Neuro-Vascular Approach to Diagnosis and Treatment Of Preclinical Alzheimer's Disease

Abstract (up to 30 lines) Retina, the only visible part of the brain, provides a unique window into early pathological changes in numerous diseases such as diabetic neuropathies, Alzheimer’s (AD), vascular dementia and age-related decline. The overall goal of this pilot study is to leverage our expertise in retinal physiology and high-resolution noninvasive multiphoton imaging to rigorously diagnose early changes in retinal structure, neuronal activity, and blood flow in the eyes of living mice. There is a critical need for early diagnosis because classical symptoms of AD, including memory decline and behavioral changes, are manifest only after a significant and often irreversible neurovascular loss. The requested amendment fits naturally within the scope of the active award “to dissect the mechanisms responsible for early changes in vasculature and neurons that lead to neurological impairment in diabetic retinopathy (DR).” Even with an apparent distinction, the retina approach to DR and AD share conceptual and instrumental foundations. Retina is the front of the brain, with building blocks of the CNS. As such, the retina is increasingly recognized to exhibit early predictive signs of many diseases before they become a visible impairment. A recent analysis of an “eye test” for AD represents a significant initial step towards the diagnosis of preclinical AD (O’Bryhim et al., 2018). In a study of 824 subjects adjusted for age, sex, and educational background, those with diabetes had a 65% higher risk of AD compared to those without diabetes (Arvanitakis et al, 2004), indicative of diabetes being a risk factor for AD. Unfortunately, the existing biomarkers for AD rarely account for preexisting conditions, are often invasive and have low predictive power in assessing the risk of AD. To address this gap in live 5xFAD mice, an established model for familial AD, we will test a hypothesis that a combinatorial approach of simultaneously measuring retinal capillary blood flow using multiphoton imaging, physiological activity using electroretinogram, and the integrity of blood- retina barrier using fluorescein angiography is a robust early biomarker of the neurovascular pathology. We routinely conduct a similar analysis in mice starting at early age, long before any known signs of AD reported in this model. Cognitive function of mice will then be evaluated in a classical visually-guided cognitive Morris water maze task. An in vivo analysis would be concluded by a detailed immunohistochemical dissection of recognized cellular biomarkers of AD. The proposed study is expected to reveal that 5xFAD mice will exhibit symptoms of early retina capillary stalling, reduced ERG amplitude, and forecast future cognitive decline. This will form a foundation for a more expansive project to develop robust noninvasive diagnostics for early risk factors, and for testing potential AD therapies.