Splenic monocytes drive pathogenic subretinal inflammation in age-related macular degeneration.

Age-related macular degeneration (AMD) is invariably associated with the chronic accumulation of activated mononuclear phagocytes in the subretinal space. The mononuclear phagocytes are composed of microglial cells but also of monocyte-derived cells, which promote photoreceptor degeneration and choroidal neovascularization. Infiltrating blood monocytes can originate directly from bone marrow, but also from a splenic reservoir, where bone marrow monocytes develop into angiotensin II receptor (ATR1)+ splenic monocytes. The involvement of splenic monocytes in neurodegenerative diseases such as AMD is not well understood. Using acute inflammatory and well-phenotyped AMD models, we demonstrate that angiotensin II mobilizes ATR1+ splenic monocytes, which we show are defined by a transcriptional signature using single-cell RNA sequencing and differ functionally from bone marrow monocytes. Splenic monocytes participate in the chorio-retinal infiltration and their inhibition by ATR1 antagonist and splenectomy reduces the subretinal mononuclear phagocyte accumulation and pathological choroidal neovascularization formation. In aged AMD-risk ApoE2-expressing mice, a chronic AMD model, ATR1 antagonist and splenectomy also inhibit the chronic retinal inflammation and associated cone degeneration that characterizes these mice. Our observation of elevated levels of plasma angiotensin II in AMD patients, suggests that similar events take place in clinical disease and argue for the therapeutic potential of ATR1 antagonists to inhibit splenic monocytes for the treatment of blinding AMD.

Systemic infection in aged mice causes upregulation of crystallin alpha A in the RPE/choroid.

Aging changes the responsiveness of our immune defense, and this decline in immune reactivity plays an important role in the increased susceptibility to infections that marks progressing age. Aging is also the most pronounced risk factor for development of age-related macular degeneration (AMD), a disease that is characterized by dysfunctional retinal pigment epithelial (RPE) cells and loss of central vision. We have previously shown that acute systemic viral infection has a large impact on the retina in young mice, leading to upregulation of chemokines in the RPE/choroid (RPE/c) and influx of CD8 T cells in the neuroretina. In this study, we sought to investigate the impact of systemic infection on the RPE/c in aged mice to evaluate whether infection in old age could play a role in the pathogenesis of AMD. We found that systemic infection in mice led to upregulation of genes from the crystallin family in the RPE/c from aged mice, but not in the RPE/c from young mice. Crystallin alpha A (CRYAA) was the most upregulated gene, and increased amounts of CRYAA protein were also detected in the aged RPE/c. Increased CRYAA gene and protein expression has previously been found in drusen and choroid from AMD patients, and this protein has also been linked to neovascularization. Since both drusen and neovascularization are important hallmarks of advanced AMD, it is interesting to speculate if upregulation of crystallins in response to infection in old age could be relevant for the pathogenesis of AMD.

Vision-related quality of life is selectively affected by comorbidities in patients with geographic atrophy.

BACKGROUND: The atrophic late stage of age-related macular degeneration (AMD) is termed geographic atrophy (GA), and affects visual acuity (VA) as well as quality of life (QoL). Previous studies have found that best-corrected VA (BCVA), the standard vision assessment often underrepresents functional deficits. Therefore, the purpose of this study was to evaluate the correlation between atrophic lesion size, VA and QoL measured with the National Eye Institute Visual Function Questionnaire (VFQ-39) in a Danish population. Moreover, we wanted to evaluate the correlation between comorbidities, behavioural factors, and QoL. METHODS: This was prospective clinical study of 51 patients with GA in one or both eyes, of these 45 patients had bilateral GA. Patients were consecutively included between April 2021 and February 2022. All patients filled in the VFQ-39 questionnaire except the subscales "ocular pain" and "peripheral vision." Lesion size was measured from fundus autoflourescense images, and BCVA was assessed by the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. RESULTS: We found an overall low score in each VFQ-39 subscale scores reflected by GA. Lesion size and VA were both significantly associated with all VFQ-39 subscale scores except for "general health." VA showed a larger effect on QoL than lesion size. Chronic obstructive pulmonary disease (COPD) was associated with a lower score in the subscale score "general health" but none of the other subscale scores were affected. Cardiovascular disease (CVD) was associated with a lower BCVA as well as in QoL reflected in the subscale scores "poor general vision," "near activities," and "dependency" of VFQ-39. CONCLUSION: Both atrophic lesion size and visual acuity affects QoL in Danish patients with GA, who reports an overall poor QoL. CVD seems to have a negative effect on disease, as well as in VFQ-39 in several subscales, whereas COPD did not affect disease severity or vision-related subscales in VFQ-39.

Retinal telangiectasia-like lesions in a 15-year-old female with Hereditary hemorrhagic telangiectasia - a case report.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber syndrome is a bleeding disorder that can affect all parts of the body including the eyes. Different ocular abnormalities have been described in relation to HHT, but the pathogenesis of retinal involvement is still unknown. A few cases have described chorioretinal abnormalities primarily occurring in elderly patients. In this study, we present a unique case of a young female with known HHT and a series of retinal fundus images including optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) with macular telangiectasia-like lesions. CASE PRESENTATION: A young female genetically diagnosed with hereditary hemorrhagic telangiectasia (HHT), is regularly attending retinal screening since she is diagnosed with Type 1 diabetes. At one visit, abnormal retinal telangiectasia-like lesions in the macula, are observed. These abnormalities are monitored over an extended period of time with fundus imaging, and further investigated with OCT and OCTA. The patient has no visual complaints at any time and best-corrected visual acuity is 20/20 Snellen equivalent in both eyes. CONCLUSIONS: To the best of our knowledge, this is the first case to describe the occurrence of telangiectasia-like lesions in macula with secondary choriocapillaris atrophy in a patient diagnosed with HHT in such a young age.

Full-Field Electroretinography Changes Associated with Age-Related Macular Degeneration: A Systematic Review with Meta-Analyses.

BACKGROUND: The aim of this study was to systematically review the literature and to perform meta-analyses on full-field electroretinography (ffERG) between healthy controls and age-related macular degeneration (AMD) to map the extent of retinal dysfunction. SUMMARY: We systematically searched 11 databases on 3 March 2021. Eligible studies had to measure retinal function using ffERG in eyes with AMD and in healthy controls. We extracted data on a-wave and b-wave function in dark- and light-adapted ffERG and calculated summary estimates on differences between eyes with AMD and controls using weighted mean differences (WMD). Subgroup analyses were made for early and late AMD. Six studies (n = 481 eyes) were eligible for review (301 with any AMD, 180 controls). For dark-adapted data, any AMD was associated with reduced a-wave amplitude (WMD: -17.16 µV; 95% CI: -31.79 to -2.52 µV; p = 0.02) and b-wave amplitude (WMD: -28.70 µV; 95% CI: -51.40 to -6.01 µV; p = 0.01). For light-adapted data, any AMD was associated with longer a-wave implicit time (WMD: 0.92 ms; 95% CI: 0.12-1.72 ms; p = 0.02), reduced b-wave amplitude (WMD: -13.26 µV; 95% CI: -18.64 to -7.88 µV; p < 0.0001), and longer b-wave implicit time (WMD: 0.69 ms; 95% CI: 0.30-1.08 ms; p = 0.0006). Subgroup analyses found that these changes were only statistically significant in eyes with late AMD, not early AMD. KEY MESSAGES: Reduced retinal function on ffERG is present in eyes with AMD, in particular those with late AMD. These findings suggest that AMD is a pan-retinal disease with AMD-associated photoreceptor dysfunction beyond the macula.

Correlation of macular sensitivity measures and visual acuity to vision-related quality of life in patients with age-related macular degeneration.

BACKGROUND: Visual acuity is commonly used as a functional outcome measure in patients with age-related macular degeneration (AMD), despite having a weak correlation with self-perceived visual quality of life. Microperimetry is a useful method of detecting loss of macular function. We wanted to investigate the relationship between these two objective visual outcome measures and subjective vision-related quality of life, finding out which objective measure is more patient-relevant. METHODS: Fifty-one consecutive patients with AMD were recruited to the study. Participants were required to complete the Visual Function Questionnaire 39, the Early Treatment Diabetic Retinopathy Study visual acuity examination and a microperimetry assessment using the Micro Perimeter 3. One patient withdrew consent and seven patients dropped out due to cooperation difficulties under microperimetry. Forty-three patients with AMD were included in the study: twenty-eight patients with late AMD (exudative AMD) and fifteen patients with early (non-exudative) AMD. The right eye was included as standard, as was the eye with the best-corrected visual acuity. RESULTS: There was a higher correlation between vision-related quality of life and macular sensitivity (r = 0.458; p = 0.014) than between vision-related quality of life and visual acuity (r = 0.446; p = 0.018) in patients with late AMD. There was a positive correlation between vision-related quality of life and macular sensitivity in patients with early AMD (r = 0.542; p = 0.037) while the correlation between vision-related quality of life and visual acuity in these patients was not statistically significant. Composite score (r = 0.469; p = 0.012) correlated highest with the nasal outer macular sub-region and near-distance activities score (r = 0.652; p < 0.001) correlated highest with the nasal inner macular sub-region in patients with late AMD. Correlations between composite score and macular sub-regions in patients with early AMD were not significant, but near-distance activities score correlated with the nasal outer macular sub-region in these patients (r = 0.469; p = 0.012). CONCLUSIONS: Macular sensitivity as measured using microperimetry correlates with vision-related quality of life in early AMD and in late AMD, showing it to be a patient-relevant outcome measure. Furthermore, the nasal sub-regions of the macula appear to be preferred retinal loci in patients with AMD. (338 words).

The transcriptome of peripheral blood mononuclear cells in patients with clinical subtypes of late age-related macular degeneration.

BACKGROUND: Peripheral blood mononuclear cells (PBMCs) are implicated in the pathogenesis of age-related macular degeneration (AMD). We here mapped the global gene transcriptome of PBMCs from patients with different clinical subtypes of late AMD. RESULTS: We sampled fresh venous blood from patients with geographic atrophy (GA) secondary to AMD without choroidal neovascularizations (n = 19), patients with neovascular AMD without GA (n = 38), patients with polypoidal choroidal vasculopathy (PCV) (n = 19), and aged control individuals with healthy retinae (n = 20). We isolated PBMCs, extracted RNA, and used microarray to investigate gene expression. Volcano plots identified statistically significant differentially expressed genes (P < 0.05) at a high magnitude (≥30% higher/lower) for GA (62 genes), neovascular AMD (41 genes), and PCV (41 genes). These clinical subtypes differed substantially across gene expression and the following pathways identified in enrichment analyses. In a subgroup analysis, we investigated presence vs. absence of subretinal fibrosis and found 826 differentially expressed genes (≥30% higher/lower, P < 0.05) with relation to mRNA splicing, endothelial migration, and interleukin-1 signaling. CONCLUSIONS: We here map the global gene transcriptome of PBMCs related to clinical subtypes of late AMD and find evidence of subtype-specific immunological involvement. Our findings provide a transcriptomic insight into the systemic immunity associated with AMD.

Low health literacy levels in patients with chronic retinal disease.

BACKGROUND: A patient's health literacy is fundamental for navigating the health system and managing disease. This study aimed to compare the health literacy levels of patients with chronic retinal disease in Denmark. METHODS: This cross-sectional questionnaire study used the validated HLS-EU-Q16 questionnaire to determine the health literacy of 225 patients with age-related macular degeneration (AMD), diabetic macular edema (DME) or retinal vein occlusion (RVO), receiving intravitreal treatment at the retinal clinic, Zealand University Hospital, Denmark. Patients were consecutively included as participants for the study. All patients had the option of having the survey read aloud to them. RESULTS: Health literacy levels between the patient groups did not differ significantly, however, the proportion of patients with poor health literacy was high-65% of AMD patients, 73% of DME patients, and 63% of patients with RVO. CONCLUSIONS: Low health literacy of patients with retinal disease signify a need for more health literacy research in the field of retinal diseases, to secure that patients have the timely and appropriate knowledge and competencies to manage their condition.

Altered activation state of circulating neutrophils in patients with neovascular age-related macular degeneration.

BACKGROUND: Neutrophil dysfunction plays a key role in the development of diseases characterized by inflammation and angiogenesis. Here, we studied the systemic expression of neutrophil markers reflecting activation, adhesion, and resolution of inflammation in patients with neovascular age-related macular degeneration (AMD). RESULTS: This was a prospective case-control study of patients with neovascular AMD and age-matched healthy control individuals. Patients were recruited from an outpatient program, and control individuals were recruited amongst patients' relatives. Current smokers and individuals with either active immune-disease or ongoing cancer were not included, as these factors are known to affect neutrophil function. Fresh-drawn venous blood was processed for flow cytometric analysis of neutrophil markers. We determined percentages of positive cells and compared expression levels using fluorescence intensity measures. We found conditional differences on marker expression between patients with neovascular AMD (n = 29) and controls (n = 28): no differences were found when looking broadly, but several differences emerged when focusing on non-smokers. Here, patients with neovascular AMD had increased expression of the activity marker cluster of differentiation (CD) 66b (P = 0.003; Mann-Whitney U test), decreased expression of adhesion marker CD162 (P = 0.044; Mann-Whitney U test), and lower expression of the resolution of inflammation marker C-X-C chemokine receptor 2 (P = 0.044; Mann-Whitney U test). CONCLUSIONS: We present novel evidence suggesting that the activity of circulating neutrophils, sensitive to smoking, may differ in patients with neovascular AMD.

Blood expression levels of chemokine receptor CCR3 and chemokine CCL11 in age-related macular degeneration: a case-control study.

BACKGROUND: Dysregulation of the CCR3/CCL11 pathway has been implicated in the pathogenesis of choroidal neovascularisation, a common feature of late age-related macular degeneration (AMD). The aim of this study was to investigate the expression of CCR3 and its ligand CCL11 in peripheral blood in patients with neovascular AMD. METHODS: Patients with neovascular AMD and healthy controls were included. Blood samples were obtained and prepared for flow cytometry to investigate the expression of CCR3. Levels of CCL11 were measured in plasma using Cytometric Bead Array. Differences between the groups were tested using Kruskal-Wallis test and Mann-Whitney U test. RESULTS: Patients (n = 83) with neovascular AMD and healthy control persons (n = 114) were included in the study. No significant difference in the expression of CCR3 was found on CD9+ granulocytes when comparing patients suffering from neovascular AMD with any of the control groups. We did not find any alteration in CCL11 levels in patients among the age matched groups. There was no correlation between expression of CCR3/CCL11 and clinical response to treatment with anti-vascular endothelial growth factor (VEGF). CONCLUSION: Our results do not suggest a systemic alteration of the CCR3/CCL11 receptor/ligand complex in patients with neovascular AMD.

Interleukin-8 Promoter Polymorphism -251 A/T and Treatment Response in Neovascular Age-related Macular Degeneration.

Purpose: Interleukin-8 (IL-8) is a potent pro-angiogenic and pro-inflammatory chemokine, suggested to hold a role in neovascular age-related macular degeneration (nAMD). Our aim is to study the association of the single-nucleotide polymorphism -251 A/T (rs4073) in the IL-8 promoter region with the treatment response to intravitreal anti-vascular endothelial growth factor (VEGF) injections in nAMD. Patients and Methods: This is a prospective study of treatment-naïve patients with nAMD. Treatment response after a loading dose of three intravitreal anti-VEGF injections was defined as functional response based on change in visual acuity, and morphological response based on change in central retinal thickness (CRT) and intraretinal fluid on optical coherence tomography. Morphological response was categorized in good, partial, and poor responders. Blood DNA was analyzed for -251 A/T genotype. Results: The IL-8 promoter polymorphism -251 A/T was not significantly associated to functional treatment response (P=0.09). No significant association was found between genotype and morphological treatment response (P=0.799). Older age was significantly associated to good morphological responders compared to partial and poor responders (P=0.014). Conclusion: The IL-8 polymorphism -251 A/T is not associated to morphological nor functional treatment response to intravitreal anti-VEGF injections in patients with nAMD.

Microperimetry and Structural Risk Factors on OCT in Intermediate Age-Related Macular Degeneration.

PURPOSE: To determine the relationship between structural biomarkers on OCT that increase the risk of disease progression and microperimetric retinal sensitivity in patients with intermediate age-related macular degeneration (iAMD). DESIGN: Prospective cross-sectional, observational study. PARTICIPANTS: Forty-five eyes of 23 patients with iAMD. METHODS: Patients underwent OCT and microperimetry. OCT scans were evaluated for the risk factors intraretinal hyperreflective foci (HRF), hyporeflectivity within drusenoid lesions (HRDL), subretinal drusenoid deposits, double-layer sign (DLS), and drusen volume. Microperimetric retinal sensitivity was analyzed with a 33-point grid covering the macula. With a novel method of determining what part of the retina corresponded to each microperimetry point, a Voronoi diagram was constructed, dividing the macula in cells consisting of the region nearer to each point than any other. The Voronoi diagram was superimposed on the OCT, making it possible to determine the point-to-point location of the OCT risk factors. Univariable and multivariable linear mixed-effect models were used for analysis. MAIN OUTCOME MEASURES: Association between microperimetric retinal sensitivity and OCT risk factors at individual measuring points. RESULTS: One thousand four hundred seventy-nine points of retinal sensitivity and corresponding structural area on OCT were included in this study. Retinal sensitivity was significantly decreased with presence of the OCT risk factors HRF, HRDL, DLS, and drusen volume (all P < 0.001) when analyzed with the univariable linear mixed-effect model. The multivariable model showed a significant decrease of retinal sensitivity with presence of HRF (P < 0.001), DLS (P = 0.025), and greater drusen volume (P < 0.001). CONCLUSIONS: Presence of HRF, DLS, and greater drusen volume, all of which increase the risk of disease progression, is significantly and independently associated with decreased microperimetric retinal sensitivity in patients with iAMD. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Chemokine Receptor Profile of T Cells and Progression Rate of Geographic Atrophy Secondary to Age-related Macular Degeneration.

Purpose: Geographic atrophy (GA) secondary to age-related macular degeneration is a progressive retinal degenerative disease. Systemic chemokine receptors and known risk-associated single-nucleotide polymorphisms have been associated with GA pathogenesis. Because halting progression is pivotal for patients, we investigated the association of candidate chemokine receptors and progression rate (PR) of atrophic lesions in patients with GA. Methods: This prospective observational study conducted at a single center included 85 patients with GA and 45 healthy controls. Patients were followed up after 13 months on average. Serial fundus autofluorescence images were used to determine the PR of atrophic lesions. The proportion of chemokine receptors on peripheral lymphocytes were determined by flow cytometric analysis. Results: Patients with GA had a lower proportion of CCR6 on CD8+T cells compared to healthy controls. Importantly, the proportion of CCR6 on CD4+T cells was lower in patients with fast GA progression compared to patients with slow progression of disease, suggesting that dysregulation of CCR6 could be involved in progression of GA. We also found that GA patients had a markedly higher percentage of CCR5 on CD4+ and CD8+T cells compared to healthy controls. After stratification according to ARMS2 polymorphism, we found a significantly lower level of CCR5 on CD8+T cells among patients with high-risk genotypes compared with patients with the low-risk genotype. Conclusions: Our study finds that chemokine receptors are dysregulated in patients with GA and that CCR6 might be involved in GA progression, making it a potential target for intervention.

VEGF Inhibition Associates With Decreased Risk of Mortality in Patients With Neovascular Age-related Macular Degeneration.

Purpose: Controversy exists regarding the systemic safety of intravitreal VEGF inhibitors in the treatment of neovascular age-related macular degeneration (nAMD). We aimed to investigate the potential impact of VEGF inhibitor treatment on the risk of all-cause mortality and cardiovascular disease (CVD) among patients with nAMD. Design: A nationwide register-based cohort study with 16 years follow-up. Participants: Patients with nAMD exposed with VEGF inhibitors (n = 37 733) and unexposed individuals without nAMD (n = 1 897 073) aged ≥ 65 years residing in Denmark between January 1, 2007, and December 31, 2022. Methods: Cox proportional hazards analysis was conducted to assess the effect of intravitreal VEGF inhibitor treatment on all-cause mortality and incident CVD. Main Outcome Measures: In a predefined analysis plan we defined primary outcomes as hazard ratios (HRs) of all-cause mortality and a composite CVD endpoint in patients with nAMD treated with VEGF inhibitors compared with individuals without nAMD. The secondary outcomes encompassed analyses that explored the impact of the number of doses and the association between exposure and outcome over a specific time period. Results: Overall, 63.7% of patients with nAMD were women with an average age of 69.9 years (interquartile range 65.0-76.0 years). Patients exposed to VEGF inhibitors demonstrated a reduced risk of all-cause mortality compared with individuals without nAMD (HR, 0.79; 95% confidence interval [CI], 0.78-0.81), and an increased risk of composite CVD (HR, 1.04; 95% CI, 1.01-1.07). The decreased risk of all-cause mortality persisted, but there was no significant association between VEGF inhibitor treatment and CVD when patients with nAMD were grouped by the number of doses or considered exposed within 60 days postinjection. Conclusions: Our study revealed a decreased risk of all-cause mortality and a 4% increased risk of CVD among patients with nAMD exposed with VEGF inhibitors. The decreased risk of mortality is unlikely to be directly pathophysiologically related to VEGF inhibitor treatment. Instead, we speculate that patients undergoing VEGF inhibitor treatment are, on average, individuals in good health with adequate personal resources. Therefore, they also have a higher likelihood of overall survival. These findings strongly support the safety of VEGF inhibitor treatment in terms of all-cause mortality and CVD among patients with nAMD. Financial Disclosures: The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Neuroretinal degeneration in a mouse model of systemic chronic immune activation observed by proteomics.

Blindness or vision loss due to neuroretinal and photoreceptor degeneration affects millions of individuals worldwide. In numerous neurodegenerative diseases, including age-related macular degeneration, dysregulated immune response-mediated retinal degeneration has been found to play a critical role in the disease pathogenesis. To better understand the pathogenic mechanisms underlying the retinal degeneration, we used a mouse model of systemic immune activation where we infected mice with lymphocytic choriomeningitis virus (LCMV) clone 13. Here, we evaluated the effects of LCMV infection and present a comprehensive discovery-based proteomic investigation using tandem mass tag (TMT) labeling and high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS). Changes in protein regulation in the posterior part of the eye, neuroretina, and RPE/choroid were compared to those in the spleen as a secondary lymphoid organ and to the kidney as a non-lymphoid but encapsulated organ at 1, 8, and 28 weeks of infection. Using bioinformatic tools, we found several proteins responsible for maintaining normal tissue homeostasis to be differentially regulated in the neuroretina and the RPE/choroid during the degenerative process. Additionally, in the organs we observed, several important protein pathways contributing to cellular homeostasis and tissue development were perturbed and associated with LCMV-mediated inflammation, promoting disease progression. Our findings suggest that the response to a systemic chronic infection differs between the neuroretina and the RPE/choroid, and the processes induced by chronic systemic infection in the RPE/choroid are not unlike those induced in non-immune-privileged organs such as the kidney and spleen. Overall, our data provide detailed insight into several molecular mechanisms of neuroretinal degeneration and highlight various novel protein pathways that further suggest that the posterior part of the eye is not an isolated immunological entity despite the existence of neuroretinal immune privilege.

Exudative Progression of Treatment-Naïve Nonexudative Macular Neovascularization in Age-Related Macular Degeneration: A Systematic Review With Meta-Analyses.

PURPOSE: To systematically review and report the rate of exudative progression over time in patients with nonexudative macular neovascularization (MNV) in age-related macular degeneration (AMD). DESIGN: Systematic review with prevalence meta-analyses and individual participant meta-analysis. METHODS: We searched 10 literature databases on March 26, 2023, for studies of consecutive patients with treatment-naïve nonexudative MNV in AMD. The primary outcome of interest was time from diagnosis to exudative progression. We conducted meta-analyses on the prevalence of exudative progression at 1 and 2 years. Where possible, we extracted individual participant data from studies and conducted an individual participant meta-analysis and explored the exudative progression using a time-to-event curve. RESULTS: We identified 16 eligible studies with a total of 384 eyes with nonexudative MNV. Exudative progression had occurred in 20.9% (95% CI 13.1%-29.8%) of eyes at 1 year and in 30.7% (95% CI 21.8%-40.4%) at 2 years. Similar results were observed in the individual participant meta-analysis, showing exudative progression in 18.9% (95% CI 13.5%-26.3%) of eyes at 1 year and 31.3% (95% CI 24.2%-40.0%) at 2 years. Risk factors for a fast exudative progression were the presence of subretinal lipid globules, large MNV areas, rapid MNV growth, growth in pigment epithelium detachment height and width, appearance of a branching pattern, and development of a hyporeflective halo around the MNV. CONCLUSIONS: Nonexudative MNVs in AMD are at high risk of exudative progression. Recognition of these lesions may allow for better individualized follow-up regimens in which closer monitoring may facilitate earlier diagnosis of exudative progression.

Lifestyle and demographic associations with 47 inflammatory and vascular stress biomarkers in 9876 blood donors.

BACKGROUND: The emerging use of biomarkers in research and tailored care introduces a need for information about the association between biomarkers and basic demographics and lifestyle factors revealing expectable concentrations in healthy individuals while considering general demographic differences. METHODS: A selection of 47 biomarkers, including markers of inflammation and vascular stress, were measured in plasma samples from 9876 Danish Blood Donor Study participants. Using regression models, we examined the association between biomarkers and sex, age, Body Mass Index (BMI), and smoking. RESULTS: Here we show that concentrations of inflammation and vascular stress biomarkers generally increase with higher age, BMI, and smoking. Sex-specific effects are observed for multiple biomarkers. CONCLUSION: This study provides comprehensive information on concentrations of 47 plasma biomarkers in healthy individuals. The study emphasizes that knowledge about biomarker concentrations in healthy individuals is critical for improved understanding of disease pathology and for tailored care and decision support tools.

Blood-based biomarkers are circulating molecules that can help to indicate health or disease. Biomarker levels may vary depending on demographic and lifestyle factors such as age, sex, smoking status, and body mass index. Here, we examine the effects of these demographic and lifestyle factors on levels of biomarkers related to activation of the immune system and cardiovascular stress. Measurements of 47 different proteins were performed on blood samples from nearly 10,000 healthy Danish blood donors. Measurement data were linked with questionnaire data to assess effects of lifestyle. We found that immune activation and vascular stress generally increased with age, BMI, and smoking. As these measurements are from healthy blood donors they can serve as a reference for expectable effects and inflammation levels in healthy individuals. Knowledge about the healthy state is important for understanding disease progression and optimizing care.

Age-related macular degeneration is associated with increased proportion of CD56(+) T cells in peripheral blood.

PURPOSE: To examine the association between age-related changes in the T-cell compartment and prevalence of age-related macular degeneration (AMD). DESIGN: Case-control study. PARTICIPANTS: A total of 117 AMD cases and 106 controls were included prospectively. METHODS: Fresh-drawn peripheral blood samples were processed for flow cytometric analysis of T-cell populations. Plasma samples were analyzed for anti-cytomegalovirus (CMV) immunoglobulin (Ig)G and complement factor H (CFH) Y402H genotype. The diagnosis of AMD was made according to the Clinical Age-Related Maculopathy Staging System. MAIN OUTCOME MEASURES: Association between frequency of aged T cells and prevalence of AMD. RESULTS: The prevalence of AMD was associated with distinct age-related changes in the T-cell compartment. Specifically, the patients with AMD had an increased frequency of CD28(-) T cells that expressed the CD56 surface marker (patients, 34.9% vs. aged controls, 25.8%; P = 0.002). Participants in the highest tertile of CD56(+) CD28(-) T cells had an odds ratio (OR) for the presence of AMD of 3.2 (95% confidence interval [CI], 1.2-8.8) after adjustment for CFH genotype, anti-CMV IgG positivity, age, sex, and smoking history. The adjusted OR of the presence of AMD for persons having at least 1 CFH H402 risk allele increased from 3.5 (95% CI, 1.5-8.1) to 13.3 (95% CI, 3.3-53.6) for persons with at least 1 CFH H402 risk allele and above the median level of CD56(+) CD28(-) T cells. CONCLUSIONS: We found increased levels of circulating aged CD56(+) CD28(-) T cells in patients with AMD. Although this supports the notion of AMD as a systemic disease, it also suggests that the adaptive immune system is implicated in its pathogenesis.

Age-related macular degeneration.

This review investigates age-related macular degeneration (AMD) which is a degenerative retinal disease. The pathogenesis of the disease is unknown, but tobacco smoking is a significant risk factor for the development of the disease. The wet form of AMD can be treated by intraocular injection of an antibody that binds vascular endothelial growth factor (VEGF) which is involved in the disease process. The introduction of anti-VEGF treatment is a major reason why blindness secondary to wet AMD is now negligible. The demographic development can be expected to increase the demand for treatment of AMD considerably in the future.

Heart-Rate Variability Correlates to Choroidal Thickness in Central Serous Chorioretinopathy.

Purpose: Patients with central serous chorioretinopathy (CSC) have previously been shown to have a lower heart rate variability (HRV), implying a lower vagal tone. Vagal tone alters mineralocorticoids, which in turn affect the thickness of the choroid. Since increased choroidal thickness is characteristic of CSC, we wanted to investigate its correlation with HRV. Patients and Methods: In this case-control study, 21 acute CSC patients and 31 healthy controls were included. Diagnosis was confirmed by optical coherence tomography (OCT) and retinal examination. HRV was evaluated following accepted standards. Outcome measures were chosen beforehand as follows: Standard deviation of N-N intervals (SDNN), root mean square of successive differences (RMSDD), low frequency/high frequency ratio (LF/HF ratio), and standard deviation ratio from commonly used Poincare plot (SD2/SD1 ratio). Choroidal thickness was measured using OCT directly under the foveola. Results: Patients and healthy controls did not differ in health and medical characteristics in addition to CSC disease. Choroidal thickness was greatest in patients with CSC (mean±SD: 342±80 µm) compared to controls (235±60 µm, p<0.0001). A correlation was observed between LF/HF ratio and choroidal thickness in patients with CSC (Pearson correlation 0.63, p=0.02), where the CSC group had a lower LF/HF ratio (Median 2.39 ms2, IQR: 1.2-4.34 ms2) compared to controls (Median 1.2 ms2, IQR: 0.9-2.4 ms2, p=0.06) and SD2/SD1 ratio (CSC 0.59±0.2 vs controls 0.74±0.3, p=0.06). Conclusion: We found a correlation between the thickness of the choroid and the HRV-measured LF/HF ratio in patients with CSC and showed a borderline significant reduction in HRV measurements in patients with CSC. The data imply that vagal alterations exist in patients with CSC. Due to the low n, this should be considered as a pilot study. Further studies are warranted to elucidate mechanisms and validate findings.