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    Research Update 584


    Association of age-related eye diseases with cognitive frailty in older adults: a population-based study.

    Aging clinical & experimental research. 2023 Jun 3.

    Ghanbarnia MJ, Hosseini SR, Ghasemi M, Roustaei GA, Mekaniki E, Ghadimi R, Bijani A, Rasoulinejad SA.

    Background: Age-related eye diseases and cognitive frailty (CF) are both important predictors of adverse health outcomes in older adults, however, little is known about their association.

    Aims: To demonstrate the association between age-related eye diseases and cognitive frailty in a population of Iranian older adults.

    Methods: In this cross-sectional, population-based study, we included 1136 individuals (female n = 514) aged 60 years and older (mean 68.8 ± 6.7 years) who participated in the second cycle of the Amirkola Health and Aging Project (AHAP) between 2016 and 2017. Cognitive function and frailty were evaluated based on Mini-Mental State Examination (MMSE) and the FRAIL scale respectively. Cognitive frailty was defined as coexistence of cognitive impairment (CI) and physical frailty (PF), excluding confirmed cases of dementia such as Alzheimer’s disease. Cataract, diabetic retinopathy (DR), age-related macular degeneration (AMD), elevated intraocular pressure (IOP ≥ 21 mmHg) and glaucoma suspects (vertical cup to disc ratio (VCDR) ≥ 0.6) were diagnosed based on standardized grading protocols. Associations between eye diseases and cognitive frailty were evaluated through binary logistic regression analysis.

    Results: Overall, CI, PF and CF were observed in 257 (22.6%), 319 (28.1%) and 114 (10.0%) participants respectively. After adjusting for confounders and ophthalmic conditions, individuals with cataract were more likely to have CF (OR 1.66; p-value 0.043), while DR, AMD, elevated IOP and glaucoma suspects (OR 1.32, 1.62, 1.42, 1.36, respectively) were not significantly associated with CF. Furthermore, cataract was significantly associated with CI (OR 1.50; p-value 0.022), but not with frailty (OR 1.18; p-value 0.313).

    Conclusion: Older adults with cataract were more likely to have cognitive frailty and cognitive impairment. This association demonstrates the implications of age-related eye diseases beyond ophthalmology and substantiates the need for further research involving cognitive frailty in the context of eye diseases and visual impairment.

    DOI: 10.1007/s40520-023-02458-z


    Quantitative response of macular neovascularisation to loading phase of aflibercept in neovascular age-related macular degeneration.

    Eye (London, England). 2023 May 31

    Montesel A, Hagag AM, Chandra S, Muhammed RP, Thottarath S, Chandak S, Sivaprasad S.

    Purpose: To evaluate quantitative morphological changes in macular neovascularisation (MNV) network after aflibercept therapy in neovascular age-related macular degeneration (nAMD) patients.

    Methods: Consecutive treatment-naïve patients with optical coherence tomography (OCT) angiography confirmed MNV due to nAMD who completed a loading phase of intravitreal aflibercept injections. A quantitative analysis of the vascular network remodelling was performed using a computational software (Angiotool).

    Results: A total of 53 eyes of 52 patients were included in the analysis. The total MNV area decreased significantly after three aflibercept injections (p = 0.003). Total vessel area and vessel density decreased respectively of 20% and 12% at V3 (p < 0.001 in both cases). Other parameters that reduced significantly were total vessel length, average vessel length and density of vascular junctions (p = 0.018, p = 0.002, and p = 0.044, respectively). The number of vascular endpoints (p = 0.001) and lacunarity (p = 0.011) increased significantly, whilst the number of vascular junctions did not vary significantly (p = 0.068). Changes in vascular metrics were predominantly driven by MNV type 1 and 2. No clear relationship was observed between any of the vascular metrics and the macular fluid status.

    Conclusion: Although objective quantification of vascular parameters showed a significant remodelling of the MNV post-loading phase of aflibercept in type 1 and 2 MNV subtypes, none of the quantified vascular metrics correlated to the macular fluid response. These findings highlight a dissociation of anti-angiogenic and anti-permeability properties of aflibercept therapy during the loading phase.

    DOI: 10.1038/s41433-023-02574-0

    Geographic Atrophy after Reabsorption of Pigment Epithelial Detachment (GARPED) study.

    BMC ophthalmology. 2023 May 30

    Peng ET, Adrean SD.

    Background: To describe the occurrence, rate of geographic atrophy (GA) expansion, and changes in visual acuity (VA) after reabsorption of subfoveal pigment epithelial detachments (PED).

    Methods: Included patients had reabsorption of a PED followed by GA. Patients underwent clinical examination with SD-OCT. Images were classified by size with grading occurring post reabsorption. VA was recorded pre-reabsorption, post-reabsorption, and over time.

    Results: The average age of the cohort, consisting of 22 eyes from 19 participants, was 86.9 years at reabsorption. Prior to reabsorption, the VA was 20/80 and then declined to 20/200 (p = 0.001) with an average follow-up time of 30.2 months. There was no significant VA change after the initial loss with reabsorption. The average initial lesion size of GA was 0.987 mm2 with an average growth rate of 0.274 mm/year.

    Conclusions: This study longitudinally examined GA growth rate in patients with reabsorbed PEDs. These patients started with a drusenoid or serous PED, had a dramatic reduction in vision and GA that occurred in place of the PED. These GA lesions have a slower growth rate and a smaller area of onset compared to rates previously reported in the literature. They do not show significant VA change after reabsorption. As we have entered the era of GA therapy, these patients may not benefit from current treatments.

    DOI: 10.1186/s12886-023-02993-3


    The implication of Alu cDNA in the pathogenesis of ARMD.

    Current aging science. 2023 May 30.

    Nouraeinejad A.

    Age-related macular degeneration (ARMD or AMD) is a progressive, sight-threatening disease. The pathogenesis of ARMD is complex, involving many factors, such as metabolic, functional, genetic, and environmental factors. Recently, long interspersed nuclear element-1 (L1)-mediated reverse transcription (RT) of Alu RNA into cytoplasmic Alu complementary DNA (cDNA) has been associated with retinal pigment epithelium (RPE) destruction. These findings provide a strong input for a new direction in the management of ARMD, as certain human immunodeficiency virus (HIV) drugs, such as nucleoside reverse transcriptase inhibitors (NRTIs), were found to suppress inflammation and protect cells of the retina.

    DOI: 10.2174/1874609816666230530095410


    The Risk of Age-Related Macular Degeneration Is Reduced in Type 2 Diabetes Patients Who Use Metformin.

    Pharmaceuticals (Basel, Switzerland). 2023 Feb 1;

    Tseng CH.

    Background: Whether metformin may reduce the risk of age-related macular degeneration (AMD) requires confirmation. This study compared the risk of AMD between ever users and never users of metformin matched on propensity score (PS) in Taiwanese patients with type 2 diabetes mellitus.

    Methods: We enrolled study subjects from Taiwan’s National Health Insurance. A total of 423,949 patients with new onset diabetes from 1999 to 2005 were identified. After excluding ineligible patients and enrolling only patients aged between 50 and 79 years, we created 13,303 pairs of ever users and never users of metformin matched on PS. The patients were followed from 1 January 2006 to 31 December 2011. We estimated hazard ratios by Cox regression.

    Results: AMD was newly diagnosed in 506 ever users and 639 never users. The respective incidence rates (per 100,000 person-years) were 778.72 and 1016.62. The hazard ratio (HR) and 95% confidence interval (CI) for ever versus never users was 0.756 (0.673-0.850). While ever users were categorized by tertiles of cumulative duration (<31.8, 31.8-63.9 and >63.9 months) and cumulative dose (<947.1, 947.1-2193.5 and >2193.5 g) of metformin, a dose-response pattern was observed. For the respective tertiles of cumulative duration, the HRs (95% CIs) were 1.131 (0.961-1.330), 0.821 (0.697-0.967) and 0.464 (0.384-0.561), while compared to never users. For the respective tertiles of cumulative dose, the HRs (95% CIs) were 1.131 (0.962-1.329), 0.739 (0.624-0.876) and 0.525 (0.438-0.629). A risk reduction among ever users was observed for all tertiles of defined daily dose but was most remarkable for the third tertile with a defined daily dose of >0.64. Subgroup analyses suggested that the benefit of metformin could be similarly observed among men and women and for age subgroups of 50-64 and 65-79 years. However, patients with diabetic retinopathy would not be significantly benefited and metformin did not seem to be preventive for exudative AMD.

    Conclusion: In general, metformin significantly reduces the risk of AMD.

    DOI: 10.3390/ph16020224


    Disease profiles in the Indigenous Australian population are suggestive of a common complement control haplotype.

    Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases 2023 May 26;

    Dubowsky JG, Estevez JJ, Craig JE, Appukuttan B, Carr JM.

    Aboriginal and Torres Strait Islander People (respectfully referred to as Indigenous Australians herein) are disparately burdened by many infectious and chronic diseases relative to Australians with European genetic ancestry. Some of these diseases are described in other populations to be influenced by the inherited profile of complement genes. These include complement factor B, H, I and complement factor H-related (CFHR) genes that can contribute to a polygenic complotype. Here the focus is on the combined deletion of CFHR1 and 3 to form a common haplotype (CFHR3-1Δ). The prevalence of CFHR3-1Δ is high in people with Nigerian and African American genetic ancestry and correlates to a higher frequency and severity of systemic lupus erythematosus (SLE) but a lower prevalence of age-related macular degeneration (AMD) and IgA-nephropathy (IgAN). This pattern of disease is similarly observed among Indigenous Australian communities. Additionally, the CFHR3-1Δ complotype is also associated with increased susceptibility to infection with pathogens, such as Neisseria meningitidis and Streptococcus pyogenes, which also have high incidences in Indigenous Australian communities. The prevalence of these diseases, while likely influenced by social, political, environmental and biological factors, including variants in other components of the complement system, may also be suggestive of the CFHR3-1Δ haplotype in Indigenous Australians. These data highlight a need to define the Indigenous Australian complotypes, which may lead to the discovery of new risk factors for common diseases and progress towards precision medicines for treating complement-associated diseases in Indigenous and non-Indigenous populations. Herein, the disease profiles suggestive of a common complement CFHR3-1Δ control haplotype are examined.

    DOI: 10.1016/j.meegid.2023.105453


    Trends and disparities in disease burden of age-related macular degeneration from 1990 to 2019: Results from the global burden of disease study 2019.

    Front Public Health. 2023 Apr 17;

    Jiang B, Jiang C, Li J, Lu P.

    Objectives: This study aims to estimate the trends and disparities in the worldwide burden for health of AMD, overall and by age, sex, socio-demographic index (SDI), region, and nation using prevalence and years lived with disability (YLDs) from Global Burden of Disease (GBD) study 2019.

    Methods: This retrospective study presents the prevalent AMD cases and YLDs from 1990-2019, as well as the age-standardized prevalence rate (ASPR) and age-standardized YLD rate (ASYR) of AMD. To measure changes over time, estimated annual percentage changes (EAPCs) of the age-standardized rates (ASRs) were analyzed globally, then studied further by sex, SDI, region, and nation. We included data from the 2019 Global Burden of Disease (GBD) database to examine AMD prevalence and YLDs from 1990-2019 in 204 countries and territories, as well as demographic information such as age, sex, SDI, region, and nation.

    Results: Globally, the number of prevalent AMD cases increased from 3,581,329.17 (95% uncertainty interval [UI], 3,025,619.4-4,188,835.7) in 1990 to 7,792,530 (95% UI, 6,526,081.5-9,159,394.9) in 2019, and the number of YLDs increased from 296,771.93 (95% uncertainty interval [UI], 205,462.8-418,699.82) in 1990 to 564,055.1 (95% UI, 392,930.7-789,194.64) in 2019. The ASPR of AMD had a decreased trend with an EAPC of -0.15 (95% confidence interval [CI], -0.2 to -0.11) from 1990 to 2019, and the ASYR of AMD showed a decreased trend with an EAPC of -0.71 (95% confidence interval [CI], -0.78 to -0.65) during this period. The prevalence and YLDs of AMD in adults over 50 years of age showed a significant increase. The prevalence and YLDs of AMD were significantly higher in females than males, overall. The ASPRs and ASYRs in low SDI regions was greater than in high SDI regions from 1990 to 2019. In addition, increases in prevalence and YLDs differed by regions and nations, as well as level of socio-economic development.

    Conclusion: The number of prevalent cases and YLDs due to AMD increased over 30 years and were directly linked to age, sex, socio-economic status, and geographic location. These findings can not only guide public health work but also provide an epidemiological basis for global strategy formulation regarding this global health challenge.

    DOI: 10.3389/fpubh.2023.1138428


    Effective health communication for age-related macular degeneration: An exploratory qualitative study.

    Ophthalmic Physiological optics: the journal of British College of Ophthalmic Optician (Optometrists). 2023 May 30.

    Wang E, Kalloniatis M, Ly A.

    Purpose: Age-related macular degeneration (AMD) is a major cause of vision loss globally. Patients with AMD may not always understand or retain the information about AMD communicated by their eyecare practitioner. This study aims to explore the characteristics of effective health communication for AMD, from both patients’ and eyecare practitioners’ perspectives. The purpose is to provide a foundation for understanding how health communication for AMD could potentially be improved in the future.

    Methods: A total of 10 focus groups involving 17 patients with AMD and 17 optometrists were conducted via web conferencing. Each session was audio-recorded, transcribed and analysed using the Grounded Theory Methodology.

    Results: The five themes identified are as follows: (1) materials’ quality, (2) materials’ relevance, (3) contextualising for the individual, (4) contextualising for the disease and (5) support network. Participants expressed concern about the unrealistic yet common depiction of vision loss in AMD as a black patch overlying common visual scenes. They also preferred education materials tailored to a specific disease stage and the regular opportunity to ask or answer questions. Longer appointment durations and peer support (from family, friends or others with AMD) were also valued.

    Conclusion: Optometrists are encouraged to focus on three over-arching dimensions when counselling patients with AMD in routine clinical practice: (1) curating and using disease and stage-specific, impactful education materials, (2) their chairside verbal communication techniques and (3) AMD-specific opportunities for care coordination among patient family and friends, peers and other multidisciplinary members of the care support team.

    DOI: 10.1111/opo.13168


    Mechanisms of Acquired Resistance to Anti-VEGF Therapy for Neovascular Eye Diseases.

    Investigative ophthalmology & visual science. 2023 May 1

    Sharma D, Zachary I, Jia H.

    Purpose: The purpose of this study was to evaluate clinical reports of response-loss in patients with neovascular eye diseases, such as neovascular age-related macular degeneration (AMD) and diabetic macular edema (DME), after repeated anti-vascular endothelial growth factor (VEGF) therapy. To assess experimental evidence of associations of other angiogenic growth factors and endothelial glycolytic pathways with the diseases and to propose the underlying mechanisms.

    Methods: Review of published clinical studies and experimental investigations.

    Results: Intravitreal injection of anti-VEGF biologic drugs (e.g. bevacizumab, ranibizumab, and aflibercept) is the front-line treatment for neovascular AMD and DME, and acts by halting the progression of excess blood vessel growth and leakage. Despite favorable clinical results, exudation returns in a number of patients after repeated administrations over time. Patients suffering from disease recurrence may have developed an acquired resistance to anti-VEGF therapy. We have analyzed clinical and preclinical findings on changes to angiogenic signaling pathways following VEGF-targeted treatment and hypothesize that switching to alternative pathways could potentially bypass VEGF blockade, accounting for development of resistance to anti-VEGF therapy. We have also discussed potential reprogramming of ocular endothelial glycolysis in response to VEGF antagonism and proposed that metabolic adaptations could impair blood-retinal barrier function, counteracting the clinical efficacy of VEGF-targeted therapies and contributing to a decline of response to them.

    Conclusions: Future studies of the mechanisms proposed in this review may shed some light on how these adaptations result in the development of acquired resistance to anti-VEGF therapy, which should help discover new therapeutic strategies for overcoming anti-VEGF resistance and improving clinical efficacy.

    DOI: 10.1167/iovs.64.5.28