Glaucoma Neuroimaging in Humans and Experimental Animal Models

项目概要/摘要 青光眼是全球第二大致盲性疾病。这种与年龄有关的疾病的患病率是 由于人口老龄化，预计未来几年将大幅增加。目前，临床上唯一 经批准的青光眼干预以降低眼内压（IOP）为目标。然而，IOP的确切作用 脑水肿发病机制尚不清楚。此外，青光眼可能会继续进展， 有些患者甚至在将IOP降至正常水平后，这表明可能存在其他关键因素， 导致疾病。该项目的目标是通过以下方法更好地了解青光眼机制： 非侵入性地和定量地确定所述组织中的病理生理学事件和疾病进展， 视觉系统，使用新的，多参数磁共振成像（MRI）技术，在两个人类 青光眼患者和实验性青光眼模型。我们将测试青光眼的中心假设， 涉及到大脑视觉系统的损伤，除了眼睛。此外，这种损伤可能 可以通过早期神经保护治疗来改善。我们将研究其结构，代谢和功能 使用3特斯拉的人类MRI扫描仪和9.4特斯拉的动物MRI扫描仪， 使用视网膜厚度测量和视觉测量将脑MRI结果与青光眼疾病严重程度相关联 成果评估。该项目的主要目标是使用开发的体内成像模型系统， 找出结构-代谢-功能的大脑关系和眼睛-大脑-行为的关系， 用于临床和转化应用的青光眼的人和动物模型。此信息将 对于识别大脑中的青光眼机制，监测视觉系统中的青光眼进展， 系统，并指导干预视觉系统，以减少这种不可逆转的负担，但 可预防的疾病待检验的具体目标如下：目标1：检验以下假设： 实验性青光眼损害啮齿动物的视觉系统和视觉行为。我们会把眼压升高到 不同的水平和持续时间，以确定其对结构，代谢和功能的贡献， 视觉系统我们还将确定口服胆碱补充剂是否能改善神经行为 实验性青光眼对视觉系统的影响最后，我们将确定昏迷的特异性 通过比较实验性青光眼和青光眼对视觉系统的神经行为影响， 其他视网膜或视神经损伤。目的2：验证人类青光眼视力丧失的假设， 涉及视觉系统的损伤。磁共振扩散张量成像、质子磁共振波谱和功能磁共振成像， 3特斯拉将用于确定青光眼患者的结构、代谢和功能性大脑变化 都有不同程度的视力丧失体内脑部MRI测量结果将与临床评估进行比较 通过视网膜的光学相干断层扫描和Humphrey视野功能测试。视觉系统在 还将青光眼与健康对照脑和其它视网膜或视神经损伤进行比较。

Project summary/Abstract Glaucoma is the second leading cause of blindness worldwide. The prevalence of this age-related disease is expected to increase substantially in coming years because of the aging population. Currently, the only clinically approved glaucoma intervention targets at lowering intraocular pressure (IOP). However, the exact roles of IOP elevation in glaucomatous pathogenesis remain unclear. In addition, glaucoma may continue to progress in some patients even after lowering IOP to normal levels, which indicates that additional key factors may be contributing to the disease. The goal of this project is to better understand glaucoma mechanisms by determining non-invasively and quantitatively the pathophysiological events and disease progression in the visual system using novel, multi-parametric magnetic resonance imaging (MRI) techniques in both human glaucoma patients and experimental glaucoma models. We will test the central hypothesis that glaucoma involves impairments of the brain's visual system apart from the eye. Furthermore, such impairments may be ameliorated by early neuroprotective treatments. We will investigate the structural, metabolic and functional brain changes longitudinally using the 3-Tesla human MRI scanner and the 9.4-Tesla animal MRI scanner, and relate brain MRI findings with glaucoma disease severity using retinal thickness measurements and visual outcome assessments. The project’s primary objective is to use the developed in vivo imaging model system to find out the structural-metabolic-functional brain relationships and eye-brain-behavior relationships in both humans and animal models of glaucoma for clinical and translational applications. This information will be valuable for identifying glaucoma mechanisms in the brain, monitoring glaucoma progression in the visual system, and guiding interventions to the visual system, in order to reduce the burden of this irreversible but preventable disease. The Specific Aims to be tested are as follows: Aim 1: To test the hypothesis that experimental glaucoma impairs the visual system and visuomotor behavior in rodents. We will elevate IOP to different levels and durations to determine their contributions to the structure, metabolism and function of the visual system. We will also determine whether oral choline supplements can ameliorate the neurobehavioral effects of experimental glaucoma on the visual system. Lastly, we will determine the specificity of glaucomatous damages to the visual system by comparing the neurobehavioral effects between experimental glaucoma and other retinal or optic nerve injuries over time. Aim 2: To test the hypothesis that vision loss in human glaucoma involves impairments of the visual system. Diffusion tensor MRI, proton MR spectroscopy and functional MRI at 3 Tesla will be used to determine the structural, metabolic and functional brain changes in glaucoma patients with different degrees of vision loss. The in vivo brain MRI measures will be compared with clinical assessments by optical coherence tomography of the retina and Humphrey visual field functional tests. The visual system in glaucoma will also be compared with healthy control brains and other retinal or optic nerve injuries.