Biomarkers of Vision Loss in Children with Optic Pathway Gliomas

项目摘要 低级别胶质瘤是儿童中最常见的脑肿瘤，经常累及视神经， 视交叉和视束-因此它们被称为视路神经胶质瘤（OPG）。OPG通常会导致视力丧失， 1至8岁，导致终身残疾，学业和职业能力下降， 成就这项研究提案的长期目标是改善视力结果和临床 管理OPG儿童。本提案的主要目的是确定光学相干性是否 视乳头周围视网膜神经纤维层（cpRNFL）和神经节细胞内的断层扫描（OCT）测量 丛状层（GCIPL）厚度是视力（视敏度和视野）的准确生物标志物。的 主要假设是cpRNFL和GCIPL厚度的大小和位置将紧密相关 根据先前公布的数据，这两项OCT指标都会下降， 视觉功能下降，从而识别最佳治疗窗口。次要假设是， 在接受OPG治疗期间恢复视力的儿童将表现出特定的视网膜色素变性阴性 视觉诱发电位（VEP）、弥散张量成像（DTI）和容积MRI 与那些不能从治疗中恢复视力的人相比，这些人的视力具有更好的特征。建议的理由 OCT测量提供了一种客观的、可重复的视觉通路完整性评估， 将确保各中心和临床试验的一致性，无论儿童的年龄和合作能力如何 进行标准视力测试主要和次要假设将在三个特定目标中进行测试：1） 使用OCT创建OPG儿童视力丧失的结构-功能模型; 2）确定最佳的 使用纵向OCT的OPG治疗窗口;以及3）开发多模式生物标志物以预测 治疗反应并阐明视力丧失的机制。第一个目标是建立在先前发表的 数据，并将在充分把握度的多中心队列中进行验证。目标2得到初步数据的支持， 将通过使用传统和创新的统计技术， 确定视力丧失前cpRNFL/GCIPL下降的最早和最精确点-最终 确定最佳治疗窗口。目标3将确定生物标志物（PhNR、VEP、DTI和体积） MRI）在整个视觉通路上的变化取决于儿童是否经历视觉恢复或 接受OPG治疗后视力下降。该项目将对临床产生直接影响 OPG儿童的护理、视力结果和诊断监测。该项目还将提供许多 需要深入了解OPG导致视力丧失的机制，并强调未来的机会 神经保护和视力恢复策略概述了NEI大胆的目标倡议。

Project Summary Low-grade gliomas are the most common brain tumor in children and frequently involve the optic nerve, chiasm, and tract—so they are referred to as optic pathway gliomas (OPGs). OPGs cause vision loss, typically between 1 and 8 years of age, resulting in lifelong disability as well as reduced academic and vocational achievement. The long term goal of this research proposal is to improve the visual outcomes and clinical management of children with OPGs. The primary objective of this proposal is to determine if optical coherence tomography (OCT) measures of circumpapillary retinal nerve fiber layer (cpRNFL) and ganglion cell – inner plexiform layer (GCIPL) thickness are accurate biomarkers for vision (visual acuity and visual field). The primary hypothesis is that the magnitude and location of cpRNFL and GCIPL thickness will be tightly correlated to visual function and, based on previously published data, both of these OCT measures will decline before visual function declines, thereby identifying an optimal treatment window. The secondary hypothesis is that children who recover vision while being treated for their OPG will demonstrate specific photophic negative response (PhNR), visual evoked potential (VEP), diffusion tensor imaging (DTI) and volumetric MRI characteristics as compared to those that do not recover vision from treatment. The rationale for the proposed research is that OCT measures provide an objective, reproducible assessment of visual pathway integrity that will ensure consistency across centers and clinical trials regardless of the child’s age and ability to cooperate with standard vision testing. The primary and secondary hypotheses will be tested in three specific aims: 1) Create a structure-function model of vision loss for children with OPGs using OCT; 2) Identify the optimal treatment window for OPGs using longitudinal OCT; and 3) Develop multimodal biomarkers to predict treatment response and elucidate the mechanism of vision loss. The first aim builds on previously published data and will be validated in an adequately powered multicenter cohort. Aim 2, supported by preliminary data, will develop predictive models of impending vision loss by using traditional and innovative statistical techniques to identify the earliest and most precise point of cpRNFL/GCIPL decline preceding vision loss—ultimately defining the optimal treatment window. Aim 3 will determine how biomarkers (PhNR, VEP, DTI and volumetric MRI) across the entire visual pathway evolve depending on whether the child experiences visual recovery or visual loss after undergoing treatment for their OPG. This project will have an immediate impact on the clinical care, visual outcomes and diagnostic monitoring of children with OPGs. This project will also provide much needed insight into the mechanism of vision loss from OPGs and highlight future opportunities for neuroprotective and visual restoration strategies outlined by the NEI Audacious Goals Initiative.