Association between Subretinal Drusenoid Deposits and Age-Related Macular Degeneration in Multimodal Retinal Imaging.

Multimodal retinal imaging enables the detection of subretinal drusenoid deposits (SDD) with significantly greater accuracy compared to fundus photography. The study aimed to analyze a relationship between the presence of SDD, the clinical picture of AMD, and disease progression in a 3 year follow-up. A total of 602 eyes of 339 patients with a diagnosis of AMD, of which 121 (55%) had SDD confirmed in multimodal retinal imaging, were enrolled in the study. SDD was related to a more advanced stage of AMD (p = 0.008), especially with the presence of geographic atrophy (OR = 4.11, 95% CI 2.02-8.38, p < 0.001). Eyes with SDD presented significantly lower choroidal and retinal thickness (ATC: 210.5 µm, CRT: 277 µm, respectively) and volume (AVC: 0.17 mm3, CRV: 8.29 mm3, p < 0.001, respectively) compared to SDD-negative eyes (ATC: 203 µm, CRT: 277 µm; AVC: 7.08 mm3, 8.54 mm3, p < 0.001). Accordingly, the prevalence of pachychoroids and pachyvessels was significantly lower in the SDD present group than in eyes without SDD (p = 0.004; p = 0.04, respectively). Neither demographic factors, lipid profile, genetic predisposition, systemic vascular disease comorbidities, nor parameters of retinal vessels were affected by the presence of SDD. We found no effect of SDD presence on AMD progression (p = 0.12). The presence of SDD appeared to be related to local rather than systemic factors.

Does the Presence of the Cilioretinal Artery Affect the Incidence, Clinical Picture and Progression of Age-Related Macular Degeneration?

The aims of this study were to analyze the relationship between the presence of the cilioretinal artery (CRA) and the incidence, severity and progression of age-related macular degeneration (AMD) and to estimate the influence of the CRA on choroidal and retinal parameters. A total of 287 patients with AMD and 110 healthy controls were enrolled in the study. CRA occurrence was determined using color fundus images. AMD progression was assessed after 3 years. There was no difference in the incidence of CRA between the AMD and control groups (23.34% vs. 24.55%; p = 0.8). Lower-stage AMD was more frequently observed in eyes with the CRA than in eyes without the artery (p = 0.016). The CRA did not influence disease progression (p = 0.79). The CRA did not influence retinal and choroidal thickness and volume parameters or the retinal vessel caliber and functionality in either the AMD or control groups. There was no relationship between CRA presence and CFH Y402H and ARMS2 A69S risk variants. The results did not show a protective effect of the CRA on the incidence and progression of AMD. The CRA may affect the severity of AMD; however, the mechanism of this phenomenon is unclear.

Influence of Clinical and Genetic Factors on the Progression of Age-Related Macular Degeneration: A 3-Year Follow-Up.

The aim of the present study was to analyze the relationship of age-related macular degeneration (AMD) progression with clinical characteristics, demographic, and environmental risk factors that would affect disease development. In addition, the influence of three genetic AMD polymorphisms (CFH Y402H, ARMS2 A69S, and PRPH2 c.582-67T>A) on AMD progression was investigated. In total, 94 participants with previously diagnosed early or intermediate AMD in at least one eye were recalled for an updated re-evaluation after 3 years. The initial visual outcomes, medical history, retinal imaging data, and choroidal imaging data were collected to characterize the AMD disease status. Among the AMD patients, 48 demonstrated AMD progression, and 46 showed no disease worsening at 3 years. Disease progression was significantly associated with worse initial visual acuity (OR = 6.74, 95% CI = 1.24-36.79, p = 0.03) and the presence of the wet AMD subtype in fellow eyes (OR = 3.79, 95%CI = 0.94-15.2, p = 0.05). In addition, a higher risk of AMD progression appeared in the patients with active thyroxine supplementation (OR = 4.77, CI = 1.25-18.25, p = 0.002). The CC variant of CFH Y402H was associated with AMD advancement compared to the TC+TT phenotype (OR = 2.76, 95% CI: 0.98-7.79, p = 0.05). Identifying risk factors of AMD progression may lead to earlier intervention and better outcomes, preventing the expansion of the late stage of the disease.

The impact of vascular risk factors on the thickness and volume of the choroid in AMD patients.

Disturbances in choroidal microcirculation may lead to the onset and progression of age-related macular degeneration (AMD). We aimed to assess changes in the choroidal volume and thickness in the macular region in AMD eyes and to investigate whether coexisting vascular risk factors alter choroidal status. We enrolled 354 AMD patients (175 dry, 179 wet AMD) and 121 healthy controls. All participants underwent a complete ophthalmologic examination and assessment of choroidal thickness and volume. A multivariate analysis adjusted for age, sex, and smoking status revealed that wet AMD was an independent factor associated with higher average thickness of the central ring area (ATC) and average volume of the central ring area (AVC) and lower choroidal vascularity index (CVI) compared to controls (ß = + 0.18, p = 0.0007, ß = + 0.18, p = 0.0008, respectively) and to dry AMD (ß = + 0.17, p = 0.00003 for both ATC and AVC and ß = - 0.30 p < 0.0001 for CVI). ATC, AVC and average volume (AV) were lower in AMD patients with hypertension and ischaemic heart disease (IHD). The duration of hypertension was inversely correlated with ATC, AVC and AV (Rs = - 0.13, p < 0.05; Rs = - 0.12; p < 0.05, Rs = - 0.12; p < 0.05, respectively) while IHD duration negatively correlated with AV (Rs = - 0.15, p < 0.05). No such associations were observed in the control group. Our findings show that the choroidal vascular system in eyes with AMD is much more susceptible to damage in the presence than in the absence of systemic vascular disease.

Long-Term Effects of Adjuvant Intravitreal Treatment with Autologous Bone Marrow-Derived Lineage-Negative Cells in Retinitis Pigmentosa.

BACKGROUND: Autologous bone marrow-derived lineage-negative (Lin-) cells present antiapoptotic and neuroprotective activity. The aim of the study was to evaluate the safety and efficacy of novel autologous Lin- cell therapy during a 12-month follow-up period. METHODS: Intravitreal injection of Lin- cells in 30 eyes with retinitis pigmentosa (RP) was performed. The fellow eyes (FEs) were considered control eyes. Functional and morphological eye examinations were performed before and 1, 3, 6, 9, and 12 months after the injection. RESULTS: Patients whose symptoms started less than 10 years ago gained 14 ± 10 letters, while those with a longer disease duration gained 2.86 ± 8.54 letters compared to baseline at the 12-month follow-up (p = 0.021). There were significantly higher differences in response densities of P1-wave amplitudes in the first ring of multifocal ERGs in treated eyes than FE recordings in all follow-up points were detected. Accordingly, the mean deviation in 10-2 static perimetry improved significantly in the treated eyes compared with fellow eyes 12 months after the procedure. The QoL scores improved significantly and lasted until the 9-month visit. CONCLUSION: Lin- cell-based therapy is safe and effective, especially for a well-selected group of RP patients who still maintained good function of the foveal cones.

Retinal Vessel Functionality Is Linked With ARMS2 A69S and CFH Y402H Polymorphisms and Choroidal Status in AMD Patients.

Purpose: We aimed to investigate the reactivity of retinal vessels to a flickering stimulus in patients with age-related macular degeneration (AMD) and healthy participants. We also assessed whether the parameters of retinal vessels are dependent on genetic predisposition. Methods: A total of 354 patients with AMD and 121 controls were recruited for the study. All participants underwent thorough ophthalmologic examination and static and dynamic retinal vessel analysis. AMD risk polymorphisms were genotyped in the CFH and ARMS2 genes. Results: We found no differences between the AMD group and controls in central retinal arteriolar equivalent (CRAE), central retinal venular equivalent (CRVE), arteriovenous ratio (AVR), dynamic analysis of arteries (DAAs), or dynamic analysis of veins (DAVs). Eyes with early AMD presented with significantly higher AVR values than eyes with late AMD. In the AMD group, DAA correlated positively with both choroidal thickness (Rs = 0.14, P = 0.00096) and choroidal volume (Rs = 0.23, P < 0.0001), and no such associations were observed in the controls. We found significantly lower DAA (1.47 ± 1.50) in TT homozygotes for the ARMS2 A69S polymorphism in comparison with GG homozygotes (2.38 ± 1.79) and patients with GG + GT genotypes (2.28 ± 1.84). We also observed less prominent DAV (3.24 ± 1.71) in patients with TC + CC genotypes in the CFH Y402H polymorphism compared with TT homozygotes (3.83 ± 1.68). Conclusions: Our findings suggest that retinal microcirculation appears to be associated with the genetic background, choroidal parameters, and clinical features of the patients with AMD.

Genetic factors associated with age-related macular degeneration: identification of a novel PRPH2 single nucleotide polymorphism associated with increased risk of the disease.

PURPOSE: Age-related macular degeneration (AMD) is associated with multiple environmental and genetic risk factors. Two main risk factors for AMD are variants in the CFH and ARMS2/HTRA1 genes. We investigated over 2000 variants in AMD patients and controls using high-throughput sequencing methods to search for variants associated with AMD. METHODS: A total of 296 AMD patients and 100 controls were enrolled in this study. Genetic analysis was performed with the Illumina NextSeq 500 system. RESULTS: Multivariate analysis of patients and controls, adjusted for age, sex and smoking status (pack-years), revealed that three SNPs were strong risk factors independently associated with AMD: CFH Y402H, ARMS A69S and PRPH2 c.582-67T>A (rs3818086). The TC genotype in CFH Y402H was associated with 1.90-fold higher odds, and the CC genotype was associated with 5.66-fold higher odds of AMD compared with the TT genotype. The GT genotype in ARMS A69S was associated with 2.40-fold higher odds, and the TT genotype was associated with 6.75-fold higher odds of disease compared with the GG genotype. In the case of rs3818086, the A allele could be considered a 'risk' allele, since AA + TA genotypes were associated with 2.33-fold higher odds of AMD compared with the TT genotype. CONCLUSIONS: Although PRPH2 mutations have been previously implicated in various forms of retinal degeneration, to the best of our knowledge, this study is the first to show that the rs3818086 variant increases the risk for AMD more than two times. Further studies on larger cohorts are required to elucidate how this variant affects protein structure.

Dietary and Lifestyle Factors Modulate the Activity of the Endogenous Antioxidant System in Patients with Age-Related Macular Degeneration: Correlations with Disease Severity.

Age-related macular degeneration (AMD) is a common cause of blindness in the elderly population, but the pathogenesis of this disease remains largely unknown. Since oxidative stress is suggested to play a major role in AMD, we aimed to assess the activity levels of components of the antioxidant system in patients with AMD. We also investigated whether lifestyle and dietary factors modulate the activity of these endogenous antioxidants and clinical parameters of disease severity. We recruited 330 patients with AMD (39 with early, 100 with intermediate and 191 with late form of AMD) and 121 controls in this study. At enrolment, patients' dietary habits and physical activity were assessed, and each study participant underwent a thorough ophthalmologic examination. The activity of several components of the antioxidant system were measured in red blood cells and platelets using both kinetic and spectrophotometric methods. Patients with AMD consumed much lower levels of fatty fish and eggs than the control group (p = 0.008 and p = 0.04, respectively). In the nAMD group, visual acuity (VA) correlated positively with green vegetable consumption (Rs = +0.24, p = 0.004) and omega-3-rich oil intake (Rs = +0.17, p = 0.03). In the AMD group, the total physical activity MET score correlated positively with VA (Rs = +0.17, p = 0.003) and correlated negatively with the severity of AMD (Rs = -0.14, p = 0.01). A multivariate analysis of patients and controls adjusted for age, sex, and smoking status (pack-years) revealed that AMD was an independent variable associated with a lower RBC catalase (ß = -0.37, p < 0.001) and higher PLT catalase (ß = +0.25, p < 0.001), RBC GPx (ß = +0.26, p < 0.001), PLT GPx (ß = +0.16, p = 0.001), RBC R-GSSG (ß = +0.13, p = 0.009), PLT R-GSSG (ß = +0.12, p = 0.02) and RBC GSH transferase (ß = +0.23, p < 0.001) activity. The activities of components of the antioxidant system were associated with disease severity and depended on dietary habits. The observed substantial increase in the activity of many critical endogenous antioxidants in patients with AMD further indicates that the required equilibrium in the antioxidant system is disturbed throughout the course of the disease. Our findings explicitly show that a diet rich in green vegetables, fish and omega-3-rich oils, supplemented by physical exercise, is beneficial for patients with AMD, as it might delay disease progression and help retain better visual function.

Impact of Carotid Endarterectomy on Choroidal Thickness and Volume in Enhanced Depth Optical Coherence Tomography Imaging.

PURPOSE: Carotid endarterectomy (CEA) is considered an effective therapeutic method for improving ocular circulation. The choroid is a predominantly vascular tissue; thus, systemic and local vascular alterations may influence its morphology and function. The aim of the current study was to analyse changes in choroidal thickness and volume in patients with significant internal carotid artery stenosis (ICAS) before and after unilateral CEA. METHODS: The 42 eyes of the 21 asymptomatic patients included in the study were divided into two groups: those ipsilateral (EIE) and those contralateral (ECE) to CEA. All participants underwent a complete ophthalmologic examination, including enhanced depth imaging-optical coherence tomography (EDI-OCT). A comparative analysis of subfoveal thickness (CT) and choroidal volume (CV) measured in nine Early Treatment of Diabetic Retinopathy Study (ETDRS) subfields at baseline, on the 2nd day after CEA, and in the 3rd month after CEA was performed. RESULTS: In the EIE and ECE groups, no significant differences in either CT or CV values before and on the 2nd day after the CEA were observed. In the EIE group, a significant increase in CT and CV in the 3rd month after CEA compared to baseline was noted in the specific ETDRS region. Changes in CT and CV after surgery were positively correlated with the participants' physical activity status and diastolic blood pressure and negatively correlated with the participants' age and smoking status. Additionally, the analysis of changes in CV after CEA showed a positive correlation between the EIE and ECE groups. CONCLUSIONS: CT and CV fluctuations in the central and perifoveal areas visualized with EDI-OCT enabled the observation of the processes of tissue adaptation to variable blood flow conditions.

The Interplay Between Systemic Inflammatory Factors and MicroRNAs in Age-Related Macular Degeneration.

We aimed to explore the expression of systemic inflammatory factors and selected intracellular miRNAs that regulate inflammatory signaling pathways potentially involved in age-related macular degeneration (AMD) pathogenesis. A total of 179 patients with wet AMD, 175 with dry AMD and 121 controls were enrolled in the study. Soluble inflammatory factors were analyzed in plasma samples using Luminex technology. Expression of selected miRNAs was analyzed in isolated nucleated peripheral blood cells (PBNCs) using real-time qPCR. Wet AMD was an independent factor associated with higher concentrations of IL-6 (ß = +0.24, p = 0.0004), GM-CSF (ß = +0.31, p < 0.001), IFN-γ (ß = +0.58, p < 0.001), higher expression of miRNA-23a-3p (ß = +0.60, p < 0.0001), miRNA-30b (ß = +0.32, p < 0.0001), miRNA-191-5p (ß = +0.28, p < 0.0001) and lower concentration of IL-1ß (ß = -0.25, p = 0.0003), IL-5 (ß = -0.45, p < 0.001), IL-10 (ß = -0.45, p < 0.001), IL-12 (ß = -0.35, p < 0.001), lower expression of miRNA-16-5p (ß = -0.31, p < 0.0001), miRNA-17-3p (ß = -0.18, p = 0.01), miRNA-150-5p (ß = -0.18, p = 0.01) and miRNA-155-5p (ß = -0.47, p < 0.0001). Multivariate analysis revealed that dry AMD was an independent factor associated with higher concentration of GM-CSF (ß = +0.34, p < 0.001), IL-6 (ß = +0.13, p = 0.05), higher expression of miRNA-23a-3p (ß = +0.60, p < 0.0001), miRNA-126-3p (ß = +0.23, p = 0.0005), miRNA-126-5p (ß = +0.16, p = 0.01), miRNA 146a (ß = +0.14, p = 0.03), and mRNA191-5p (ß = +0.15, p = 0.03) and lower concentrations of TNF-α (ß = +0.24, p = 0.0004), IL-1ß (ß = -0.39, p < 0.001), IL-2 (ß = -0.20, p = 0.003), IL-5 (ß = -0.54, p < 0.001), IL-10 (ß = -0.56, p < 0.001), IL-12 (ß = -0.51, p < 0.001), lower expression of miRNA-16-5p (ß = -0.23, p = 0.0004), miRNA-17-3p (ß = -0.20, p = 0.003) and miRNA-17-5p (ß = -0.19, p = 0.004). Negative correlations between visual acuity and WBC, lymphocyte count, TNF-α, IL-1 ß, IL-2, IL-4, IL-6, IL-10 concentrations and miRNA-191-5p, as well as positive correlations between visual acuity and miRNA-126-3p, -126-5p, and -155-5p PBNCs expression were found in AMD patients. No such correlations were found in the control group. Our results may suggest the role of both intra- and extracellular mechanisms implicated in inflammatory response regulation in multifactorial AMD pathogenesis.

Associations of microRNAs, Angiogenesis-Regulating Factors and CFH Y402H Polymorphism-An Attempt to Search for Systemic Biomarkers in Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) remains the leading cause of blindness in elderly people, but the pathophysiology of this disease is still largely unknown. We investigated the systemic expression of angiogenesis-regulating growth factors and selected miRNAs known to regulate angiogenesis in AMD patients. We also focused on possible correlations of their expression with the presence of CFH Y402H or ARMS A69S risk variants. A total of 354 AMD patients and 121 controls were enrolled in this study. The levels of angiogenesis-regulating factors were analyzed in plasma samples using Luminex technology. The expression of selected miRNAs was analyzed in peripheral blood plasma using real-time qPCR. The genetic analysis was performed with an Illumina NextSeq500 system. AMD was an independent factor associated with lower levels of angiogenin (ß = -0.29, p < 0.001), endostatin (ß = -0.18, p < 0.001), FGF-basic (ß = -0.18, p < 0.001), PlGF (ß = -0.24, p < 0.001), miRNA-21-3p (ß = -0.13, p = 0.01) and miRNA-155-5p (ß = -0.16, p = 0.002); and with higher levels of FGF-acidic (ß = 0.11, p = 0.03), miRNA-23a-3p (ß = 0.17, p < 0.001), miRNA-126-5p (ß = 0.13, p = 0.009), miRNA-16-5p (ß = 0.40, p < 0.001), miRNA-17-3p (ß = 0.13, p = 0.01), miRNA-17-5p (ß = 0.17, p < 0.001), miRNA-223-3p (ß = 0.15, p = 0.004), and miRNA-93 (ß = 0.11, p = 0.04). The expression of analyzed miRNA molecules significantly correlated with the levels of tested angiogenesis-regulating factors and clinical parameters in AMD patients, whereas such correlations were not observed in controls. We also found an association between the CFH Y402H polymorphism and miRNA profiles, whereby TT homozygotes showed evidently higher expression of miRNA-16-5p than CC homozygotes or TC heterozygotes (p = 0.0007). Our results suggest that the balance between systemic pro- and anti-angiogenic factors and miRNAs is vital in multifactorial AMD pathogenesis.

Retinal vessel dynamic functionality in the eyes of asymptomatic patients with significant internal carotid artery stenosis.

BACKGROUND: The goal of this study was to assess the retinal microvascular function in asymptomatic patients with hemodynamically significant internal carotid artery stenosis (ICAS) and to assess the potential efficacy of carotid endarterectomy (CEA) for the improvement of vessel functionality. METHODS: Retinal vessel caliber and reactions to flicker stimulation were assessed in both eyes of 65 asymptomatic patients with unilateral hemodynamically significant ICAS and 34 healthy subjects. Subsequently, the recruited ICAS patients were referred for standard unilateral CEA procedure. The full ophthalmologic examination of both eyes and vessel analysis were performed 1 day before and 3 months after CEA. RESULTS: The venous responses to flicker stimulation were significantly lower in the EIS (eyes ipsilateral to stenosis) and ECS (eyes contralateral to stenosis) compared with those in the controls (P<0.0001 and P<0.0001, respectively). No changes were identified in retinal vascular flicker responses after CEA in both groups of eyes compared with the baseline values. We observed a decrease in CRVE (central retinal venular equivalent) after the CEA both in eyes ipsilateral (P=0.01) and contralateral (P=0.04) to CEA. Likewise, a decrease in CRAE (central retinal arteriolar equivalent) was identified in the eyes ipsilateral to CEA (P<0.001). CONCLUSIONS: This outcome strongly indicates that microvascular dysfunction is long-lasting despite the recovery of the flow in the carotid artery.