Multiple Neuroinvasive Pathways in COVID-19

Molecular Neurobiology https://doi.org/10.1007/s12035-020-02152-5 Multiple Neuroinvasive Pathways in COVID-19 Dmitri Bougakov 1 2 & Kenneth Podell & Elkhonon Goldberg 1,3 Received: 8 July 2020 / Accepted: 25 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020 Abstract COVID-19 is a highly infectious viral disease caused by the novel coronavirus SARS-CoV-2. While it was initially regarded as a strictly respiratory illness, the impact of COVID-19 on multiple organs is increasingly recognized. The brain is among the targets of COVID-19, and it can be impacted in multiple ways, both directly and indirectly. Direct brain infection by SARS-CoV-2 may occur via axonal transport via the olfactory nerve, eventually infecting the olfactory cortex and other structures in the temporal lobe, and potentially the brain stem. A hematogenous route, which involves viral crossing of blood–brain barrier, is also possible. Secondary mechanisms involve hypoxia due to respiratory failure, as well as aberrant immune response leading to various forms of encephalopathy, white matter damage, and abnormal blood clotting resulting in stroke. Multiple neurological symptoms of COVID-19 have been described. These involve anosmia/ageusia, headaches, seizures, mental confusion and delirium, and coma. There is a growing concern that in a number of patients, long-term or perhaps even permanent cognitive impairment will persist well after the recovery from acute illness. Furthermore, COVID-19 survivors may be at increased risk for developing neurodegenerative diseases years or decades later. Since COVID-19 is a new disease, it will take months or even years to characterize the exact nature, scope, and temporal extent of its long-term neurocognitive sequelae. To that end, rigorous and systematic longitudinal follow-up will be required. For this effort to succeed, appropriate protocols and patient registries should be developed and put in place without delay now. Keywords COVID-19 . NeuroCovid . Encephalopathy . Cognitive impairment . Neurocognitive sequelae The Current COVID-19 Pandemic The current COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Based on World Health Organization definitions, the disease is named coronavirus disease—COVID-19; however, the virus causing the disease is severe acute respiratory syndrome coronavirus 2—SARS-CoV-2. The disease was first identified in Wuhan, China at the end of 2019, and has rapidly spread throughout the world resulting in a global pandemic [1]. Based on Johns Hopkins University Coronavirus Resource Center, as of the second week of June 2020, 188 countries and regions have been affected, and more and 7 million people were infected, with more than 400,000 deaths [2]. Unfortunately, these numbers continue to grow. Our current knowledge of the novel COVID-19 disease is limited, but new findings are accumulating rapidly. Initially, it was thought to be strictly an upper respiratory disease (hence its categorization as a SARS virus); however, as more details emerge, COVID-19 clearly can have both direct and secondary impact on the brain. In this article, we attempt to summarize what has been learned so far about the effect of COVID19 on the brain. This knowledge will undoubtedly expand very rapidly, and new findings and theories will emerge. Nevertheless, the sheer magnitude of the current impact of this pandemic justifies surveying the current knowledge in face of the limitations of an incomplete and rapidly evolving disease picture. We hope that this review will aid in the future research, diagnosis, and treatment of the neurological aspects of the COVID-19. * Elkhonon Goldberg Coronaviruses 1 Luria Neuroscience Institute, New York, NY, USA 2 Houston Methodist Hospital and Weill Cornell Medical College, Houston, TX, USA 3 NYU Grossman School of Medicine, New York, NY, USA Coronaviruses are a group of related viruses found in mammals, including humans and bats, and birds. The name coronavirus originated from the visualized findings of spike-like glycoproteins on the surface membrane of the virus making it Mol Neurobiol appear to have a crown (“corona” in Latin) [3]. The disease that they cause may range from asymptomatic/mild to lethal. Based on the Center for Disease Control (CDC) [4], seven strains of coronaviruses affecting humans have been identified, four of them leading to mostly mild illness, and three leading to severe, potentially lethal illness. The following coronaviruses usually lead to mild, cold-like illness in humans: 229E; NL63; OC43; and HKU1; however, a wide spectrum of disease presentation, including a severe disease course, has been known to occur in children [5]. The following coronaviruses can lead to severe illness primarily in adult humans: severe acute respiratory syndrome coronavirus (SARS-CoV); Middle East respiratory syndrome coronavirus (MERS-CoV); and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Cellular Mechanisms of Infection and Their Implications The spike glycoproteins serve a crucial role in viral binding to cellular receptors, more specifically to angiotensin-conversion enzyme 2 (ACE2). ACE2 is quite ubiquitous in the organism and serves multiple physiological roles, including blood pressure control and inflammation. SARS-CoV-2 has a high affinity to ACE2 receptors which are present in bronchial epithelial cells, endothelial cells, and neurons and on the surface of cells in multiple organs and anatomical locations, e.g., nasal, cavity, lungs, heart, kidneys, and intestines. SARS-CoV-2 attacks the organism by attaching itself to ACE2 via its spike protein, which allows its RNA to enter the healthy cell permitting the virus to replicate through a complex sequence of steps [6, 7]. The ubiquity of ACE2 in multiple organs may account for the multiplicity and heterogeneity of COVID-19 symptoms. Based on animal models, all coronaviruses including human (e.g., SARS-CoV) and animal (e.g., bat coronavirus RaTG13) require ACE2 as the cell entry receptor by binding CoV spike glycoprotein to cell membranes [8]. SARSCov-2 has a particularly strong affinity for ACE2 [9, 10]. ACE2 is also expressed in the nasal cavity epithelia, and it has been hypothesized that olfactory epithelium is a common early infection site. According to this hypothesis, SARS-CoV2 then enters the brain via the olfactory nerve and olfactory bulb [11]. It has been also reported that ACE2 is expressed in multiple brain structures. These include the brainstem, cortex, striatum, and hypothalamus [12–14]. Furthermore, ACE2 is expressed both in neurons and in glial cells throughout the brain, which makes both types of cells potentially vulnerable to the virus [14]. It has been suggested that ACE2 may influence GABA (gamma-aminobutyric acid) neurotransmission in the amygdala and possibly elsewhere in the brain, pointing to another possible target of the virus [15]. (...truncated)