Imaging-based biomarkers in neurodegenerative eye diseases

<p dir="ltr">The aim of this thesis was to assess imaging-based biomarkers in the two most common neurodegenerative eye diseases, glaucoma and age-related macular degeneration, using multiple imaging modalities. The studies were conducted at the Departments of Ophthalmology of the Ludwig-Maximilians-University, Munich, Germany (Study 1), University of Zurich, Zurich, Switzerland (Study 2) and the Division of Eye and Vision of the Department of Clinical Neuroscience at the Karolinska Institutet, Stockholm, Sweden (Study 3 and Study 4).</p><p dir="ltr">Study 1 was a single-centre, prospective case-control study involving participants with open-angle glaucoma and healthy controls. Radial optical coherence tomography scans of the optic nerve head were used for imaging- based biomarker analysis. The biomarkers based on the Bruch's membrane opening of the optic nerve head showed a strong structure-function relation with visual field sensitivities. The novel biomarkers proposed by this study, perpendicular rim width and perpendicular rim area, showed stronger structure- function correlations than the pre-existing minimum rim width and minimum rim area, respectively. A robust structure-function correlation supports the potential use of Bruch's membrane-based imaging biomarkers for glaucoma screening.</p><p dir="ltr">Study 2 was a single-centre, retrospective observational study involving participants with neovascular age-related macular degeneration. Optical coherence tomography volume scans of the macula were used to assess deposit type and macular neovascularisation type as imaging-based biomarkers. The study found that soft drusen were associated with a macular neovascularisation type 1 which is located under the retinal pigment epithelium. Subretinal drusenoid deposits were associated with a macular neovascularisation type 2 which is located between the retinal pigment epithelium and the neurosensory retina and a macular neovascularisation type 3 which originates intraretinally. The different neovascularisation types have different disease courses and treatment responses. Thus, the deposit type can be used to predict the neovascularisation type. This can help to individualize follow-ups and treatment strategies for patients with early and intermediate age-related macular degeneration.</p><p dir="ltr">Study 3 was a single-centre, prospective observational study involving participants with non-neovascular, 'dry' age-related macular degeneration with geographic atrophy using fundus autofluorescence images. Characteristics of the geographic atrophy lesions (configuration, location towards the fovea, laterality of atrophy affection) were used as imaging-based biomarkers to evaluate their impact on the growth rate of the atrophies over a long-term follow-up period up to 123 months. Geographic atrophy lesions in this study grew at a rate of 1.597 mm2/yr (0.264 mm/yr in square root transformed format). Participants with a bilateral affection by geographic atrophy showed faster growth of their lesions. A multifocal lesion configuration was a risk factor for faster lesion growth. Lesions that did not affect the fovea yet (fovea-sparing) also showed a risk for faster growth. In a combined statistical model fovea status seemed to have the strongest influence on square root transformed geographic atrophy growth. The findings of this study can help to identify the patients that are at highest risk for lesion progression and to lose their central vision. These patients might benefit most from upcoming treatments for non-neovascular age-related macular degeneration.</p><p dir="ltr">Study 4 was a single-centre prospective cross-sectional study involving participants with geographic atrophy in non-neovascular age-related macular degeneration. A commercially available adaptive optics-based retinal camera was used for high-resolution imaging of the atrophy lesions and their surrounding border zone (junctional zone) at a photoreceptor level. The width of the border zone was used as an imaging-based biomarker to describe the border zone in vivo at an unprecedented level of detail. It was found that the border zone around the atrophies had a broad minimum-to-maximum range of 86.73 to 686.03 um in width with a high intraindividual variability. A trend toward narrower border zones in multifocal and fovea-involving lesions was seen but the difference was not statistically significant. The adaptive optics-based lesion area measurements produced comparable results to other established imaging modalities, demonstrating the precision and reliability of the adaptive optics-based camera. Adaptive-optics images could reveal remaining photoreceptors in the fovea and pathological changes that were not visible with all the other imaging techniques.</p><p dir="ltr">Modern imaging modality-derived biomarkers can contribute to a better understanding of the two most common neurodegenerative eye diseases, glaucoma and age-related macular degeneration. They may be a valuable addition to the toolset necessary for individual risk stratification, screening, follow-up scheduling and disease prediction in precision eye care.</p><h3 dir="ltr">List of scientific papers</h3><p dir="ltr">I. <b>Muth DR</b>, Hirneiß CW. Structure-Function Relationship Between Bruch's Membrane Opening-Based Optic Nerve Head Parameters and Visual Field Defects in Glaucoma. Invest Ophthalmol Vis Sci. 2015 May;56(5):3320-8. <a href="https://doi.org/10.1167/iovs.14-15845">https://doi.org/10.1167/iovs.14-15845</a></p><p dir="ltr">II. <b>Muth DR</b>, Toro MD, Bajka A, Jonak K, Rieder R, Kohler MM, Gunzinger JM, Souied EH, Engelbert M, Freund KB, Zweifel SA. Correlation between Macular Neovascularization (MNV) Type and Druse Type in Neovascular Age-Related Macular Degeneration (AMD) Based on the CONAN Classification. Biomedicines. 2022 Sep 22;10(10):2370. <a href="https://doi.org/10.3390/biomedicines10102370">https://doi.org/10.3390/biomedicines10102370</a></p><p dir="ltr">III. <b>Muth DR</b>, Quérat L, Venkataraman AP, Dominguez-Vicent A, Petrovski G, Williams PA, Locri F, Zweifel SA, Kvanta A. Long-Term Natural History of Treatment-Naïve Geographic Atrophy in Age- Related Macular Degeneration. Transl Vis Sci Technol. 2025 May 1;14(5):5. <a href="https://doi.org/10.1167/tvst.14.5.5">https://doi.org/10.1167/tvst.14.5.5</a></p><p dir="ltr">IV. <b>Muth DR</b>, Venkataraman AP, Dominguez-Vicent A, Petrovski G, Williams PA, Brautaset R, Nilsson M, Zweifel SA, Kvanta A. High- Resolution Assessment of the Geographic Atrophy Border Zone Using Adaptive Optics Imaging. [Manuscript]</p>