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Purpose: To investigate the xenobiotic profiles of patients with neovascular age-related macular degeneration (nAMD) undergoing anti-vascular endothelial growth factor (anti-VEGF) intravitreal therapy (IVT) to identify biomarkers indicative of clinical phenotypes through advanced AI methodologies., Methods: In this cross-sectional observational study, we analyzed 156 peripheral blood xenobiotic features in a cohort of 46 nAMD patients stratified by choroidal neovascularization (CNV) control under anti-VEGF IVT. We employed Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) for measurement and leveraged an AI-driven iterative Random Forests (iRF) approach for robust pattern recognition and feature selection, aligning molecular profiles with clinical phenotypes., Results: AI-augmented iRF models effectively refined the metabolite spectrum by discarding non-predictive elements. Perfluorooctanesulfonate (PFOS) and Ethyl β-glucopyranoside were identified as significant biomarkers through this process, associated with various clinically relevant phenotypes. Unlike single metabolite classes, drug metabolites were distinctly correlated with subretinal fluid presence., Conclusions: This study underscores the enhanced capability of AI, particularly iRF, in dissecting complex metabolomic data to elucidate the xenobiotic landscape of nAMD and environmental impact on the disease. The preliminary biomarkers discovered offer promising directions for personalized treatment strategies, although further validation in broader cohorts is essential for clinical application., Competing Interests: Declarations. Potential Conflicts: Steffen E. Künzel: Consultant for Algeacare GmbH. Dominik Frentzel: None. Leonie Flesch: None. Vitus Knecht: None. Anne Rübsam: Consultant for Novartis and Bayer; Speaking honoria from Bayer, Novartis and Roche; Research support from Deutsche Forschungsgemeinschaft (DFG) (RU 2020/3–1). Bodo Lange: CEO and shareholder of Alacris Theranostics GmbH. Felix Dreher: Employee of Alacris Theranostics GmbH. Moritz Schuette: Employee of Alacris Theranostics GmbH. Marie-Laure Yaspo: CSO and shareholder of Alacris Theranostics GmbH. Alexandre Dubrac: None. Hans Lehrach: head of company board, and shareholder of Alacris Theranostics GmbH. Antonia M. Joussen: Consultant to and speaker honorarium from Bayer, Novartis, AbbVie, Roche. Research support from Novartis, Boehringer Ingelheim. Oliver Zeitz: Consultant for Bayer, Novartis, Allergan, Roche Omeicos, Oxular, SamChungDan Pharma, Boehringer Ingelheim; Grant support from Bayer, Novartis, Boehringer Ingelheim; Speaker honorarium from Allergan, Bayer, Novartis, Roche. Ethical Approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the Charité University Medicine and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study. This article does not contain any studies with animals performed by any of the authors., (© 2024. The Author(s).)

Background: To longitudinally investigate the impact of best-corrected visual acuity (BCVA), non-modifiable risk factors, modifiable habits, and disease course on the vision-related quality of life (VRQOL) of patients with central serous chorioretinopathy (CSCR). Methods: We longitudinally enrolled 109 CSCR patients and 42 non-diseased control participants from our clinic. In addition to clinical examination, the National Eye Institute Visual Function Questionnaire (NEI-VFQ-39) was employed for assessments, along with questions pertaining to various aspects of lifestyle habits. Alongside the cross-sectional analyses, the VRQOL of CSCR patients was tracked longitudinally over one year. Results: Consistent with prior studies, CSCR patients reported a lower VRQOL compared to non-diseased participants (79.3 ± 14.1 for CSCR and 92.6 ± 7.6 for CTRL; p < 0.0001), but fared better than those with other ocular conditions. No significant associations were observed between BCVA, any non-modifiable risk factors, or interventions, and VRQOL, both in cross-sectional and longitudinal contexts (cross-sectional BCVA with VRQOL: Pearson r correlation 0.173, p = 0.072). Among modifiable habits, sleep duration ( p = 0.036), perceived quality of sleep rhythm ( p = 0.006), hours of physical activity ( p = 0.036), and the presence of non-ocular conditions ( p = 0.001) were significantly correlated with VRQOL. Notably, enhanced sleep duration (+4.232 vs. -0.041 non-enhanced at 3 months, p = 0.033) and higher perceived quality of sleep rhythm (+6.248 vs. +0.094 non-higher, p = 0.009) showed a positive correlation with improved VRQOL over time. Conclusions: The study reveals that VRQOL has minimal dependence on BCVA or other clinical factors, suggesting that patient-reported outcome measures (PROMs) could serve as alternative endpoints in clinical studies for more holistic patient welfare assessment. Furthermore, the strong correlations between VRQOL and modifiable lifestyle habits indicate potential therapeutic value in targeting these areas for intervention.

Purpose: We aimed to determine the impact of artificial sweeteners (AS), especially saccharin, on the progression and treatment efficacy of patients with neovascular age-related macular degeneration (nAMD) under anti-vascular endothelial growth factor (anti-VEGF-A) treatment., Methods: In a cross-sectional study involving 46 patients with nAMD undergoing intravitreal anti-VEGF therapy, 6 AS metabolites were detected in peripheral blood using liquid chromatography - tandem mass spectrometry (LC-MS/MS). Disease features were statistically tested against these metabolite levels. Additionally, a murine choroidal neovascularization (CNV) model, induced by laser, was used to evaluate the effects of orally administered saccharin, assessing both imaging outcomes and gene expression patterns. Polymerase chain reaction (PCR) methods were used to evaluate functional expression of sweet taste receptors in a retinal pigment epithelium (RPE) cell line., Results: Saccharin levels in blood were significantly higher in patients with well-controlled CNV activity (P = 0.004) and those without subretinal hyper-reflective material (P = 0.015). In the murine model, saccharin-treated mice exhibited fewer leaking laser scars, lesser occurrence of bleeding, smaller fibrotic areas (P < 0.05), and a 40% decrease in mononuclear phagocyte accumulation (P = 0.06). Gene analysis indicated downregulation of inflammatory and VEGFR-1 response genes in the treated animals. Human RPE cells expressed taste receptor type 1 member 3 (TAS1R3) mRNA and reacted to saccharin stimulation with changes in mRNA expression., Conclusions: Saccharin appears to play a protective role in patients with nAMD undergoing intravitreal anti-VEGF treatment, aiding in better pathological lesion control and scar reduction. The murine study supports this observation, proposing saccharin's potential in mitigating pathological VEGFR-1-induced immune responses potentially via the RPE sensing saccharin in the blood stream.

There is early evidence of extraocular systemic signals effecting function and morphology in neovascular age-related macular degeneration (nAMD). The prospective, cross-sectional BIOMAC study is an explorative investigation of peripheral blood proteome profiles and matched clinical features to uncover systemic determinacy in nAMD under anti-vascular endothelial growth factor intravitreal therapy (anti-VEGF IVT). It includes 46 nAMD patients stratified by the level of disease control under ongoing anti-VEGF treatment. Proteomic profiles in peripheral blood samples of every patient were detected with LC-MS/MS mass spectrometry. The patients underwent extensive clinical examination with a focus on macular function and morphology. In silico analysis includes unbiased dimensionality reduction and clustering, a subsequent annotation of clinical features, and non-linear models for recognition of underlying patterns. The model assessment was performed using leave-one-out cross validation. The findings provide an exploratory demonstration of the link between systemic proteomic signals and macular disease pattern using and validating non-linear classification models. Three main results were obtained: (1) Proteome-based clustering identifies two distinct patient subclusters with the smaller one ( n = 10) exhibiting a strong signature for oxidative stress response. Matching the relevant meta-features on the individual patient's level identifies pulmonary dysfunction as an underlying health condition in these patients. (2) We identify biomarkers for nAMD disease features with Aldolase C as a putative factor associated with superior disease control under ongoing anti-VEGF treatment. (3) Apart from this, isolated protein markers are only weakly correlated with nAMD disease expression. In contrast, applying a non-linear classification model identifies complex molecular patterns hidden in a high number of proteomic dimensions determining macular disease expression. In conclusion, so far unconsidered systemic signals in the peripheral blood proteome contribute to the clinically observed phenotype of nAMD, which should be examined in future translational research on AMD.

Background: Non-neovascular age-related macular degeneration (AMD) is not yet treatable. This article summarises current clinical research approaches. The reasons for the current lack of success are analysed., Methods: Literature and databank search., Results: The number of therapeutic approaches and mechanisms is limited. Only reduction in lipofuscin containing deposits is specific for AMD. Further approaches include modulation of inflammation and neuroprotection. Confirmatory studies have failed to demonstrate efficacy in AMD, i.e. slowing or stopping AMD progression., Discussion: To increase the probability of success for future developments, the pharmacological target space needs to be broadened. This may be achieved by application of molecular network analyses. As visual acuity is commonly not primarily affected by non-neovascular AMD, research on patient perspective is required to define reasonable target profiles for future therapies., Competing Interests: Oliver Zeitz: Beratungstätigkeit für Bayer, Mitarbeiter der Bayer AG bis 30.09.2016, Beratungstätigkeit für Omeicos Therapeutics, Boehringer-Ingelheim, Refententätigkeit für Bayer und Novartis. Ira Seibel: Referententätigkeit für Bayer, Novartis, Pharm-Allergan. Antonia M. Joussen: Beratungstätigkeit für Bayer AG, Novartis, Allergan, Omeicos., (Georg Thieme Verlag KG Stuttgart · New York.)