Introduction:
From the beginning of the COVID-19 outbreak, simultaneously with
treatment measures, health and preventive measures such as strict
quarantine, social distancing, hand washing, disinfection of various
surfaces, and wearing a mask among others, as health protocols to reduce
and cut off the transmission chain were on the agenda of governments and
health organizations [1, 2]. SARS-CoV-2 infects target cells
primarily via interaction of the receptor-binding domain of the S
protein with the cellular angiotensin-converting enzyme 2 (ACE2)
receptor after activation of the S protein by transmembrane serine
protease 2 (TMPRSS2) [3]. The S protein is composed of two
functional subunits, S1 and S2; S1 is responsible for receptor binding,
whereas S2 (the C-terminal domain) is specifically responsible for
viral-cellular membrane fusion [4,5]. Although SARS-CoV-2 primarily
targets the respiratory tract, causing fever, dry cough, sore throat,
fatigue, and dyspnoea [6], the virus also results in dysfunction of
multiple organ systems outside the lung, including the kidneys, liver,
brain, heart, gastrointestinal tract and other organ, as ACE2 and other
candidate receptors are also expressed in these tissues [7].
In fact, the central nervous system (CNS) complications have been
observed in more than 30% of individuals with COVID-19 presenting with
a higher infection severity. Emerging studies have revealed the
neuroinvasive potential of SARS-CoV-2, with neurological manifestations
ranging from lethargy, headache, loss of smell and taste, delirium,
insomnia, brain inflammation, stroke, brain haemorrhage to cognitive
impairment [8].
Various studies using cultured cells, animal models, and brain tissues
from patients who died of COVID-19, have independently revealed the
capacity of SARS-CoV-2 to invade the CNS [9]. Supporting evidence
from a postmortem study indicated the presence of viral RNA and proteins
in the brains of more than half (21 of 40) of German patients who died
of COVID-19 [10]. In addition, the presence of SARS-CoV-2 in the
cerebrospinal fluid (CSF) of infected individuals also confirms CNS
infection. Notably, by employing well-characterized human brain
organoids, researchers have visualized widespread infectivity of
SARS-CoV-2 and extensive death of virus-infected and nearby neuronal
cells, and found that the viral infection can be abrogated by
pretreatment with an ACE2 antibody or administration of CSF obtained
from patients with COVID-19 [11]. Moreover, brain imaging studies
have revealed the presence of multiple haemorrhagic lesions and changes
in the brain structure of patients infected with SARS-CoV-2, even in
milder cases [12]. Together, this evidence implies that SARS-CoV-2
has the ability to enter the CNS and cause neurological conditions.
In a recent study, diffuse neural inflammatory markers were found in
>80% of COVID-19 patient brains, processes which could
contribute to the observed neurological symptoms [13]. Furthermore,
another pair of frequent symptoms of infection by SARS-CoV-2 are
hyposmia and hypogeusia, the loss of the ability to smell and taste,
respectively. Interestingly, hyposmia has been reported in early-stage
Alzheimer’s disease (AD), and AD type II astrocytosis has been observed
in neuropathology studies of COVID-19 patients [14].