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Abstract

Considering the neurological and neuropsychiatric manifestations of coronavirus disease 2019 (COVID-19), its early diagnosis is crucial. This Viewpoint aims to highlight these manifestations through multimodal neuroimaging studies reflecting neurochemical and structural impairment.
Brain Imaging in COVID-19
Avantika Samkaria and Pravat Kumar Mandal*
Cite This: https://doi.org/10.1021/acschemneuro.1c00467
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ABSTRACT: Considering the neurological and neuropsychiatric manifestations of coronavirus disease 2019 (COVID-19), its early
diagnosis is crucial. This Viewpoint aims to highlight these manifestations through multimodal neuroimaging studies reecting
neurochemical and structural impairment.
KEYWORDS: COVID-19, neuroimaging, neurochemical impairment, structural impairment, neuropsychiatric manifestation,
neurological manifestation
1. INTRODUCTION
Coronavirus disease 2019 (COVID-19) presents devastating
pulmonary manifestations, including pneumonia, cough, fever,
and myalgia. Its common neurological manifestations include
anosmia, cerebrovascular disease, and encephalopathy. Evi-
dence further suggests that severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) aects various brain regions
linking the brain stem, eyes, mouth, and nose. Magnetic
resonance imaging (MRI), computed tomography (CT), and
MR spectroscopy (MRS) of the brain are used for the
evaluation of metabolic and structural abnormalities involving
enlarged volumes of various brain regions, such as olfactory
cortices, hippocampus, and cingulate gyrus.
1
Concerning the
cases of neurological and neuropsychiatric abnormalities in the
COVID-19 survivors, the viral footprint in the brain is well
established. The knowledge of clinicoradiological manifesta-
tions should be considered of upmost priority which can be
used for patient care and better understanding of the disease.
The suggested pathways, described by the researchers, of
SARS-CoV-2 entry in the brain are (i) cytokine storm, the
unexpected massive inux of proinammatory cytokines that
likely disrupt the bloodbrain barrier (BBB) leading to the
structural and functional abnormality of the brain; (ii)
endothelial dysfunction, endothelial cell damage and endothe-
liitis that potentially cause BBB injury and cerebral vascular
thrombosis, resulting in cerebral microhemorrhages or brain
edema; and (iii) hypoxia, elderly group with comorbidities,
such as chronic hypertension and diabetes mellitus, that
demonstrate neurological complications. Severe hypoxic brain
damage further impairs small vessels, leading to periventricular
neuronal demyelination or white matter microhemorrhages
and widespread small vessel thrombosis.
2. BRAIN IMAGINING-BASED FEATURES
For the prognosis and diagnosis of COVID-19-induced
neurological manifestations, the application of noninvasive
neuroimaging techniques is paramount as described below.
CT provides images of internal organs, bones, and blood
vessels. CT scans of patients with COVID-19 have revealed
intracerebral hemorrhage (ICH) in the right hemisphere with
intraventricular loss of graywhite matter dierentiation in the
left occipital and temporal lobes. The literature also mentions
the high proportion of hemorrhagic events, white matter
abnormalities, and ischemic infarction in patients with severe
COVID-19.
2
MRI is a unique noninvasive technique used to monitor
structural details of the brain. MRI-based ndings in COVID-
19 patients include atrophy and gliosis involving the left
temporo-parietal lobe, i.e., hemorrhagic rim enhancing lesions
within the medial temporal lobes of the patients.
2
Data from
patients with/without ICH lesions suggest that hemorrhagic
complications are frequently associated with those under
intensive care. Axial diusion and gradient-echo sequences in
these patients reveal acute infarcts and microhemorrhages
(Figure 1).
Fluid-Attenuated Inversion Recovery (FLAIR). Accord-
ing to the literature, FLAIR images from patients with COVID-
19 demonstrate hyperintense signal changes in the right mesial
temporal lobe and slight hippocampal atrophy; extensive
patchy areas of abnormal signal involving bilateral frontopar-
ietal white matter; cortical FLAIR signal abnormality in frontal,
parietal, occipital, and temporal lobes; and multiple areas of
restricted diusion associated with edema. Susceptibility-
weighted imaging has revealed extensive superimposed
hemorrhages in the parietooccipital region. Such images
further exhibit nonconuent multifocal white matter hyper-
intense lesions along with variable intensication. Such
hemorrhages indicate clinical implications as they are often
associated with severe respiratory conditions.
Diusion-Weighted Imaging (DWI). DWI indicates
hyperintensity along the walls of the temporal horn of the
Received: July 14, 2021
Accepted: July 26, 2021
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right lateral ventricle and acute ischemic stroke with the foci of
hyperintensity scattered within the left carotid territory
associated with neurological symptoms, such as headache
and transient generalized seizure.
Diusion Tensor Imaging (DTI). DTI maps have shown
that patients recovered from COVID-19 are more likely to
have enlarged hippocampi, olfactory cortices, Heschls gyrus,
cingulate gyrus, insulas, and Rolandic operculum. These
patients presented statistically signicant higher bilateral gray
matter volumes indicating disruption in microstructures.
MRS studies reect metabolite abnormalities. In one study,
multivoxel MRS imaging was performed in three distinct
patients with COVID-19 having white matter disorder and
recent cardiac arrest with mild white matter abnormality and
without any abnormality. The patient with white matter
abnormality presented the abnormality of choline and N-
acetyl-aspartate concentrations. The patient with white matter
disorder showed more pronounced alterations reecting
neuroinammation.
1
3. CLINICAL MANIFESTATIONS
Patients with severe COVID-19 potentially demonstrate
cytokine storm syndrome that triggers ischemic strokes.
Other anomalies include ICH, hypoxicischemic encephalop-
athy, and ischemic stroke. White matter in the subcortical
region of the brain protects nerve bers from injury. White
matter abnormalities are reportedly the most persistent
neuroimaging pattern observed in these patients. The
abnormalities are presented as converging hyperintensities on
T2/FLAIR of MRI along with unnatural restricted diusion
and hypointensities on CT and T1W imaging in deep white
matter, subcortical and middle cerebellar peduncles, corpus
callosum, and corticospinal tracts, causing nonspecic neuro-
logical signs. COVID-19-associated coagulopathy often
presents cerebral venous thrombosis and large vessel occlusion.
COVID-19 and Psychiatric Disorder. COVID-19-asso-
ciated systemic and neuroinammatory changes are linked to
substantial increase in the brain neuroglial reactivity,
proinammatory molecules, and altered neurochemical prole.
Environmental stress caused by social restrictions, pandemic
fears, and intensive therapy also promotes neuropsychiatric
pathologies, including bipolar disorder, obsessive-compulsive
disorder, post-traumatic stress disorder, and major depressive
disorder. Notably, many patients with COVID-19 present
psychosis without any psychiatric history. Patients with
headache, dysgeusia, and anosmia and those requiring oxygen
therapy scored low in attention, memory, and executive
function tests in contrast to asymptomatic patients. Patients
presenting clinical hypoxia and headache scored less in the
global cognitive index, indicating cognitive dysfunction.
When assisted with psychiatric and neuropsychological
evaluations, noninvasive neuroimaging techniques, including
MRI and MRS, eciently detect COVID-19-associated
neurological alterations and establish a correlation between
these alterations.
Abnormal metabolite concentration is observed in various
neurological disorders. In this context, MRS is potentially
benecial for analyzing any neurochemical alterations, such as
in glutamate, glutamine, γ-aminobutyric acid, and glutathione.
Reportedly, glutathione and its precursors N-acetyl-cysteine
and α-lipoic acid likely constitute a novel treatment approach
for addressing respiratory distress cytokine storm syndrome in
patients with COVID-19 pneumonia.
4. IMPORTANCE OF NEUROIMAGING STUDIES
Studies involving asymptomatic patients with minimal/no
pulmonary damage have indicated that the neurological impact
of COVID-19 is not factored due to the pulmonary illness.
4
Even in patients without respiratory manifestations, the
neuroimaging ndings have revealed T2 hyperintense signal
abnormalities and intracerebral hemorrhage resulting in
confusion, amnesia, and hemiparesis.
4
These clinical manifes-
tations are predominantly reported in patients with multiple
vascular risk factors and those with severe COVID-19.
Development of profound neurologic symptoms is reported
in patients with COVID-19. These can be associated with
severe as well as fatal complications such as encephalitis or
ischemic stroke.
5
Neuroradiological ndings also reveal that clinical diversities
arising during the course of COVID-19 are associated with the
severity of the viral infection. Abnormalities in the cranial
nerves are exclusively conned to mild infection, whereas
hemorrhages are commonly associated with severe infection.
Patients with severe COVID-19 display extreme forms of
abnormalities.
The comparative analysis of brain images before and after
COVID-19 infection shows signicant deleterious eects of the
infection on the olfactory and gustatory cortical systems. Such
patients reputedly illustrate severe eects on gray matter
volume and thickness, suggesting neuronal damage. Hence,
extensive reliable longitudinal data are required for better
comprehension of COVID-19 and its neurological manifes-
tations.
Figure 1. MRI images from 61-year-old man with COVID-19: (A, B)
acute infarcts within the bilateral cerebral white matter (blue arrows)
and left occipital hemorrhagic infarct (green arrow) (images obtained
using axial diusion sequence); (C, D) innumerable microhemorrh-
ages throughout the bilateral cerebral hemispheres (red arrows)
(images obtained using gradient-echo sequences). Copyright
permission was obtained to reproduce Figure 1 from the publisher.
3
ACS Chemical Neuroscience pubs.acs.org/chemneuro Viewpoint
https://doi.org/10.1021/acschemneuro.1c00467
ACS Chem. Neurosci. XXXX, XXX, XXXXXX
B
5. CONCLUSION
In patients with COVID-19, brain imaging eciently detects
neurological impairment. Considering future implications,
longitudinal cohort studies involving MRI, MRS, and neuro-
psychological evaluation are planned. Upcoming cohort studies
will investigate depleted antioxidant GSH level and its role in
the major causes of the excessive inammatory response linked
to severe COVID-19 induced neurological/neuropsychiatric
outcome.
AUTHOR INFORMATION
Corresponding Author
Pravat Kumar Mandal Neuroimaging and
Neurospectroscopy (NINS) Laboratory, National Brain
Research Centre, Gurgaon 122051, India; Florey Institute of
Neuroscience and Mental Health, Melbourne 3010,
Australia; orcid.org/0000-0003-4999-2808;
Email: pravat.mandal@gmail.com,pravat@nbrc.ac.in,
pravat.mandal@orey.edu.au
Author
Avantika Samkaria Neuroimaging and Neurospectroscopy
(NINS) Laboratory, National Brain Research Centre,
Gurgaon 122051, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acschemneuro.1c00467
Notes
The authors declare no competing nancial interest.
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ACS Chemical Neuroscience pubs.acs.org/chemneuro Viewpoint
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ACS Chem. Neurosci. XXXX, XXX, XXXXXX
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... Even though these excellent bioimaging procedures offer a wide scope, the cost, technological barriers, biocompatibility with markers contribute to the limitations of these techniques [63]. Brain imaging for the prognosis and diagnosis of SARS-CoV-2 induced neurological concerns can be also addressed using Fluid-Attenuated Inversion Recovery images, Diffusion-Weighted Imaging, Diffusion Tensor Imaging [64]. ...
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Brain MR Spectroscopic Findings in 3 Consecutive Patients with COVID-19: Preliminary Observations
  • Rapalino, O.