Biomedical Perspectives of Acute and Chronic Neurological and Neuropsychiatric Sequelae of COVID-19

Abstract

The incidence of infections from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent for coronavirus disease 2019 (COVID-19), has dramatically escalated following the initial outbreak in China, in late 2019, resulting in a global pandemic with millions of deaths. Although the majority of infected patients survive, and the rapid advent and deployment of vaccines have afforded increased immunity against SARS-CoV-2, long-term sequelae of SARS-CoV-2 infection have become increasingly recognized. These include, but are not limited to, chronic pulmonary disease, cardiovascular disorders, and proinflammatory-associated neurological dysfunction that may lead to psychological and neurocognitive impairment. A major component of cognitive dysfunction is operationally categorized as "brain fog" which comprises difficulty concentrating, forgetfulness, confusion, depression, and fatigue. Multiple parameters associated with long-term neuropsychiatric sequelae of SARS-CoV-2 infection have been detailed in clinical studies. Empirically elucidated mechanisms associated with the neuropsychiatric manifestations of COVID-19 are by nature complex, but broad-based working models have focused on mitochondrial dysregulation, leading to systemic reductions of metabolic activity and cellular bioenergetics within the CNS structures. Multiple factors underlying the expression of brain fog may facilitate future pathogenic insults, leading to repetitive cycles of viral and bacterial propagation. Interestingly, diverse neurocognitive sequelae associated with COVID-19 are not dissimilar from those observed in other historical pandemics, thereby providing a broad and integrative perspective on potential common mechanisms of CNS dysfunction subsequent to viral infection. Poor mental health status may be reciprocally linked to compromised immune processes and enhanced susceptibility to infection by diverse pathogens. By extrapolation, we contend that COVID-19 may potentiate the severity of neurological/neurocognitive deficits in patients afflicted by well-studied neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. Accordingly, the prevention, diagnosis, and management of sustained neuropsychiatric manifestations of COVID-19 are pivotal health care directives and provide a compelling rationale for careful monitoring of infected patients, as early mitigation efforts may reduce short- and long-term complications.

Keywords: COVID-19; Central nervous system; SARS-CoV-2; anxiety; brain fog; cognitive impairment; depression; long COVID; microglia; mitochondria; neuroinflammation; neuropsychiatric disease.

Fig. (1)

Theoretical pathways developed by eminent theoretical biologists strongly suggest that ssDNA and dsDNA genomes have evolved from primordial RNA constructs in protocellular and protoviral packages. Within the primordial RNA world, we surmise that the persistence of protocellular and protoviral genetic material was insured by packaging into protective phospholipid-and protein-based membrane vesicles. Accordingly, within the realm of the last universal common ancestor (LUCA) theory, co-evolution of DNA viruses within archaea and prokaryotes and RNA viruses within eukaryotes likely emerged due to extensive adaptive complexity or differentiation of viral membranes [49, 50]. In simple terms, viral-mediated horizontal transfer of genetic information may be physically dependent on conformational matching or shape recognition processes driving high-affinity binding interactions of complementary viral and extracellular host membrane domains. Thus, given over 3.5 billion years of viral and cellular co-evolution, it is not surprising that intracellular communication between infective and replicating viruses and host mitochondria is extensive due to the endosymbiont origin of these eukaryotic organelles. Currently, these strong evolutionary considerations underlie the existential role of SARS-CoV-2 to effectively hijack host mitochondrial energy production to drive replicative processes. COVID-19 may also result in chronic alteration of brain metabolism resulting in long-term cognitive and affective behavioral deficits.

Fig. (2)

A summary of the direct and indirect mechanisms by which SARS-CoV-2 affects the CNS, leading to neuropsychiatric symptoms; direct routes of access to the brain, disruption of the blood brain barrier, trans-synaptic, optic and olfactory nerve channels. Once these entry routes are breached, the virus may directly infect neurons and other supportive non-neuronal cells. SARS-CoV-2 then co-opt mitochondrial function, disrupting autophagy to facilitate propagation. Alternatively, even brief episodes of systemic hypoxia alter mitochondrial function leading to direct impairment of susceptible, metabolically-demanding organs, including the brain. The release of cytokines in response to overwhelming infection may trigger uncontrolled and cascading inflammation that may disrupt the BBB and lead to neurocognitive symptoms.

Fig. (3)

The diagram illustrates a balance between what is regarded as normal behavior and which is multifaceted and emerges as appropriate behavior given a dynamic input and appropriate output. In this process, for the most part, the mind is self-aware, instituting conscious decision-making. As discussed in the text, viral infections, such as SARS-CoV-2, have the potential to disrupt these processes and alter a person’s mental state. The altered mental state still allows the person to be functional, but with reduced behavioral efficacy. In part, we surmise this is due to altering mitochondrial energy processes since maintaining a normal mental state requires a high level of energy availability. Significantly, a similar alteration of a normal mental state may occur with the use of antibiotics, which target bacteria as well as the “power house of the cell”, i.e., mitochondria given their prokaryotic origin [72]. This further demonstrates the susceptibility and sensitivity of cognition to its energy requirements (Fig. 3). Thus, it is surmised that viral-induced modifications of energy availability benefit viral survival because carefully thought-out preventative behaviors may be compromised.