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    Research Update 555

    FEATURED ARTICLE

    Prevalence and risk factors for age-related macular degeneration in a population-based cohort study of older adults in Northern Ireland using multimodal imaging: NICOLA Study.

    The British Journal of Ophthalmology. 2022 Oct 10

    Hogg RE, Wright DM, Quinn NB, Muldrew KA, Hamill B, Smyth L, McKnight AJ, Woodside J, Tully MA, Cruise S, McGuinness B, Young IS, Kee F, Peto T, Chakravarthy U.

    Purpose: To report prevalence and risk factor associations for age-related macular degeneration (AMD) and AMD features from multimodal retinal grading in a multidisciplinary longitudinal population-based study of aging in Northern Ireland.

    Study design: Population-based longitudinal cohort study.

    Methods: Retinal imaging at the Norther Ireland Cohort for the Longitudinal Aging Study health assessment included stereo Colour Fundus Photography (CFP) (Canon CX-1, Tokyo, Japan) and Spectral-Domain Optical Coherence Tomography (SD-OCT) ((Heidelberg Retinal Angopgraph (HRA)+OCT; Heidelberg Engineering, Heidelberg, Germany). Medical history and demographic information was obtained during a home interview. Descriptive statistics were used to describe the prevalence of AMD and individual AMD features. Multiple imputation followed by multiple regression modelling was used to explore risk factor associations including relationships with AMD genetic risk score.

    Results: Retinal images from 3386 participants were available for analysis. Mean age of the sample was 63.4 (SD 9.01, range: 36-99). Population weighted prevalence of AMD using colour grading in those over 55 years was: no drusen: 6 0.4%; drusen <63 μm: 15.9%; drusen 63-125 µm: 13.7%; drusen >125 µm or pigmentary changes: 8.3%; late AMD: 1.6%. Prevalence of AMD features in those over 55 years was: OCT drusen 27.5%, complete outer retinal pigment epithelium and outer retinal atrophy (cRORA) on OCT was 4.3%, reticular drusen 3.2% and subretinal drusenoid deposits 25.7%. The genetic risk score was significantly associated with drusen and cRORA but less so for SDD alone and non-significant for hyperpigmentation or vitelliform lesions.

    Conclusions: Multimodal imaging-based classification has provided evidence of some divergence of genetic risk associations between classical drusen and SDD. Our findings support an urgent review of current AMD severity classification systems.

    DOI: 10.1136/bjo-2021-320469

    DRUG TREATMENT

    Macular Atrophy Incidence, Progression, and Visual Acuity Effects in 5-Year Treatment of Neovascular Age-Related Macular Degeneration.

    Ophthalmic Surgery, Lasers Imaging Retina. 2022 Oct

    Richardson QR, Zhang Y, Deiner MS, Wang ST, Bhisitkul JM, Arnold BF, Bhisitkul RB.

    Background and objective: Macular atrophy (MA) contributes to declining vision during prolonged anti-vascular endothelial growth factor (VEGF) treatment in neovascular age-related macular degeneration (nAMD) so greater understanding of its incidence, evolution, and impact on visual acuity is merited.

    Materials and methods: This is a retrospective review of nAMD patients receiving anti-VEGF therapy for ≥ 5 years. Near-infrared reflectance images and vision data were extracted every 6 months. MA lesion areas were measured using ImageJ.

    Results: Vision showed a mean decline of -1.2 letters/year. Eyes with MA showed a greater decrease of -1.6 letters/year compared to eyes without MA (-0.7 letters/year). Cumulative incidence of MA was 38% at 5 years. MA was significantly associated with declining vision, showing a -0.7 letter decrease for every 1 mm2 increase in lesion size.

    Conclusion: Over a 5-year course of nAMD treatment, MA affected most eyes, and MA progression was significantly associated with vision decline.

    DOI: 10.3928/23258160-20220914-01

    The 0.19-mg fluocinolone acetonide intravitreal implant reduces treatment burden in diabetic macular edema.

    American Journal of Ophthalmology. 2022 Oct 9

    Merrill PT, Holekamp N, Roth D, Kasper J, Grigorian R; PALADIN Study Group.

    Purpose: To assess treatment burden in patients with diabetic macular edema (DME) following the 0.19-mg fluocinolone acetonide (FAc) intravitreal implant (ILUVIEN®).

    Design: Prospective and retrospective analyses of a 36-month, phase 4, open-label, observational study.

    Methods: Setting: Multicenter PATIENT POPULATION: Included patients had DME and previously received corticosteroid treatment without a clinically significant rise in intraocular pressure (IOP) (N=202 eyes in 159 patients). Patients were not randomized.

    Observation procedures: Prospective, observational treatment burden data were analyzed for their relationship to safety and functional efficacy outcomes across 36 months.

    Main outcome measures: Outcomes included the mean number of yearly treatments, supplemental-free probability over time, best-corrected visual acuity (BCVA), and monitoring of IOP-related events.

    Results: Over 36 months, the mean number of yearly treatments decreased from 3.5 pre-FAc to 1.7 post-FAc; at 36 months, 68.3% of patients required 0 to 2 treatments per year. Post-FAc, the percent of eyes requiring supplemental therapy decreased vs pre-FAc (P<0.0001 for each). Through 36 months, 25% of FAc-treated eyes did not require supplemental treatment. At 36 months, mean BCVA increased by 4.5 letters vs a decline of 6.4 letters in the 36 months pre-FAc. IOP elevations >25 mmHg occurred in 18.2% of eyes that did not receive supplemental treatment post-FAc vs 27.2% of eyes that received supplemental treatments, which included additional intraocular steroids.

    Conclusions: Over 36 months, the FAc implant is associated with improved visual outcomes and better disease control as measured by a significant reduction in yearly treatment burden in patients with DME.

    DOI: 10.1016/j.ajo.2022.09.017

    BIOMARKERS

    Optical Coherence Tomography Biomarkers for Conversion to Exudative Neovascular Age-related Macular Degeneration.

    American Journal of Ophthalmology. 2022 Oct 10

    Wakatsuki Y, Hirabayashi K, Yu HJ, Marion KM, Corradetti G, Wykoff CC, Sadda SR.

    Purpose: To identify optical coherence tomography (OCT) biomarkers, including thin and thick double layer sign (DLS) for the progression from intermediate AMD (iAMD) to exudative macular neovascularization (MNV) over 24 months.

    Design: Retrospective cohort study METHODS: Setting: Retina Consultants of Texas

    Patient population: 458 eyes of 458 subjects with iAMD in at least one eye with 24 months of follow-up data.

    Main outcomes measures: The following biomarkers were assessed at baseline: high central drusen volume (≥0.03 mm3), intraretinal hyperreflective foci (IHRF), subretinal drusenoid deposits, hyporeflective drusen cores, thick DLS, thin DLS, and central choroidal thickness. A binary logistic regression was computed to investigate the association between baseline OCT covariates and the conversion to exudative MNV within 24 months. In addition, fellow eye status was also included in the model.

    Results: During follow-up, 18.1% (83/458) of eyes with iAMD progressed to exudative MNV. Thick DLS, IHRF, and fellow eye exudative MNV were found to be independent predictors for the development of exudative MNV within 2 years. The baseline frequencies, odds ratios, 95% confidence intervals, and p-values for these biomarkers were as follows: thick DLS (9.6%, 4.339, 2.178-8.644; p<0.001), IHRF (36.0%, 2.340, 1.396-3.922; p=0.001), and fellow eye exudative MNV (35.8%, 1.694, 1.012-2.837; p=0.045).

    Conclusions: Thick DLS, IHRF, and fellow eye exudative MNV were associated with an increased risk of progression from iAMD to exudative MNV. These biomarkers which are readily identified by review of OCT volume scans may aid in risk prognostication for patients and for identifying patients for early intervention trials.

    DOI: 10.1016/j.ajo.2022.09.018

    DIAGNOSIS AND IMAGING

    Choroidal vascular density in diabetic retinopathy assessed with swept-source optical coherence tomography.

    Retina  2022 Oct 10

    Nakano H, Hasebe H, Murakami K, Nakamura Y, Fukuchi T.

    Purpose: We aimed to assess choroidal vascularity by diabetic retinopathy stage using the choroidal vascular density (CVD) obtained from swept source optical coherence tomography (SS-OCT) en face images.

    Methods: This prospective, cross-sectional, multicenter study included patients from Niigata City General Hospital and Saiseikai Niigata Hospital between October 2016 and October 2017. CVD was obtained by binarizing SS-OCT en face images of patients with diabetes and those with diabetic retinopathy (DR), patients without DR, and healthy age-matched volunteers.

    Results: Patients were allocated to the healthy control (n=28), no DR (n=23), non-proliferative DR (NPDR) without diabetic macular edema (DME) (n=50), NPDR+DME (n=38), and proliferative diabetic retinopathy (PDR) or any previous treatment with panretinal photocoagulation (n=26) groups. Investigation of the choriocapillaris slab level indicated that the no DR group had significantly high CVD values (p<0.05) and the PDR groups had significantly low CVD values (p<0.01). Investigation of the large choroidal vessel level indicated that the NPDR+DME and PDR groups had significantly lower CVD values than the control group (p<0.05 and p<0.01, respectively).

    Conclusion: We found that at the choriocapillaris slab level, the no DR group had a higher CVD and the NPDR with DME and PDR groups had a lower CVD than the control group. At the level of the large choroidal vessels, the NPDR with DME and PDR groups had a lower CVD than the control. There were significant differences in choroidal vasculature found using CVD obtained from SS-OCT en face images of diabetes and DR patients.

    DOI: 10.1097/IAE.0000000000003644

    Evaluation of macular microvascular structure with optical coherence tomography angiography in children with history of treatment for retinopathy of prematurity

    Graefes Arch Clin Exp Ophthalmol. 2022 Sep 26.

    Kılıçarslan O, Akar S, Yılmaz Çebi A, Hagverdiyeva S, Arvas S.

    Purpose: To compare macula vascular parameters in optical coherence tomography angiography (OCTA) of children with history of retinopathy of prematurity (ROP) who were treated with laser photocoagulation (LPC) or intravitreal Bevacizumab therapy.

    Methods: Forty eyes of 28 ROP children treated with LPC and 36 eyes of 22 ROP children treated with intravitreal Bevacizumab and 40 eyes of 40 age-gender matched term children were included the study. Capillary plexus densities in macula, FAZ parameters, outer retina and choriocapillaris flow rates, and central foveal thickness were measured.

    Results: Foveal superficial and deep capillary plexus densities were found significantly higher in LPC and intravitreal Bevacizumab injection (IBI) groups compared to control group. FAZ area was found significantly lower in LPC and IBI groups compared to control group (p ‹ 0.001). Higher foveal superficial capillary plexus density, higher central foveal thickness, and lower FAZ area were found to be associated with poorer visual acuity in correlation analysis (p ‹ 0.05). In IBI group, earlier anti-VEGF therapy was found to be associated with lower foveal superficial capillary plexus density.

    Conclusion: Microvascular characteristics such as FAZ area and capillary plexus densities of macula are deteriorated in ROP. There is no significant difference between the treatment alternatives of ROP in terms of macular microvascular parameters.

    DOI: 10.1007/s00417-022-05834-z

    PATIENT EXPERIENCE

    Association of visual health with depressive symptoms and brain imaging phenotypes among middle-aged and older adults

    JAMA Network Open 2022 Oct 3

    Xiayin Zhang, Xianwen Shang, Ishith Seth, Yu Huang, Yaxin Wang, Yingying Liang, Zijing Du, Guanrong Wu, Yunyan Hu, Shunming Liu, Yijun Hu, Mingguang He, Zhuoting Zhu, Xiaohong Yang, Honghua Yu

    Importance: Vision loss and depression are common conditions with major health implications. However, mechanisms of the association of visual health (across the full acuity spectrum) with depression remain unclear.

    Objective: To characterize the association between visual health and depression and investigate the association between depression and brain microstructure and macrostructure in subgroups divided by visual acuity.

    Design, Setting, and Participants: In the UK Biobank Study cohort, 114 583 volunteers were included at baseline from March to June 2006 to July 2010. Habitual distance visual acuity was examined using the logarithm of the minimum angle of resolution (LogMAR) characters. Depression was identified based on Patient Health Questionnaire (PHQ) or through an interview-based psychiatric diagnosis. Subgroup participants completed multimodal magnetic resonance imaging (MRI) of the brain and PHQ evaluation during the imaging visit after 2014. Data were analyzed from May 5 to August 9, 2022.

    Main Outcomes and Measures: Depression, depressive symptoms, and imaging-derived phenotypes from T1-weighted and diffusion MRI.

    Results: Of the 114 583 participants from the UK Biobank Study, 62 401 (54.5%) were women, and the mean (SD) age was 56.8 (8.1) years (range, 39-72 years). A 1-line worse visual acuity (0.1 LogMAR increase) was associated with 5% higher odds of depression (odds ratio, 1.05 [95% CI, 1.04-1.07]) after adjustment for age, sex, race and ethnicity, Townsend index, educational qualifications, smoking, alcohol consumption, obesity, physical activity, history of hypertension, diabetes, hyperlipidemia, and family history of depression. Of the 7844 participants eligible for MRI analysis, there were linear associations between PHQ score and the left volume of gray matter in supracalcarine cortex (coefficient, 7.61 [95% CI, 3.90-11.31]) and mean isotropic volume fraction (ISOVF) in the right fornix (cres) and/or stria terminalis (coefficient, 0.003 [95% CI, 0.001-0.004]) after correction for multiple comparison. In addition, their association could be moderated by visual acuity, whereby increased PHQ score was associated with higher ISOVF levels only among those with poorer visual acuity (P = .02 for interaction).

    Conclusions and Relevance: This study suggests an association between visual health and depression and that the diffusion characteristic of ISOVF in the fornix (cres) and/or stria terminalis is associated with depressive symptoms in participants with poorer visual acuity.

    DOI: 10.1001/jamanetworkopen.2022.35017

    Multi-res: An interface for improving reading without central vision.

    Vision Research. 2022 Oct 8

    Snell J, van Kempen T, Olivers CNL.

    Loss of sharp foveal vision, as is inherent to Macular Degeneration (MD), severely impacts reading. One strategy for preserving patients’ reading ability involves a one-by-one serial visual presentation (SVP) of words, whereby words are viewed extrafoveally. However, the method is limited as patients often retain the natural tendency to foveate words, thus bringing those words in the scotomal region. Additionally, SVP offers no compensation for the fact that orthographic input is degraded outside the fovea. Addressing these issues, here we tested a novel interface wherein texts are presented word-by-word, but with multiple repetitions (Multi-Res) of each word being displayed simultaneously around the fovea. We hypothesized that the Multi-Res setup would lead readers to make fewer detrimental eye movements, and to recognize words faster as a consequence of multiplied orthographic input. We used eye-tracking to simulate a gaze-contingent foveal scotoma in normally-sighted participants, who read words either in classic SVP or in Multi-Res mode. In line with our hypotheses, reading was drastically better in the Multi-Res condition, with faster recognition, fewer saccades and increased oculomotor stability. We surmise that the Multi-Res method has good potential for improving reading in central vision loss, over and above classic SVP techniques.

    DOI: 10.1016/j.visres.2022.108129

    REVIEWS

    The role of the adaptive immune system and T cell dysfunction in neurodegenerative diseases.

    Journal of Neuroinflammation. 2022 Oct 8

    DeMaio A, Mehrotra S, Sambamurti K, Husain S.

    The adaptive immune system and associated inflammation are vital in surveillance and host protection against internal and external threats, but can secondarily damage host tissues. The central nervous system is immune-privileged and largely protected from the circulating inflammatory pathways. However, T cell involvement and the disruption of the blood-brain barriers have been linked to several neurodegenerative diseases including Parkinson’s disease, Alzheimer’s disease, and multiple sclerosis. Under normal physiological conditions, regulatory T cells (Treg cells) dampen the inflammatory response of effector T cells. In the pathological states of many neurodegenerative disorders, the ability of Treg cells to mitigate inflammation is reduced, and a pro-inflammatory environment persists. This perspective review provides current knowledge on the roles of T cell subsets (e.g., effector T cells, Treg cells) in neurodegenerative and ocular diseases, including uveitis, diabetic retinopathy, age-related macular degeneration, and glaucoma. Many neurodegenerative and ocular diseases have been linked to immune dysregulation, but the cellular events and molecular mechanisms involved in such processes remain largely unknown. Moreover, the role of T cells in ocular pathologies remains poorly defined and limited literature is available in this area of research. Adoptive transfer of Treg cells appears to be a vital immunological approach to control ocular pathologies. Similarities in T cell dysfunction seen among non-ocular neurodegenerative diseases suggest that this area of research has a great potential to develop better therapeutic agents for ocular diseases and warrants further studies. Overall, this perspective review article provides significant information on the roles of T cells in numerous ocular and non-ocular neurodegenerative diseases.

    DOI: 10.1186/s12974-022-02605-9