Vascular dysfunction in glaucoma

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.