Microstructural determinants of dark adaptation and effects of retinoid administration in age-related macular degeneration

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Age-related macular degeneration (AMD) is the most common cause for blindness in industrialised countries. A key role in pathology is attributed to the complex of Bruch Membrane (BrM) and Choriocapillaris (CC). Impairments of this complex include both, barrier effects of diffuse and focal extracellular deposits and vascular limitations. Based on these observations, various therapeutic innovations aimed towards the BrM-CC-complex interchange barrier have been proposed. However, since BrM is not represented on state-of-the-art retinal imaging and visual acuity is often preserved in early stages, a surrogate marker for early alterations in AMD is needed. Dark adaptation (DA) is a measure for recovery of photoreceptors after bleaching and its impairment has in the past been shown to be associated with early disease stages in AMD.The overall objective of the project is to identify functionally validated structural endpoints to detect and monitor early disease stages and their progression, to optimize these for potential applications in clinical interventional trials and to employ these in a clinical trial of Vitamin A substitution in AMD.First, functional alterations assessed by DA and structural alterations assessed with multimodal imaging will be correlated and a model based on structure-derived variables will be developed to predict retinal function (DA). It is yet unknown, if dark adaptation impairment is fully paralleled by concurrent changes in retinal microstructure at the specific location of the DA stimulus visible on state-of-the-art multimodal imaging. Of specific interest is a possible structure-function dissociation, as a means of additional contributors to retinal dysfunction supervening explainable dysfunction by structural data. Furthermor, environmental and non-eye specific factors will be included in the multidimensional model to predict retinal dysfunction and its progression over 5 years. Specifically, patient specific data such as age, behavioral factors (e.g. history of smoking) and genetic risk factors (e.g. SNPs in the ARMS2/HTRA1 gene as well as others) will be included. A specific focus will be to elucidate if these factors have an impact on the retinal structure and subsequently on function (i.e. by choroidal alterations in patients with history of smoking) or if they imply structure-independent impairment of dark adaptation.Next, the optimization of DA test protocols for rod function (test location and device choice) will be addressed. This will consider repeatability and the spatial pattern of dysfunction of the two most relevant DA devices, the AdaptDx and Medmont Dark-Adapted Chromatic Perimeter.The final step will be the application of the previously obtained results in a Vitamin A substitution trial to clarify, if locations with a structure-function dissociation exhibit a pronounced improvement of DA. This would indicate a pathologic process on the level of BrM not represented on multimodal imaging.