Phase 1 Clinical Trial of Elamipretide in Dry Age-Related Macular Degeneration and Noncentral Geographic Atrophy: ReCLAIM NCGA Study.

Purpose: Assess the safety, tolerability, and feasibility of subcutaneous administration of the mitochondrial-targeted drug elamipretide in patients with dry age-related macular degeneration (AMD) and noncentral geographic atrophy (NCGA) and to perform exploratory analyses of change in visual function. Design: Phase 1, single-center, open-label, 24-week clinical trial with preplanned NCGA cohort. Participants: Adults ≥ 55 years of age with dry AMD and NCGA. Methods: Participants received subcutaneous elamipretide 40-mg daily; safety and tolerability assessed throughout. Ocular assessments included normal-luminance best-corrected visual acuity (BCVA), low-luminance BCVA (LLBCVA), normal-luminance binocular reading acuity (NLBRA), low-luminance binocular reading acuity (LLBRA), spectral-domain OCT, fundus autofluorescence (FAF), and patient self-reported function by low-luminance questionnaire (LLQ). Main Outcome Measures: Primary end point was safety and tolerability. Prespecified exploratory end-points included changes in BCVA, LLBCVA, NLBRA, LLBRA, geographic atrophy (GA) area, and LLQ. Results: Subcutaneous elamipretide was highly feasible. All participants (n = 19) experienced 1 or more nonocular adverse events (AEs), but all AEs were either mild (73.7%) or moderate (26.3%); no serious AEs were noted. Two participants exited the study because of AEs (conversion to neovascular AMD, n = 1; intolerable injection site reaction, n = 1), 1 participant discontinued because of self-perceived lack of efficacy, and 1 participant chose not to continue with study visits. Among participants completing the study (n = 15), mean ± standard deviation (SD) change in BCVA from baseline to week 24 was +4.6 (5.1) letters (P = 0.0032), while mean change (SD) in LLBCVA was +5.4 ± 7.9 letters (P = 0.0245). Although minimal change in NLBRA occurred, mean ± SD change in LLBCVA was -0.52 ± 0.75 logarithm of the minimum angle of resolution units (P = 0.005). Mean ± SD change in GA area (square root transformation) from baseline to week 24 was 0.14 ± 0.08 mm by FAF and 0.13 ± 0.14 mm by OCT. Improvement was observed in LLQ for dim light reading and general dim light vision. Conclusions: Elamipretide seems to be well tolerated without serious AEs in patients with dry AMD and NCGA. Exploratory analyses demonstrated possible positive effect on visual function, particularly under low luminance. A Phase 2b trial is underway to evaluate elamipretide further in dry AMD and NCGA.

Phase 1 Clinical Trial of Elamipretide in Intermediate Age-Related Macular Degeneration and High-Risk Drusen: ReCLAIM High-Risk Drusen Study.

Purpose: To assess safety, tolerability, and feasibility of subcutaneous administration of the mitochondrial-targeted drug elamipretide in patients with intermediate age-related macular degeneration (AMD) and high-risk drusen (HRD) and to perform exploratory analyses of change in visual function. Design: Phase 1, single-center, open-label, 24-week clinical trial with preplanned HRD cohort. Participants: Adult patients ≥55 years of age with intermediate AMD and HRD. Methods: Participants received subcutaneous elamipretide 40 mg daily, with safety and tolerability assessed throughout the study. Ocular assessments included normal-luminance best-corrected visual acuity (BCVA), low-luminance best-corrected visual acuity (LLVA), normal-luminance binocular reading acuity (NLRA), low-luminance binocular reading acuity (LLRA), spectral-domain OCT, fundus autofluorescence (FAF), mesopic microperimetry, dark adaptation, and low-luminance questionnaire (LLQ). Main Outcome Measures: The primary end point was safety and tolerability. Prespecified exploratory end points included changes from baseline in BCVA, LLVA, NLRA, LLRA, retinal pigment epithelium (RPE)-drusen complex (DC) volume by OCT, FAF, mesopic microperimetry, dark adaptation, and LLQ results. Results: Subcutaneous administration of elamipretide was highly feasible. All participants with HRD (n = 21) experienced 1 or more adverse events (AEs), but all were mild (57%) or moderate (43%), with the most common events related to injection site reactions. No serious systemic AEs occurred. One participant discontinued because of injection site reaction, 1 participant withdrew because they did not wish to continue study visits, and 1 participant withdrew after experiencing transient visual impairment. Among the 18 participants who completed the study, mean change in BCVA from baseline to 24 weeks was +3.6 letters (P = 0.014) and LLVA was +5.6 letters (P = 0.004). Compared with baseline, mean NLRA improved by -0.11 logarithm of the minimum angle of resolution (logMAR) units (P = 0.001), and LLRA by -0.28 logMAR units (P < 0.0001). Significant improvements were found in 6 of 7 subscales of the LLQ (P <0.0015). No significant changes were observed for RPE-DC volume, FAF, mesopic microperimetry, or dark adaptation. Conclusions: Elamipretide appeared to be generally safe and well tolerated in treating intermediate AMD and HRD. Exploratory analyses demonstrate a positive effect on visual function, particularly under low-luminance conditions. Further study of elamipretide for treatment of intermediate AMD with HRD is warranted.

Incidence of Referable Retinal Disease in Diabetic Patients at a Primary Care Practice.

Purpose: This work tests the feasibility of remote ophthalmic imaging to identify referable retinal abnormalities and assesses the effectiveness of color fundus photography (CFP) vs optical coherence tomography (OCT) for this purpose. Methods: This prospective, nonrandomized study included 633 patients with diabetes at Duke Primary Care. Undilated patients underwent screening with CFP and OCT camera (MaestroCare, Topcon). Images were graded independently for interpretability and the presence of predetermined retinal disease. Retinal disease was classified as diabetic retinopathy (DR) referable to a retina specialist or incidental findings referable to either a retina specialist or a general ophthalmologist, depending on severity. Results: Mean (SD) age of screened patients was 66 (13) years, and 49% were women. The average glycated hemoglobin A1c level was 7.6 % (SD, 1.7%), and 30% of the patients were on insulin. The average duration of diabetes was 5.9 (SD, 7.3) years. Remote images from OCT were significantly more interpretable than CFP (98% vs 83%, respectively; P < .001). Referral rates were 9% for DR and 28% for incidental findings. Among patients with DR, OCT and CFP were helpful in 58% and 87% of cases, respectively (P < .001). Conclusions: Remote diagnosis of ophthalmic imaging at the point of service may allow for early identification of retinal disease and timely referral and treatment. Our approach showed that OCT had significantly better interpretability, while CFP was more helpful in identifying DR. These findings may be important when choosing the screening device in a specific context.

Immunological Aspects of Age-Related Macular Degeneration.

Increasing evidence over the past two decades points to a pivotal role for immune mechanisms in age-related macular degeneration (AMD) pathobiology. In this chapter, we will explore immunological aspects of AMD, with a specific focus on how immune mechanisms modulate clinical phenotypes of disease and severity and how components of the immune system may serve as triggers for disease progression in both dry and neovascular AMD. We will briefly review the biology of the immune system, defining the role of immune mechanisms in chronic degenerative disease and differentiating from immune responses to acute injury or infection. We will explore current understanding of the roles of innate immunity (especially macrophages), antigen-specific immunity (T cells, B cells, and autoimmunity), immune amplifications systems, especially complement activity and the NLRP3 inflammasome, in the pathogenesis of both dry and neovascular AMD, reviewing data from pathology, experimental animal models, and clinical studies of AMD patients. We will also assess how interactions between the immune system and infectious pathogens could potentially modulate AMD pathobiology via alterations in in immune effector mechanisms. We will conclude by reviewing the paradigm of "response to injury," which provides a means to integrate various immunologic mechanisms along with nonimmune mechanisms of tissue injury and repair as a model to understand the pathobiology of AMD.

Cerebral white matter connectivity, cognition, and age-related macular degeneration.

Age-related macular degeneration (AMD) is a common retina disease associated with cognitive impairment in older adults. The mechanism(s) that account for the link between AMD and cognitive decline remain unclear. Here we aim to shed light on this issue by investigating whether relationships between cognition and white matter in the brain differ by AMD status. In a direct group comparison of brain connectometry maps from diffusion weighted images, AMD patients showed significantly weaker quantitative anisotropy (QA) than healthy controls, predominantly in the splenium and left optic radiation. The QA of these tracts, however, did not correlate with the visual acuity measure, indicating that this group effect is not directly driven by visual loss. The AMD and control groups did not differ significantly in cognitive performance.Across all participants, better cognitive performance (e.g. verbal fluency) is associated with stronger connectivity strength in white matter tracts including the splenium and the left inferior fronto-occipital fasciculus/inferior longitudinal fasciculus. However, there were significant interactions between group and cognitive performance (verbal fluency, memory), suggesting that the relation between QA and cognitive performance was weaker in AMD patients than in controls.This may be explained by unmeasured determinants of performance that are more common or impactful in AMD or by a recruitment bias whereby the AMD group had higher cognitive reserve. In general, our findings suggest that neural degeneration in the brain might occur in parallel to AMD in the eyes, although the participants studied here do not (yet) exhibit overt cognitive declines per standard assessments.

Incomplete response to Anti-VEGF therapy in neovascular AMD: Exploring disease mechanisms and therapeutic opportunities.

Intravitreal anti-vascular endothelial growth factor (VEGF) drugs have revolutionized the treatment of neovascular age-related macular degeneration (NVAMD). However, many patients suffer from incomplete response to anti-VEGF therapy (IRT), which is defined as (1) persistent (plasma) fluid exudation; (2) unresolved or new hemorrhage; (3) progressive lesion fibrosis; and/or (4) suboptimal vision recovery. The first three of these collectively comprise the problem of persistent disease activity (PDA) in spite of anti-VEGF therapy. Meanwhile, the problem of suboptimal vision recovery (SVR) is defined as a failure to achieve excellent functional visual acuity of 20/40 or better in spite of sufficient anti-VEGF treatment. Thus, incomplete response to anti-VEGF therapy, and specifically PDA and SVR, represent significant clinical unmet needs. In this review, we will explore PDA and SVR in NVAMD, characterizing the clinical manifestations and exploring the pathobiology of each. We will demonstrate that PDA occurs most frequently in NVAMD patients who develop high-flow CNV lesions with arteriolarization, in contrast to patients with capillary CNV who are highly responsive to anti-VEGF therapy. We will review investigations of experimental CNV and demonstrate that both types of CNV can be modeled in mice. We will present and consider a provocative hypothesis: formation of arteriolar CNV occurs via a distinct pathobiology, termed neovascular remodeling (NVR), wherein blood-derived macrophages infiltrate the incipient CNV lesion, recruit bone marrow-derived mesenchymal precursor cells (MPCs) from the circulation, and activate MPCs to become vascular smooth muscle cells (VSMCs) and myofibroblasts, driving the development of high-flow CNV with arteriolarization and perivascular fibrosis. In considering SVR, we will discuss the concept that limited or poor vision in spite of anti-VEGF may not be caused simply by photoreceptor degeneration but instead may be associated with photoreceptor synaptic dysfunction in the neurosensory retina overlying CNV, triggered by infiltrating blood-derived macrophages and mediated by Müller cell activation Finally, for each of PDA and SVR, we will discuss current approaches to disease management and treatment and consider novel avenues for potential future therapies.

Deep learning-based single-shot prediction of differential effects of anti-VEGF treatment in patients with diabetic macular edema.

Anti-vascular endothelial growth factor (VEGF) agents are widely regarded as the first line of therapy for diabetic macular edema (DME) but are not universally effective. An automatic method that can predict whether a patient is likely to respond to anti-VEGF therapy can avoid unnecessary trial and error treatment strategies and promote the selection of more effective first-line therapies. The objective of this study is to automatically predict the efficacy of anti-VEGF treatment of DME in individual patients based on optical coherence tomography (OCT) images. We performed a retrospective study of 127 subjects treated for DME with three consecutive injections of anti-VEGF agents. Patients' retinas were imaged using spectral-domain OCT (SD-OCT) before and after anti-VEGF therapy, and the total retinal thicknesses before and after treatment were extracted from OCT B-scans. A novel deep convolutional neural network was designed and evaluated using pre-treatment OCT scans as input and differential retinal thickness as output, with 5-fold cross-validation. The group of patients responsive to anti-VEGF treatment was defined as those with at least a 10% reduction in retinal thickness following treatment. The predictive performance of the system was evaluated by calculating the precision, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC). The algorithm achieved an average AUC of 0.866 in discriminating responsive from non-responsive patients, with an average precision, sensitivity, and specificity of 85.5%, 80.1%, and 85.0%, respectively. Classification precision was significantly higher when differentiating between very responsive and very unresponsive patients. The proposed automatic algorithm accurately predicts the response to anti-VEGF treatment in DME patients based on OCT images. This pilot study is a critical step toward using non-invasive imaging and automated analysis to select the most effective therapy for a patient's specific disease condition.

Aldosterone as a mediator of severity in retinal vascular disease: Evidence and potential mechanisms.

Diabetic retinopathy (DR) and retinal vein occlusion (RVO) are the two most common retinal vascular diseases and are major causes of vision loss and blindness worldwide. Recent and ongoing development of medical therapies including anti-vascular endothelial growth factor and corticosteroid drugs for treatment of these diseases have greatly improved the care of afflicted patients. However, severe manifestations of retinal vascular disease result in persistent macular edema, progressive retinal ischemia and incomplete visual recovery. Additionally, choroidal vascular diseases including neovascular age-related macular degeneration (NVAMD) and central serous chorioretinopathy (CSCR) cause vision loss for which current treatments are incompletely effective in some cases and highly burdensome in others. In recent years, aldosterone has gained attention as a contributor to the various deleterious effects of retinal and choroidal vascular diseases via a variety of mechanisms in several retinal cell types. The following is a review of the role of aldosterone in retinal and choroidal vascular diseases as well as our current understanding of the mechanisms by which aldosterone mediates these effects.

Evaluation of a Remote Diagnosis Imaging Model vs Dilated Eye Examination in Referable Macular Degeneration.

Importance: In improving clinical outcomes, developing a sustainable, transformative care delivery model is important for accessible, efficient, low-cost, high-quality community-based imaging and diagnosis of retinal diseases. Objective: To test the feasibility and accuracy of the remote diagnosis imaging model as a clinical screening tool to facilitate the identification of referable macular degeneration. Design, Setting, and Participants: A nonrandomized study of 159 patients was conducted in sites with a relatively high disease prevalence (Duke University Health System endocrinology clinic and 2 Duke University Health System assisted living centers in North Carolina). All patients underwent remote diagnosis imaging, defined as color fundus photography (CFP) and optical coherence tomography (OCT) of nondilated pupils, acquired by nonexpert imagers using a retinal imaging device located at the point of service. The criterion standard examination was defined as a traditional dilated eye examination performed by retinal specialists. Deidentified remote diagnosis images were graded for interpretability and presence of referable macular degeneration, defined as any condition requiring a retinal specialist attention. Data analysis was performed from November 20, 2015, to February 10, 2019. Main Outcomes and Measures: Primary outcome was feasibility of the remote retinal imaging. Secondary outcomes were operational characteristics and diagnostic and referral accuracy. Results: Of the 159 patients included in the study, the mean (SD) age of enrolled participants was 65 (17) years, with a female to male ratio of 1.3 to 1. Most patients were white (111 [69.8%]), 44 were black patients (27.7%), approximately 1% were Asian patients and Hispanic patients, and 2 patients declined to disclose their race/ethnicity. Thirty-five eyes (22.0%) were determined to require referral to the retinal specialist by criterion standard examination. Remote diagnosis image interpretability was better when OCT was used compared with CFP (241 [96.4%] vs 164 [65.6%]). Remote diagnosis had high diagnostic accuracy in identifying referable macular degeneration: OCT and CFP both had 94% sensitivity (95% CI, 84%-98%), and OCT had specificity higher than for CFP (93% [95% CI, 87%-96% ] vs 63% [95% CI, 53%-71%]). Substantial agreement was found between the criterion standard and OCT (κ = 0.83; 95% CI, 0.76-0.91; P < .001) and between the criterion standard and CFP (κ = 0.76; 95% CI, 0.64-0.87; P < .001). The nonvalidated patient satisfaction survey revealed that 122 participants (76.7%; mean score, 4.16; 95% CI, 3.98-4.35) preferred remote imaging over the standard care examination. Conclusions and Relevance: Remote diagnosis imaging and a standard examination by a retinal specialist appeared equivalent in identifying referable macular degeneration in patients with high disease prevalence; these results may assist in delivering timely treatment and seem to warrant future research into additional metrics.

Longitudinal Study of Visual Function in Dry Age-Related Macular Degeneration at 12 Months.

PURPOSE: To report the 1-year progression of visual impairment on psychophysical tests of visual function in patients with early and intermediate age-related macular degeneration (AMD). DESIGN: Prospective, observational study. PARTICIPANTS: Patients with early and intermediate AMD were enrolled from the existing population at the Duke Eye Center, and healthy age-matched control participants were recruited from family members or friends of the AMD patients and from the Duke Optometry and Comprehensive Eye Clinics. METHODS: Patients and control participants recruited during the baseline study were assessed at both 6 and 12 months after the initial study visit. Measurements of visual function included best-corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), low-luminance deficit (LLD), microperimetry percent-reduced threshold (PRT), microperimetry average threshold (AT), and cone contrast tests (CCTs). MAIN OUTCOME MEASURES: Changes in BCVA, LLVA, LLD, microperimetry PRT, microperimetry AT, and CCT results from baseline to 6 months and to 12 months were assessed. RESULTS: Eighty-five patients completed the 12-month examination (19 control participants, 27 early AMD patients, and 39 intermediate AMD patients). Longitudinal analysis detected significant changes from baseline within each group in microperimetry PRT and AT and in the intermediate AMD group only for BCVA and CCT results (P < 0.05). CONCLUSIONS: Microperimetry and CCT are able to detect functional changes resulting from progression of dry AMD within a period as short as 12 months. These functional markers may be useful end points in future clinical trials that assess the effect of potential treatments for AMD.

Aldosterone Exposure Causes Increased Retinal Edema and Severe Retinopathy Following Laser-Induced Retinal Vein Occlusion in Mice.

Purpose: To determine the effects of aldosterone exposure on retinal edema and retinopathy in a mouse model of retinal vein occlusion (RVO). Methods: RVO was induced immediately following intravenous injection of Rose bengal (66 mg/kg) using a 532-nm wavelength laser to place three to seven applications at 80 mW and 50-µm spot size directed at the superior retinal vein one disc diameter away from the nerve. Negative control consisted of placing an equal number of laser spots without targeting the vein. Male and female C57BL/6J mice aged 7 to 9 months with confirmed absence of Crb1rd8 were used. Aldosterone pellets releasing a daily dose of 0.83 µg/day were implanted subcutaneously 4 weeks prior to RVO. Retinal imaging by optical coherence tomography (OCT) was performed using a Micron IV rodent imaging system. Retinas were analyzed by immunohistochemistry using standard techniques. Retinal imaging and tissue analysis were performed 2, 4, and 7 days following RVO. Comparisons were made using Student's t-test, ANOVA, and Pearson's χ2. Results: RVO caused retinal edema in the form of cystic spaces and retinal thickening detectable by both OCT and histology. RVO also caused Müller glia (MG) dysfunction manifest as upregulated glial fibrillary acidic protein (GFAP) and altered localization of aquaporin 4 (AQP4) and Kir4.1. Treatment with aldosterone caused a significant increase in retinal edema and more severe retinopathy manifest as retinal whitening and extensive intraretinal hemorrhage. MG dysfunction was more severe and persistent in aldosterone-treated mice. Finally, aldosterone greatly increased the number of infiltrating mononuclear phagocytes following RVO. Conclusions: Systemic aldosterone exposure causes a more severe RVO phenotype manifest as increased severity and duration of retinal edema and more severe retinopathy. The effects of aldosterone may be mediated by MG dysfunction and increased infiltration of mononuclear phagocytes. This suggests that small increases in aldosterone levels may be a risk factor for severe RVO.

Evaluation of inner retinal layers as biomarkers in mild cognitive impairment to moderate Alzheimer's disease.

Inner retina in Alzheimer's Disease (AD) may experience neuroinflammation resulting in atrophy. The objective of our study was to determine whether retinal GCIPL (ganglion cell-inner plexiform layer) or nerve fiber layer (NFL) thickness may serve as noninvasive biomarkers to diagnose AD. This cross-sectional case-control study enrolled 15 mild cognitive impairment (MCI) patients, 15 mild-moderate AD patients, and 18 cognitively normal adults. NFL and GCIPL thicknesses on optical coherence tomography (OCT) were measured using Duke Optical Coherence Tomography Retinal Analysis Program (DOCTRAP) and Spectralis software. We demonstrated that regional thicknesses of NFL or GCIPL on macular or nerve OCTs did not differ between groups. However, a multi-variate regression analysis identified macular areas with a significant thickening or thinning in NFL and GCIPL in MCI and AD patients. Our primary findings controvert previous reports of thinner NFL in moderate-to-severe AD. The areas of thickening of GCIPL and NFL in the macula adjacent to areas of thinning, as revealed by a more complex statistical model, suggest that NFL and GCIPL may undergo dynamic changes during AD progression.

Visual Function Metrics in Early and Intermediate Dry Age-related Macular Degeneration for Use as Clinical Trial Endpoints.

PURPOSE: To evaluate and quantify visual function metrics to be used as endpoints of age-related macular degeneration (AMD) stages and visual acuity (VA) loss in patients with early and intermediate AMD. DESIGN: Cross-sectional analysis of baseline data from a prospective study. METHODS: One hundred and one patients were enrolled at Duke Eye Center: 80 patients with early AMD (Age-Related Eye Disease Study [AREDS] stage 2 [n = 33] and intermediate stage 3 [n = 47]) and 21 age-matched, normal controls. A dilated retinal examination, macular pigment optical density measurements, and several functional assessments (best-corrected visual acuity, macular integrity assessment mesopic microperimety, dark adaptometry, low-luminance visual acuity [LLVA] [standard using a log 2.0 neutral density filter and computerized method], and cone contrast test [CCT]) were performed. Low-luminance deficit (LLD) was defined as the difference in numbers of letters read at standard vs low luminance. Group comparisons were performed to evaluate differences between the control and the early and intermediate AMD groups using 2-sided significance tests. RESULTS: Functional measures that significantly distinguished between normal and intermediate AMD were standard and computerized (0.5 cd/m2) LLVA, percent reduced threshold and average threshold on microperimetry, CCTs, and rod intercept on dark adaptation (P < .05). The intermediate group demonstrated deficits in microperimetry reduced threshhold, computerized LLD2, and dark adaptation (P < .05) relative to early AMD. CONCLUSIONS: Our study suggests that LLVA, microperimetry, CCT, and dark adaptation may serve as functional measures differentiating early-to-intermediate stages of dry AMD.

Association of Low Luminance Questionnaire With Objective Functional Measures in Early and Intermediate Age-Related Macular Degeneration.

Purpose: To determine whether Low Luminance Questionnaire (LLQ) scores are associated with objective measures of visual function in early and intermediate age-related macular degeneration (AMD). Methods: Cross-sectional study of subjects with early AMD Age-Related Eye Disease Study (AREDS) stage 2, N = 33), intermediate AMD (AREDS stage 3, N = 47), and age-matched healthy controls (N = 21). Subjects were interviewed with the LLQ. Psychophysical tests performed included best-corrected visual acuity (BCVA), mesopic microperimetry, dark adaptometry (DA), low luminance visual acuity (LLVA), and cone contrast test (CCT). Low luminance deficit (LLD) was the difference in the number of letters read under photopic versus low luminance settings. The relationship between LLQ and visual function test scores was assessed with linear regression. Results: Subjects with intermediate AMD had significantly lower LLQ composite scores (mean = 75.8 ± 16.7; median = 76, range [29, 97]) compared with early AMD (mean = 85.3 ± 13.3; median = 88, range [50, 100], P = 0.007) or controls (mean = 91.4 ± 6.5; median = 94, range [79, 99], P < 0.001) in the overall cohort. LLQ composite scores were associated with computerized BCVA (ß = 0.516), computerized LLVA at two background luminance (1.3 cd/m2, ß = 0.660; 0.5 cd/m2, ß = 0.489) along with their respective computerized LLDs (ß = -0.531 and -0.467), rod intercept (ß = -0.312), and CCT green (ß = 0.183) (all P < 0.05). Only the computerized LLVAs and computerized LLDs remained statistically significant after adjusting for AMD versus control status (P < 0.05). Among AMD subjects, LLQ composite scores were significantly associated with the computerized LLVAs (ß = 0.622 and 0.441) and LLDs (ß = -0.795 and -0.477) at both the 1.3 and 0.5 cd/m2 luminance levels, respectively, and these associations remained significant after adjusting for AMD severity (P < 0.05). Conclusions: Among subjects with early and intermediate AMD, LLQ scores were significantly associated with computerized LLVA and LLD. LLQ is a useful patient-centered functional measure of visual impairment in early and intermediate AMD.

Relating Sensory, Cognitive, and Neural Factors to Older Persons' Perceptions about Happiness: An Exploratory Study.

Despite increased rates of disease, disability, and social losses with aging, seniors consistently report higher levels of subjective well-being (SWB), a construct closely related to happiness, than younger adults. In this exploratory study, we utilized an available dataset to investigate how aspects of health commonly deteriorating with age, including sensory (i.e., vision and hearing) and cognitive status, relate to variability in self-described contributors to happiness. Community-dwelling seniors (n = 114) responded to a single-item prompt: "name things that make people happy." 1731 responses were categorized into 13 domains of SWB via structured content analysis. Sensory health and cognition were assessed by Snellen visual acuity, pure-tone audiometry, and in-person administration of the Brief Test of Adult Cognition by Telephone (BTACT) battery. A subset of eligible participants (n = 57) underwent functional magnetic resonance imaging (fMRI) to assess resting state functional connectivity (FC) within a previously described dopaminergic network associated with reward processing. SWB response patterns were relatively stable across gender, sensory status, and cognitive performance with few exceptions. For example, hearing-impaired participants listed fewer determinants of SWB (13.59 vs. 17.16; p < 0.001) and were less likely to name things in the "special events" category. Participants with a higher proportion of responses in the "accomplishments" domain (e.g., winning, getting good grades) demonstrated increased FC between the ventral tegmental area and nucleus accumbens, regions implicated in reward and motivated behavior. While the framework for determinants of happiness among seniors was largely stable across the factors assessed here, our findings suggest that subtle changes in this construct may be linked to sensory loss. The possibility that perceptions about determinants of happiness might relate to differences in intrinsic connectivity within reward-related brain networks also warrants further investigation.

Language processing in age-related macular degeneration associated with unique functional connectivity signatures in the right hemisphere.

Age-related macular degeneration (AMD) is a retinal disease associated with significant vision loss among older adults. Previous large-scale behavioral studies indicate that people with AMD are at increased risk of cognitive deficits in language processing, particularly in verbal fluency tasks. The neural underpinnings of any relationship between AMD and higher cognitive functions, such as language processing, remain unclear. This study aims to address this issue using independent component analysis of spontaneous brain activity at rest. In 2 components associated with visual processing, we observed weaker functional connectivity in the primary visual cortex and lateral occipital cortex in AMD patients compared with healthy controls, indicating that AMD might lead to differences in the neural representation of vision. In a component related to language processing, we found that increasing connectivity within the right inferior frontal gyrus was associated with better verbal fluency performance across all older adults, and the verbal fluency effect was greater in AMD patients than controls in both right inferior frontal gyrus and right posterior temporal regions. As the behavioral performance of our patients is as good as that of controls, these findings suggest that preservation of verbal fluency performance in AMD patients might be achieved through higher contribution from right hemisphere regions in bilateral language networks. If that is the case, there may be an opportunity to promote cognitive resilience among seniors with AMD or other forms of late-life vision loss.

A Quantitative Approach to Predict Differential Effects of Anti-VEGF Treatment on Diffuse and Focal Leakage in Patients with Diabetic Macular Edema: A Pilot Study.

PURPOSE: We use semiautomated segmentation of fluorescein angiography (FA) to determine whether anti-vascular endothelial growth factor (VEGF) treatment for diabetic macular edema (DME) differentially affects microaneurysm (MA)-associated leakage, termed focal leakage, versus non-MA-associated leakage, termed diffuse leakage. METHODS: We performed a retrospective study of 29 subjects treated with at least three consecutive injections of anti-VEGF agents for DME (mean 4.6 injections; range, 3-10) who underwent Heidelberg FA before and after anti-VEGF therapy. Inclusion criteria were macula center involving DME and at least 3 consecutive anti-VEGF injections. Exclusion criteria were macular edema due to cause besides DME, anti-VEGF within 3 months of initial FA, concurrent treatment for DME besides anti-VEGF, and macular photocoagulation within 1 year. At each time point, total leakage was semiautomatically segmented using a modified version of our previously published software. Microaneurysms were identified by an expert grader and leakage within a 117 µm radius of each MA was classified as focal leakage. Remaining leakage was classified as diffuse leakage. The absolute and percent changes in total, diffuse, and focal leakage were calculated for each subject. RESULTS: Mean pretreatment total leakage was 8.2 mm2 and decreased by a mean of 40.1% (P < 0.0001; 95% confidence interval [CI], [-28.6, -52.5]) following treatment. Diffuse leakage decreased by a mean of 45.5% (P < 0.0001; 95% CI, [-31.3, -59.6]) while focal leakage decreased by 17.9% (P = 0.02; 95% CI, [-1.0, -34.8]). The difference in treatment response between focal and diffuse leakage was statistically significant (P = 0.01). CONCLUSIONS: Anti-VEGF treatment for DME results in decreased diffuse leakage but had relatively little effect on focal leakage as assessed by FA. This suggests that diffuse leakage may be a marker of VEGF-mediated pathobiology. Patients with predominantly focal leakage may be less responsive to anti-VEGF therapy. TRANSLATIONAL RELEVANCE: Fluorescein angiography can define focal and diffuse subtypes of diabetic macular edema and these may respond differently to anti-VEGF treatment.

Intravitreal Anti-VEGF Injections Reduce Aqueous Outflow Facility in Patients With Neovascular Age-Related Macular Degeneration.

Purpose: We assess the effect of intravitreal anti-VEGF injections on tonographic outflow facility. Methods: Patients with age-related macular degeneration who had received unilateral intravitreal anti-VEGF injections were recruited into two groups, those with ≤10 and those with ≥20 total anti-VEGF injections. Intraocular pressure and tonographic outflow facility of injected and uninjected fellow eyes were measured and compared between groups. Risk factors for development of reduced outflow facility also were assessed. Results: Outflow facility was 12% lower in the injected eyes of patients who received ≥20 anti-VEGF injections, compared to contralateral uninjected eyes (P = 0.02). In contrast, there was no facility reduction for patients with ≤10 anti-VEGF injections (P = 0.4). In patients with ocular hypertension in the uninjected eye (IOP > 21 mm Hg, n = 5), the outflow facility of injected eyes was on average 46% lower (P = 0.01) than in the uninjected fellow eyes. This was significantly greater than the difference observed in patients with IOP ≤ 21 mm Hg in the uninjected eye (P = 2 × 10-4). In patients with ocular hypertension in the injected eye (n = 6) the differences in facility and IOP between contralateral eyes were significantly greater than in patients with IOP ≤ 21 mm Hg in the injected eye (P = 2 × 10-4 and P = 7 × 10-4, respectively). Conclusions: Chronic anti-VEGF injections significantly reduce outflow facility in patients with AMD. The greatest facility reduction is observed in patients with baseline ocular hypertension. Ophthalmologists who administer anti-VEGF injections should be aware of these findings and monitor patients closely for changes in IOP or evidence of glaucoma, especially in those with pre-existing ocular hypertension.

Enhanced visualization of peripheral retinal vasculature with wavefront sensorless adaptive optics optical coherence tomography angiography in diabetic patients.

Optical coherence tomography angiography (OCTA) is a promising technique for non-invasive visualization of vessel networks in the human eye. We debut a system capable of acquiring wide field-of-view (>70°) OCT angiograms without mosaicking. Additionally, we report on enhancing the visualization of peripheral microvasculature using wavefront sensorless adaptive optics (WSAO). We employed a fast WSAO algorithm that enabled wavefront correction in <2 s by iterating the mirror shape at the speed of OCT B-scans rather than volumes. Also, we contrasted ∼7° field-of-view OCTA angiograms acquired in the periphery with and without WSAO correction. On average, WSAO improved the sharpness of microvasculature by 65% in healthy eyes and 38% in diseased eyes. Preliminary observations demonstrated that the location of 7° images could be identified directly from the wide field-of-view angiogram. A pilot study on a normal subject and patients with diabetic retinopathy showed the impact of utilizing WSAO for OCTA when visualizing peripheral vasculature pathologies.