黄斑ジストロフィー

PURPOSE: To evaluate whether baseline well-delineated hyperreflective material (wdHRM) is associated with short-term visual outcome in treatment-naïve neovascular age-related macular degeneration (nAMD), whether this association differs by macular neovascularisation (MNV) subtype, and how wdHRM relates to atrophy-related OCT biomarkers. METHODS: Multicentre observational analysis of 2036 treatment-naïve eyes (PRECISE cohort) completing three monthly aflibercept 2 mg injections. Best-corrected visual acuity (BCVA) at Visit 4 (V4) was modelled against baseline wdHRM using adjusted multivariable linear regression. Secondary analyses assessed subtype interaction and eye-level association with atrophy-related OCT biomarkers. RESULTS: Mean BCVA improved from 58.0 to 62.6 letters by V4. Baseline wdHRM was present in 14.6% of eyes, and foveal-involving wdHRM independently predicted lower V4 BCVA (β =-6.60 letters, 95%confidence interval [CI]-8.18 to -5.02; p < 0.001). Foveal-involving baseline choroidal hypertransmission (HTM) showed a stronger adverse association (β =-8.98, 95%CI-10.97 to -6.98; p < 0.001). The wdHRM association differed by subtype (interaction p = 0.016), with adjusted BCVA reductions of -10.6 letters in Type 3 MNV, -4.8 in Type 2/mixed MNV, -4.1 in Type 1 MNV, and -1.0 in polypoidal choroidal vasculopathy. By V4, wdHRM increased to 21.0% and was associated with HTM and greater outer retinal disruption. CONCLUSIONS: In treatment-naïve nAMD, baseline wdHRM is independently associated with poorer short-term visual outcome, particularly in Type 3 MNV. Short-term visual outcome should be interpreted in relation to both fibrosis-related and atrophy-related OCT biomarkers.

PURPOSE: Dark adaptation (DA) has emerged as a potential functional outcome for assessing age-related macular degeneration (AMD). While reticular pseudodrusen (RPD) have been linked to poorer DA, most studies to date have focused on qualitative RPD presence/absence or comprised small cross-sectional cohorts. This work aimed to assess how automated quantification of RPD area and volume relates to rod-mediated DA and its longitudinal decline in non-advanced AMD. DESIGN: Prospective cross-sectional and longitudinal study. PARTICIPANTS: Patients with non-advanced AMD and controls, all aged above 50, from the Massachusetts Eye and Ear AMD Biomarkers Study. METHODS: All subjects underwent baseline multimodal retinal imaging and DA testing with a 20-minute extended protocol (AdaptDx, MacuLogix). Rod intercept time (RIT) and area under the dark adaptation curve (AUDAC) were calculated. A deep learning algorithm was employed to quantify RPD en face area (mm2) and volume (mm3), which were square- and cube-root transformed respectively for analysis. RPD extent within the DA testing locus was also measured. Linear mixed-effect models evaluated the relationship of RPD burden with DA metrics, accounting for age, sex, smoking, classic drusen volume and inter-eye correlation. MAIN OUTCOME MEASURES: Association between RPD burden and dark adaptation (RIT and AUDAC) on a cross-sectional and longitudinal basis RESULTS: We included 545 eyes (52 early AMD, 285 intermediate AMD, 208 controls) from 310 patients (mean 69.6±7.4 years). 128 (23.5%) had RPD. Greater RPD en-face area and volume were associated with prolonged RIT (β 1.59, p=0.002 and β 9.29, p=9.78 x 10-5 respectively) and higher AUDAC (β 0.032, p=2.15 x 10-4 and β 0.166, p=5.88x10-5 respectively). Overall macular RPD burden, rather than local density at the DA testing locus, was independently associated with worse AUDAC (β 0.005, p=0.001). In longitudinal analyses (n=204 eyes, mean 2.8±1.8 years), RPD presence (β 0.011, p=0.0067), en face area (β 0.012, p=4.48 x 10-4), and volume (β 0.054, p=2.11 x 10-4) were all significantly associated with a faster rate of AUDAC decline over time, and were predictive of AUDAC at any subsequent visit (β 0.048, p=6.72 x 10-5 and β 0.198, p=2.02 x 10-4). CONCLUSIONS: Quantitative RPD burden is independently associated with impaired rod-mediated DA and with subsequent functional decline, supporting its value as a prognostic structural biomarker for risk stratification and progression monitoring in non-advanced AMD.

Individuals of the same chronological age differ in biological aging, and scalable, noninvasive markers are needed. The deep learning-derived retinal age gap (RAG) is a promising measure of retinal aging, but its associations with real-world health determinants remain unclear. We developed a multi-task model to predict retinal age using 29,530 fundus images from 7535 participants in a health screening cohort and evaluated RAG in cohort A for lifestyle, socioeconomic, and systemic factors (n = 5606) and cohort B for ocular diseases (n = 1810). The bias-corrected multi-task model trained on mixed data achieved the best performance, with a mean absolute error of 2.656 years and a Pearson correlation of 0.921 in cohort A and 2.529 years and 0.938 in cohort B. Higher RAG was significantly associated with smoking (ex-smokers, β = +0.46 years; current smokers, β = +0.50 years) and with clinical diabetes (+2.52 years); both survived false discovery rate (FDR) and Bonferroni correction, and the diabetes association persisted across all sequential covariate-adjustment sets. Married participants had lower RAG (β = -0.46 years), significant after FDR correction only. Hypertension and hyperlipidemia were not associated with RAG. In cohort B, RAG was significantly higher in eyes with age-related macular degeneration (β = +0.60 years) and cataract (β = +1.86 years) than in normal controls, both surviving corrections. RAG, an imaging-derived age-prediction residual, is therefore associated with lifestyle, systemic, and ocular health. Whether it reflects biological aging requires longitudinal validation against established aging biomarkers; at present, RAG suits population-level characterization better than individual-level risk stratification.

PURPOSE: Angiopoietin-like protein 4 (ANGPTL4) is a multifunctional cytokine regulating angiogenesis, vascular permeability, and inflammation that is elevated, along with vascular endothelial growth factor (VEGF), in multiple ocular neovascular disorders, including ischemic retinopathies and neovascular age-related macular degeneration. However, the downstream signaling pathways that contribute to the effects of ANGPTL4 in ocular disease remain unclear. METHODS: A phospho-kinase Proteome Profiler array was used to map pathways activated by recombinant ANGPTL4 in immortalized murine retinal endothelial cells (iRECs). Candidate signaling routes were assessed using pharmacologic inhibition and siRNA-mediated knockdown to define their roles in ANGPTL4-driven angiogenesis and effector upregulation. Findings were validated following intraocular ANGPTL4 delivery in C57BL/6J mice. RESULTS: ANGPTL4 robustly activated the c-Jun N-terminal kinase (JNK)/c-Jun and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) axes in iRECs, a signature recapitulated in neurosensory retina in vivo. Inhibition of either pathway significantly reduced ANGPTL4-induced angiogenesis, identifying these pathways as critical effectors of ANGPTL4 signaling. ANGPTL4 induced secretion of VEGF, soluble vascular cell adhesion molecule 1 (sVCAM1), T-cell immunoglobulin and mucin domain 1 (TIM-1), and proliferin; however, only VEGF and sVCAM1 depended on JNK/c-Jun and JAK2/STAT5. CONCLUSIONS: ANGPTL4 functions as a signaling hub that integrates different cues to activate JNK/c-Jun and JAK2/STAT5 and upregulate the expression of key pathogenic proteins including VEGF and sVCAM1. This work establishes these cascades as previously unrecognized effectors of ANGPTL4 signaling in the retina and brings important insight into the critical role that ANGPTL4 plays in neovascular retinal disease.

Vascular endothelial growth factor (VEGF) is an important driver of abnormal retinal neovascularization and increased vascular permeability. VEGF overexpression is associated with a number of retinal conditions, such as diabetic macular edema (DME), and neovascular age-related macular degeneration (nAMD). Anti-VEGF treatments have been the most common for these conditions and have improved vision by reducing abnormal blood vessel formation and leakage. This narrative review addressed the fact that the pharmacological properties, safety profiles, and cost-effectiveness of the currently marketed anti-VEGF intravitreal agents (i.e. bevacizumab, ranibizumab, aflibercept, brolucizumab, pegaptanib, and recently faricimab) differ and therefore, each of these agents, have their own unique molecular structure, target specificity, duration of action in the eye, and systemic circulation, each of which will affect the dosing intervals and treatment burden as well as the safety and adverse events associated with each drug. Aflibercept is a high-binding-affinity decoy receptor and is therefore distinct from faricimab, which is a dual-action (VEGF-A and angiopoietin-2) inhibitor. By contrast, ranibizumab, bevacizumab, brolucizumab, and pegaptanib are anti-angiogenic agents with different VEGF blockade profiles, which ultimately lead to distinct clinical outcomes and pharmacokinetic profiles. While anti-VEGF therapies are highly effective, the outcomes regarding safety, efficacy, and cost depend heavily on the study design and reflect the actual treatment paradigm and continuum of care within the healthcare system. The various attributes of agents should help personalize a patient's treatment approach while also addressing potential challenges related to the safety, efficacy, and longevity of treatment for retinal diseases.