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Neurobiology of COVID-19: how can the virus affect the brain?

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Severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) causes the coronavirus disease 2019 (COVID-19), which has been declared a public health emergency of international interest, with confirmed cases in most countries. COVID-19 presents manifestations that can range from asymptomatic or mild infections up to severe manifestations that lead to hospitalization and death. A growing amount of evidence indicates that the virus may cause neuroinvasion. Postmortem brain study findings have included edema, hemorrhage, hydrocephalus, atrophy, encephalitis, infarcts, swollen axons, myelin loss, gliosis, neuronal satellitosis, hypoxic-ischemic damage, arteriolosclerosis, leptomeningeal inflammation, neuronal loss, and axon degeneration. In addition, the COVID-19 pandemic is causing dangerous effects on the mental health of the world population, some of which can be attributed to its social impact (social distancing, financial issues, and quarantine). There is also a concern that environmental stressors, enhanced by psychological factors, are contributing to the emergence of psychiatric outcomes during the pandemic. Although clinical studies and diagnosing SARS-CoV-2-related neurological disease can be challenging, they are necessary to help define the manifestations and burden of COVID-19 in neurological and psychiatric symptoms during and after the pandemic. This review aims to present the neurobiology of coronavirus and postmortem neuropathological hallmarks.
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SPECIAL ARTICLE
Neurobiology of COVID-19: how can the virus affect the
brain?
Jaqueline S. Generoso,
1
0000-0000-0000-0000
Joa
˜oL.Barichello de Quevedo,
1
Matias Cattani,
1
Bruna F. Lodetti,
1
Lucas Sousa,
1
Allan Collodel,
1
0000-0000-0000-0000
Alexandre P. Diaz,
2
0000-0000-0000-0000
Felipe Dal-Pizzol
1
0000-0000-0000-0000
1
Laborato
´rio de Fisiopatologia Experimental, Programa de Po
´s-Graduac¸a
˜o em Cie
ˆncias da Sau
´de, Universidade do Extremo Sul Catarinense,
Criciu
´ma, SC, Brazil.
2
Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center at
Houston, Houston, TX, USA.
Severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) causes the coronavirus
disease 2019 (COVID-19), which has been declared a public health emergency of international
interest, with confirmed cases in most countries. COVID-19 presents manifestations that can range
from asymptomatic or mild infections up to severe manifestations that lead to hospitalization and
death. A growing amount of evidence indicates that the virus may cause neuroinvasion. Postmortem
brain study findings have included edema, hemorrhage, hydrocephalus, atrophy, encephalitis, infarcts,
swollen axons, myelin loss, gliosis, neuronal satellitosis, hypoxic-ischemic damage, arteriolosclerosis,
leptomeningeal inflammation, neuronal loss, and axon degeneration. In addition, the COVID-19
pandemic is causing dangerous effects on the mental health of the world population, some of which
can be attributed to its social impact (social distancing, financial issues, and quarantine). There is also
a concern that environmental stressors, enhanced by psychological factors, are contributing to the
emergence of psychiatric outcomes during the pandemic. Although clinical studies and diagnosing
SARS-CoV-2-related neurological disease can be challenging, they are necessary to help define the
manifestations and burden of COVID-19 in neurological and psychiatric symptoms during and after the
pandemic. This review aims to present the neurobiology of coronavirus and postmortem
neuropathological hallmarks.
Keywords: Coronavirus-2; COVID-19; SARS-CoV-2; neurobiology; psychiatric disorders
Introduction
Emerging pathogens have become significant challenges
for public health worldwide.
1
Coronaviruses are envel-
oped viruses with RNA as genetic material. They are
commonly found among humans, other mammals, and
birds. In some species, the virus can cause diseases in
the respiratory tract, intestinal tract, and liver, as well as
neurological disorders in humans.
2
By 2019, two viruses
of the coronavirus family had caused major epidemic
outbreaks of respiratory diseases: severe acute respira-
tory syndrome (SARS), from 2002 to 2004, and the
Middle East respiratory syndrome (MERS) in 2012.
3
At
the end of December 2019, the World Health Organiza-
tion (WHO) was notified that in Wuhan, China, cases of
pneumonia of unknown etiology
4
were occurring and
spreading rapidly to other parts of China, Asia, Europe,
and later to the Americas.
5
In January 2020, the virus was
isolated from airway epithelial cells of patients affected by
the disease. The etiologic agent was identified as a new
coronavirus; however, it was different from severe acute
respiratory syndrome coronavirus (SARS-CoV) and Mid-
dle East respiratory syndrome coronavirus (MERS-CoV).
6
The new virus was named severe acute respiratory
syndrome-related coronavirus-2 (SARS-CoV-2)
7
and it
causes coronavirus disease 2019 (COVID-19). The
COVID-19 pandemic, with confirmed cases in most
countries, has been declared a public health emergency
of international interest.
8
COVID-19 symptoms range
from asymptomatic or mild infections (approximately
80%) to severe signs that lead to hospitalization and
death.
9
Transmission occurs from person to person
mainly through respiratory droplets, which are usually
released when the infected person coughs or sneezes,
and direct contact, similar to the human influenza virus,
SARS-CoV and MERS-CoV.
8
To a lesser extent, trans-
mission can occur through contaminated surfaces.
10
However, recent evidence supports that transmission
can also occur via aerosols, mostly indoors where there is
insufficient ventilation and long-term exposure to high
concentrations of aerosols.
11,12
The approximate incuba-
tion period from exposure to symptom onset is 4 to
Correspondence: Jaqueline S. Generoso, Laborato
´rio de Fisiopato-
logia Experimental, Programa de Po
´s-Graduac¸a
˜o em Cie
ˆncias da
Sau
´de, Universidade do Extremo Sul Catarinense, Av. Universita
´ria,
1105, Bairro Universita
´rio, CEP 88806-000 Criciu
´ma, SC, Brazil.
E-mail: jsg@unesc.net
Submitted Sep 07 2020, accepted Dec 09 2020.
How to cite this article: Generoso JS, Barichello de Quevedo JL,
Cattani M, Lodetti BF, Sousa L, Collodel A, et al. Neurobiology of
COVID-19: how can the virus affect the brain? Braz J Psychiatry.
2021;00:000-000. http://dx.doi.org/10.150/1516-4446-2020-1488
Braz J Psychiatry. 2021 xxx-xxx;00(00):000-000
doi:10.1590/1516-4446-2020-1488
Brazilian Psychiatric Association
00000000-0002-7316-1185
6 days,
12,13
and 97.5% of symptomatic patients have
symptoms within 11 days of infection.
12
The most fre-
quent clinical symptoms are fever, dry cough, fatigue,
dyspnea, anosmia, ageusia, gastrointestinal symptoms,
or some combination of these.
14
Shortness of breath
usually occurs between 5 to 8 days after the first
symptoms and is suggestive of disease worsening.
14,15
Risk factors for COVID-19 complications include old
age (465 years), cardiovascular disease, chronic lung
disease, hypertension, diabetes, obesity,
16
and autoim-
mune diseases (rheumatoid arthritis, lupus, or psoria-
sis).
17
By December 2020, more than 67.2 million cases
had been confirmed worldwide, resulting in more than
1.5 million deaths.
18
According to the WHO report, more
than 26.2 million cases and 720,228 deaths have been
confirmed in the Americas; in Europe, there have been
more than 18.4 million cases and 412,362 deaths; in
Southeast Asia, there have been more than 10.7 million
cases and 163,454 deaths; in the Mediterranean there
have been more than 4.04 million cases and 102,160
deaths; in Africa there have been over 1.4 million cases
and 33,512 deaths; and in the Western Pacific there have
been over 800,000 cases and 17,261 deaths.
19
This
review aims to present the neurobiology of the corona-
virus and its postmortem neuropathological hallmarks.
The coronavirus: severe acute respiratory syndrome-
related coronavirus 2 (SARS-CoV-2)
Although scientists have developed precise techniques
and have quickly identified the new coronavirus, it is
necessary to investigate its viral structure, colonization
and pathogenic mechanisms, and the future conse-
quences of infection on survivors.
20
SARS-CoV-2 is a spherical b-coronavirus that received
this name due to its high similarity to SARS-CoV (79.5%).
Since they belong to the same family, Coronaviridae, they
share several similarities.
21
SARS-CoV-2 is an enveloped
virus with a single-stranded positive RNA genome of
approximately 30 kb, with a receptor-binding domain
(RBD) structure similar to that of SARS-CoV.
22
Open
reading frames (ORFs) ORF1a and ORF1b have also
been identified in its sequencing, which encode a variety
of structural and non-structural proteins that play an
essential role in viral survival and virulence power.
23
The
four structural proteins encoded by ORFs include spike
(S) proteins, membrane (M) proteins, nucleocapsid (N)
proteins, and envelope (E) proteins,
24
which are all
necessary to produce a structurally complete viral
particle
25
(Figure 1).
Protein S is a highly immunogenic homotrimeric
glycoprotein (ranging from 9 to 12 nm) in the outer
portion of the virus, which gives the appearance of a solar
corona.
26
It is one of the main targets of neutralizing
antibodies after host infection and therapeutic and
vaccine focus.
27
This protein is essential for virus fixation
on the surface of host cells, where the RBD of protein S
mediates the interaction with angiotensin-converting
enzyme 2 (ACE2).
28
There are two functional subunits
of this protein: the S1 subunit, which is responsible for
binding to the host cell’s receptor, and the S2 subunit,
which is responsible for fusion between the viral and
cellular membranes, facilitating viral entry into the cell.
27
Protein S can access the endoplasmic reticulum using an
N-terminal signal sequence, and it is strongly associated
with glycosylated N.
29
Another essential component of SARS-CoV-2 is protein
M. This approximately 25-30 kDa protein is the most
abundant in the virus, can bind to all other structural
proteins, and is responsible for defining the shape of
the viral envelope.
30
The interaction between M and N
proteins can stabilize and form nucleocapsids, promoting
completion of viral assembly.
31
Protein M exists as a
dimer and can have two conformations: M
LONG,
which is
Figure 1 Schematic representation of new coronavirus structure. Severe acute respiratory syndrome-related coronavirus-2
(SARS-CoV-2) is a spherical b-coronavirus with a positive-sense RNA with four main structural proteins: spike (S) and
membrane (M) glycoproteins, as well as envelope (E) and nucleocapsid (N) proteins. The receptor-binding domain (RBD) of
protein S interacts with angiotensin-converting enzyme 2 (ACE2) on the surface of host cells.
Braz J Psychiatry. 2021;00(00)
2JS Generoso et al.
associated with rigidity, spike clusters and the curvature
of the membrane, and M
COMPACT,
which is associated
with flexibility and low spike density.
32
In addition, the
interaction between M and S is essential for the fixation
of S in the endoplasmic reticulum – Golgi intermediate
compartment/Golgi complex and its incorporation into
new virions.
33
The N protein, another structural protein of the virus,
consists of two domains: an N-terminal domain and a
C-terminal domain.
31
This protein is closely linked to the
genetic material forming the nucleocapsid. It is thus
involved in processes related to the viral genome, such
as RNA transcription and replication, and the response
of host cells to viral infections.
34,35
It is also involved in
assembly and viral budding, resulting in the complete
formation of the virion.
36
Protein N is still intensely
phosphorylated and can generate structural changes,
increasing affinity for viral RNA.
33
The last and smallest structural component is protein E
(8 to 12 kDa), which has a role in viral production and
maturation.
37
This membrane protein has ion channel
activity with an N-terminal ectodomain and a C-terminal
endodomain.
36
Proteins E, M, and S are incorporated into
the lipid envelope of the virion. While protein S is involved
in fusion with host membranes and protein M in envelope
formation and budding, protein E is not essential for virus
replication. However, if it is absent, it can result in virus
attenuation and prejudice viral maturation.
38
The mechanism of pathogenicity
Many aspects of the pathogenesis of COVID-19 must be
understood. Fundamental processes in the life cycle of
SARS-CoV-2 in the host include binding, penetration,
biosynthesis, maturation, and release. Upon invasion, the
virus binds to the host’s receptors (binding) and enters
cells through endocytosis or membrane fusion (penetra-
tion). Afterward, the viral content is released, and the
viral RNA enters the cell’s nucleus for replication. The
viral mRNA is soon copied and used for the production of
viral proteins (biosynthesis), and new viruses are orga-
nized (maturation) and released.
39
Reports of devastating damage to the cardiovas-
cular system, intestines, kidneys, and brain in COVID-
19 patients have surfaced more frequently.
40
Blood
coagulation can constrict the vessels, resulting in pul-
monary embolism, ischemic stroke, or ischemia in the
extremities.
40,41
The host cell infection mechanism of SARS-CoV-2 is
similar to that of SARS-CoV; it is mediated mainly by the
ACE2 cell surface receptor
42
and less frequently by
CD147.
23
ACE2 is a glycoprotein expressed in the
epithelium of the airways, lungs parenchyma, vascular
endothelium, heart, kidneys, and small intestine.
43
How-
ever, ACE2 receptors are also expressed in regions of the
human brain, such as the motor cortex and posterior
cingulate, nigra substance, ventricles, middle temporal
gyrus, olfactory bulb, ventrolateral medulla, solitary tract
nucleus, and vagus nerve. Some central nervous system
(CNS) cells, including neurons, microglia, astrocytes, and
oligodendrocytes, can also express ACE2.
43,44
SARS-CoV-2 can access the CNS can occur in two
ways: hematogenous dissemination or the neural path-
way.
45
Hematogenous dissemination occurs through
leukocytes, which serve as a dissemination vehicle for
the CNS through the blood-brain barrier (BBB) or blood-
cerebrospinal fluid barrier.
46
Access to the CNS can occur
by expressing ACE2 in vascular endothelial cells
44
or by
infected leukocytes that cross the BBB, which is known as
a Trojan horse mechanism.
46
The intense inflammatory
response of COVID-19 can lead to increased permeability
of the BBB, allowing infected cells, cytokines, and even
the virus to pass into the CNS.
47
Neural access involves
transporting the virus through the nasal cavity and
rhinopharynx through the olfactory and trigeminal nerves,
while the lower respiratory tract is accessed through the
vagus nerve.
48
The virus then spreads via transsynaptic
transfer using endocytosis/exocytosis and the vesicle’s
fast axonal transport mechanism to move along micro-
tubules to neuronal cell bodies
44
(Figure 2).
To enter cells, SARS-CoV-2 uses protein S to bind to
the ACE2 receptor via the RBD of the S1 subunit.
20
Therefore, viral internalization is facilitated by type 2 trans-
membrane serine protease (TMPRSS2), which cleaves
ACE2 and the S1/S2 subunit site and allows the fusion
of the viral and cellular membranes, a process carried
out by the S2 subunit.
49
The virus enters the host cell by
endocytosis, releases its genetic material and uses its
machinery to translate and replicate RNA and release
new viruses
42
(Figure 3).
The host’s immune system can detect SARS-CoV-2
through viral RNA, glycoproteins, and other virus mole-
cules, also known as pathogen-associated molecular
patterns.
50
These patterns are recognized by pattern
recognition receptors, such as Toll-like receptors, which
are present in antigen-presenting cells, such as macro-
phages and monocytes.
51
Protein S can be recognized
by TLR4
52
and, after recognition, intracellular signaling
begins through signal transmission from the cytoplasmic
domain of the TLR to interleukin-1 receptor-associated
with kinase 4 (IRAK-4).
53
IRAK-4 activation is mediated
by myeloid differentiation protein 88. IRAK-4 stimulates
tumor necrosis factor receptor-associated factor 6, and
this cascade results in the release of the nuclear trans-
cription factor-kappa B and the mitogen-activated pro-
tein kinase pathway, which activates gene expression
of proinflammatory molecules, such as tumor necrosis
factor-alpha (TNF-a), interleukin (IL)-1b, IL-6, IL-8, IL-33,
interferon (IFN)-a, IFN-g, and chemokines.
30
During viral
replication, endosomal receptors TLR3 and TLR7 can
also recognize viral RNA, resulting in nuclear activa-
tion and translocation of interferon regulatory factor-3
and nuclear transcription factor-kappa B, which indu-
ces the production of type I IFN (IFN-a) and pro-
inflammatory cytokines.
54
After release, IFN-acan bind
to IFN-a/breceptor, activate the Janus kinase pathway
and the signal transducer and activator of transcription
(STAT), STAT1 and STAT2, which form complexes with
interferon regulatory factor-9, initiating the transcription
of IFN-stimulated genes. Together, the expression of
cytokines, IFNs, and IFN-stimulated genes establish an
innate immune response that prevents viral replication in
Braz J Psychiatry. 2021;00(00)
How can the COVID-19 affect the brain? 3
infected cells
54,55
(Figure 3). However, the coronavirus
has developed strategies to survive in host cells, including
the formation of vesicles that prevent recognition by
pattern recognition receptors and the use of structural
and non-structural proteins that can suppress the activa-
tion of IFNs, which are closely associated with disease
severity.
56
Post-mortem brain studies
Autopsy tissue samples are essential to understanding
the effect and consequences of COVID-19 on the brain.
Here we report the results of autopsies of brain samples
from patients who died of COVID-19. The following areas
of the brain were studied in the reviewed papers: the
frontal and occipital lobes, olfactory bulb, cingulate gyrus,
corpus callosum, hippocampus, basal ganglia, thalamus,
cerebellum, midbrain, pons, medulla, neocortex, brain-
stem, gyrus rectus, cerebral and cerebellar white and
grey matter, and the lateral ventricles. Macroscopically,
the studies revealed the presence of edema,
57-59
hemor-
rhagic lesions,
57-62
hydrocephalus,
63
atrophy,
64
low brain
weight,
65
encephalitis,
66
asymmetry in the olfactory bulb,
58
and infarcts.
67,68
Microscopically, the results included
positive astrocyte reactivity evaluated for GFAP, swollen
axons
57
and loss of myelin,
57,62
gliosis and neuronal
satellitosis,
69
hypoxic-ischemic damage,
67,68,70
mild or
moderate arteriolosclerosis, leptomeningeal inflamma-
tion, microglial nodules,
67
neuron loss,
66,71
axon
degeneration,
62,66
diffuse or focal spongiosis, vascular
congestion, and focal ischemic necrosis.
59
For more details
about the post-mortem brain studies, see Table 1.
Neurological manifestations of coronavirus
As the SARS-CoV-2 pandemic progresses, a growing
body of evidence indicates that the virus can cause
neuroinvasion and affect the CNS in several ways.
79,80
The virus can gain access to the CNS via the neural
pathway (olfactory nerve and nasal cavity) or the hema-
togenous pathway (infected leukocytes and endothelial
cells from the BBB).
44,45
Neurotropism is also a common
feature of the SARS-CoV and MERS-CoV viruses, and it
has been reported that the endothelium, glial cells, and
neurons express ACE2, which makes them a potential
target for SARS-CoV-2.
81
Neurological manifestations during COVID-19 infection
can be caused directly by the virus in the CNS or by the
host’s immune response and systemic complications.
79
After gaining access to the CNS, the virus can cause
immune cell infiltration and activate inflammatory path-
ways through the secretion of cytokines and chemokines
and activate thrombotic pathways, which contribute to
tissue damage and cause microangiopathy, respec-
tively.
79,82
Nonspecific symptoms include headache,
dizziness, anosmia, ageusia, hypoplasia, and neuralgia
(the latter four involving cranial nerves),
47
in addition to
sleep disorders, stroke, impaired consciousness, coma,
Figure 2 Mechanisms of central nervous system entry. Access to the central nervous system (CNS) through the blood-brain
barrier (BBB) can occur by expressing angiotensin-converting enzyme 2 (ACE2) in vascular endothelial cells or by infected
leukocytes that cross through the BBB, known as a Trojan horse mechanism (hematogenous pathway). Neural access involves
transporting the virus through the nasal cavity and rhinopharynx through the olfactory and trigeminal nerves and the lower
respiratory tract through the vagus nerve (neural pathway). CSF = cerebrospinal fluid; MDD = major depressive disorder;
SARS-CoV-2 = severe acute respiratory syndrome-related coronavirus-2.
Braz J Psychiatry. 2021;00(00)
4JS Generoso et al.
seizure, and encephalopathy.
8,44,83
Severe COVID-19
patients may have marked vascular dysfunction, which is
seen in high levels of D-dimer and procoagulant factors.
Thus, thromboembolic complications, including stroke,
are commonly seen in these patients.
84
The occurrence
of stroke in COVID-19 patients has been reported in some
studies.
47,85
During SARS-CoV-2 infection, coagulopathy
and inflammation can cause thrombosis in cerebral blood
vessels and cardiac embolism, leading to ischemic stroke.
The presence of pre-existing comorbidities, including
advanced age, cardiovascular diseases, and cerebral
microvascular dysfunction can be a significant risk fac-
tor for stroke in COVID-19 patients.
86
Reports of
meningoencephalitis
87
and intracerebral hemorrhage in
affected patients
88
also indicate that the CNS is invaded
by SARS-CoV-2.
Mao et al.
47
were the first to report neurological injury in
COVID-19 patients. This study included 214 patients from
Wuhan, China, who were hospitalized and tested positive
for SARS-CoV-2 infection. The neurological alterations
were divided into manifestations of the CNS, peripheral
nervous system, and skeletal muscle injury. A total of
78 patients (36.4%) had neurological manifestations, of
which 53 (24.8%) were in the CNS, most often includ-
ing dizziness (36 [16.8%]) and headache (28 [13.1%]).
There were peripheral nervous system manifestations in
Figure 3 Severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) entry and pathophysiology of coronavirus
disease 2019 (COVID-19): 1) to enter inside of the cells, SARS-CoV-2 uses spike protein (S) to bind to the angiotensin-
converting enzyme 2 (ACE2) receptor via the receptor-binding domain (RBD). Viral internalization is facilitated by type 2
transmembrane serine protease (TMPRSS2), which allows the fusion of the viral and cellular membranes. The virus enters the
host cell by endocytosis, releases its genetic material, and uses its machinery to translate and replicate RNA and release new
viruses; 2) recognition of pathogen-associated molecular patterns (PAMPs), including viral RNA and glycoproteins, by pattern
recognition receptors (PRRs), such as Toll-like receptor (TLR)3, 4 and 7; 3) after recognition, cell signaling begins with the
transmission of the signal from the cytoplasmic domain of the TLR to receptor-associated with kinase 4 (IRAK-4), which is
mediated by myeloid differentiation protein 88 (MyD88). Afterwards, nuclear transcription factor kappa B (NF-kB) and mitogen-
activated protein kinases (MAPKs) activate genes for proinflammatory molecule expression, including tumor necrosis factor-
alpha (TNF-a), interleukin (IL)-1b, IL-6, IL-18, and interferon-alpha (IFN-a); 4) TLR3 and TLR7 recognize viral RNA, resulting in
nuclear activation and translocation of interferon regulatory factor 3 (IRF3) and NF-kB, which induce the production of IFN-a
and proinflammatory cytokines. IFN-acan bind to the IFN-a/breceptor (IFNAR), activate the Janus kinase pathway (JAK) and
signal transducer and activator of transcription (STAT), initiating the transcription of IFN-stimulated genes (ISGs); 5) the
expression of proinflammatory mediators establish an innate immune response. TIRAP = Toll-interleukin 1 receptor (TIR)
domain-containing adaptor protein; TRAF6 = tumor necrosis factor receptor-associated factor 6; TRAM = TRIF-related adaptor
molecule; TRIF = TIR-domain-containing adapter-inducing interferon-b.
Braz J Psychiatry. 2021;00(00)
How can the COVID-19 affect the brain? 5
Table 1 Outcomes in postmortem brain tissues of patients affected by coronavirus disease 2019 (COVID-19)
Author
Sample size,
sex, and age Primary disease Brain region studied
Technique and
markers Main findings
Barton
72
n=2, 2 ~, age
42 and 77
Obesity, hypertension, deep vein
thrombosis, splenectomy,
pancreatitis, myotonic
dystrophy
NR H&E The study found no gross
abnormalities in the CNS of either
patient, including no abnormalities
in brain weight.
The study did not investigate any
further into the effects of COVID-
19 on the CNS.
Bradley
61
n=14, 8 ~and 6
#, age 673.5
Arterial hypertension,
hyperlipidemia, type II DM,
obesity, OSA, heart failure,
atrial fibrillation, CAD, CKD,
COPD, renal disease,
osteoporosis, aortic stenosis,
breast cancer
All H&E Of the 14 patients, only six had
brain examinations.
Intraparenchymal hemorrhage was
observed in one patient, while
scattered punctate subarachnoid
hemorrhages and punctate
microhemorrhages in the
brainstem were observed in
another.
The other four patients showed no
diagnostic alternations in the brain.
Bulfamante
73
n=1, #, age 54 NR Olfactory nerve, gyrus
rectus, and brainstem
Ultrastructural
analysis
Severe and widespread tissue
damage was observed in the
neurons, glia, nerve axons, and
myelin sheath. The damage from
the olfactory nerve to the gyrus
rectus, and to the brainstem was
less severe. Various particles
referable to virions of SARS-CoV-
2 were observed.
Conklin
62
n=16, 5 ~/11 #,
age 663.5
NR Cerebral and cerebellar
white and grey matter
H&E, MRI, RT-
qPCR
Eleven of 16 patients had lesions,
with eight having 410 lesions.
Of these eight patients, four had
lesions involving the corpus
callosum, and the other four had
lesions involving subcortical and
deep white matter.
Uncal and tonsillar herniation,
diffuse discoloration of the grey-
white matter junction, and
numerous punctuate
hemorrhages were found.
Significant loss of axon and
myelin was also noted.
Continued on next page
Braz J Psychiatry. 2021;00(00)
6JS Generoso et al.
Table 1 (continued )
Author
Sample size,
sex, and age Primary disease Brain region studied
Technique and
markers Main findings
Coolen
58
n=19, 14 ~and
5#, age 6
77.0
Hypertension, cardiac disorders,
CKD, DM, COPD
All MRI Parenchymal brain MRI
abnormalities were documented in
four of the 19 patients.
Abnormalities included sub-
cortical macro-and micro-
hemorrhages, swelling induced by
supratentorial white matter
changes, and hazy hyperintensity
in the MRI.
DIC was the predicted cause of one
hemorrhage while the second
remains unclear. Four separate
decedents had asymmetric
olfactory bulbs. Finally, no
changes were found in the
brainstem expect for a capillary
telangiectasia in one patient.
Jaunmuktane
68
n=2, 1 ~and 1
#, age 50 and
60
Asthma, DM, hypertension All CD3,
CD34,
CD68,
MRI,
SMI31, SMI94
Patient 1 was found to suffer from
multifocal brain infarcts. The MCA
and PCA infarcts were likely
caused by local thrombosis or
hypertension.
The second patient, who died from
multiorgan failure, suffered from
cortical and white matter
microlesions likely caused by
vascular injury, immune-
mediated, or hypoxia.
CD68 highlights many more lesions
than MRI or microscopic
examination. CD34 showed blood
vessels within some white matter
microlesions. SMI31 revealed
swollen axons in neurofilament
staining, but SMI94 showed no
demyelination.
Lacy
63
n=1 ~, age 58 Type 2 DM, obesity, HLD, mild
intermittent asthma, chronic
lower extremity swelling with
ulceration
Brain Gross
examination
and H&E
The brain (1,221 g) presented
hydrocephalus ex-vacuo.
The frontal horns measured 2.8 cm
at the level of the temporal poles.
Lax
64
n=11, 8 #and 3
~, age 680.5
Arterial hypertension,
DM type 2, ischemic stroke,
dementia, pulmonary embolism
Brain Dissection A brain autopsy was performed in
only one patient, showing atrophy
and arteriosclerotic changes but
no acute alterations.
Continued on next page
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How can the COVID-19 affect the brain? 7
Table 1 (continued )
Author
Sample size,
sex, and age Primary disease Brain region studied
Technique and
markers Main findings
Menter
74
n=21, 17 #and
4~,age6
76.0
HTN, obesity, CVD, DM, chronic
neurological condition, COPD,
malignancy, CLD, CKD,
immunosuppression
Brain H&E A small number of RNA copies of
the virus were found in the brain.
Brain analysis revealed no
inflammatory infiltrates or
neuronal necrosis. Three of the
four brains examined presented
mild hypoxic injury.
Nunes Duarte-
Neto
69
n=10, 5 ~and 5
#, age 69
(33-83)
Systemic arterial hypertension,
DM, chronic cardiopathy,
COPD, renal disease,
neoplasia
NR Hematoxylin,
H&E, MIA-US,
and qRT-PCR
Reactive gliosis in the brain was
found in eight out of nine autopsies.
Other findings included neuronal
satellitosis, small vessel disease,
and perivascular hemorrhages.
Alterations to the cerebral cortex,
potentially caused by the viral
infection, were also found.
Paniz-
Mondolfi
60
n=1, #, age 74 Parkinson’s disease Frontal lobes CRP, D-dimer
level, ferritin,
RT-PCR,
TEM
The postmortem sample indicated
viral particles in the frontal lobe.
Individual and small vesicles of
pleomorphic viral-like particles
were present. Transcellular
Penetration of the active pathogen
through the brain microvascular
endothelial cells was recorded.
Neural cell bodies demonstrated
distended cytoplasmic vacuoles
with enveloped viral particles and
centers of electron density. The
presence of SARS-CoV-2 was
later confirmed through RT-PCR.
Puelles
75
n=22, 16 ~and
6#, age 6
75.9
Cardiovascular condition,
respiratory condition, brain
disorder, CKD, metabolic
condition
NR RT-PCR The highest levels of SARS-CoV-2
copies per cell were found in the
respiratory system, although
lower levels were discovered in
the brain and other organs.PCR
confirmed the presence of SARS-
CoV-2 in the brains of eight/21
patients. The study suggests that
brain tropism increases with the
number of preexisting conditions.
The findings indicate that COVID-
19 has broad organotropism.
Continued on next page
Braz J Psychiatry. 2021;00(00)
8JS Generoso et al.
Table 1 (continued )
Author
Sample size,
sex, and age Primary disease Brain region studied
Technique and
markers Main findings
Reichard
57
n=1, #, age 71 CAD Frontal lobes and corpus
callosum
H&E, LFB,
GFAP, and PAS
The postmortem brain sample
presented mild brain swelling and
hemorrhagic lesions disseminated
throughout the cerebral
hemispheric white matter.
There were foci of intraparenchymal
blood in the white matter, with
macrophages on the periphery of
the lesions.
Reactive astrocytes were observed
in the white matter. At the same
time, APP immunostaining
showed swollen and damaged
axons on the periphery of the
hemorrhagic foci.
The brain sample also presented
the loss of myelin and positive
macrophages.
Remmelink
59
n=17, 12 #and
5~,age6
72.0
Arterial hypertension, DM,
cerebrovascular disease, CAD,
cancer
Frontal lobe H&E, RT-PCR A brain autopsy was performed on
eleven patients, with SARS-CoV-
2 RNA detected in nine.
The post-mortem analysis found
cerebral hemorrhage or
hemorrhagic suffusion, focal
ischemic necrosis, edema and/or
vascular congestion, and diffuse
or focal spongiosis.
No evidence of viral encephalitis or
vasculitis, isolated neuronal
necrosis, or perivascular
lymphocytic infiltration was found.
Schaller
76
n=10 ,7 ~and 3
#, mean age
79 (64-90)
Arterial hypertension,
arteriosclerosis, atrial
fibrillation, CKD, COPD, DM,
obesity, hypothyroidism,
adenocarcinoma - lung, CAD,
CML, CLL, cardiomyopathy,
fatty liver disease, dementia,
HCM, hyperthyroidism
NR H&E Postmortem examination of 10
patients showed no
morphologically detectable
pathology in the brain. No
evidence was found of
encephalitis or central nervous
vasculitis.
Skok
77
n=28, 17 #and
11 ~, age 6
82.9
NR Lateral ventricles and
corpus callosum
qPCR No viral RNA was found in brain
tissue or CSF samples.
No brain autopsy was performed.
Continued on next page
Braz J Psychiatry. 2021;00(00)
How can the COVID-19 affect the brain? 9
Table 1 (continued )
Author
Sample size,
sex, and age Primary disease Brain region studied
Technique and
markers Main findings
Solomon
67
n=18, 14 #and
4~,age6
62.0
DM, HTN, CVD, HLD, CKD, prior
stroke, dementia, treated
anaplastic astrocytoma
Frontal and occipital lobe,
olfactory bulb, cingulate
gyrus, corpus callosum,
hippocampus, BG,
thalamus, cerebellum,
midbrain, pons, and
medulla
H&E, CD45,
RT-PCR (qRT-
PCR) for the
SARS-CoV-2
All 18 patients had acute hypoxic-
ischemic damage in the cerebrum
and cerebellum and were SARS-
CoV-2-positive in the frontal/
olfactory medulla.
A loss of neurons was detected in
the cerebral cortex, hippocampus,
and cerebellar Purkinje cell layer.
Eight out of 18 patients presented
mild arteriolosclerosis, three had
chronic infarcts, five had
moderate arteriolosclerosis, four
presented pathological features of
Alzheimer’s disease, two showed
pathological features of Lewy
body disease, four had
Alzheimer’s type II astrocytosis,
three had focal leptomeningeal
chronic inflammation, one had a
recurrent or residual anaplastic
astrocytoma, and one had a single
microglial nodule.
Suess &
Hausmann
78
n=1, #, age 59 Hypertension, type II DM NR CD-68, H&E,
PAS, and
TTF-1
The autopsy of the subject, whose
coronavirus infection was
confirmed by a pharyngeal swab
test, found no abnormalities in
brain weight and no major lesions.
von Weyhern
66
n=6, 4 #and 2
~, age 669.0
HTN, COPD, CRF, PHT, PAD,
CAD, atrial fibrillation, alcohol
abuse
Hippocampus, neocortex,
cerebellum, and
brainstem nuclei
H&E, LFB, and
IHC
Brain examination revealed
localized perivascular and
interstitial encephalitis with
neuronal cell loss and axon
degeneration in the dorsal motor
nuclei of the vagus nerve, CNV,
nucleus tractus solitarii, dorsal
raphe nuclei, and fasciculus
longitudinalis medialis, but no
territorial infarctions.
Petechial bleeding was observed in
four of the six patients.
Continued on next page
Braz J Psychiatry. 2021;00(00)
10 JS Generoso et al.
19 (8.9%), including ageusia (12 [5.6%]) and anosmia
(11 [5.1%]). Twenty-three patients (10.7%) had a skeletal
muscle injury. Neurological manifestations were also
more common in patients with severe infections and
included acute cerebrovascular disease, impaired con-
sciousness, and skeletal muscle injury, in addition to a
more intense inflammatory response, lymphopenia, and
increased levels of C-reactive protein.
47
In another study
with 60 patients affected by COVID-19, 41 (68.33%) had
neurological symptoms, including mood oscillation in
41.67%, fatigue in 26.67%, headache in 25%, altered
vision in 21.67%, myalgia in 15%, reduced mobility in
11.67%, memory loss in 13.33%, ageusia in 6.67%,
numbness in 6.67%, tremors in 6.67%, anosmia in 3.33%,
and hearing loss in 1.67%. Three months after recovery,
more than 50% of the patients still had neurological
symptoms.
89
Encephalitis, micro-hemorrhage, hemor-
rhage, encephalopathy, and cerebral venous embolism
have also been reported as consequences of COVID-19
infection.
87,90
Zhang et al.
91
evaluated 82 patients
diagnosed with COVID-19 and found impaired conscious-
ness in 17 (21%). A case series study analyzed 27
patients under the age of 18. Neurological manifestations
occurred in 14.8%, such as encephalopathy, headache,
brainstem signs with dysarthria or dysphagia, meningism
and cerebellar ataxia, muscle weakness, and reduced
reflexes.
92
A French study of 58 patients found that 40
(69%) were agitated after sedation was discontinued, and
confusion was observed in 26 (65%) in the intensive care
unit according to the Confusion Assessment Method.
Some patients also had larger leptomeningeal spaces
(13.62%), and bilateral frontotemporal hypoperfusion was
observed in eight patients. Two asymptomatic patients
had small acute ischemic strokes, and one patient had a
subacute ischemic stroke. Forty-five patients were eval-
uated after hospital discharge and 15 (33%) showed
inattention, disorientation or poorly organized movements
in response to the command.
93
Psychiatric manifestations associated with coronavirus
Several studies have addressed the impact of COVID-19
on mental health. Psychiatric manifestations can arise
due to the direct effects of the virus entering the CNS or to
the indirect effects of immune response,
94
as well as to
additional social stressors, which can contribute to the
incidence and exacerbation of psychiatric disorders.
95
Preclinical studies have shown an association between
depressive-like behavior and high levels of tumor necrosis
factor-alpha in the brain in an experimental model of
pneumococcal meningitis.
96,97
Persistent inflammatory
response and behavioral deficits have been observed
in adult offspring of female rats submitted to maternal
immune activation, which suggests that inflammation
could increase the risk of psychiatric disorders.
98
In fact,
previous studies support that immune response partici-
pates in the pathophysiology of mental illnesses such as
depression, bipolar disorders,
99-101
and suicidal beha-
vior.
102,103
Specifically regarding COVID-19, Ruan
et al.
104
showed that patients affected by the virus have
high levels of inflammatory markers, which were predictors
Table 1 (continued )
Author
Sample size,
sex, and age Primary disease Brain region studied
Technique and
markers Main findings
Wichmann
65
n=12, 9 ~and 3
#, age 673.0
CAD, arterial hypertension,
obesity, type 2 DM, atrial
fibrillation, asthma, CKD,
Parkinson’s, COPD, dementia,
epilepsy, granulomatous
pneumopathy, NSCLC, PAD,
trisomy 21, ulcerative colitis
NR AE1/AE3, and
H&E
Four patients had detectable viral
RNA in the brain. The authors
suspected that one patient had
septic encephalomalacia,
although confirmation is pending
brain dissection. Another patient
was found to have below average
brain weight.
APP = amyloid precursor protein; BG = basal ganglia; CAD = coronary artery disease; CD = clusters of differentiation; CKD = chronic kidney disease; CLD = chronic liver disease; CLL = chronic
lymphocytic leukemia; CML = chronic myelogenous leukemia; NV = trigeminal nerves; CNS = central nervous system; COPD = chronic obstructive pulmonary disease; CRF = chronic renal
failure; CRP = C-reactive protein; CSF = cerebrospinal fluid; CVD = cardiovascular disease; DIC = disseminated intravascular coagulation; DM = diabetes mellitus; GFAP = glial fibrillary acidic
protein; H&E = hematoxylin-eosin stain; HCM = hypertrophic cardiomyopathy; HLD = hyperlipidemia; HTN = hypertension; IHC = immunochemistry; LFB = luxol fast blue; MCA = middle
cerebral artery; MIA-US = ultrasound-guided minimally invasive autopsy; MRI = magnetic resonance imaging; NR = not reported; NSCLC = non-small cell lung cancer; OSA = obstructive sleep
apnea; PAD = peripheral artery disease; PAS = periodic acid-Schif; PCA = posterior cerebral artery; PCR = reverse transcription polymerase chain reaction; PHT = pulmonary hypertension;
qPCR = quantitative polymerase chain reaction; qRT-PCR = real-time quantitative reverse transcription; RT-PCR = reverse transcription polymerase chain reaction; SARS-CoV-2 =
coronavirus-2 of the severe acute respiratory syndrome; SMI = serious mental illness; TEM = transmission electron microscopy; TTF-1 = thyroid transcription factor-1.
Braz J Psychiatry. 2021;00(00)
How can the COVID-19 affect the brain? 11
of mortality due to the disease. A potential link between
inflammation due to COVID-19 and psychiatric manifesta-
tions has also been demonstrated in the literature. Gouse
et al.
105
reported a case in which a patient admitted with
COVID-19 symptoms presented clinical signs of catatonia
(mutism, posturing, staring, verbigeration, grimacing, echo-
lalia, stereotypy, rigidity, waxy flexibility, automatic obedi-
ence, echolalia) along with peaking proinflammatory
markers. Mazza et al. investigated the role of inflammatory
markers in anxiety and depression among COVID-19
survivors.
106
A total of 402 adults (65.9% male, age range
18-87 years) with COVID-19 were assessed while in the
emergency department (clinical and laboratory evaluation)
and about 30 days after hospital treatment (psychiatric
assessment). It was found that more than half of the
patients presented psychiatric symptoms in the pathologi-
cal range of at least one psychopathological dimension.
Moreover, the baseline systemic immune-inflammation
index (platelets neutrophils/lymphocytes) was positively
associated with depression and anxiety scores.
106
Asimilar
finding was reported by Hu et al.,
107
in which patients with
COVID-19 presented a high frequency of depressive
(45.9%), anxiety (38.8%), and insomnia (54.1%) symp-
toms, which were positively and significantly associated
with higher levels of IL-1b.
The social stressors associated with the pandemic,
including physical distancing as a mechanism to prevent
its spread, financial issues, and the quarantine itself, can
lead to an additional risk of psychiatric disorders.
108
Biological, psychological, and sociocultural factors could
also interact to determine the impact of the COVID-19 on
mental health.
109
A representative panel survey published
by the Center for Surveillance, Epidemiology, and
Laboratory Services of the U.S. Centers for Disease
Control and Prevention reported an increase in the
prevalence of anxiety disorder (approximately three
times), depressive disorder (approximately four times),
and suicidal ideation (approximately two times) during
June 24-30, 2020 compared to previous years (2018 or
2019).
110
Regarding the latter, the findings were remark-
able among young adults (18-34 years old) and those who
had not completed high school, with 25.5 and 30%,
respectively, reporting that had seriously considered
suicide in the past 30 days.
110
Krishnamoorthy et al.
111
reviewed the prevalence of mental disorders, psychiatric
symptoms, and mental distress among COVID-19
patients, healthcare workers, and the general population
during the COVID-19 pandemic. The pooled effect size
for patients with COVID-19 was larger than that of
healthcare workers or the general population for depres-
sion (42, 25, and 24%, respectively), anxiety (37, 24, and
26%, respectively), post-traumatic stress symptoms
(96, 13, and 15%, respectively), and poor sleep quality
(82, 43, and 34%, respectively).
111
Considering 12-month
mood disorder and anxiety prevalences of 9.5 and 18.1%,
respectively, from a 2001-2003 U.S. survey, the rates
reported by Krishnamoorthy et al. during the COVID-19
pandemic
111
are substantial.
112
The apparent higher risk
of psychiatric disorders among patients with COVID-19
raises concerns about the safety of available treatments,
especially pharmacological treatments. An international,
multi-disciplinary working group of experts published
evidence-based recommendations for the appropriate
management of psychotropics in patients with COVID-
19.
113
It recommended special care regarding the
potential interaction between COVID-19 treatments and
psychotropic medications, the risk of respiratory depres-
sion, cardiovascular effects, and thromboembolism, in
addition evaluating the dosage of patients currently in
treatment.
113
Clinicians should also consider evidence-
based telehealth psychotherapeutic and psychoeducation
interventions due to their efficacy and feasibility.
114,115
In an editorial, da Silva et al.
95,116
identified some mental
health topics worthy of attention, including inadequate
access to health services, especially in developing
countries. A recent retrospective cohort study by Williams
et al.
117
showed that between March 1 and May 31, 2020,
the first diagnosis of psychiatric problems was 50% lower
than expected based on previous years, which suggests
considerable underdiagnosis. The authors warned of a
potential overload in the mental health system due to
reduced access during the pandemic.
Longitudinal studies are necessary to evaluate the
biological and environmental risk factors, as well as the
protective interventions, that have shaped the impact of
COVID-19 on mental health. Regarding protective factors,
institutional support and resilience were found as media-
tors of the relationship between COVID-19-related stres-
sors and psychological distress, which suggests the
potential benefits of interventions that address both dur-
ing a public health emergency.
118
In a study of medical
workers during the COVID-19 outbreak, resilience was
negatively correlated with depression and anxiety and
was positively correlated with active coping styles.
119
Some programs have been implemented to build resi-
lience, such as the Mount Sinai Center for Stress,
Resilience, and Personal Growth,
120
the Psychological
Resilience Model,
121
and CopeColumbia.
122
Some of
these initiatives include principles from psychotherapeutic
interventions, such as cognitive-behavioral and accep-
tance and commitment therapies. Interestingly, a sys-
tematic review on the association between psychological
interventions and immune system function found decrea-
sed proinflammatory cytokines and increased immune
cell counts over time following treatment, especially for
cognitive behavior therapy and multiple or combined
psychosocial interventions.
123
Moutier
124
argues that
this is a moment when evidence-based strategies for
suicide prevention should be prioritized and maximi-
zed in the public health agenda at the community and
federal levels. Despite the severe consequences asso-
ciated with the pandemic, the knowledge acquired
during this period can provide positive lessons for the
field of mental health, both in terms of primary preven-
tion and intervention.
125
Conclusion
In conclusion, it must be pointed out that with the increasing
number SARS-CoV-2 infections and the pandemic’s poten-
tially long-lasting social stressors, many patients will have
neurological and psychiatric manifestations that could result
Braz J Psychiatry. 2021;00(00)
12 JS Generoso et al.
in a considerable burden for these individuals, their families,
and society. Psychiatric symptoms will not be limited only to
patients affected by COVID-19, since environmental stres-
sors are highly associated with the etiology and pathophy-
siology of psychiatric disorders.
126,127
Although clinical and epidemiological studies and
diagnosing brain disease associated with SARS-CoV-2
can be challenging, they are necessary to help define the
COVID-19 burden during and after the pandemic.
Acknowledgements
The authors would like to thank Universidade do Extremo
Sul Catarinense (UNESC), Conselho Nacional de Desen-
volvimento Cientı
´fico e Tecnolo
´gico (CNPq), and Fun-
dac¸a
˜o de Amparo a
`Pesquisa e Inovac¸a
˜o de Santa
Catarina (FAPESC). APD is supported by the Brain &
Behavior Research Foundation (NARSAD) Young Inves-
tigator Grant.
Disclosure
The authors report no conflicts of interest.
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How can the COVID-19 affect the brain? 15
... Patients with Coronavirus disease 2019 (COVID- 19) can present with a range of neuropsychiatric disorders, including delirium 1 -6 . Delirium in COVID-19 can reflect multiple factors, including inflammation, endothelial damage, increased oxidative stress, hypoxemia, iatrogenic factors, and potentially direct infection of the central nervous system by SARS-CoV-2 7,8 . ...
... Table 1 shows the characteristics of the 100 patients. Most (92%) were male, mean age was 46 years, 27% had asymptomatic COVID-19 (i.e., no characteristic physical symptoms of COVID- 19), and 35% had a past psychiatric history. Significant recent psychosocial stress, which is largely related to the pandemic, was recorded in the notes of 48 patients. ...
... Nearly one quarter of the patients in the full cohort of 100 patients reported self-harm thoughts or attempts. The diverse psychiatric symptoms seen in the full cohort could reflect the effects of psychosocial stressors, such as quarantine, social distancing, and financial difficulties, the physical effects of SARS-coV2 including potential direct neurotoxic effects and iatrogenic factors 19 . ...
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Introduction: Coronavirus disease 2019 (COVID-19) can present with various neuropsychiatric manifestations. This study reports on patients with COVID-19 who were referred to the consultation-liaison (CL) psychiatry services in Qatar and compares the clinical and sociodemographic characteristics of those diagnosed with delirium versus other psychiatric diagnoses. Methods: This is a retrospective review of the first 100 consecutive patients with COVID-19 who were referred to the CL services. Results: Within the total cohort (n=100), most patients (92%) were male, and the mean age was 46 years. About 27% of patients had asymptomatic COVID-19, 35% had a past psychiatric history, and 48% reported pandemic related psychosocial stress. Delirium was the most common psychiatric diagnosis (n=29), followed by acute stress reaction/adjustment disorder, depression, mania, anxiety, non-affective psychosis, and dementia. Among patients with delirium, agitation was the most common symptom (76%), 86% were treated with psychotropic medications, and 17% died. Higher age, longer hospital stays, lower oxygen saturation, lower lymphocytic count, and higher C-reactive protein (CRP) values were significantly associated with delirium versus other psychiatric diagnoses. Higher age and lower oxygen saturations predicted delirium. Conclusion: Delirium was associated with a range of clinical variables and had significant mortality, despite the relatively young age of the patients. COVID-19 should be considered in patients presenting with delirium. Finally, early identification and management of delirium should be integral to COVID-19 protocols.
... 20 Other reports showed an association of SARS-CoV-2 infection with diseases of the cerebral microvasculature, encephalopathy, agitation, and confusion, which might be related to cytokine-mediated changes in frontal perfusion and function. 21,22 It is now well established that SARS-CoV-2 neuroinvasion through the trigeminal and vagus nerves 9 and bloodbrain barrier disruption [23][24][25] are the mechanisms of viral entry into neural tissue, causing direct effects beyond those caused by peripheral infection. 26 Activity of the viral spike protein (S) seems to be deeply implicated in bloodbrain barrier disruption and leakage. ...
... The plausibility of this hypothesis is further strengthened by evidence that HDPs regulate the release of neurotransmitters such as serotonin, norepinephrine, dopamine, and glutamate, 38,61 whose unbalance underlies COVID-19 clinical manifestations. 4,6,20,23,24,28 HDPs modulate the dynamics of neurohormones, such as adrenocorticotropin and oxytocin, which are capable of defining behaviors. 37,49 Recently, we have reported the effects of two HDPs, LVV-hemorphin 7 (LVV-H7) and LVV-hemorphin 6 (LVV-H6), on the organization of Table 1 Bioactive peptides derived from aand b-globin chains behavioral responses to aversion, locomotion/exploration, and depressive-like behaviors in rodent experimental models. ...
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Follow-up of patients affected by COVID-19 has unveiled remarkable findings. Among the several sequelae caused by SARS-CoV-2 viral infection, it is particularly noteworthy that patients are prone to developing depression, anxiety, cognitive disorders, and dementia as part of the post-COVID-19 syndrome. The multisystem aspects of this disease suggest that multiple mechanisms may converge towards post-infection clinical manifestations. The literature provides mechanistic hypotheses related to changes in classical neurotransmission evoked by SARS-CoV-2 infection; nonetheless, the interaction of peripherally originated classical and non-canonic peptidergic systems may play a putative role in this neuropathology. A wealth of robust findings shows that hemoglobin-derived peptides are able to control cognition, memory, anxiety, and depression through different mechanisms. Early erythrocytic death is found during COVID-19, which would cause excess production of hemoglobin-derived peptides. Following from this premise, the present review sheds light on a possible involvement of hemoglobin-derived molecules in the COVID-19 pathophysiology by fostering neuroscientific evidence that supports the contribution of this non-canonic peptidergic pathway. This rationale may broaden knowledge beyond the currently available data, motivating further studies in the field and paving ways for novel laboratory tests and clinical approaches.
... However, despite the large amount of information available on the disease, there is little work conducted to characterize its pathological manifestations in the tissues of different systems of the body (Al Nemer, 2020;Skok et al., 2021; Table 1). Studies carried out on the anatomical brain pathology during autopsy reveal morphological alterations in the frontal and occipital lobes, olfactory bulb, cingulate gyrus, corpus callosum, hippocampus, basal ganglia, thalamus, cerebellum, midbrain, middle pons, medulla, brainstem, and the lateral ventricles (Barone et al., 2021;Caramaschi et al., 2021;Generoso et al., 2021). The most common gross findings are edema (Reichard et al., 2020), hemorrhagic lesions (Paniz-Mondolfi et al., 2020;Reichard et al., 2020), hydrocephalus (Lacy et al., 2020), atrophy and low brain mass (Lax et al., 2020;Wichmann et al., 2020), olfactory bulb asymmetry (Coolen et al., 2020), and infarcts (Solomon et al., 2020). ...
... Furthermore, the components of the innate system contribute to the activation of antigen-specific cells, which amplify their Midbrain, basal ganglia, thalamus. Solomon et al., 2020;von Weyhern et al., 2020;Generoso et al., 2021 Brain morphological and macroscopic changes Edema, hemorrhagic lesions, hydrocephalus, atrophy and low brain mass, infarcts. Paniz-Mondolfi et al., 2020;Reichard et al., 2020;Wichmann et al., 2020 Brain regions expressing ACE2 and TMPRSS2 ...
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Evidence suggests that SARS-CoV-2 entry into the central nervous system can result in neurological and/or neurodegenerative diseases. In this review, routes of SARS-Cov-2 entry into the brain via neuroinvasive pathways such as transcribrial, ocular surface or hematogenous system are discussed. It is argued that SARS-Cov-2-induced cytokine storm, neuroinflammation and oxidative stress increase the risk of developing neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Further studies on the effects of SARS-CoV-2 and its variants on protein aggregation, glia or microglia activation, and blood-brain barrier are warranted.
... Recent studies show different routes of entry for the COVID-19 virus into the CNS [79,80] (Fig. 2). The first route of entry would be through the olfactory epithelium, crossing the cribriform plate of the ethmoid bone and reaching the olfactory bulb from which it could spread to different areas of the brain [81]. ...
Article
Many coronavirus disease 2019 (COVID-19)-recovered patients report signs and symptoms and are experiencing neurological, psychiatric, and cognitive problems. However, the exact prevalence and outcome of cognitive sequelae is unclear. Even though the severe acute respiratory syndrome coronavirus 2 has target brain cells through binding to angiotensin-converting enzyme 2 (ACE2) receptor in acute infection, several studies indicate the absence of the virus in the brain of many COVID-19 patients who developed neurological disorders. Thus, the COVID-19 mechanisms for stimulating cognitive dysfunction may include neuroinflammation, which is mediated by a sustained systemic inflammation, a disrupted brain barrier, and severe glial reactiveness, especially within the limbic system. This review explores the interplay of infected lungs and brain in COVID-19 and its impact on the cognitive function.
... Plusieurs études suggèrent que les particules de SARS-CoV-2 sont neuroinvasives [142]. Ayant déjà entraîné des pertes neuronales durant l'infection initiale, cellesci peuvent être empirées dans les semaines qui suivent. ...
Article
Résumé Les syndromes d’hypersomnolence d’origine centrale (c.-à-d. narcolepsie de type-1, narcolepsie de type-2 et hypersomnie idiopathique), la dépression ainsi qu’un sous-type du syndrome post-COVID-19 peuvent être confondus lors de l’établissement d’un diagnostic. Ce défi diagnostique s’explique par un symptôme clinique caractéristique retrouvé dans les quatre conditions, la somnolence diurne excessive, un chevauchement phénotypique considérable entre la narcolepsie de type-2 et l’hypersomnie idiopathique ainsi qu’une symptomatologie dysphorique pouvant être présente autant dans les hypersomnolences centrales que dans un sous-type du syndrome post-COVID-19. Considérant l’importance d’un diagnostic valide sur l’efficacité des traitements et des interventions futures, il est essentiel de définir précisément ces quatre conditions. Dans cette revue, nous reprendrons les critères diagnostiques, les présentations cliniques et les connaissances actuelles en ce qui a trait à la pathophysiologie de ces troubles en portant une attention particulière aux éléments distinctifs de la narcolepsie de type-2, de l’hypersomnie idiopathique, des épisodes dépressifs avec hypersomnolence et du syndrome post-COVID-19 avec somnolence. Bien que de nombreuses études se soient penchées sur les valeurs diagnostiques des différents outils employés dans l’identification des hypersomnolences centrales, très peu de marqueurs physiologiques ont été identifiés. Une meilleure compréhension de ces conditions cliniques pourrait permettre l’identification de marqueurs objectifs spécifiques à chaque condition réduisant ainsi la possibilité d’une erreur diagnostique et optimisant les plans de traitement.
... One review demonstrates the virus infects tissue via the ACE2 receptor, also expressed on vascular endothelial cells that allows infected lymphocytes to enter the SAS. The virus is reported to move up nerves, crossing synapses, and entering the CNS via a "Trojan Horse" mechanism [928]. Neuroimaging, brain autopsy, and LPs demonstrate spinal cord and LM involvement are consistent with neurologic residuals in recovered patients [929][930][931]. ...
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Background & importance: This patient and public-involved systematic review originally focused on arachnoiditis, a supposedly rare "iatrogenic chronic meningitis" causing permanent neurologic damage and intractable pain. We sought to prove disease existence, causation, symptoms, and inform future directions. After 63 terms for the same pathology were found, the study was renamed Diseases of the Leptomeninges (DLMs). We present results that nullify traditional clinical thinking about DLMs, answer study questions, and create a unified path forward. Methods: The prospective PRISMA protocol is published at Arcsology.org. We used four platforms, 10 sources, extraction software, and critical review with ≥2 researchers at each phase. All human sources to 12/6/2020 were eligible for qualitative synthesis utilizing R. Weekly updates since cutoff strengthen conclusions. Results: Included were 887/14286 sources containing 12721 DLMs patients. Pathology involves the subarachnoid space (SAS) and pia. DLMs occurred in all countries as a contributor to the top 10 causes of disability-adjusted life years lost, with communicable diseases (CDs) predominating. In the USA, the ratio of CDs to iatrogenic causes is 2.4:1, contradicting arachnoiditis literature. Spinal fusion surgery comprised 54.7% of the iatrogenic category, with rhBMP-2 resulting in 2.4x more DLMs than no use (p<0.0001). Spinal injections and neuraxial anesthesia procedures cause 1.1%, and 0.2% permanent DLMs, respectively. Syringomyelia, hydrocephalus, and arachnoid cysts are complications caused by blocked CSF flow. CNS neuron death occurs due to insufficient arterial supply from compromised vasculature and nerves traversing the SAS. Contrast MRI is currently the diagnostic test of choice. Lack of radiologist recognition is problematic. Discussion & conclusion: DLMs are common. The LM clinically functions as an organ with critical CNS-sustaining roles involving the SAS-pia structure, enclosed cells, lymphatics, and biologic pathways. Cases involve all specialties. Causes are numerous, symptoms predictable, and outcomes dependent on time to treatment and extent of residual SAS damage. An international disease classification and possible treatment trials are proposed.
... Hypoxic-ischemic encephalopathy (HIE), also referred to as hypoxic/anoxic brain injury, is defined as a diffuse cerebral insult due to oxygen deprivation resulting from systemic conditions, including prolonged or severe hypoxemia, hypotension (mean arterial blood pressure below 65 mm Hg) or cardiac arrest, and leading to new cerebral dysfunction or characteristic findings on cross-sectional imaging of the brain, i.e., computed tomography or magnetic resonance [31,32]. ...
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Since the very beginning of the COVID-19 pandemic, numerous researchers have made an effort to determine the molecular composition of the SARS-CoV-2 virus, and the exact pathomechanism through which the virus exerts such a devastating effect on the host/infected organism. Recent scientific evidence highlights the affinity of the virus towards ACE2 receptors, which are widespread in multiple human systems, including the central nervous system (CNS) and cerebral vessels. Such an affinity may explain endothelial dysfunction and damage that is observed in COVID-positive patients in histopathological studies, with subsequent dysregulation of the cerebral circulation leading to transient or acute cerebrovascular accidents. In this paper, we aimed to evaluate the effects of COVID-related hypoxemia and direct viral invasion on the cerebral circulation, with special respect to the postulated pathomechanism, vulnerable groups of patients, clinical course and outcomes, as well as diagnostic imaging findings.
... The pathological mechanisms of Long COVID is not too well understood, however many articles support that it is related to the neuroinvasion of SARS-CoV-2 in the initial infection through the ACE2 receptor [20], as detailed in other sections of this article. The initial infection may have led to inflammation and oxidative stress in the brain tissue affecting areas of the brain such as the hippocampus, cortical atrophy, and ischemic vascular changes [21][22][23]. The brain of a group of 785 post-COVID participants was analyzed through magnetic resonance imaging in the United Kingdom and showed a reduction of the gray matter in the orbitofrontal cortex and parahippocampal gyrus, reduction of global brain size, and markers of tissue damage to the olfactory cortex [20]. ...
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In December 2019, a novel coronavirus was isolated from the respiratory epithelium of patients with unexplained pneumonia in Wuhan, China. This pathogen, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causes a pathogenic condition that has been termed coronavirus disease 2019 (COVID-19) and has reached pandemic proportions. As of 17 September 2020, more than 30 million confirmed SARS-CoV-2 infections have been reported in 204 different countries, claiming more than 1 million lives worldwide. Accumulating evidence suggests that SARS-CoV-2 infection can lead to a variety of clinical conditions, ranging from asymptomatic to life-threatening cases. In the early stages of the disease, most patients experience mild clinical symptoms, including a high fever and dry cough. However, 20% of patients rapidly progress to severe illness characterized by atypical interstitial bilateral pneumonia, acute respiratory distress syndrome and multiorgan dysfunction. Almost 10% of these critically ill patients subsequently die. Insights into the pathogenic mechanisms underlying SARS-CoV-2 infection and COVID-19 progression are emerging and highlight the critical role of the immunological hyper-response - characterized by widespread endothelial damage, complement-induced blood clotting and systemic microangiopathy - in disease exacerbation. These insights may aid the identification of new or existing therapeutic interventions to limit the progression of early disease and treat severe cases.
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Psychological distress among healthcare providers is concerning during COVID-19 pandemic due to extreme stress at healthcare facilities, including HIV clinics in China. The socioecological model suggests that psychological distress could be influenced by multi-level factors. However, limited COVID-19 research examined the mechanisms of psychological distress among HIV healthcare providers. This study examined organizational and intrapersonal factors contributing to psychological health during COVID-19 pandemic. Data were collected via online anonymous surveys from 1029 HIV healthcare providers in Guangxi, China during April-May 2020. Path analysis was utilized to test a mediation model among COVID-19 stress-ors, institutional support, resilience, and psychological distress (PHQ-4). Thirty-eight percent of the providers experienced psychological distress (PHQ-4 score > 3). Institutional support and resilience mediated the relationship between COVID-19 stressors and psychological distress. Psychological distress was common among Chinese HIV healthcare providers during COVID-19 pandemic. Psychological health intervention should attend to institutional support and resilience.
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During the novel coronavirus disease 2019 (COVID-19) outbreak, traditional face-to-face psychological interventions have been suspended due to high risks of rapid transmission. Developing an effective online model of psychological intervention is deemed necessary to deal with the mental health challenges brought up by this disease. An integrated psychological intervention model coined 'COVID-19 Psychological Resilience Model' was developed in Chengdu, China including live media, 24-hour hotline consultations, online video intervention and on-site crisis intervention sessions to provide services to those in need. A total of 45 episodes of live media programs on COVID-19 outbreak-related psychological problems were broadcasted with over 10 million views. A total of 4,236 hotline consultations were completed. More than 50% of the clients had positive feedback about the hotline consultations. A total of 223 cases received online video intervention, of which 84.97% were redirected from the hotline consultation and 15.03% from COVID-19-designated hospital and community-based observation spots. Seventy one-on-one psychological interventions were conducted with 39 COVID-19 patients, and one-third were treated with medication. Additionally, 5 training sessions were conducted to 98 frontline medical staff. This 'COVID-19 Psychological Resilience Model' is proven effective to the general population during the COVID-19 pandemic. We have greatly improved the overall mental health of our target population during the COVID-19 pandemic. This model could provide valuable experiences and serve as a reference guide for other countries to offer effective psychological intervention, and reduce detrimental negative mental health outcomes in public health emergency.
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Background: To date, research on the indirect impact of the COVID-19 pandemic on the health of the population and the health-care system is scarce. We aimed to investigate the indirect effect of the COVID-19 pandemic on general practice health-care usage, and the subsequent diagnoses of common physical and mental health conditions in a deprived UK population. Methods: We did a retrospective cohort study using routinely collected primary care data that was recorded in the Salford Integrated Record between Jan 1, 2010, and May 31, 2020. We extracted the weekly number of clinical codes entered into patient records overall, and for six high-level categories: symptoms and observations, diagnoses, prescriptions, operations and procedures, laboratory tests, and other diagnostic procedures. Negative binomial regression models were applied to monthly counts of first diagnoses of common conditions (common mental health problems, cardiovascular and cerebrovascular disease, type 2 diabetes, and cancer), and corresponding first prescriptions of medications indicative of these conditions. We used these models to predict the expected numbers of first diagnoses and first prescriptions between March 1 and May 31, 2020, which were then compared with the observed numbers for the same time period. Findings: Between March 1 and May 31, 2020, 1073 first diagnoses of common mental health problems were reported compared with 2147 expected cases (95% CI 1821 to 2489) based on preceding years, representing a 50·0% reduction (95% CI 41·1 to 56·9). Compared with expected numbers, 456 fewer diagnoses of circulatory system diseases (43·3% reduction, 95% CI 29·6 to 53·5), and 135 fewer type 2 diabetes diagnoses (49·0% reduction, 23·8 to 63·1) were observed. The number of first prescriptions of associated medications was also lower than expected for the same time period. However, the gap between observed and expected cancer diagnoses (31 fewer; 16·0% reduction, -18·1 to 36·6) during this time period was not statistically significant. Interpretation: In this deprived urban population, diagnoses of common conditions decreased substantially between March and May 2020, suggesting a large number of patients have undiagnosed conditions. A rebound in future workload could be imminent as COVID-19 restrictions ease and patients with undiagnosed conditions or delayed diagnosis present to primary and secondary health-care services. Such services should prioritise the diagnosis and treatment of these patients to mitigate potential indirect harms to protect public health. Funding: National Institute of Health Research.
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Background: To investigate the resilience of non-local medical workers sent to support local medical workers in treating the outbreak of 2019 novel coronavirus disease (COVID-19). Methods: In February 2020, non-local medical workers who had been sent to Wuhan as support staff to respond to the COVID-19 outbreak were asked to complete an online survey composed of the Connor Davidson Resilience Scale (CD-RISC), Hospital Anxiety Depression Scale (HADS) and Simplified Coping Style Questionnaire (SCSQ). Results: Survey responses from 114 non-local medical workers were analyzed. CD-RISC scores were high (67.03 ± 13.22). The resilience level was highest for physicians (73.48 ± 11.49), followed by support staff, including health care assistants, technicians (67.78 ± 12.43) and nurses (64.86 ± 13.46). Respondents differed significantly in the levels of education, training/support provided by the respondent's permanent hospital (where he or she normally works), and in their feelings of being adequately prepared and confident to complete tasks (P < 0.05). Resilience correlated negatively with anxiety (r = -.498, P < 0.01) and depression (r = -.471, P < 0.01) but positively with active coping styles (r = .733, P < 0.01). Multiple regression analysis showed that active coping (β = 1.314, p < 0.05), depression (β = -.806, p < 0.05), anxiety (β = - 1.091, p < 0.05), and training/support provided by the respondent's permanent hospital (β = 3.510, p < 0.05) were significant associated with resilience. Conclusion: Our data show that active coping, depression, anxiety, and training/support provided by the respondent's permanent hospital are associated with resilience. Managers of medical staff should use these data to develop psychosocial interventions aimed at reinforcing the resilience of medical workers during highly stressful and prolonged medical emergencies, as seen during the COVID-19 outbreak.
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The persistence of SARS-CoV-2 after death of infected individuals is unclear. The aim of this study was to investigate the presence of SARS-CoV-2 RNA in different organs in correlation with tissue damage and post-mortem viral dynamics in COVID-19 deceased. Twenty-eight patients (17 males, 11 females; age 66–96 years; mean 82.9, median 82.5 years) diagnosed with COVID-19 were studied. Swabs were taken post-mortem during autopsy (N = 19) from the throat, both lungs, intestine, gallbladder, and brain or without autopsy (N = 9) only from the throat. Selective amplification of target nucleic acid from the samples was achieved by using primers for ORF1a/b non-structural region and the structural protein envelope E-gene of the virus. The results of 125 post-mortem and 47 ante-mortem swabs were presented as cycle threshold (Ct) values and categorized as strong, moderate, and weak. Viral RNA was detected more frequently in the lungs and throat than in the intestine. Blood, bile, and the brain were negative. Consecutive throat swabs were positive up to 128 h after death without significant increase of Ct values. All lungs showed diffuse alveolar damage, thrombosis, and infarction and less frequently bronchopneumonia irrespective of Ct values. In 30% the intestine revealed focal ischemic changes. Nucleocapsid protein of SARS-CoV-2 was detected by immunohistochemistry in bronchial and intestinal epithelium, bronchial glands, and pneumocytes. In conclusion, viral RNA is still present several days after death, most frequently in the respiratory tract and associated with severe and fatal organ damage. Potential infectivity cannot be ruled out post-mortem.
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Objective COVID-19 is an international public health crisis, putting substantial burden on medical centers and increasing the psychological toll on health care workers (HCW). Methods This paper describes CopeColumbia, a peer support program developed by faculty in a large Urban Medical Center's Department of Psychiatry to support emotional well-being and enhance the professional resilience of HCW. Results Grounded in evidence-based clinical practice and research, peer support was offered in three formats: groups, individual sessions, and town halls. Also, psychoeducational resources were centralized on a website. A Facilitator's Guide informed group and individual work by including: (1) emotional themes likely to arise (e.g., stress, anxiety, trauma, grief, and anger) and (2) suggested facilitator responses and interventions, drawing upon evidence-based principles from peer support, stress and coping models, and problem-solving, cognitive behavioral, and acceptance and commitment therapies. Feedback from group sessions was overwhelmingly positive. Approximately 1/3 of individual sessions led to treatment referrals. Conclusions Lessons learned include: (1) there is likely an ongoing need for both well-being programs and linkages to mental health services for HCW, (2) the workforce with proper support, will emerge emotionally resilient, and (3) organizational support for programs like CopeColumbia is critical for sustainability.
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The COVID-19 pandemic is anticipated to have a prolonged adverse mental health impact on health care workers (HCWs). The supportive services implemented by the Mount Sinai Hospital System in New York for its workers culminated in the founding of the Mount Sinai Center for Stress, Resilience, and Personal Growth (CSRPG). CSRPG is an innovative mental health and resilience-building service that includes strong community engagement, self- and clinical-administered screening, peer co-led resilience training workshops, and care matching. The long-term sustainability of similar programs across the United States will require federal funding.