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.

Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-Acute Sequelae of SARS-CoV-2: More in Common Than Not?

TOPIC IMPORTANCE: Postacute sequelae of SARS-CoV-2 (PASC) is a long-term consequence of acute infection from COVID-19. Clinical overlap between PASC and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has been observed, with shared symptoms, including intractable fatigue, postexertional malaise, and orthostatic intolerance. The mechanistic underpinnings of such symptoms are poorly understood. REVIEW FINDINGS: Early studies suggest deconditioning as the primary explanation for exertional intolerance in PASC. Cardiopulmonary exercise testing reveals perturbations related to systemic blood flow and ventilatory control associated with acute exercise intolerance in PASC, which are not typical of simple detraining. Hemodynamic and gas exchange derangements in PASC have substantial overlap with those observed with ME/CFS, suggestive of shared mechanisms. SUMMARY: This review illustrates exercise pathophysiological commonalities between PASC and ME/CFS that will help guide future diagnostics and treatment.

COVID-19, neurovascular thrombotic problem and short summary on blood coagulation disorder: a brief review.

COVID-19 is the present global public health problem. This respiratory viral infection can manifest atypical presentation including neurological presentations. An important neurological problem in COVID-19 is neurovascular thrombosis. The basic pathogenesis of thrombosis in neurological system is explainable by the basic principle of thrombohemostasis. A hypercoagulability is a possible problem seen in some COVID-19 cases. In this brief review, the authors summarize venous and arterial thrombosis of neurovascular system as a complication of COVID-19. The updated pathophysiology of COVID-associated blood coagulation disorder is discussed. In addition, consideration regarding new COVID-19 vaccine related thrombotic adverse event is also raised.

Spectrum of common and uncommon neurovascular and neurological manifestations of COVID-19 on cross-sectional imaging

COVID-19 is an emerging and re-emerging disease that is caused by SARS CoV-2, a neurotropic virus that frequently involves the central nervous system in ad-dition to the lungs. Findings on neuroimaging can be observed in a significant percentage of active COVID-19 and post-COVID patients, especially those who are/ have been critically ill. Accurate diagnosis of such cases on imaging aids in appropriate patient management and prevention of permanent neurological deficits. The features of CNS involvement in COVID-19 can be broadly categorized as the more common neurovas-cular and relatively uncommon neurological manifes-tations. Several pathophysiological mechanisms have been proposed for the patterns of CNS involvement and corresponding neuroimaging features in COVID-19. We have outlined the pathophysiology and indications for neuroimaging in COVID-19 and extensively discussed the neuroimaging features of the entire spectrum of neurovascular and neurological manifestations, in-cluding the rare and diagnostically challenging ones, through case-based illustrations. As new strains of COVID-19 continue to emerge, radiologists need to be aware of the imaging features of various neurological and neurovascular manifestations of CNS involvement in COVID-19 as timely diagnosis is vital in preventing or limiting permanent neurological deficits in such cases. © 2022, Zita Medical Managent. All rights reserved.

Association between Brain Injury Markers and Testosterone in Critically-Ill COVID-19 Male Patients.

Accumulating data suggest that various neurologic manifestations are reported in critically-ill COVID-19 patients. Although low testosterone levels were associated with poor outcomes, the relationship between testosterone levels and indices of brain injury are still poorly understood. Therefore, we aimed to explore whether testosterone levels are associated with glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), biomarkers of brain injury, in patients with a severe form of COVID-19. The present study was conducted on 65 male patients aged 18-65 with severe COVID-19. Blood samples were collected at three time points: upon admission to ICU, 7 days after, and 14 days after. In patients with neurological sequels (n = 20), UCH-L1 serum concentrations at admission were markedly higher than in patients without them (240.0 (155.4-366.4) vs. 146.4 (92.5-243.9) pg/mL, p = 0.022). GFAP concentrations on admission did not differ between the groups (32.2 (24.2-40.1) vs. 29.8 (21.8-39.4) pg/mL, p = 0.372). Unlike GFAP, UCH-L1 serum concentrations exhibited a negative correlation with serum testosterone in all three time points (r = -0.452, p < 0.001; r = -0.430, p < 0.001 and r = -0.476, p = 0.001, respectively). The present study suggests that the traumatic brain injury biomarker UCH-L1 may be associated with neurological impairments seen in severe COVID-19. Moreover, a negative correlation between UCH-L1 and serum testosterone concentrations implies that testosterone may have a role in the development of neurological sequels in critically-ill COVID-19 patients.

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.

Non-ischemic neurovascular emergencies at a supra-regional medical center during the SARS-CoV2-pandemia.

OBJECTIVE: To assess the impact of the lockdown in Germany due to the SARS-CoV2-pandemic on the incidence and the outcome of neurovascular emergencies at a tertiary medical center. METHODS: From March 16th, 2020 (first lockdown in Germany) to January 31st, 2021, all neurosurgical emergencies were included and compared to a longitudinal case-cohort. Cases were descriptively recorded and retrospectively analyzed with respect to incidence and outcome. RESULTS: All emergencies referred to our tertiary medical center decreased by 10% during the pandemic, whereas, neurosurgical emergencies increased by 18.4% (764 vs. 905 cases). Number of specific non-ischemic neurovascular emergencies increased by 29% (95 vs. 123 cases). The difference was not statistically significant (p = 0.53). Mortality rate increased dramatically by 40% during the pandemic throughout all neurovascular cases. As all included patients were negative PCR-tested for SARS-CoV2 the observed increase is unrelated to the virus infection. CONCLUSION: Unexpectedly, according to our data neurovascular emergencies raised in number and severity during the pandemic in Germany at our tertiary referral center. Furthermore, the case fatality increased. Even though our data lack proof of evidence for these findings, we might suggest two possible explanations for the absolute increase in numbers: firstly, patients might have refused to seek medical help while suffering only mild symptoms. Furthermore, as numerous lower-level medical centers restricted admissions, the referral times of patients in need of neurosurgical attention increased. We, therefore, suggest that even in a pandemic situation like the SARS-CoV2/COVID-19, it seems of utmost importance to retain dedicated neurovascular competence in designated centers to care for these emergencies.

Brain dural arteriovenous fistulas in the COVID-19 Era: A warning and rationale for association.

OBJECTIVES: Brain dural arteriovenous fistulas(bDAVFs) are anomalous connections between dural arteries and cerebral veins or sinuses. Cerebral venous thrombosis(CVT) often precedes or coincides with bDAVFs and is considered a risk factor for these vascular malformations. Recently, vaccine-induced thrombotic thrombocytopenia causing CVTs has been associated with COVID-19 vaccines. Concurrently with the start of massive vaccination in our region, we have observed a fivefold increase in the average incidence of bDAVFs. Our objective is to raise awareness of the potential involvement of COVID-19 vaccines in the pathogenesis of bDAVF. METHODS: A retrospective review of demographic, clinical, radiological, COVID-19 infection and vaccination data of patients diagnosed with bDAVFs between 2011 and 2021 was conducted. Patients were divided into two cohorts according to their belonging to pre- or post-COVID-19 vaccination times. Cohorts were compared for bDAVFs incidences and demographic and clinical features. RESULTS: Twenty-one bDAVFs were diagnosed between 2011 and 2021, 7 of which in 2021. The mean age was 57.7 years, and 62 % were males. All cases except one were treated; of them, 85 % exclusively managed with surgery. All treated cases were successfully occluded. The incidence in 2021 was significantly higher than that in the prevaccination period (1.72 vs 0.35/100,000/year;p = 0.036; 95 %Confidence Interval=0.09-2.66). Cohorts were not different in age, sex, hemorrhagic presentation, dural sinus thrombosis or presence of prothrombotic or cardiovascular risk factors. CONCLUSION: The significant increase in the incidence of bDAVF following general vaccination policies against COVID-19 observed in our region suggests a potential correlation between these two facts. Our findings need confirmation from larger cohorts and further pathogenic research.

Neurovascular injury with complement activation and inflammation in COVID-19.

The underlying mechanisms by which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to acute and long-term neurological manifestations remains obscure. We aimed to characterize the neuropathological changes in patients with coronavirus disease 2019 and determine the underlying pathophysiological mechanisms. In this autopsy study of the brain, we characterized the vascular pathology, the neuroinflammatory changes and cellular and humoral immune responses by immunohistochemistry. All patients died during the first wave of the pandemic from March to July 2020. All patients were adults who died after a short duration of the infection, some had died suddenly with minimal respiratory involvement. Infection with SARS-CoV-2 was confirmed on ante-mortem or post-mortem testing. Descriptive analysis of the pathological changes and quantitative analyses of the infiltrates and vascular changes were performed. All patients had multifocal vascular damage as determined by leakage of serum proteins into the brain parenchyma. This was accompanied by widespread endothelial cell activation. Platelet aggregates and microthrombi were found adherent to the endothelial cells along vascular lumina. Immune complexes with activation of the classical complement pathway were found on the endothelial cells and platelets. Perivascular infiltrates consisted of predominantly macrophages and some CD8+ T cells. Only rare CD4+ T cells and CD20+ B cells were present. Astrogliosis was also prominent in the perivascular regions. Microglial nodules were predominant in the hindbrain, which were associated with focal neuronal loss and neuronophagia. Antibody-mediated cytotoxicity directed against the endothelial cells is the most likely initiating event that leads to vascular leakage, platelet aggregation, neuroinflammation and neuronal injury. Therapeutic modalities directed against immune complexes should be considered.

Intracranial Aneurysm Rupture after SARS-CoV2 Infection: Case Report and Review of Literature.

BACKGROUND: SARS-CoV virus infection results in a dysbalanced and severe inflammatory response with hypercytokinemia and immunodepression. Viral infection triggers systemic inflammation and the virus itself can potentially cause vascular damage, including blood-brain barrier (BBB) disruption and alterations in the coagulation system, which may result in cardiovascular and neurovascular events. Here, we review the literature and present a case of COVID-19 infection leading to an aneurysmal subarachnoid haemorrhage (aSAH). CASE DESCRIPTION: A 61-year-old woman presented with dyspnea, cough, and fever. She had a history of hypertension and was overweight with a body mass-index of 34. There was no history of subarachnoid hemorrhage in the family. Due to low oxygen saturation (89%) she was admitted into ICU. A chest CT showed a typical picture of COVID-19 pneumonia. The PCR-based test of an oropharyngeal swab was COVID-19-positive. In addition to oxygen support she was prescribed with favipiravir and hydroxychloroquine. She experienced a sudden headache and lost consciousness on the second day. Computer tomography (CT) with CT-angiography revealed a subarachnoid haemorrhage in the basal cisterns from a ruptured anterior communicating artery aneurysm. The aneurysm was clipped microsurgically through a left-sided standard pterional approach and the patient was admitted again to the intensive care unit for further intensive medical treatment. Post-operatively, the patient showed slight motor dysphasia. No other neurological deficits. CONCLUSION: Systemic inflammation and ventilator support-associated blood pressure fluctuations may trigger aneurysmal subarachnoid haemorrhage secondary to COVID-19 infection. COVID-19 infection could be considered as one of the possible risk factors leading to instability and rupture of intracranial aneurysm.

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.

The microvascular hypothesis underlying neurologic manifestations of long COVID-19 and possible therapeutic strategies.

With the ongoing distribution of the coronavirus disease (COVID) vaccines, the pandemic of our age is ending, leaving the world to deal with its well-documented aftereffects. Long COVID comprises a variety of symptoms, of which the neurological component prevails. The most permeating theory on the genesis of these symptoms builds upon the development of microvascular dysfunction similar to that seen in numerous vascular diseases such as diabetes. This can occur through the peripheral activation of angiotensin-converting enzyme 2 receptors, or through exacerbations of pro-inflammatory cytokines that can remain in circulation even after the infection diminishes. Several drugs have been identified to act on the neurovascular unit to promote repair, such as gliptins, and others. They also succeeded in improving neurologic outcome in diabetic patients. The repurposing of such drugs for treatment of long COVID-19 can possibly shorten the time to recovery of long COVID-19 syndrome.

SARS-CoV-2 deregulates the vascular and immune functions of brain pericytes via Spike protein.

Coronavirus disease 19 (COVID-19) is a respiratory illness caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). COVID-19 pathogenesis causes vascular-mediated neurological disorders via elusive mechanisms. SARS-CoV-2 infects host cells via the binding of viral Spike (S) protein to transmembrane receptor, angiotensin-converting enzyme 2 (ACE2). Although brain pericytes were recently shown to abundantly express ACE2 at the neurovascular interface, their response to SARS-CoV-2 S protein is still to be elucidated. Using cell-based assays, we found that ACE2 expression in human brain vascular pericytes was increased upon S protein exposure. Pericytes exposed to S protein underwent profound phenotypic changes associated with an elongated and contracted morphology accompanied with an enhanced expression of contractile and myofibrogenic proteins, such as α-smooth muscle actin (α-SMA), fibronectin, collagen I, and neurogenic locus notch homolog protein-3 (NOTCH3). On the functional level, S protein exposure promoted the acquisition of calcium (Ca2+) signature of contractile ensheathing pericytes characterized by highly regular oscillatory Ca2+ fluctuations. Furthermore, S protein induced lipid peroxidation, oxidative and nitrosative stress in pericytes as well as triggered an immune reaction translated by activation of nuclear factor-kappa-B (NF-κB) signaling pathway, which was potentiated by hypoxia, a condition associated with vascular comorbidities that exacerbate COVID-19 pathogenesis. S protein exposure combined to hypoxia enhanced the production of pro-inflammatory cytokines involved in immune cell activation and trafficking, namely macrophage migration inhibitory factor (MIF). Using transgenic mice expressing the human ACE2 that recognizes S protein, we observed that the intranasal infection with SARS-CoV-2 rapidly induced hypoxic/ischemic-like pericyte reactivity in the brain of transgenic mice, accompanied with an increased vascular expression of ACE2. Moreover, we found that SARS-CoV-2 S protein accumulated in the intranasal cavity reached the brain of mice in which the nasal mucosa is deregulated. Collectively, these findings suggest that SARS-CoV-2 S protein impairs the vascular and immune regulatory functions of brain pericytes, which may account for vascular-mediated brain damage. Our study provides a better understanding for the mechanisms underlying cerebrovascular disorders in COVID-19, paving the way to develop new therapeutic interventions.

Intracranial Hemorrhage in Patients with Coronavirus Disease 2019 (COVID-19): A Case Series.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic is an ongoing public health emergency. While most cases end in asymptomatic or minor illness, there is growing evidence that some COVID-19 infections result in nonconventional dire consequences. We sought to describe the characteristics of patients with intracranial hemorrhage who were infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Also, with the existing literature, we raise the idea of a possible association between SARS-CoV-2 infection and intracranial hemorrhage and propose possible pathophysiological mechanisms connecting the two. METHODS: We retrospectively collected and analyzed intracranial hemorrhage cases who were also positive for SARS-CoV-2 from 4 tertiary-care cerebrovascular centers. RESULTS: We identified a total of 19 patients consisting of 11 males (58%) and 8 females (42%). Mean age was 52.2, with 95% younger than 75 years of age. With respect to COVID-19 illness, 50% had mild-to-moderate disease, 21% had severe disease, and 20% had critical disease requiring intubation. Of the 19 cases, 12 patients had intraparenchymal hemorrhage (63%), 6 had subarachnoid hemorrhage (32%), and 1 patient had a subdural hematoma (5%). A total of 43% had an intracerebral hemorrhage score of 0-2 and 57% a score of 3-6. Modified Rankin Scale cores at discharge were 0-2 in 23% and 3-6 in 77%. The mortality rate was 59%. CONCLUSIONS: Our series sheds light on a distinct pattern of intracerebral hemorrhage in COVID-19-positive cases compared with typical non-COVID-19 cases, namely the severity of hemorrhage, high mortality rate, and the young age of patients. Further research is warranted to delineate a potential association between SARS-CoV-2 infection and intracranial hemorrhage.

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.