Blood brain barrier disruption following COVID-19 infection and neurological manifestations

Neurological manifestations have been reported following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The presence of SARS-CoV-2 in brains of affected individuals has been documented. However, the exact route of entry into the brain and subsequent post-infection consequences are not fully understood. Blood–brain barrier (BBB) is an interface between systemic circulation and central nervous system (CNS) that strictly regulates entry of specific molecules from blood to the brain. The functional component of BBB is neurovascular unit (NVU) and any alterations in the structure or function of BBB is detrimental to the CNS functions. Evidence suggests that SARS-CoV-2 infection disrupts BBB integrity and functions directly or indirectly. This chapter highlights the likely mechanisms involved in entry of SARS-CoV-2 into the brain. Further, the alterations in BBB have been implicated in neurological symptoms observed in SARS-CoV-2 patients. Moreover, systemic inflammation and other peripheral factors post infection also contribute to the disruption of BBB. The key protein of SARS-CoV-2, spike protein (S1) induces significant alterations in BBB properties. Entry of S1 protein into brain triggers a proinflammatory cascade that affects BBB integrity. Therefore, understanding the pathophysiological mechanisms in BBB dysfunction and subsequent neurological manifestations along with long-term effects on brain particularly Alzheimer's disease (AD) following coronavirus disease 2019 (COVID-19) is of utmost importance. © 2023 Elsevier Inc. All rights reserved.

[Psychological, psychiatric and neurological aspects of COVID-19]. / Psikhologicheskie, psikhiatricheskie i nevrologicheskie aspekty COVID-19.

OBJECTIVE: To analyze neurological, psychological and psychiatric aspects of COVID-19, as well as to study the current state of the problem. MATERIAL AND METHODS: The study included 103 patients with COVID-19. The main research method was clinical/psychopathological. To study the impact of activities related to the care of patients with COVID-19 in a hospital setting, the medical and psychological state of 197 hospital workers involved in the treatment of patients with COVID-19 was assessed. The level of anxiety distress was assessed with the Psychological Stress Scale (PSM-25), distress indicators corresponded to values of more than 100 points. The severity of anxiety and depressive symptoms was assessed using the Hospital Anxiety and Depression Scale (HADS). RESULTS: When considering psychopathological disorders in the context of COVID-19, it is necessary to distinguish between two main groups of disorders: mental disorders during the pandemic, and mental disorders directly caused by the causative agent SARS-CoV-2. The analysis of psychological and psychiatric aspects in various periods of the initial stage of COVID-19 showed that each of them was characterized by specific features depending on the nature of the influence of different pathogenic factors. In the structure of nosogenic mental disorders in patients with COVID-19 (103 patients), the following clinical forms were identified: acute reaction to stress (9.7%), anxiety-phobic disorders (41.7%), depressive symptoms (28.1%), hyponosognosic nosogenic reactions (20.5%). At the same time, the majority of the patients had manifestations of somatogenic asthenia (93.2%). A comparative analysis of neurological and psychological/psychiatric aspects of COVID-19 showed that the main mechanisms of the impact of highly contagious coronaviruses, including the SARS-CoV-2, on the central nervous system are: cerebral thrombosis and cerebral thromboembolism, damage to the neurovascular unit, neurodegeneration, including that induced by cytokines, and immune-mediated demyelinating nerve damage. CONCLUSION: Neurological and psychological/psychiatric aspects of COVID-19 should be taken into account both at the stage of disease treatment and in the post-infection period due to the pronounced neurotropism of SARS-CoV-2 and its effect on the neurovascular unit. Along with helping patients, an important aspect is the preservation of the mental health of medical personnel working in hospitals for infectious diseases, due to special working conditions and a high level of professional stress.

A year in review: brain barriers and brain fluids research in 2022.

This aim of this editorial is to highlight progress made in brain barrier and brain fluid research in 2022. It covers studies on the blood-brain, blood-retina and blood-CSF barriers (choroid plexus and meninges), signaling within the neurovascular unit and elements of the brain fluid systems. It further discusses how brain barriers and brain fluid systems are impacted in CNS diseases, their role in disease progression and progress being made in treating such diseases.

Pathophysiology of reversible cerebral vasoconstriction syndrome.

Reversible cerebral vasoconstriction syndrome (RCVS) is a complex neurovascular disorder being recognized during the past two decades. It is characterized by multiple abrupt severe headaches and widespread cerebral vasoconstrictions, with potential complications such as ischemic stroke, convexity subarachnoid hemorrhage, intracerebral hemorrhage and posterior reversible encephalopathy syndrome. The clinical features, imaging findings, and dynamic disease course have been delineated. However, the pathophysiology of RCVS remains elusive. Recent studies have had substantial progress in elucidating its pathogenesis. It is now believed that dysfunction of cerebral vascular tone and impairment of blood-brain barrier may play key roles in the pathophysiology of RCVS, which explains some of the clinical and radiological manifestations of RCVS. Some other potentially important elements include genetic predisposition, sympathetic overactivity, endothelial dysfunction, and oxidative stress, although the detailed molecular mechanisms are yet to be identified. In this review, we will summarize what have been revealed in the literature and elaborate how these factors could contribute to the pathophysiology of RCVS.

Neurological Complications of SARS-CoV-2 Infection and COVID-19 Vaccines: From Molecular Mechanisms to Clinical Manifestations.

Coronavirus Disease 2019 (COVID-19) is an infectious disease, caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), that reached pandemic proportions in 2020. Despite the fact that it was initially characterized by pneumonia and acute respiratory distress syndrome, it is now clear that the nervous system is also compromised in one third of these patients. Indeed, a significant proportion of COVID-19 patients suffer nervous system damage via a plethora of mechanisms including hypoxia, coagulopathy, immune response to the virus, and the direct effect of SARS-CoV-2 on endothelial cells, neurons, astrocytes, pericytes and microglia. Additionally, a low number of previously healthy individuals develop a variety of neurological complications after receiving COVID-19 vaccines and a large proportion of COVID-19 survivors experience longlasting neuropsychiatric symptoms. In conclusion, COVID-19 is also a neurological disease, and the direct and indirect effects of the virus on the nervous system have a significant impact on the morbidity and mortality of these patients. Here we will use the concept of the neurovascular unit, assembled by endothelial cells, basement membrane, perivascular astrocytes, neurons and microglia, to review the effects of SARS-CoV-2 in the nervous system. We will then use this information to review data published to this date on the neurological manifestations of COVID-19, the post- COVID syndrome and COVID-19 vaccines.

Central Nervous System Pericytes Contribute to Health and Disease.

Successful neuroprotection is only possible with contemporary microvascular protection. The prevention of disease-induced vascular modifications that accelerate brain damage remains largely elusive. An improved understanding of pericyte (PC) signalling could provide important insight into the function of the neurovascular unit (NVU), and into the injury-provoked responses that modify cell-cell interactions and crosstalk. Due to sharing the same basement membrane with endothelial cells, PCs have a crucial role in the control of endothelial, astrocyte, and oligodendrocyte precursor functions and hence blood-brain barrier stability. Both cerebrovascular and neurodegenerative diseases impair oxygen delivery and functionally impair the NVU. In this review, the role of PCs in central nervous system health and disease is discussed, considering their origin, multipotency, functions and also dysfunction, focusing on new possible avenues to modulate neuroprotection. Dysfunctional PC signalling could also be considered as a potential biomarker of NVU pathology, allowing us to individualize therapeutic interventions, monitor responses, or predict outcomes.

The blood-brain barrier is dysregulated in COVID-19 and serves as a CNS entry route for SARS-CoV-2.

Neurological complications are common in COVID-19. Although SARS-CoV-2 has been detected in patients' brain tissues, its entry routes and resulting consequences are not well understood. Here, we show a pronounced upregulation of interferon signaling pathways of the neurovascular unit in fatal COVID-19. By investigating the susceptibility of human induced pluripotent stem cell (hiPSC)-derived brain capillary endothelial-like cells (BCECs) to SARS-CoV-2 infection, we found that BCECs were infected and recapitulated transcriptional changes detected in vivo. While BCECs were not compromised in their paracellular tightness, we found SARS-CoV-2 in the basolateral compartment in transwell assays after apical infection, suggesting active replication and transcellular transport of virus across the blood-brain barrier (BBB) in vitro. Moreover, entry of SARS-CoV-2 into BCECs could be reduced by anti-spike-, anti-angiotensin-converting enzyme 2 (ACE2)-, and anti-neuropilin-1 (NRP1)-specific antibodies or the transmembrane protease serine subtype 2 (TMPRSS2) inhibitor nafamostat. Together, our data provide strong support for SARS-CoV-2 brain entry across the BBB resulting in increased interferon signaling.

Glymphatic System as a Gateway to Connect Neurodegeneration From Periphery to CNS.

The classic concept of the absence of lymphatic vessels in the central nervous system (CNS), suggesting the immune privilege of the brain in spite of its high metabolic rate, was predominant until recent times. On the other hand, this idea left questioned how cerebral interstitial fluid is cleared of waste products. It was generally thought that clearance depends on cerebrospinal fluid (CSF). Not long ago, an anatomically and functionally discrete paravascular space was revised to provide a pathway for the clearance of molecules drained within the interstitial space. According to this model, CSF enters the brain parenchyma along arterial paravascular spaces. Once mixed with interstitial fluid and solutes in a process mediated by aquaporin-4, CSF exits through the extracellular space along venous paravascular spaces, thus being removed from the brain. This process includes the participation of perivascular glial cells due to a sieving effect of their end-feet. Such draining space resembles the peripheral lymphatic system, therefore, the term "glymphatic" (glial-lymphatic) pathway has been coined. Specific studies focused on the potential role of the glymphatic pathway in healthy and pathological conditions, including neurodegenerative diseases. This mainly concerns Alzheimer's disease (AD), as well as hemorrhagic and ischemic neurovascular disorders; other acute degenerative processes, such as normal pressure hydrocephalus or traumatic brain injury are involved as well. Novel morphological and functional investigations also suggested alternative models to drain molecules through perivascular pathways, which enriched our insight of homeostatic processes within neural microenvironment. Under the light of these considerations, the present article aims to discuss recent findings and concepts on nervous lymphatic drainage and blood-brain barrier (BBB) in an attempt to understand how peripheral pathological conditions may be detrimental to the CNS, paving the way to neurodegeneration.

Neurological consequences of neurovascular unit and brain vasculature damages: potential risks for pregnancy infections and COVID-19-babies.

Intragravidic and perinatal infections, acting through either direct viral effect or immune-mediated responses, are recognized causes of liability for neurodevelopmental disorders in the progeny. The large amounts of epidemiological data and the wealth of information deriving from animal models of gestational infections have contributed to delineate, in the last years, possible underpinning mechanisms for this phenomenon, including defects in neuronal migration, impaired spine and synaptic development, and altered activation of microglia. Recently, dysfunctions of the neurovascular unit and anomalies of the brain vasculature have unexpectedly emerged as potential causes at the origin of behavioral abnormalities and psychiatric disorders consequent to prenatal and perinatal infections. This review aims to discuss the up-to-date literature evidence pointing to the neurovascular unit and brain vasculature damages as the etiological mechanisms in neurodevelopmental syndromes. We focus on the inflammatory events consequent to intragravidic viral infections as well as on the direct viral effects as the potential primary triggers. These authors hope that a timely review of the literature will help to envision promising research directions, also relevant for the present and future COVID-19 longitudinal studies.

Pericytes Within A Pulmonary Neurovascular Unit in Coronavirus Disease 2019 Elicited Pathological Changes.

A pericyte-centered theory suggesting that embolisms occurring within the microvasculature of a neurovascular unit that can result in either parenchymal hemorrhage or intravascular congestion is presented here. Dysfunctional microvascular pericytes are characterized by their location in the neurovascular unit, either on the arteriole or venule side. Pathophysiological and pathological changes caused by coronavirus disease 2019 (COVID-19) include pulmonary hypertension, edema, focal hemorrhage, microvascular congestion, and thrombosis. In this paper, the application of the pericytes-centered hypothesis to COVID-19 has been presented by proposing the concept of a pulmonary neurovascular unit (pNVU). The application of this concept implies that human lungs contain approximately 300 million pNVUs. This concept of existing local regulation of microvascular blood flow is supported by the observation of pathophysiology in pulmonary embolism and in acute high-altitude illness. The autonomic control seen in these three disease states matches blood flow with oxygen supply in each pNVU to maintain physiological blood oxygen saturation level. This paper illustrates how the malfunction of microvascular pericytes may cause focal hemorrhage, edema or microvascular congestion and thrombosis. A bypass existing in each pNVU would autonomically deviate blood flow from a COVID-19-affected pNVU to other healthy pNVUs. This action would prevent systemically applied medicines from reaching the therapeutic threshold in COVID-19-affected pNVUs. While testing this hypothesis with experimental evidence is urgently needed, supporting therapy aimed at improving microcirculation or rebuilding the physiological function of microvascular pericytes is recommended as a potentially effective treatment of COVID 19.

Severe acute respiratory syndrome coronavirus 2 may be an underappreciated pathogen of the central nervous system.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a highly contagious respiratory disease referred to as COVID-19. However, emerging evidence indicates that a small but growing number of COVID-19 patients also manifest neurological symptoms, suggesting that SARS-CoV-2 may infect the nervous system under some circumstances. SARS-CoV-2 primarily enters the body through the epithelial lining of the respiratory and gastrointestinal tracts, but under certain conditions this pleiotropic virus may also infect peripheral nerves and gain entry into the central nervous system (CNS). The brain is shielded by various anatomical and physiological barriers, most notably the blood-brain barrier (BBB) which functions to prevent harmful substances, including pathogens and pro-inflammatory mediators, from entering the brain. The BBB is composed of highly specialized endothelial cells, pericytes, mast cells and astrocytes that form the neurovascular unit, which regulates BBB permeability and maintains the integrity of the CNS. In this review, potential routes of viral entry and the possible mechanisms utilized by SARS-CoV-2 to penetrate the CNS, either by disrupting the BBB or infecting the peripheral nerves and using the neuronal network to initiate neuroinflammation, are briefly discussed. Furthermore, the long-term effects of SARS-CoV-2 infection on the brain and in the progression of neurodegenerative diseases known to be associated with other human coronaviruses are considered. Although the mechanisms of SARS-CoV-2 entry into the CNS and neurovirulence are currently unknown, the potential pathways described here might pave the way for future research in this area and enable the development of better therapeutic strategies.