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    Research update: 520

    The latest research highlights for 22 November 2021.


    Reticular pseudodrusen: A critical phenotype in age-related macular degeneration 

    Prog Retin Eye Res.2021 Nov 6;101017. 

    Zhichao Wu, Erica L Fletcher, Himeesh Kumar, Ursula Greferath, Robyn H Guymer


    Reticular pseudodrusen (RPD), or subretinal drusenoid deposits (SDD), refer to distinct lesions that occur in the subretinal space. Over the past three decades, their presence in association with age-related macular degeneration (AMD) has become increasingly recognized, especially as RPD have become more easily distinguished with newer clinical imaging modalities. There is also an increasing appreciation that RPD appear to be a critical AMD phenotype, where understanding their pathogenesis will provide further insights into the processes driving vision loss in AMD. However, key barriers to understanding the current evidence related to the independent impact of RPD include the heterogeneity in defining their presence, and failure to account for the confounding impact of the concurrent presence and severity of AMD pathology. This review thus critically discusses the current evidence on the prevalence and clinical significance of RPD and proposes a clinical imaging definition of RPD that will help move the field forward in gathering further key knowledge about this critical phenotype. It also proposes a putative mechanism for RPD formation and how they may drive progression to vision loss in AMD, through examining current evidence and presenting novel findings from preclinical and clinical studies. 

    DOI: 10.1016/j.preteyeres.2021.101017 


    The effect of systemic levels of TNF-alpha and complement pathway activity on outcomes of VEGF inhibition in neovascular AMD 

    Eye (Lond).2021 Nov 8. 

    Adnan H Khan, Charles O Pierce, Gabriella De Salvo, Helen Griffiths, Marie Nelson, Angela J Cree, Geeta Menon, Andrew J Lotery

    Background/objectives: Systemic levels of pro-inflammatory cytokines and activated complement components affect the risk and/or progression of neovascular age-related macular degeneration (AMD). This study investigated the effect of serum pro-inflammatory cytokine levels and complement pathway activity on the clinical response to vascular endothelial growth factor (VEGF) inhibition in neovascular AMD. 

    Methods: Sixty-five patients with a new diagnosis of neovascular AMD were observed over a six-month period in a single-centre, longitudinal cohort study. At each visit, the visual acuity score (VAS), central macular thickness (CMT), serum levels of CRP, pro-inflammatory cytokines (TNF-α, IL-1β, IL-2, IL-6 and IL-8), and complement pathway activity were measured. Participant DNA samples were sequenced for six complement pathway single nucleotide polymorphisms (SNPs) associated with AMD. 

    Results: A statistically significant difference in VAS was observed for serum levels of TNF-α only: there was a gain in VAS (from baseline) of 1.37 for participants below the 1st quartile of mean concentration compared to a reduction of 2.71 for those above the 3rd quartile. Statistical significance was maintained after Bonferroni correction (P value set at <0.006). No significant differences in CMT were observed. In addition, statistically significant differences, maintained after Bonferroni correction, were observed in serum complement activity for participants with the following SNPs: CFH region (rs1061170), SERPING1 (rs2511989) and CFB (rs641153). Serum complement pathway components did not significantly affect VAS. 

    Conclusions: Lower serum TNF-α levels were associated with an increase in visual acuity after anti-VEGF therapy. This suggests that targeting pro-inflammatory cytokines may augment treatment for neovascular AMD. 

    DOI: 10.1038/s41433-021-01824-3 


    Dietary omega-3 polyunsaturated fatty acids and fish intake and risk of age-related macular degeneration

    Clin Nutr.2021 Oct 12;40(12):5662-5673. 

    Hong Jiang, Xin Shi, Yahui Fan, Duolao Wang, Baoyu Li, Jin Zhou, Cheng Pei, Le Ma

    Background & aims: Epidemiologic studies are inconsistent regarding the association of dietary omega-3 polyunsaturated fatty acids (PUFA) and/or fish intake with risk of age-related macular degeneration (AMD) incidence and progression. The objective was to determine these associations by conducting a meta-analysis of available studies. 

    Methods: Three electronic databases were searched for studies that quantified dietary omega-3 PUFA and/or fish intake from inception to December 2020 without language restriction. Three investigators independently assessed for inclusion and extracted data. Study-specific risk estimates were combined using random-effects model. Potential dose-response associations were explored with the use of generalized least-squares trend estimation. 

    Results: 21 studies were included in the meta-analysis. Higher dietary intakes of omega-3 PUFA was significantly associated with 14% (relative risk [RR]: 0.86, 95% confidence interval [CI]: 0.77, 0.96) and 29% (RR: 0.71, 95% CI: 0.55, 0.91) lower risk of early and late AMD, respectively. The dose-response analysis showed a 6% and 22% decrease in the risk of early and late AMD for each additional 1 g/d omega-3 PUFA intake. For individual omega-3 PUFA, the intake of eicosapentaenoic acid and docosahexaenoic acid was inversely associated with lower AMD risk, whereas no association was found for the alpha-linolenic acid. Consistent inverse associations were also found between fish intake and AMD. The pooled RRs comparing extreme categories of fish intake were 0.79 (95% CI: 0.70, 0.90) and 0.71 (95% CI: 0.60, 0.85) for early and late AMD risk, respectively. Every 15 g/d of fish consumption was associated with 13% and 14% lower early and late AMD. In addition, fish intake was associated with a significantly reduced risk of AMD progression (RR: 0.73, 95% CI: 0.53, 1.00). 

    Conclusions: A high intake of dietary omega-3 PUFA or fish was associated with a reduced risk of developing of AMD, which further supports that consumption of omega-3 PUFA-rich foods may be a new avenue nutritional approach to preventing AMD. 

    DOI: 10.1016/j.clnu.2021.10.005 

    Assessing bidirectional associations between cognitive impairment and late age-related macular degeneration in the Age-Related Eye Disease Study 2 

    Alzheimers Dement.2021 Nov 10.

    Jimmy T Le, Elvira Agrón, Tiarnan D L Keenan, Traci E Clemons, Willa D Brenowitz, Kristine Yaffe, Emily Y Chew, AREDS2 Research Group

    Introduction: We aimed to investigate bidirectional associations between cognitive impairment and late age-related macular degeneration (AMD). 

    Methods: Participants in the Age-Related Eye Disease Study 2 (AREDS2) received annual eye examinations and cognitive function testing (e.g., Modified Telephone Interview for Cognitive Status [TICS-M]). We examined bidirectional associations between cognitive impairment (e.g., a TICS-M score < 30) and late AMD at 5 and 10 years. 

    Results: Five thousand one hundred eighty-nine eyes (3157 participants; mean age 72.7 years) were analyzed and followed for a median of 10.4 years. Eyes of participants with cognitive impairment at baseline were more likely to progress to late AMD at 5 years (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.08-1.43) and 10 years (HR, 1.20; 95% CI, 1.05-1.37) than eyes of participants without cognitive impairment. Worse baseline AMD severity was not associated with developing cognitive impairment. 

    Discussion: Cognitive impairment is associated with late AMD progression in AREDS2. Our finding highlights the importance of eyecare for people with cognitive impairment. 

    DOI: 10.1002/alz.12473 


    Atypical bilateral presentation in idiopathic macular telangiectasia type 1 

    Arch Soc Esp Oftalmol (Engl Ed).2021 Nov;96(11):602-606. 

    H E Tapia Quijada, C Mantolan Sarmiento, M Serrano García, N Betancor Caro


    Idiopathic macular telangiectasia type 1 (MacTel 1) almost always occurs unilaterally. In this article, we report the case of a 73-year-old man with no significant history diagnosed with MacTel 1 but with atypical bilateral presentation, something very rare in this disease. The usefulness of multimodal imaging studies, including optical coherence tomography angiography (OCTA), is highlighted to differentiate it from macular telangectasia type 2 (MacTel 2). The patient’s condition was characterized by cystoid macular edema (CME) with discreet results with treatment with a dexamethasone implant. However, aflibercept therapy showed favorable results, but with recurrences when extending the doses. 

    DOI: 10.1016/j.oftale.2020.09.017 


    Running to save sight: The effects of exercise on retinal health and function 

    Clin Exp Ophthalmol.2021 Nov 6. 

    Joshua A Chu-Tan, Max Kirkby, Riccardo Natoli


    The benefits of exercise to human health have long been recognised. However only in the past decade have researchers started to discover the molecular benefits that exercise confers, especially to the central nervous system. These discoveries include the magnitude of molecular messages that are communicated from skeletal muscle to the central nervous system. Despite these advances in understanding, very limited studies have been conducted to decipher the molecular benefits of exercise in retinal health and disease. Here, we review the latest work on the effects of exercise on the retina and discuss its effects on the wider central nervous system, with a focus on demonstrating the potential applicability and comparative molecular mechanisms that may be occurring in the retina. This review covers the key molecular pathways where exercise exerts its effects: oxidative stress and mitochondrial health; inflammation; protein aggregation; neuronal health; and tissue crosstalk via extracellular vesicles. Further research on the benefits of exercise to the retina and its molecular messages within extracellular vesicles is highly topical in this field of research. 

    DOI: 10.1111/ceo.14023 

    Novel Treatments for Diabetic Macular Edema and Proliferative Diabetic Retinopathy 

    Curr Diab Rep.2021 Nov 1;21(10):43. 

    Nhon T Le, Zachary A Kroeger, Weijie Violet Lin, Arshad M Khanani, Christina Y Weng

    Purpose of review: Diabetic retinopathy (DR), a common cause of vision loss, is projected to increase worldwide, and is associated with significant morbidity. The current standard-of-care treatments can preserve and significantly improve vision in many patients affected by DR. However, challenges such as heavy treatment burden and refractory disease remain. The purpose of this review is to highlight and discuss investigative agents in development for the treatment of DR. 

    Recent findings: There are several novel agents with unique mechanisms that may offer greater durability and efficacy compared to existing drugs. Some target new pathways, others leverage a slow-release delivery system, and some modify gene expression through a single-dose treatment. While unfavorable adverse events, such as intraocular inflammation, have been observed with longer-durability agents, many investigational products show excellent efficacy and safety profiles. The outcomes of ongoing and future trials may revolutionize the current treatment paradigm for DR. 

    DOI: 10.1007/s11892-021-01412-5