Cognitive impairment and dementia are major medical, social, and economic public health issues worldwide with significant implications for life quality in older adults. The leading causes are Alzheimer’s disease (AD) and vascular cognitive impairment/dementia (VCID). In both conditions, pathological alterations of the cerebral microcirculation play a critical pathogenic role. Currently, the main pathological biomarkers of AD—β-amyloid peptide and hyperphosphorylated tau proteins—are detected either through cerebrospinal fluid (CSF) or PET examination. Nevertheless, given that they are invasive and expensive procedures, their availability is limited. Being part of the central nervous system, the retina offers a unique and easy method to study both neurodegenerative disorders and cerebral small vessel diseases in vivo. Over the past few decades, a number of novel approaches in retinal imaging have been developed that may allow physicians and researchers to gain insights into the genesis and progression of cerebromicrovascular pathologies. Optical coherence tomography (OCT), OCT angiography, fundus photography, and dynamic vessel analyzer (DVA) are new imaging methods providing quantitative assessment of retinal structural and vascular indicators—such as thickness of the inner retinal layers, retinal vessel density, foveal avascular zone area, tortuosity and fractal dimension of retinal vessels, and microvascular dysfunction—for cognitive impairment and dementia. Should further studies need to be conducted, these retinal alterations may prove to be useful biomarkers for screening and monitoring dementia progression in clinical routine. In this review, we seek to highlight recent findings and current knowledge regarding the application of retinal biomarkers in dementia assessment.

BackgroundThis study aimed to determine the relationship between image quality and measurement repeatability of optical coherence tomography angiography (OCTA) parameters in patients with non-proliferative diabetic retinopathy.MethodsA total of 100 eyes of 50 patients were included in the study. Three OCTA images were obtained consecutively during one session of imaging in all patients using the RTVue AngioVue OCTA device. We applied the signal strength index (SSI) provided by the RTVue system to define scan quality. Superficial vessel density (VD) in the central 3 × 3 mm macular and in the perifoveal region, as well as foveal avascular zone (FAZ) area were evaluated by the AngioAnalytics software for each scan from three consecutive measurements, whereby measurement repeatability of the OCTA parameters were calculated. The effect of SSI value on OCTA parameters, as well as on measurement errors was assessed.ResultsValues of SSI ranged from 30 to 85 with an overall mean of 61.79 ± 10.38. Mean SSI values showed significant positive correlation with the mean retinal capillary vessel density values, but not with non-flow area. Repeatability of OCTA parameters was generally improved with higher SSI values. We calculated a mean correction factor of 0.22% (95% CI 0.20–0.24 µm; p < 0.001) for VD at the 3 × 3 mm macular scan, 0.23% (95% CI 0.21–0.26%; p < 0.001) for perifoveal VD and − 0.001 mm2 (95% CI − 0.001 to 0.002; p = 0.001) for the non-flow area for each unit increase in SSI for the comparison of images with different SSI values.ConclusionsThe influence of image quality on OCTA metrics should be considered for image comparisons during follow-up to avoid misinterpretation of small changes in OCTA parameters in patients with diabetes.

Oncogenic activation of the epidermal growth factor receptor (EGFR) signaling pathway occurs in a variety of tumor types, albeit in human melanoma, the contribution of EGFR is still unclear. The potential role of EGFR was analyzed in four BRAF-mutant, one NRAS-mutant and one wild-type NRAS-BRAF-carrying human melanoma cell lines. We have tested clinically available reversible tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, irreversible EGFR-TKI pelitinib and a reversible experimental compound PD153035 on in-vitro proliferation, apoptosis, migration as well as in-vivo metastatic colonization in a spleen-liver model. The presence of the intracellular domain of EGFR protein and its constitutive activity were demonstrated in all cell lines. Efficacies of EGFR-TKIs showed significant differences, and irreversible inhibition had the strongest antitumor potential. Compared with BRAF-mutant cells, wild-type BRAF was associated with relative resistance against gefitinib. In combination with gefitinib, selective mutant BRAF-inhibitor vemurafenib showed additive effect in all BRAF-mutant cell lines. Treatment of BRAF-mutant cells with gefitinib or pelitinib attenuated in-vitro cell migration and in-vivo colonization. Our preclinical data suggest that EGFR is a potential target in the therapy of BRAF-mutant malignant melanoma; however, more benefits could be expected from irreversible EGFR-TKIs and combined treatment settings.

In this study, we aimed at investigating the impact of deterministic signal loss on image quality and, thus, on optical coherence tomography angiography (OCTA) measurements performed by the RTVue-XR Avanti System. Methods: Absorptive filters with different optical densities (ODs) were used to simulate signal loss in a controlled way in 30 eyes from 15 healthy subjects. Scan Quality (SQ), provided by the AngioVue software, was applied as a measure of image quality. Results: Assessing the effect of decreased light transmittance on SQ values as well as that of attenuated image quality on OCTA parameters revealed a strong systematic dependence between these quantities. Attenuated image quality was associated with significantly decreased macular and peripapillary vessel density (VD) values, and we calculated a correction factor of 2.27% to 3.97% for a one-unit change in SQ for the different VD parameters. Conclusions: Our findings suggest that the influence of systematic changes in image quality on OCTA parameters needs to be considered during patient follow-up in order to make valid assessment of progression. Translational Relevance: For accurate evaluation of longitudinal changes in OCTA parameters, equal scan quality or using a correction factor is suggested.

Carotid artery stenosis (CAS) is a consequence of systemic atherosclerotic disease affecting the aging populations of the Western world. CAS is frequently associated with cognitive impairment. However, the mechanisms contributing to the development of vascular cognitive impairment (VCI) associated with CAS are multifaceted and not fully understood. In addition to embolization and decreased blood flow due to the atherosclerotic lesion in the carotid artery, microcirculatory dysfunction in the cerebral circulation also plays a critical role in CAS-related VCI. To better understand the microvascular contributions to cognitive decline associated with CAS and evaluate microvascular protective effects of therapeutic interventions, it is essential to examine the structural and functional changes of the microvessels in the central nervous system (CNS). However, there are some limitations of in vivo brain vascular imaging modalities. The retinal microvasculature provides a unique opportunity to study pathogenesis of cerebral small vessel disease and VCI, because the cerebral circulation and the retinal circulation share similar anatomy, physiology and embryology. Similar microvascular pathologies may manifest in the brain and the retina, thus ocular examination can be used as a noninvasive screening tool to investigate pathological changes in the CNS associated with CAS. In this review, ocular signs of CAS and the retinal manifestations of CAS-associated microvascular dysfunction are discussed. The advantages and limitation of methods that are capable of imaging the ocular circulation (including funduscopy, fluorescein angiography, Doppler sonography, optical coherence tomography [OCT] and optical coherence tomography angiography [OCTA]) are discussed. The potential use of dynamic retinal vessel analysis (DVA), which allows for direct visualization of neurovascular coupling responses in the CNS, for understanding microvascular contributions to cognitive decline in CAS patients is also considered.

Carotid artery stenosis (CAS) is among the leading causes of mortality and permanent disabilities in the Western world. CAS is a consequence of systemic atherosclerotic disease affecting the majority of the aging population. Optical coherence tomography angiography (OCTA) is a novel imaging technique for visualizing retinal blood flow. It is a noninvasive, fast method for qualitative and quantitative assessment of the microcirculation. Cerebral and retinal circulation share similar anatomy, physiology, and embryology; thus, retinal microvasculature provides a unique opportunity to study the pathogenesis of cerebral small vessel disease in vivo. In this study, we aimed to analyze the effect of systemic risk factors on retinal blood flow in the eyes of patients with significant carotid artery stenosis using OCT angiography. A total of 112 eyes of 56 patients with significant carotid stenosis were included in the study. We found that several systemic factors, such as decreased estimated glomerular filtration rate (eGFR), hypertension, and carotid occlusion have a significant negative effect on retinal blood flow, while statin use and carotid surgery substantially improve ocular microcirculation. Neither diabetes, clopidogrel or acetylsalicylic acid use, BMI, serum lipid level, nor thrombocyte count showed a significant effect on ocular blood flow. Our results demonstrate that a systematic connection does exist between certain systemic risk factors and retinal blood flow in this patient population. OCTA could help in the assessment of cerebral circulation of patients with CAS due to its ability to detect subtle changes in retinal microcirculation that is considered to represent changes in intracranial blood flow.

Age-related macular degeneration (AMD) is a progressive neurodegenerative disease affecting the central area (macula lutea) of the retina. Research on the pathogenic mechanism of AMD showed complex cellular contribution governed by such risk factors as aging, genetic predisposition, diet, and lifestyle. Recent studies suggested that microbiota is a transducer and a modifier of risk factors for neurodegenerative diseases, and mitochondria may be one of the intracellular targets of microbial signaling molecules. This review explores studies supporting a new concept on the contribution of microbiota—mitochondria disorders to AMD. We discuss metabolic, vascular, immune, and neuronal mechanism in AMD as well as key alterations of photoreceptor cells, retinal pigment epithelium (RPE), Bruch’s membrane, choriocapillaris endothelial, immune, and neuronal cells. Special attention was paid to alterations of mitochondria contact sites (MCSs), an organelle network of mitochondria, endoplasmic reticulum, lipid droplets (LDs), and peroxisomes being documented based on our own electron microscopic findings from surgically removed human eyes. Morphometry of Bruch’s membrane lipids and proteoglycans has also been performed in early AMD and aged controls. Microbial metabolites (short-chain fatty acids, polyphenols, and secondary bile acids) and microbial compounds (lipopolysaccharide, peptidoglycan, and bacterial DNA)—now called postbiotics—in addition to local effects on resident microbiota and mucous membrane, regulate systemic metabolic, vascular, immune, and neuronal mechanisms in normal conditions and in various common diseases. We also discuss their antioxidant, anti-inflammatory, and metabolic effects as well as experimental and clinical observations on regulating the main processes of photoreceptor renewal, mitophagy, and autophagy in early AMD. These findings support an emerging concept that microbiota-mitochondria disorders may be a crucial pathogenic mechanism of early AMD; and similarly, to other age-related neurodegenerative diseases, new treatment approaches should be targeted at these disorders.

Purpose To detect immunoglobulins in aqueous humour of AMD patients after repeated administration of intravitreal aflibercept. Patients and methods Twenty-one patients (age: 77.85 ± 9.21 years) previously treated with intravitreal aflibercept due to wet type age-related macular degeneration (AMD group) and 18 age-matched control subjects (age: 69.75 ± 12.67 years) were included in this study. Patients in the AMD group received a mean of 5 intravitreal injections (min: 1 max: 17) prior to the cataract surgery. Samples of aqueous humour (50 μl) were obtained by anterior chamber paracentesis as the first step of routine cataract surgery. The IgG content of the samples was analysed by an in-house developed ELISA system. Results A significant increase in nonspecific IgG levels in the AMD group was detected compared to the control group (13.37 ± 6.65 vs. 9.44 ± 6.55 μg/ml; p = 0.03). In 11 patients, intraocular anti-aflibercept immunoglobulins could be detected (0.05 ± 0.01 μg/ml) which was significantly higher than the limit of detection for anti-aflibercept (0.04 μg/ml; p = 0.001). No correlation was found between the number of injections or the type of CNV and the aqueous level of anti-aflibercept (r = 0.02; p = 0.95). Conclusion According to our results, penetration of non-specific systemic antibodies through the impaired blood-retinal barrier is higher in patients with neovascular AMD than in subjects with an intact structural barrier. Evaluation of neutralizing antibodies to anti-VEGF agents in the aqueous humour can lead us to understanding tachyphylaxis and changes in intraocular immune mechanisms due to AMD.