Neuron-Specific Enolase-What Are We Measuring?

Since the discovery of the neuron-specific protein by Moore and McGregor in 1965, tens of thousands of studies have investigated the basic and applied significance of neuron-specific enolase (NSE). This promising biomarker, according to many researchers, has not found widespread use in clinical practice, particularly in acute cerebrovascular accidents. Moreover, the several studies refuting the usefulness of serum NSE measurement in critically ill patients leads us to consider the reasons for such contradictory conclusions. In this article, we have analyzed the main directions in the study of NSE and expressed our perspective on the reasons for the contradictory results and the difficulties in implementing the results of these studies in clinical practice. In our opinion, the method of the enzyme-linked immunosorbent assay (ELISA) used in the majority of the studies is inappropriate for the evaluation of NSE as a marker of central nervous system damage, because it does not allow for the differentiation of heterodimers of enolases and the assessment of the enzymatic activity of this group of enzymatic proteins. Therefore, the methodological approach for the evaluation of NSE (γγ-enolase) as a biomarker needs to be elaborated and improved. Furthermore, the specificity of the applied research methods and the appropriateness of the continued use of the term "neuron-specific enolase" must be addressed.

Spectrum of Thrombotic Complications in Fatal Cases of COVID-19: Focus on Pulmonary Artery Thrombosis In Situ.

COVID-19-related thrombosis affects the venous and arterial systems. Data from 156 autopsies of COVID-19 patients were retrospectively analyzed to investigate the pattern of thrombotic complications and factors associated with pulmonary artery thrombosis and thromboembolism. Thrombotic complications were observed in a significant proportion (n = 68, 44%), with pulmonary artery thrombosis the most frequently identified thrombotic event (42, 27%). Multivariate analysis revealed that the length of hospital stay (OR 1.1, p = 0.004), neutrophil infiltration in the alveolar spaces (OR 3.6, p = 0.002), and the absence of hyaline membranes (OR 0.1, p = 0.01) were associated with thrombotic complications. Neutrophil infiltration in the alveolar spaces (OR 8, p < 0.001) and the absence of hyaline membranes (OR 0.1, p = 0.003) were also independent predictors of pulmonary artery thrombosis. The association of pulmonary artery thrombosis with an absence of hyaline membranes suggests it occurs later in the course of COVID-19 infection. As neutrophil infiltration in the alveolar spaces may indicate bacterial infection, our studies suggest the consideration of bacterial infections in these critically ill patients.

Morphologic Findings in the Cerebral Cortex in COVID-19: Association of Microglial Changes with Clinical and Demographic Variables.

Despite the enormous interest in COVID-19, there is no clear understanding of the mechanisms underlying the neurological symptoms in COVID-19. Microglia have been hypothesized to be a potential mediator of the neurological manifestations associated with COVID-19. In most existing studies to date, morphological changes in internal organs, including the brain, are considered in isolation from clinical data and defined as a consequence of COVID-19. We performed histological immunohistochemical (IHC) studies of brain autopsy materials of 18 patients who had died from COVID-19. We evaluated the relationship of microglial changes with the clinical and demographic characteristics of the patients. The results revealed neuronal alterations and circulatory disturbances. We found an inverse correlation between the integral density Iba-1 (microglia/macrophage-specific marker) IHC staining and the duration of the disease (R = -0.81, p = 0.001), which may indicate a reduced activity of microglia and do not exclude their damage in the long-term course of COVID-19. The integral density of Iba-1 IHC staining was not associated with other clinical and demographic factors. We observed a significantly higher number of microglial cells in close contact with neurons in female patients, which confirms gender differences in the course of the disease, indicating the need to study the disease from the standpoint of personalized medicine.

Serum Levels of VEGF-A and Its Receptors in Patients in Different Phases of Hemorrhagic and Ischemic Strokes.

Vascular endothelial growth factors (VEGFs) are important regulators of angiogenesis, neuroprotection, and neurogenesis. Studies have indicated the association of VEGF dysregulation with the development of neurodegenerative and cerebrovascular diseases. We studied the changes in serum levels of VEGF-A, VEGFR-1, and VEGFR-2 in patients at various phases of ischemic and hemorrhagic strokes. Quantitative assessment of VEGF-A, VEGFR-1, and VEGFR-2 in serum of patients with hemorrhagic or ischemic stroke was performed by enzyme immunoassay in the hyper-acute (1−24 h from the onset), acute (up to 1−7 days), and early subacute (7 days to 3 months) phases of stroke, and then compared with the control group and each other. Results of our retrospective study demonstrated different levels of VEGF-A and its receptors at various phases of ischemic and hemorrhagic strokes. In ischemic stroke, increased VEGFR-2 level was found in the hyper-acute (p = 0.045) and acute phases (p = 0.024), while elevated VEGF-A and reduced VEGFR-1 levels were revealed in the early subacute phase (p = 0.048 and p = 0.012, respectively). In hemorrhagic stroke, no significant changes in levels of VEGF-A and its receptors were identified in the hyper-acute phase. In the acute and early subacute phases there was an increase in levels of VEGF-A (p < 0.001 and p = 0.006, respectively) and VEGFR-2 (p < 0.001 and p = 0.012, respectively). Serum levels of VEGF-A and its receptors in patients with hemorrhagic and ischemic stroke indicate different pathogenic pathways depending on the phase of the disease.

The Role of Von Willebrand Factor in the Pathogenesis of Pulmonary Vascular Thrombosis in COVID-19.

The increased plasma levels of von Willebrand factor (VWF) in patients with COVID-19 was reported in many studies, and its correlation with disease severity and mortality suggest its important role in the pathogenesis of thrombosis in COVID-19. We performed histological and immunohistochemical studies of the lungs of 29 patients who died from COVID-19. We found a significant increase in the intensity of immunohistochemical reaction for VWF in the pulmonary vascular endothelium when the disease duration was more than 10 days. In the patients who had thrombotic complications, the VWF immunostaining in the pulmonary vascular endothelium was significantly more intense than in nonsurvivors without thrombotic complications. Duration of disease and thrombotic complications were found to be independent predictors of increased VWF immunostaining in the endothelium of pulmonary vessels. We also revealed that bacterial pneumonia was associated with increased VWF staining intensity in pulmonary arterial, arteriolar, and venular endothelium, while lung ventilation was an independent predictor of increased VWF immunostaining in arterial endothelium. The results of the study demonstrated an important role of endothelial VWF in the pathogenesis of thrombus formation in COVID-19.

Effect of Xenon Treatment on Gene Expression in Brain Tissue after Traumatic Brain Injury in Rats.

The overactivation of inflammatory pathways and/or a deficiency of neuroplasticity may result in the delayed recovery of neural function in traumatic brain injury (TBI). A promising approach to protecting the brain tissue in TBI is xenon (Xe) treatment. However, xenon's mechanisms of action remain poorly clarified. In this study, the early-onset expression of 91 target genes was investigated in the damaged and in the contralateral brain areas (sensorimotor cortex region) 6 and 24 h after injury in a TBI rat model. The expression of genes involved in inflammation, oxidation, antioxidation, neurogenesis and neuroplasticity, apoptosis, DNA repair, autophagy, and mitophagy was assessed. The animals inhaled a gas mixture containing xenon and oxygen (ϕXe = 70%; ϕO2 25-30% 60 min) 15-30 min after TBI. The data showed that, in the contralateral area, xenon treatment induced the expression of stress genes (Irf1, Hmox1, S100A8, and S100A9). In the damaged area, a trend towards lower expression of the inflammatory gene Irf1 was observed. Thus, our results suggest that xenon exerts a mild stressor effect in healthy brain tissue and has a tendency to decrease the inflammation following damage, which might contribute to reducing the damage and activating the early compensatory processes in the brain post-TBI.