Vascular dysfunction in glaucoma

虽然阿尔茨海默病(AD)最初被认为是一种大脑疾病，但人们很早就知道AD 患者有各种各样的视力障碍，人们对这种疾病的眼部方面越来越感兴趣。 大脑中异常的淀粉样蛋白和tau聚集体是阿尔茨海默病的特征，但血管病理导致或 会导致许多患者患上痴呆症。脑血流量减少，血脑屏障受损，以及 脑淀粉样血管病存在于血管性痴呆和AD患者中。在视网膜中，异常 淀粉样蛋白和视网膜血管丢失在AD中已有报道。而血管功能障碍与AD有关 在大脑的病理生理学方面，它在多大程度上对视网膜AD的病理作用仍不确定。 我们的实验室率先将多参数磁共振成像应用于高分辨率特定椎板的成像 视网膜和视神经的血液流动。我们有令人信服的初步数据表明 视网膜疾病，如青光眼，支持视网膜和视神经血流障碍的作用 神经退行性变。我们父母奖的目的是调查血管功能障碍与 青光眼退行性变，并测试改善血流的治疗效果。我们已经开发出一种 一套严谨的工具来研究眼睛的血管功能障碍和神经退行性变，包括新的磁共振成像， 光学成像和组织学技术。此外，在大脑中，我们已经证明了治疗阿尔茨海默病小鼠 这可以预防脑血管功能障碍，还可以减少淀粉样蛋白的负担和认知缺陷。在此，我们 建议利用我们的方法来研究AD患者的眼血管和神经功能障碍。 青光眼和阿尔茨海默病有几个相似之处，这表明可能有一些共同的途径。 在眼部，两者都涉及视网膜神经节细胞(RGC)和视神经退行性变。此外，血管 功能障碍是这两种疾病的发病机制之一。据报道，视网膜血管密度降低 青光眼和阿尔茨海默病。由于青光眼和视网膜阿尔茨海默病的病理相似，研究 比较两者中血管功能障碍和神经退行性变的关系可以提供独特的见解 对两者的发病机制进行探讨。 鉴于这些相似之处，本附录的目的是将我们的研究扩展到AD的研究。目标 1)评估眼血管功能障碍与淀粉样蛋白堆积、视力丧失、 阿尔茨海默病模型中的神经变性和2)检测预防血管功能障碍的治疗是否可以缓解 淀粉样蛋白堆积和防止视力丧失和眼睛中的神经退化，以严格评估 血管功能障碍与阿尔茨海默病视网膜变性的关系。我们的中央 假设血管功能障碍在视网膜AD的发病机制中起作用，因此预防治疗 血管功能障碍可以防止神经退行性变，最终保护AD患者的视力。

While Alzheimer’s disease (AD) is primarily considered a brain disease, it has long been known that AD patients have various visual disturbances, and there is increasing interest in the ocular aspects of the disease. Abnormal amyloid and tau aggregates in the brain are the hallmarks of AD, but vascular pathology causes or contributes to dementia in many patients. Reduced cerebral blood flow, impaired blood brain barrier, and cerebral amyloid angiopathy are present in patients with vascular dementia and AD. In the retina, abnormal amyloid and retinal vascular loss has been reported in AD. While vascular dysfunction is associated with AD pathophysiology in the brain, it remains uncertain to what extent it contributes to retinal AD pathology. Our laboratory pioneered the application of multiparametric MRI to image high-resolution lamina-specific blood flow of the retina and optic nerve. We have compelling preliminary data that blood flow is reduced in retinal diseases, such as glaucoma, supporting a role for blood flow impairment in retinal and optic nerve neurodegeneration. The aim of our parent award is to investigate the association of vascular dysfunction with glaucomatous degeneration and test the effects of treatments to improve blood flow. We have developed a rigorous set of tools to investigate vascular dysfunction and neurodegeneration in the eye, including novel MRI, optical imaging, and histology techniques. Additionally, in the brain, we have shown that treatment of AD mice that prevents cerebrovascular dysfunction also reduces amyloid burden and cognitive deficits. Herein, we propose to utilize our methods to investigate ocular vascular and neuronal dysfunction in AD. There are several similarities between glaucoma and AD, suggesting there may be some shared pathways. In the eye, both involve retinal ganglion cell (RGC) and optic nerve neurodegeneration. Furthermore, vascular dysfunction contributes to the pathogenesis of both. Reduced retinal vascular density has been reported in both glaucoma and AD. With the similarities of the pathology of glaucoma and AD in the retina, studies comparing the association of vascular dysfunction and neurodegeneration in both could provide unique insight into the pathogenesis of both. Given these similarities, the aim of this supplement is to extend our studies to investigate AD. The goals are to 1) evaluate the relationship between ocular vascular dysfunction with amyloid accumulation, vision loss, and neurodegeneration in a model of AD and 2) test if treatment to prevent vascular dysfunction can mitigate amyloid accumulation and prevent visual loss and neurodegeneration in the eye, to rigorously assess the association between vascular dysfunction and the development of retinal degeneration in AD. Our central hypothesis is that vascular dysfunction contributes to AD pathogenesis in the retina, so treatments to prevent vascular dysfunction could prevent neurodegeneration and ultimately preserve vision in AD.