Development and Feasibility of an eHealth Diabetes Prevention Program Adapted for Older Adults-Results from a Randomized Control Pilot Study.

Lifestyle programs that reduce health risks and support weight loss (WL) in older adults face adherence and attendance challenges due to reduced energy requirements, impaired mobility, lack of transportation, and low social support. Tailored lifestyle and weight management programs are needed to better support healthy aging for older adults. Here, we developed and piloted an age-adapted, remotely delivered modification of the Diabetes Prevention Program (DPP). The modification includes age-appropriate goals, visuals, and examples; flexible dietary composition; remote classroom and fitness-monitoring technology; and standardized online classroom materials employing pedagogical and behavior change theory. The modifications were designed to safeguard fidelity and to boost adherence, engagement, and knowledge integration, with the convenience of a fully remote WL program for diverse older adults. Six-month pilot data are presented from older adults (55-85 years, body mass index (BMI) 27-39.9 kg/m2, N = 20) randomly allocated to an online DPP intervention with weight, diet, and activity monitored remotely, or into a waitlisted control. The intervention achieved 100% attendance and adherence to self-monitoring. The intervention group mean (±SD) body weight change was -9.5% (±4.1); 90% lost ≥ 5%. By contrast, the control group gained 2.4% (±1.8). Once thought incompatible with older adults, remote interventions are feasible for older adults and can support fidelity, adherence, engagement, and clinically significant WL. Standardized materials are provided for future implementation.

Spinal Anesthesia Reduces Perioperative Polypharmacy and Opioid Burden in Patients Over 65 Who Undergo Transforaminal Lumbar Interbody Fusion.

BACKGROUND: Polypharmacy and opioid administration are thought to increase the risk of postoperative cognitive dysfunction and delirium in elderly patients. Spinal anesthesia (SA) holds potential to reduce perioperative polypharmacy in spine surgery. As more geriatric patients undergo spine surgery, understanding how SA can reduce polypharmacy and opioid administration is warranted. We aim to compare the perioperative polypharmacy and dose of administered opioids in patients ≥65 years who undergo transforaminal lumbar interbody fusion (TLIF) under SA versus general anesthesia (GA). METHODS: A retrospective analysis of 200 patients receiving a single-surgeon TLIF procedure at a single academic center (2014-2021) was performed. Patients underwent the procedure with SA (n = 120) or GA (n = 80). Demographic, procedural, and medication data were extracted from the medical record. Opioid consumption was quantified as morphine milligram equivalents (MME). Statistical analyses included χ2 or Student's t-test. RESULTS: Patients receiving SA were administered 7.45 medications on average versus 12.7 for GA patients (P < 0.001). Average perioperative opioid consumption was 5.17 MME and 20.2 MME in SA and GA patients, respectively (P < 0.001). The number of patients receiving antiemetics and opioids remained comparable postoperatively, with a mean of 32.2 MME in the GA group versus 27.5 MME in the SA group (P = 0.14). Antiemetics were administered less often as a prophylactic in the SA group (32%) versus 86% in the GA group (P < 0.001). CONCLUSIONS: SA reduces perioperative polypharmacy in patients ≥65 years undergoing TLIF procedures. Further research is necessary to determine if this reduction correlates to a decrease the incidence of postoperative cognitive dysfunction and delirium.

Diet composition, adherence to calorie restriction, and cardiometabolic disease risk modification.

Calorie restriction (CR) is a promising approach for attenuating the risk of age-related disease. However, the role of diet composition on adherence to CR and the effects of CR on cardiometabolic markers of healthspan remains unknown. We used the Geometric Framework for Nutrition approach to examine the association between macronutrient composition and CR adherence during the 2-year CALERIE trial. Adult participants without obesity were randomized to a 25% CR intervention or an ad libitum intake control. Correlations of cardiometabolic risk factors with macronutrient composition and standard dietary pattern indices [Alternate Mediterranean Diet Index (aMED), Dietary Inflammatory Index (DII), and Healthy Eating Index (HEI)] were also evaluated by Spearman's correlation at each time point. The mean age was 38.1 ± 7.2 years at baseline and the mean BMI was 25.1 ± 1.7. The study population was 70% female. The CR group, but not the control, consumed a higher percentage reported energy intake from protein and carbohydrate and lower fat at 12 months compared to baseline; comparable results were observed at 24 months. Protein in the background of higher carbohydrate intake was associated with greater adherence at 24 months. There was no correlation between macronutrient composition and cardiometabolic risk factors in the CR group. However, statistically significant correlations were observed for the DII and HEI. These findings suggest that individual self-selected macronutrients have an interactive but not independent role in CR adherence. Additional research is required to examine the impact of varying macronutrient compositions on adherence to CR and resultant modification to cardiometabolic risk factors.

No Effect of Calorie Restriction or Dietary Patterns on Spatial Working Memory During a 2-Year Intervention: A Secondary Analysis of the CALERIE Trial.

BACKGROUND: The effect of calorie restriction (CR) on cognitive function is not well understood, and the impact of the dietary patterns consumed during CR has not been investigated. OBJECTIVES: We analyzed the combined association of CR and dietary quality with spatial working memory (SWM) in healthy adults without obesity. METHODS: The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial was a 2-y, multisite clinical trial. This trial was registered at clinicaltrials.gov as NCT00427193. Participants were randomized to a 25% reduction in EI (n = 143) or an ad libitum Control (n = 76). The Dietary Inflammatory Index (DII) and the Healthy Eating Index (HEI) captured dietary quality, with a lower DII and higher HEI score indicating a healthier diet. The Cambridge Neuropsychological Test Automated Battery battery was used to assess SWM. Longitudinal associations between each dietary pattern index and SWM for CR and Control were assessed by multivariable negative binomial models that included baseline, 12-mo, and 24-mo visits. RESULTS: Participants were aged 38.1 ± 7.2 y with a BMI of 25.1 ± 1.7 kg/m2. A total of 70% of the participants were female. Baseline mean DII and HEI scores were -0.15 (range: -3.77, 4.21) and 59.1 (24.1, 91.0) and did not differ between groups. Improvements in DII and HEI were significantly different between CR and Control over 2 y (both P-interaction = 0.001). In longitudinal analyses, there was no association of either index with SWM. Furthermore, though within-group improvements in SWM were observed at 12 mo, there was no statistically significant difference between CR (SWM errors: 9.0; 95% CI: 1.9, 41.6) and Control (11.7; 95% CI: 2.6, 53.5; P > 0.99), holding DII constant. Comparable results were observed at 24 mo and for the HEI. CONCLUSIONS: Dietary quality during CR was not associated with measures of SWM over 2 y in healthy adults without obesity. These results suggest that, in healthy populations, dietary patterns and CR may have a limited impact on working memory. Further research is required to understand the concurrent effect of these nutritional strategies.

Randomized controlled trial of a novel lifestyle intervention used with or without meal replacements in work sites.

OBJECTIVE: Lifestyle interventions have had limited effectiveness in work sites when evaluated in randomized trials. This study assessed the effectiveness of a novel lifestyle intervention for weight loss (Healthy Weight for Living [HWL]) implemented with or without meal replacements (MR) in work sites. HWL used a new behavioral approach emphasizing reducing hunger and building healthy food preferences, and, unlike traditional lifestyle interventions, it did not require calorie counting. METHODS: Twelve work sites were randomized to an 18-month intervention (n = 8; randomization within work sites to HWL, HWL + MR) or 6-month wait-listed control (n = 4). Participants were employees with overweight or obesity (N = 335; age = 48 [SD 10] years; BMI = 33 [6] kg/m2 ; 83% female). HWL was group-delivered in person or by videoconference. The primary outcome was 6-month weight change; secondary outcomes included weight and cardiometabolic risk factors measured at 6, 12, and 18 months in intervention groups. RESULTS: Mean 6-month weight change was -8.8% (95% CI: -11.2% to -6.4%) for enrollees in HWL and -8.0% (-10.4% to -5.5%) for HWL + MR (p < 0.001 for both groups vs. controls), with no difference between interventions (p = 0.40). Clinically meaningful weight loss (≥5%) was maintained at 18 months in both groups (p < 0.001). CONCLUSIONS: A new lifestyle intervention approach, deliverable by videoconference with or without MR, supported clinically impactful weight loss in employees.

Randomized trial of a novel lifestyle intervention compared with the Diabetes Prevention Program for weight loss in adult dependents of military service members.

BACKGROUND: Lifestyle interventions are the first-line treatment for obesity, but participant weight loss is typically low. OBJECTIVES: We evaluated the efficacy of an alternative lifestyle intervention [Healthy Weight for Living (HWL)] compared with a modified Diabetes Prevention Program (m-DPP). HWL was based on a revised health behavior change model emphasizing hunger management and the development of healthy food preferences. m-DPP was a standard Diabetes Prevention Program implemented with counselor time matched to HWL. Participants were adult dependents of military personnel and had overweight or obesity. METHODS: Participants were randomly assigned to HWL (n = 121) or m-DPP (n = 117), delivered primarily by group videoconference with additional midweek emails. The primary outcome was 12-mo weight change. Secondary outcomes included 6-mo changes in cardiometabolic risk factors and diet. Intention-to-treat (ITT) and complete case (CC) analyses were performed using linear mixed models. RESULTS: Retention did not differ between groups (72% and 66% for HWL and m-DPP at 12 mo, respectively; P = 0.30). Mean ± SE adjusted 12-mo weight loss in the ITT cohort was 7.46 ± 0.85 kg for HWL and 7.32 ± 0.87 kg for m-DPP (P = 0.91); in the CC cohort, it was 7.83 ± 0.82 kg for HWL and 6.86 ± 0.88 kg for m-DPP (P = 0.43). Thirty-eight percent of HWL and 30% of m-DPP completers achieved ≥10% weight loss (P = 0.32). Improvements in systolic blood pressure, LDL cholesterol, triglycerides, fasting glucose, general health, sleep, and mood were similar across groups; improvements in diastolic blood pressure were greater in m-DPP. Adjusted group mean reductions in energy intake were not significantly different between groups, but HWL participants were more adherent to their dietary prescription for lower glycemic index and high fiber and protein (P = 0.05 to <0.001 for ITT). CONCLUSIONS: HWL and m-DPP showed equivalent and clinically impactful mean weight loss with cardiometabolic benefits. These results identify an alternative approach for behavioral treatment of overweight and obesity.This trial was registered at clinicaltrials.gov as NCT02348853.

Healthy Aging-Nutrition Matters: Start Early and Screen Often.

The amount of time spent in poor health at the end of life is increasing. This narrative review summarizes consistent evidence indicating that healthy dietary patterns and maintenance of a healthy weight in the years leading to old age are associated with broad prevention of all the archetypal diseases and impairments associated with aging including: noncommunicable diseases, sarcopenia, cognitive decline and dementia, osteoporosis, age-related macular degeneration, diabetic retinopathy, hearing loss, obstructive sleep apnea, urinary incontinence, and constipation. In addition, randomized clinical trials show that disease-specific nutrition interventions can attenuate progression-and in some cases effectively treat-many established aging-associated conditions. However, middle-aged and older adults are vulnerable to unhealthy dietary patterns, and typically consume diets with inadequate servings of healthy food groups and essential nutrients, along with an abundance of energy-dense but nutrient-weak foods that contribute to obesity. However, based on menu examples, diets that are nutrient-dense, plant-based, and with a moderately low glycemic load are better equipped to meet the nutritional needs of many older adults than current recommendations in US Dietary Guidelines. These summary findings indicate that healthy nutrition is more important for healthy aging than generally recognized. Improved public health messaging about nutrition and aging, combined with routine screening and medical referrals for age-related conditions that can be treated with a nutrition prescription, should form core components of a national nutrition roadmap to reduce the epidemic of unhealthy aging.

Association of counselor weight status and demographics with participant weight loss in a structured lifestyle intervention.

OBJECTIVE: There is substantial variability in the effectiveness of group lifestyle interventions for weight loss. We examined associations between intervention weight loss counselors and participant weight loss and program engagement in a structured lifestyle intervention. METHODS: Data were from 575 adults (87% female, 51 (12) years, baseline BMI: 32.4 (7.2) kg/m2) in an 11-week structured group lifestyle program. Participants self-enrolled in groups led by 11 weight loss counselors based on meeting times. All weight loss counselors received the same training. Linear mixed models were used to evaluate counselor predictors of participant percent (%) weight loss and program engagement (weight reporting throughout 11 weeks). RESULTS: Of the 575 participants, 415 (72%) defined as complete reporters, i.e. reported weight weekly, lost a mean 7.3% weight (range: +3.1% to 16.2%). Participant weight loss differed between weight loss counselors (p = 0.003), and adjusted mean participant weight loss by weight loss counselor ranged from 6% to 9%. Weight loss was greater for weight loss counselors with a graduate degree in nutrition than weight loss counselors with another graduate degree (8.3% versus 6.4%, p = 0.05), but was not different between weight loss counselors with and without graduate degrees. Higher counselor BMI was associated with higher participant weight loss (p = 0.005). CONCLUSIONS: These results demonstrate the potential for quantitatively important effects of weight loss counselor characteristics on participant success and engagement in structured lifestyle interventions, indicating a need for research in this area.

Effects of food supplementation on cognitive function, cerebral blood flow, and nutritional status in young children at risk of undernutrition: randomized controlled trial.

OBJECTIVE: To assess the effects of food supplementation on improving working memory and additional measures including cerebral blood flow in children at risk of undernutrition. DESIGN: Randomized controlled trial. SETTING: 10 villages in Guinea-Bissau. PARTICIPANTS: 1059 children aged 15 months to 7 years; children younger than 4 were the primary population. INTERVENTIONS: Supervised isocaloric servings (≈1300 kJ, five mornings each week, 23 weeks) of a new food supplement (NEWSUP, high in plant polyphenols and omega 3 fatty acids, within a wide variety and high fortification of micronutrients, and a high protein content), or a fortified blended food (FBF) used in nutrition programs, or a control meal (traditional rice breakfast). MAIN OUTCOME MEASUREMENTS: The primary outcome was working memory, a core executive function predicting long term academic achievement. Additional outcomes were hemoglobin concentration, growth, body composition, and index of cerebral blood flow (CBFi). In addition to an intention-to-treat analysis, a predefined per protocol analysis was conducted in children who consumed at least 75% of the supplement (820/925, 89%). The primary outcome was assessed by a multivariable Poisson model; other outcomes were assessed by multivariable linear mixed models. RESULTS: Among children younger than 4, randomization to NEWSUP increased working memory compared with the control meal (rate ratio 1.20, 95% confidence interval 1.02 to 1.41, P=0.03), with a larger effect in the per protocol population (1.25, 1.06 to 1.47, P=0.009). NEWSUP also increased hemoglobin concentration among children with anemia (adjusted mean difference 0.65 g/dL, 95% confidence interval 0.23 to 1.07, P=0.003) compared with the control meal, decreased body mass index z score gain (-0.23, -0.43 to -0.02, P=0.03), and increased lean tissue accretion (2.98 cm2, 0.04 to 5.92, P=0.046) with less fat (-5.82 cm2, -11.28 to -0.36, P=0.04) compared with FBF. Additionally, NEWSUP increased CBFi compared with the control meal and FBF in both age groups combined (1.14 mm2/s×10-8, 0.10 to 2.23, P=0.04 for both comparisons). Among children aged 4 and older, NEWSUP had no significant effect on working memory or anemia, but increased lean tissue compared with FBF (4.31 cm2, 0.34 to 8.28, P=0.03). CONCLUSIONS: Childhood undernutrition is associated with long term impairment in cognition. Contrary to current understanding, supplementary feeding for 23 weeks could improve executive function, brain health, and nutritional status in vulnerable young children living in low income countries. Further research is needed to optimize nutritional prescriptions for regenerative improvements in cognitive function, and to test effectiveness in other vulnerable groups. TRIAL REGISTRATION: ClinicalTrials.gov NCT03017209.

Development of a Videoconference-Adapted Version of the Community Diabetes Prevention Program, and Comparison of Weight Loss With In-Person Program Delivery.

INTRODUCTION: Effective, standardized, and easily accessible weight management programs are urgently needed for military beneficiaries. Videoconference interventions have the potential for widespread scaling, and can provide both real time interaction and flexibility in delivery times regardless of location, but there is little information on their effectiveness and acceptability. MATERIALS AND METHODS: This study as part of a larger weight loss trial describes the videoconference adaption of Group Lifestyle Balance (GLB) program, a community group-based Diabetes Prevention Program intervention, and provides a comparison of weight loss and meeting attendance between in-person and videoconference delivery modes over 12 weeks in adult family members of military service members. Forty-three participants were enrolled from two military installations and received either the videoconference-adapted or an in-person GLB program in a non-randomized trial design. Differences in program attendance and percent weight lost at 12 weeks were compared by independent samples t-tests and nonparametric methods. Group differences in the percentage of weight lost over the 12-week period were analyzed using a linear mixed model. RESULTS: All GLB intervention components were successfully delivered by videoconference with minor adaptations for the different delivery mechanism. Participant retention was 70% and 96% in the in-person and videoconference groups, respectively (p = 0.04). Completing participants in both groups lost a significant percent body weight over the 12 week intervention (p < 0.001) and there was no difference in percent body weight after 12 weeks of intervention (6.2 ± 3.2% and 5.3 ± 3.4% for in-person and videoconference at 12 weeks, respectively; p = 0.60). CONCLUSION: This study describes the first videoconference adaption of the GLB program for use in military families. Attrition was lower in the videoconference group, and there were a similar levels of weight loss in both groups regardless of delivery modality. Videoconference weight loss interventions are effective and feasible for scaling to support healthy weight management in military as well as civilian populations.

Corneal incision architecture: VICTUS femtosecond laser vs manual keratome.

PURPOSE: To evaluate anatomical differences between laser (VICTUS) and manual constructed phacoemulsification incisions. SETTING: Study was conducted at the Hospital de Olhos Paulista, Sao Paulo, Brazil. DESIGN: This is a prospective, observational, consecutive nonrandomized cohort. PATIENTS AND METHODS: Sixteen patients (18 eyes) had phacoemulsification surgery, nine eyes had manual incisions and nine eyes had femtosecond incisions. All incisions were performed by the same surgeon. All incisions were evaluated at the 1st and 30th postoperative day with anterior segment optical coherence tomography to evaluate anatomical features. Inclusion criterion was presence of low visual acuity due to cataract. Exclusion criteria were other ocular pathologies, previous trauma, or corneal wound healing disease, as any intra or postoperative complication. Three different corneal specialists analyzed wound architecture features (epithelial or endothelial gap, incision edema, number of planes, Descemet's detachment, and loss of wound sealing) at both visits. ImageJ (National Institutes of Health) software was also used to analyze anatomical features of incisions. RESULTS: Almost all incisions had edema at the first postoperative day. All femto incisions were triplanar, as intended, unlike manual incisions, which showed two uniplanar incisions (P=0.009). All laser incisions presented partial loss of wound sealing, while five keratome incisions had no loss of wound sealing at the first postoperative day (P=0.03). CONCLUSION: These findings support the hypothesis that laser constructed incisions are more precisely constructed than manual, although corneal wound healing was similar between the two groups at the 30th postoperative day, with a tendency to a faster anatomical improvement in the keratome group.

Measured energy content of frequently purchased restaurant meals: multi-country cross sectional study.

OBJECTIVE: To measure the energy content of frequently ordered meals from full service and fast food restaurants in five countries and compare values with US data. DESIGN: Cross sectional survey. SETTING: 223 meals from 111 randomly selected full service and fast food restaurants serving popular cuisines in Brazil, China, Finland, Ghana, and India were the primary sampling unit; 10 meals from five worksite canteens were also studied in Finland. The observational unit was frequently ordered meals in selected restaurants. MAIN OUTCOME MEASURE: Meal energy content, measured by bomb calorimetry. RESULTS: Compared with the US, weighted mean energy of restaurant meals was lower only in China (719 (95% confidence interval 646 to 799) kcal versus 1088 (1002 to 1181) kcal; P<0.001). In analysis of variance models, fast food contained 33% less energy than full service meals (P<0.001). In Finland, worksite canteens provided 25% less energy than full service and fast food restaurants (mean 880 (SD 156) versus 1166 (298); P=0.009). Country, restaurant type, number of meal components, and meal weight predicted meal energy in a factorial analysis of variance (R2=0.62, P<0.001). Ninety four per cent of full service meals and 72% of fast food meals contained at least 600 kcal. Modeling indicated that, except in China, consuming current servings of a full service and a fast food meal daily would supply between 70% and 120% of the daily energy requirements for a sedentary woman, without additional meals, drinks, snacks, appetizers, or desserts. CONCLUSION: Very high dietary energy content of both full service and fast food restaurant meals is a widespread phenomenon that is probably supporting global obesity and provides a valid intervention target.

Are Gluten-Free Diets More Nutritious? An Evaluation of Self-Selected and Recommended Gluten-Free and Gluten-Containing Dietary Patterns.

Gluten-free (GF) eating patterns are frequently perceived to be healthier than gluten-containing (GC) ones, but there has been very little research to evaluate this viewpoint. The effect of GF eating patterns on dietary composition was assessed using two independent approaches. One approach compared macronutrients and typical shortfall nutrients between MyPlate example menus developed with either GC or equivalent GF foods. In this analysis, the GF menus were significantly lower in protein, magnesium, potassium, vitamin E, folate, and sodium (p = 0.002⁻0.03), with suggestive trends towards lower calcium and higher fat (p = 0.06⁻0.08). The second approach was a meta-analysis of seven studies comparing information on the nutrient intakes of adults with celiac disease following a GF diet with control subjects eating a GC diet, and differences were evaluated using paired t-tests or Wilcoxon Signed rank tests. In this analysis, consuming a GF diet was associated with higher energy and fat intakes, and lower fiber and folate intakes compared to controls (p < 0.001 to p = 0.03). After adjusting for heterogeneity and accounting for the large mean effect size (-0.88 ± 0.09), the lower fiber remained significant (p < 0.001). These combined analyses indicate that GF diets are not nutritionally superior except for sodium, and in several respects are actually worse.

Associations Between Vitamin D Intake and Progression to Incident Advanced Age-Related Macular Degeneration.

Purpose: There is growing evidence of the importance of nutrition in age-related macular degeneration (AMD), but no prospective studies have explored the impact of vitamin D. We evaluated the association between vitamin D intake and progression to advanced AMD. Methods: Among 2146 participants (3965 eyes), 541 (777 eyes) progressed from early or intermediate AMD to advanced disease (mean follow-up: 9.4 years) based on ocular imaging. Nutrients were log transformed and calorie adjusted. Survival analysis was used to assess associations between incident advanced disease and vitamin D intake. Neovascular disease (NV) and geographic atrophy (GA) were evaluated separately. Combined effects of dietary vitamin D and calcium were assessed based on high or low consumption of each nutrient. Results: There was a lower risk of progression to advanced AMD in the highest versus lowest quintile of dietary vitamin D intake after adjustment for demographic, behavioral, ocular, and nutritional factors (hazard ratio [HR]: 0.60; 95% confidence interval [CI]: 0.43-0.83; P trend = 0.0007). Similar results were observed for NV (HR: 0.59; 95% CI: 0.39-0.89; P trend = 0.005) but not GA (HR: 0.83; 95% CI: 0.53-1.30; P trend = 0.35). A protective effect was observed for advanced AMD among participants with high vitamin D and low calcium compared to the group with low levels for each nutrient (HR: 0.67; 95% CI: 0.50-0.88; P = 0.005). When supplement use was considered, the effect was in the protective direction but was not significant. Conclusions: A diet rich in vitamin D may prevent or delay progression to advanced AMD, especially NV. Additional exploration is needed to elucidate the potential protective role of vitamin D and its contribution to reducing visual loss.

Optical Coherence Tomography Features Preceding the Onset of Advanced Age-Related Macular Degeneration.

Purpose: Age-related macular degeneration (AMD) is a progressive disease with multifactorial etiology. There is a need to identify clinical features that are harbingers of advanced disease. We evaluated morphologic features of the retina and choroid on optical coherence tomography (OCT) to determine if they predict progression to advanced disease. Methods: Progressors transitioned from early or intermediate AMD to advanced disease (n = 40 eyes), and were matched on baseline AMD grade and follow-up interval to nonprogressors who did not develop advanced AMD (n = 40 eyes). Features of the neurosensory retina, photoreceptors, retinal pigment epithelium (RPE), and choroid were evaluated. Logistic regression was used to evaluate univariate associations between features and progression to overall advanced AMD, geographic atrophy (GA), and neovascular disease (NV). Multivariate associations based on stepwise regression models were also assessed. Results: Ellipsoid zone disruption was associated with progression to overall advanced AMD and NV (odds ratios [ORs]: 17.9 and 30.6; P < 0.001), with a similar trend observed for GA. Drusenoid RPE detachment, RPE thickening, and retinal pigmentary hyperreflective material were significantly associated with higher risk of progression to advanced AMD (ORs: 5.0-8.5) and NV (ORs: 10.8-17.2). Pigmentary hyperreflective material was associated with progression to GA (OR: 7.5, P = 0.009). Total retinal thickness, pigmentary hyperreflective material, nascent GA features, and choroidal vessel abnormalities were independently associated with progression to advanced AMD in a multivariate stepwise model. Conclusions: Abnormalities in the photoreceptors, retinal thickness, RPE, and choroid were associated with higher risk of developing advanced AMD. These findings provide insights into disease progression, and may be helpful to identify earlier endpoints for clinical studies.

Distribution and Quantification of Choroidal Macrophages in Human Eyes With Age-Related Macular Degeneration.

PURPOSE: Increasing evidence suggests a role for macrophages in the pathogenesis of age-related macular degeneration (AMD). This study examined choroidal macrophages and their activation in postmortem eyes from subjects with and without AMD. METHODS: Choroids were incubated with anti-ionized calcium-binding adapter molecule 1 (anti-IBA1) to label macrophages, anti-human leukocyte antigen-antigen D-related (anti-HLA-DR) as a macrophage activation marker, and Ulex europaeus agglutinin lectin to label blood vessels. Whole mounts were imaged using confocal microscopy. IBA1- and HLA-DR-positive (activated) cells were counted in submacula, paramacula, and nonmacula, and cell volume and sphericity were determined using computer-assisted image analysis. RESULTS: In aged control eyes, the mean number of submacular IBA1+ and HLA-DR+ macrophages was 433/mm2 and 152/mm2, respectively. In early AMD eyes, there was a significant increase in IBA1+ and HLA-DR+ cells in submacula compared to those in controls (P = 0.0015 and P = 0.008, respectively). In eyes with neovascular AMD, there were significantly more HLA-DR+ cells associated with submacular choroidal neovascularization (P = 0.001). Mean cell volume was significantly lower (P ≤ 0.02), and sphericity was significantly higher (P ≤ 0.005) in all AMD groups compared to controls. CONCLUSIONS: The average number of IBA1+ macrophages in submacular and paramacular choroid was significantly higher in early/intermediate AMD compared to that in aged controls. HLA-DR+ submacular macrophages were significantly increased in all stages of AMD, and they were significantly more round and smaller in size in the submacular AMD choroid, suggesting their activation. These findings support the concept that AMD is an inflammatory disease.

Histopathological Insights Into Choroidal Vascular Loss in Clinically Documented Cases of Age-Related Macular Degeneration.

IMPORTANCE: Age-related macular degeneration (AMD) is a multifactorial disease with genetic and environmental factors contributing to risk. Histopathologic changes underlying AMD are not fully understood, particularly the relationship between choriocapillaris (CC) dysfunction and phenotypic variability of this disease. OBJECTIVE: To examine histopathologic changes in the CC of eyes with clinically documented AMD. DESIGN, SETTING, AND PARTICIPANTS: The study was designed in 2011. Tissues were collected post mortem (2012-2016), and histopathological images were obtained from participants enrolled in AMD studies since 1988. Clinical records and images were collected from participants as standard protocol. Eyes without AMD (n = 4) and eyes with early (n = 9), intermediate (n = 5), and advanced stages of AMD (geographic atrophy, n = 5; neovascular disease, n = 13) were evaluated. Choroidal vasculature was labeled using Ulex europaeus agglutinin lectin and examined using confocal microscopy. MAIN OUTCOMES AND MEASURES: A standardized classification system was applied to determine AMD stage. Ocular records and images were reviewed and histopathologic analyses performed. Viability of the choroidal vasculature was analyzed for each AMD stage. RESULTS: All participants were white. Fourteen were male, and 16 were female. The mean age was 90.5 years among AMD patients and 88.5 years among control participants. Submacular CC dropout without retinal pigment eipthelial (RPE) loss was observed in all cases with early stages of AMD. Higher vascular area loss for each AMD stage was observed compared with control participants: 20.5% in early AMD (95% CI, 11.2%-40.2%; P < .001), 12.5% in intermediate AMD (95% CI, 2.9%-21.4%; P = .01), 39.0% loss in GA (95% CI, 32.1%-45.4%; P < .001), and 38.2% loss in neovascular disease where RPE remained intact (95% CI, 27.7%-47.9%; P < .001). Hypercellular, apparent neovascular buds were adjacent to areas of CC loss in 22.2% of eyes with early AMD and 40% of eyes with intermediate AMD. CONCLUSIONS AND RELEVANCE: Retinal pigment epithelial atrophy preceded CC loss in geographic atrophy, but CC loss occurred in the absence of RPE atrophy in 2 of 9 eyes with early-stage AMD. Given the cross-sectional nature of this study and the small number of eyes evaluated, definitive conclusions regarding this progression cannot be determined with certainty. We speculate that neovascular buds may be a precursor to neovascular disease. Hypoxic RPE resulting from reduced blood supply might upregulate production of vascular endothelial growth factor, providing the stimulus for neovascular disease.

Response to AREDS supplements according to genetic factors: survival analysis approach using the eye as the unit of analysis.

BACKGROUND/AIMS: The Age-Related Eye Disease Study (AREDS) reported the beneficial impact of antioxidant and zinc supplements on the risk of progression to advanced stages of age-related macular degeneration (AMD). We evaluated the role of genetic variants in modifying the relationship between supplementation and progression to advanced AMD. METHODS: Among 4124 eyes (2317 subjects with a genetic specimen), 882 progressed from no AMD, early or intermediate AMD to overall advanced disease, including geographic atrophy (GA) and neovascular disease (NV) over the course of the clinical trial. Survival analysis using individual eyes as the unit of analysis was used to assess the effect of supplementation on AMD outcomes, with adjustment for demographic, environmental, ocular and genetic covariates. Interaction effects between supplement groups and individual complement factor H (CFH) Y402H and age-related maculopathy susceptibility 2 (ARMS2) genotypes, and composite genetic risk groups combining the number of risk alleles for both loci, were evaluated for their association with progression. RESULTS: Among antioxidant and zinc supplement users compared with the placebo group, subjects with a non-risk genotype for CFH (TT) had a lower risk of progression to advanced AMD (HR: 0.55, 95% CI 0.32 to 0.95, p=0.033). No significant treatment effect was apparent among subjects who were homozygous for the CFH risk allele (CC). A protective effect was observed among high-risk ARMS2 (TT) carriers (HR: 0.52, 95% CI 0.33 to 0.82, p=0.005). Similar results were seen for the NV subtype but not GA. CONCLUSIONS: The effectiveness of antioxidant and zinc supplementation appears to differ by genotype. Further study is needed to determine the biological basis for this interaction. TRIAL REGISTRATION NUMBER: NCT00594672, pre-results.

Dietary folate, B vitamins, genetic susceptibility and progression to advanced nonexudative age-related macular degeneration with geographic atrophy: a prospective cohort study.

BACKGROUND: There is growing evidence of the importance of nutrition in age-related macular degeneration (AMD), but few studies have explored associations with folate and B vitamins. No effective therapeutic strategy for geographic atrophy (GA) is available, and prevention could be of great value. OBJECTIVE: We investigated associations between dietary folate, B vitamins, and progression to GA and whether these associations might be modified by genetic susceptibility. DESIGN: Among 2525 subjects (4663 eyes) in the Age-Related Eye Disease Study, 405 subjects (528 eyes) progressed to GA over 13 y. Folate and B vitamins were log transformed and calorie adjusted separately for men and women. Ten loci in 7 AMD genes [complement factor H, age-related maculopathy susceptibility 2/high-temperature requirement A serine peptidase 1, complement component 2, complement component 3, complement factor B, collagen type VIII α 1, and RAD51 paralog B] were examined. Survival analysis was used to assess associations between incident GA and dietary intake of folate and B vitamins. Interaction effects between these nutrients and genetic variation on AMD risk were also evaluated. Subjects with at least one eye free of advanced AMD at baseline were included in these analyses. RESULTS: There was a reduced risk of progression to GA with increasing intake of thiamin, riboflavin, and folate after adjusting for age, sex, and total energy intake (P-trend = 0.01, 0.03, and 0.001, respectively). After adjustment for demographic, behavioral, ocular, and genetic covariates, trends remained statistically significant for folate (P-trend = 0.007) and were borderline for thiamin (P-trend = 0.05). Riboflavin did not retain statistical significance (P-trend = 0.20). Folate was significantly associated with lower risk of incident GA among subjects homozygous for the complement component 3 (C3) R102G rs2230199 nonrisk genotype (CC) (HR = 0.43; 95% CI: 0.27, 0.70; P = 0.0005) but not subjects carrying the risk allele (G) (P = 0.76). Neither folate nor any B vitamin was significantly associated with neovascular AMD. CONCLUSIONS: High folate intake was associated with a reduced risk of progression to GA. This relation could be modified by genetic susceptibility, particularly related to the C3 genotype. This trial was registered at clinicaltrials.gov as NCT00594672.