Novel Clinical and Ocular Imaging Outcomes with Long-Term Follow-Up in MS

多发性硬化症长期随访的新颖临床和眼部影像结果

• 批准号: 7634165
• 负责人: LAURA BALCER
• 金额: $ 65.95万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7634165
• 关键词: Accounting; Acute; Address; Age; Anterior; Area; Blindness; Clinical; Clinical Trials; Cohort Studies; Control Groups; Cornea; Data; Data Analyses; Diagnosis; Dimensions; Disease; Enrollment; Equation; Eye; Financial compensation; Functional disorder; Future; Health Surveys; Image; Inflammation; Investigation; Lasers; Letters; Longitudinal Studies; Measures; Modeling; Multiple Sclerosis; Multiple Sclerosis Lesions; Nerve Degeneration; Neurologic; Neurons; Neuroprotective Agents; Optic Nerve; Optic Neuritis; Optical Coherence Tomography; Outcome; Outcome Assessment; Pathway interactions; Patients; Pattern; Phase III Clinical Trials; Quality of life; Recovery; Recruitment Activity; Relative (related person); Resolution; Retina; Retinal; Role; SF-36; Sample Size; Scanning; Site; Structure; Testing; Texas; Therapeutic; Thick; Time; Treatment Efficacy; Vision; Vision research; Visit; Visual; Visual Acuity; Visual Pathways; Visual impairment; base; cohort; disability; follow-up; functional loss; health related quality of life; insight; macula; neuron loss; next generation; novel; polarimetry; retinal nerve fiber layer; treatment effect; treatment trial; trend; ultra high resolution

DESCRIPTION (provided by applicant): Visual dysfunction is a common and frequently irreversible cause of disability in multiple sclerosis (MS). The anterior visual pathways, including the optic nerves, retina, chiasm, and tracts, are frequent sites for inflammation and demyelization, and axonal neuronal degeneration within these structures is a final common pathway to permanent visual loss. Recognized by MS experts as a critical dimension for clinical trial outcomes assessment, vision has been an important area of study that has resulted in identification of low-contrast letter acuity as a new measure. Low-contrast letter acuity detects even subtle visual impairment not captured by high-contrast visual acuity (VA) and demonstrated treatment effects in two recent phase 3 trials. Non-invasive ocular imaging, including optical coherence tomography (OCT) and scanning laser polarimetry with variable corneal compensation (GDx), has also become increasingly recognized in MS as a potential marker for axonal and neuronal loss. Retinal nerve fiber layer (RNFL) thinning and reductions in total macular volume correlate with reductions in low-contrast acuity at a single time point, and preliminary data suggest that RNFL axonal loss over time is associated with worsening visual function, even in the absence of acute optic neuritis (ON). These unique structure-function correlations make the anterior visual pathways an attractive model for examining therapeutic efficacy in MS clinical trials, particularly for the anticipated next generation of trials that will involve neuroprotective agents. While our cross-sectional, preliminary longitudinal, and clinical trial data represent a significant step toward refining and validating visual and ocular imaging outcomes for MS and ON, important questions remain that can only be addressed by large-scale collaborative studies of uniformly studied, heterogeneous MS cohorts and of patients with acute ON. This proposal will use the anterior visual pathways as a model for examining correlations of structure and function (vision and quality of life) in MS: Aim 1: Refine and validate low-contrast letter acuity, RNFL thickness by OCT (OCT-3 and ultra-high resolution) and GDx, and total macular volume by OCT as potential measures for clinical trials in MS. Aim 2: Using acute optic neuritis (ON) as a specific model, examine the timing of changes in RNFL thickness and macular volume, and define how OCT and GDx measures may provide insight into patterns across retinal quadrants and relative timing of axonal, neuronal, and functional loss for an MS lesion. Aim 3: Determine how low-contrast letter acuity, RNFL thickness, and total macular volume impact vision specific and overall health-related quality of life (HRQOL) in longitudinal studies of MS and ON.

描述（由申请人提供）：视觉功能障碍是多发性硬化症（MS）残疾的常见且常常不可逆转的原因。前视觉通路，包括视神经、视网膜、交叉和视束，是炎症和脱髓鞘的常见部位，这些结构内的轴突神经元变性是导致永久性视力丧失的最终常见途径。视力被多发性硬化症专家认为是临床试验结果评估的一个关键维度，一直是一个重要的研究领域，导致低对比度字母敏锐度被确定为一种新的衡量标准。低对比度字母视敏度甚至可以检测高对比度视敏度 (VA) 无法捕捉到的细微视力障碍，并在最近的两项 3 期试验中证明了治疗效果。非侵入性眼部成像，包括光学相干断层扫描 (OCT) 和具有可变角膜补偿 (GDx) 的扫描激光偏振测定法，在多发性硬化症中也越来越被认为是轴突和神经元损失的潜在标志。视网膜神经纤维层 (RNFL) 变薄和黄斑总体积减少与单个时间点低对比度敏锐度的降低相关，初步数据表明，随着时间的推移，RNFL 轴突损失与视功能恶化相关，即使没有急性视神经炎 (ON)。这些独特的结构-功能相关性使前视觉通路成为检查多发性硬化症临床试验中治疗效果的有吸引力的模型，特别是对于预期涉及神经保护剂的下一代试验。虽然我们的横断面、初步纵向和临床试验数据代表了朝着完善和验证 MS 和 ON 的视觉和眼部成像结果迈出的重要一步，但仍然存在重要问题，只能通过对统一研究的异质性 MS 队列和急性 ON 患者进行大规模合作研究来解决。该提案将使用前视觉通路作为模型，检查 MS 中结构和功能（视力和生活质量）的相关性：目标 1：细化和验证低对比度字母敏锐度、OCT（OCT-3 和超高分辨率）和 GDx 的 RNFL 厚度以及 OCT 的总黄斑体积，作为 MS 临床试验的潜在指标。目标 2：使用急性视神经炎 (ON) 作为特定模型，检查 RNFL 厚度和黄斑体积变化的时间，并定义 OCT 和 GDx 测量如何深入了解视网膜象限的模式以及 MS 病变的轴突、神经元和功能损失的相对时间。目标 3：在 MS 和 ON 的纵向研究中确定低对比度字母敏锐度、RNFL 厚度和总黄斑体积如何影响特定视力和整体健康相关生活质量 (HRQOL)。