Retinal imaging in epidemiological studies

Abstract

Retinal imaging in population-based studies not only enhances our understanding of retinal diseases but, due to its high resolution and velocity, also holds great potential in the study of brain diseases. This is attributed to the possibility of direct visualization of retinal vascular and nervous tissue, being the retina part of the central nervous system. The Rhineland Study, based in Bonn, Germany, provides an ideal framework for investigating retinal and brain markers, as well as their relationship and changes across the lifespan. This population-based study integrates state-of-the-art imaging of both retina and brain, with a primary objective of examining healthy aging. In this thesis, I provide an outline of my work in this direction, largely conducted in the Rhineland Study. <br /> Initially, I focus on grading methods and prevalence of age-related macular degeneration (AMD), the most common cause of blindness, in the first 5000 participants of the Rhineland Study. AMD classifications and consequently, epidemiological data, mainly rely on older imaging methods. I provide examples of how integration of better imaging, including optical coherence tomography (OCT), enables better AMD endophenotyping, as it enables better detection of markers of high severity in intermediate AMD, such as reticular pseudodrusen (RPD). In the first 5000 individuals of the Rhineland Study, we observed a prevalence of 498 (10.5%) with early AMD, 401 (8.5%) with intermediate AMD, and 35 (0.7%) with late AMD, while reticular pseudodrusen (RPD) were graded in 93 (1.96%) of individuals. Multimodal imaging also enables better differentiation of AMD from its main differential diagnoses in a population-based setting, such as pachychoroid disease, for which we observed a prevalence of 2.9% (N=206). Furthermore, utilizing OCT paves the way for the utilization of automated segmentation methods, such as an algorithm for automated drusen detection, which can lead to better AMD phenotyping. In this respect, I also investigated the distribution and comparability of drusen volume between two different algorithms in the MACUSTAR cohort, a multicenter cohort study focusing on generating clinical endpoints in intermediate AMD and integrating deep retinal imaging phenotyping of the recruited subjects. <br /> Furthermore, to advance our understanding of the validity of retinal markers for neurodegeneration, I investigated the association between retinal markers and plasma levels of neurofilament light chain (NfL). Plasma NfL rises in most neurological diseases and reflects neuroaxonal damage, thus being a marker of age-related brain atrophy and neurodegeneration. We observed that in the general population, aging is the main driver of an association between inner retinal atrophy and plasma NfL levels, and that the presence of neurological diseases or cardiovascular risk factors can determine their association. Hence, shared neuronal injury might drive neuronal pathology in the brain and in the retina, thereby determining their association. However, previous studies also observed that structures in the visual pathway, from the retina to the visual cortex in the occipital lobe, can undergo transneuronal neurodegeneration in the presence of visual impairment or localized visual pathway structures pathology. This could partly explain the association between visual and cognitive impairment since visual structures account for a large amount of brain activity and are in synaptic connection with temporal lobe cognitive structures. For these reasons, I later investigated the conjoint associations between visual impairment, retinal and both global and local brain atrophy, including visual pathway and hippocampal lobe (as an important cognitive structure) in the Rhineland Study. I also aimed to estimate the relative contribution of transneuronal neurodegeneration versus common neuronal injury to the previously observed association between retinal and brain atrophy. We observed that retinal atrophy can reflect loss of integrity in both visual and cognitive pathway structures, as well as global brain measures. Interestingly, we also observed that visual impairment showed similar associations. This is of particular interest as it highlights the importance of visual preservation as a preventative measure for brain health, even in a population-based study with a relatively low proportion of visually impaired individuals. I also observed that most of the effect of the association between retinal and brain atrophy can be attributed to a common neuronal injury mechanism. Overall, my research further reinforces the utilization of retinal readouts, in particular atrophy in the inner retina and in the ganglion cell layer, as universal markers of neurodegeneration. <br /> Based on this work, I conclude that integration of forefront retinal imaging in population-based studies not only holds significant potential for advancing our understanding of retinal diseases such as AMD, but also for serving as overarching markers of brain structure and neurodegeneration.