Early Detection of Alzheimer's Disease using Noninvasive Retinal Fluorescence Imaging - PROJECT SUMMARY Alzheimer's disease (AD) is a devastating neurodegenerative disease that places a significant physical, emo- tional and financial burden on patients, their caregivers, and society at large. Current estimates indicate that >50 million individuals globally are living with AD, and this number is projected to surge to 150 million by 2050. While the exact pathogenesis remains undefined, AD is characterized by aggregation of abnormal extracellular amy- loid-beta (Aβ) plaques and intracellular tau neurofibrillary tangles, which may precede symptom onset by up to a decade. Recent advances in Aβ clearing therapies for AD have shown promising efficacy in slowing cognitive and functional decline. However, these treatments only benefit those in the earlier stages of AD, and curative intervention for late-stage AD does not yet exist. In light of emerging therapies, early diagnosis of AD would substantially improve patient quality of life and reduce the rapidly escalating AD health care costs. However, symptoms of early stages of AD are often mild and difficult to quantify, making accurate early-stage diagnosis a significant challenge. Tremendous efforts have been focused on the development of Aβ-targeted contrast for AD diagnosis. While Aβ-specific positron emission tomography (PET) brain imaging is now FDA approved, it is ex- pensive, requires radiotracers and patient exposure to ionizing radiation, rendering it unsuitable for early diag- nostic screening on a large population. Since the retina is a neurosensory extension of the brain, the strong connection between retina and cerebral pathology makes the retina a promising target for the development of novel imaging tools for early AD diagnosis. It’s been shown that Aβ accumulation in the retina of AD patients can mirror brain pathology, especially in the primary visual cortex. In this proposal, we aim to develop the first fluo- rescence-based, non-invasive imaging technology for the early detection of AD by visualizing and quantifying Aβ content throughout the retina using topically applied, near-infrared (NIR) Aβ-specific fluorophores formulated in eye drops. The proposed contrast agents represent remarkable opportunities for the discovery of a NIR fluor- ophore with superior specificity and sensitivity for Aβ. These fluorophores will undergo extensive validation stud- ies in rodent AD models and in human AD brain and retina tissues. Preclinical pharmacology and toxicology of the eye-drop formulated NIR Aβ-specific fluorophores will be completed. In parallel, the capabilities of a NIR ultrawide field fluorescence scanning laser ophthalmoscope to provide a comprehensive view of Aβ in the retina will be demonstrated. Finally, sensitivity assessment for early AD detection using fluorophore eye drops and retinal fluorescence imaging will be quantified in rodent AD models with varying Aβ burden. Topical ocular ad- ministration of AD-specific fluorescent contrast agents offers significant advantages, including non-invasive ad- ministration with the potential for self-administration, simple application that can increase patient compliance, and low cost that can facilitate mass screening programs. Overall, our approach has the ultimate translational goal of enabling truly non-invasive screening for early AD across large populations through simple eye drops.
