Functional Optical Tomography of the Retina in Mouse Models with Neurodegenerative Diseases

The retina is a thin yet sophisticated ocular tissue that converts light into electrical signals for vision processing. There are six types of neurons, ten distinct layers, and three vascular plexuses. Retinal neurodegenerative diseases, such as age-related macular degeneration (AMD), inherited retinal disorders (IRDs), and diabetic retinopathy (DR), are caused by dysfunction of different cell types. As part of the central nervous system (CNS), pathological hallmarks of cerebral neurodegenerative diseases, such as Alzheimer's disease (AD), are also reflected in the retina. Currently, there is no outright cure for retinal and cerebral neurodegenerative diseases. Early detection is thus essential for their prediction, diagnosis, and prognosis. A key strategy for early detection is to be vigilant for changes in early functional abnormality of retinal cells. Optical mapping of intrinsic signal changes in the retina promises a non-invasive technique for objective functional testing. Optical coherence tomography (OCT) has been widely used to conduct depth-resolved functional imaging of the retina. The research in this thesis aimed to scrutinize functional aspects of neural and vascular activities in the retina as well as their defects caused by neurodegenerative diseases. Our hypothesis is that both retinal- and cerebral-neurodegenerative diseases may directly impair functions of different retinal cells before showing morphological abnormalities, and cellular dysfunctions may be detected by optical tomographic techniques. As a functional extension of OCT, intrinsic signal optoretinography (ORG) study has been done with a retinal neurodegenerative mouse model. ORG is analogous to electroretinography (ERG). ORG generally refers to the non-invasive, optical imaging of functional activity in the retina. OCT-based ORG can provide objective assessment of retinal function with layer specificity. We developed a custom-built spectral domain OCT system for ORG measurement in mouse retinas. Different light conditions were applied to examine both light-evoked phototransduction response and dark-induced morphophysiological changes. We analyzed intrinsic optical signal (IOS) changes and alterations of hyper-reflective OCT bands. IOS data processing was refined, and imaging protocols were optimized in this study. As another functional extension of OCT, OCT angiography (OCTA) study has been done with a retinal neurodegenerative mouse model and a cerebral neurodegenerative mouse model. OCTA is a non-invasive imaging modality that generates volumetric data of vascular structure in the eye. We developed a custom-built OCTA system and advanced speckle-variance-based decorrelation algorithms for vessel map construction. In addition, a simple but robust artery-vein classification method was devised in this study. We investigated retinal vascular degeneration in both retinal- and cerebral neurodegenerative mouse models. We also observed the hyaloid vascular system in vivo and its degeneration in mouse pups. Quantitative vascular information was generated and compared between different strains in this study. In summary, the research in this thesis enhanced our understanding of the optophysiological response of the retina under different light conditions and established an experimental basis for future clinical applications. Abnormal signatures of OCTA features found in this study will also be beneficial in understanding pathophysiological mechanisms of the retinal and hyaloid vascular system. Above all, limitations of the present study and arising hypothesis rooted from intriguing observations in this study would provide valuable scientific questions to answer in future study.