translaminar pressure gradient (TLPG = TLP/LC thickness), adding a morphological component to TLP. Hence, the goal of this project is to test the hypotheses that IOP, TLP, and TLPG fluctuations independently contribute to eye-specific susceptibility to glaucoma onset and progression after accounting for differential mean IOP in fellow eyes, and confirm the recent finding that CSFP and IOP are coupled via neural pathways. In this project, we will perform mechanical compliance testing to quantify LC deformations in vivo in response to controlled acute TLP challenge, in an animal model of unilateral glaucoma instrumented with continuous IOP, CSFP, TLP, and TLPG telemetry. We will then determine the relationships between axonal and visual function loss per unit of differential mean IOP in fellow eyes and 1) transient and diurnal IOP fluctuation, 2) TLP and TLPG (mean and fluctuation) and 3) LC deformations in response to acute TLP challenge, measured while the eye is normal and after glaucoma onset and progression. Impact: If results show that IOP fluctuations, TLP and/or TLPG contribute to glaucoma pathogenesis and progression in addition to mean IOP, new therapeutic approaches could be developed to modulate these factors to treat glaucoma.