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7296 wileyonlinelibrary.com/journal/alz Alzheimer’s Dement. 2024;20:7296–7319.
Received: 14 December 2023 Revised: 16 May 2024 Accepted: 31 May 2024
DOI: 10.1002/alz.14089
REVIEW ARTICLE
Parallel electrophysiological abnormalities due to COVID-19
infection and to Alzheimer’s disease and related dementia
Yang Jiang1,2Jennifer Neal1Pradoldej Sompol2,3Görsev Yener4,5
Xianghong Arakaki6Christopher M. Norris2,3Francesca R. Farina7
Agustin Ibanez8,9,10 Susanna Lopez11 Abdulhakim Al-Ezzi6Voyko Kavcic12
Bahar Güntekin13,14 Claudio Babiloni11,15 Mihály Hajós16,17
1Aging Brain and Cognition Laboratory, Department of Behavioral Science, College of Medicine, University of Kentucky,Lexington, Kentucky, USA
2Sanders Brown Center on Aging, College of Medicine, University of Kentucky, Lexington, Kentucky,USA
3Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, Kentucky,USA
4Faculty of Medicine, Dept of Neurology, ˙
Izmir University of Economics, ˙
Izmir, Turkey
5IBG: International Biomedicine and Genome Center, ˙
Izmir, Turkey
6Cognition and Brain Integration Laboratory, Department of Neurosciences, Huntington Medical Research Institutes, Pasadena, California, USA
7University of Chicago, Chicago, Illinois, USA
8BrainLat: Latin American Brain Health Institute, Universidad Adolfo Ibañez, Santiago, Chile
9Cognitive Neuroscience Center, Universidad de San Andrés, Victoria, Buenos Aires, Argentina
10GBHI: Global Brain Health Institute, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland
11Department of Physiology and Pharmacology “V. Erspamer,”, Sapienza University of Rome, Rome, Italy
12Institute of Gerontology, Wayne State University, Detroit, Michigan, USA
13Research Institute for Health Sciences and Technologies (SABITA),Istanbul Medipol University, Istanbul, Turkey
14Department of Biophysics, School of Medicine, Istanbul Medipol University, Istanbul, Turkey
15Hospital San Raffaele Cassino, Cassino, Frosinone, Italy
16Cognito Therapeutics, Cambridge, Massachusetts, USA
17Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
Correspondence
Yang Jiang, Aging Brain and Cognition
Laboratory, Department of Behavioral Science,
and Sanders Brown Center on Aging,
University of Kentucky College of Medicine,
113 Medical Behavioral Science Building, 1100
Veterans Drive,Lexington, KY 40536-0086,
USA.
Email: yjiang@uky.edu
Funding information
United States National Institute of Health;
National Institute of Aging, Grant/Award
Numbers: P01AG078116, P30AG072946,
R01AG063857, R01AG057234,
R01AG054484, R56AG060608,
Abstract
Many coronavirus disease 2019 (COVID-19) positive individuals exhibit abnormal
electroencephalographic (EEG) activity reflecting “brain fog” and mild cognitive
impairments even months after the acute phase of infection. Resting-state EEG
abnormalities include EEG slowing (reduced alpha rhythm; increased slow waves)
and epileptiform activity. An expert panel conducted a systematic review to present
compelling evidence that cognitive deficits due to COVID-19 and to Alzheimer’s
disease and related dementia (ADRD) are driven by overlapping pathologies and
neurophysiological abnormalities. EEG abnormalities seen in COVID-19 patients
resemble those observed in early stages of neurodegenerative diseases, particularly
ADRD. It is proposed that similar EEG abnormalities in Long COVID and ADRD are due
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any
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© 2024 The Author(s). Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
JIANG ET AL.7297
1R21AG046637; United States Department of
Veterans Affairs, Grant/Award Number:
5I21RX003173; Alzheimer’s Association,
Grant/AwardNumbers: SG-20-725707,
HAT-07-60437, AARF-21-848281;
ANID/FONDECYT Regular,Grant/Award
Numbers: 1210195, 1210176, 1220995;
ANID/PIA/ANILLOS, Grant/Award Number:
ACT210096; FONDEF, Grant/Award
Numbers: ID20I10152, ID22I10029;
ANID/FONDAP, Grant/Award Numbers:
15150012, 15150012; Takeda, Grant/Award
Number: CW2680521; MULTI-PARTNER
CONSORTIUM TO EXPAND DEMENTIA
RESEARCH IN LATINAMERICA; Tau
Consortium; Global Brain Health Institute;
HORIZON 2021, Grant/Award Number:
H2021-MSCA-DN-2021; Marie
Skłodowska-Curie Doctoral Networks,
Grant/AwardNumbers: 101071485,
PNRR-MAD-2022-12376415; Italian Ministry
of University, Scientific and Technological
Research, Grant/AwardNumber:
2010SH7H3F
to parallel neuroinflammation, astrocyte reactivity, hypoxia, and neurovascular injury.
These neurophysiological abnormalities underpinning cognitive decline in COVID-19
can be detected by routine EEG exams. Future research will explore the value of EEG
monitoring of COVID-19 patients for predicting long-term outcomes and monitoring
efficacy of therapeutic interventions.
KEYWORDS
ACE2, Alzheimer’s disease and related dementia, astrocytes, background frequency, brain fog,
coronavirus and EEG, COVID-19, encephalopathy, inflammatory cytokine storm, Long COVID,
long COVID, resting EEG, SARS-CoV-2
Highlights
∙Abnormal intrinsic electrophysiological brain activity, such as slowing of EEG,
reduced alpha wave, and epileptiform are characteristic findings in COVID-19
patients. EEG abnormalities have the potential as neural biomarkers to identify neu-
rological complications at the early stage of the disease, to assist clinical assessment,
and to assess cognitive decline risk in Long COVID patients.
∙Similar slowing of intrinsic brain activity to that of COVID-19 patients is typi-
cally seen in patients with mild cognitive impairments, ADRD. Evidence presented
supports the idea that cognitive deficits in Long COVID and ADRD are driven
by overlapping neurophysiological abnormalities resulting, at least in part, from
neuroinflammatory mechanisms and astrocyte reactivity.
∙Identifying common biological mechanisms in Long COVID-19 and ADRD can
highlight critical pathologies underlying brain disorders and cognitive decline. It elu-
cidates research questions regarding cognitive EEG and mild cognitive impairment
in Long COVID that have not yet been adequately investigated.
1INTRODUCTION
This review is written to highlight the relevance of neurophysiolog-
ical evaluation of coronavirus disease 2019 (COVID-19) patients in
support of their clinical care and to highlight similarities between
potential pathological mechanisms that contribute to the neurological
consequences of COVID-19 infection and neurodegenerative diseases,
including Alzheimer’s disease (AD). Abnormal electrophysiological
brain activity is a characteristic finding in COVID-19 patients who
exhibit reduced power in the resting state electroencephalographic
(rsEEG) alpha rhythm (8–12 Hz; arousal state and attention). Addition-
ally, both COVID-19 and ADRDpatients show widespread increases in
power of delta (<4 Hz) rhythms.
These changes are often accompanied by mild cognitive impairment
(MCI) such as memory problems and brain fog. Similar slowing of rest-
ing brain activity is typically seen in patients with MCI and Alzheimer’s
disease and related dementias (ADRD). Here we present evidence
that abnormal EEG and related cognitive deficits in COVID-19 and
ADRD are driven by overlapping neurophysiological abnormalities.
These neurophysiological abnormalities can be detected by routine
EEG exams.
2LONG COVID, NEUROLOGICAL AND
COGNITIVE SYMPTOMS, AND EEG SIGNATURES
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infec-
tion can induce “Long COVID,” a postacute sequela of COVID-19
that refers to persistent symptoms continuing for months or longer
after the initial SARS-CoV-2 infection. The persistent symptoms affect
multiple physiological systems with respiratory, cardiovascular, neuro-
logical, and psychological symptoms.1One study found that 76% of
individuals with mild-to-moderate COVID-19 experienced at least one
persistent symptom 6 months after their initial infection.2Another
study found that 52% of COVID-19 survivors experienced persis-
tent symptoms 3 months after infection. These persistent symptoms
can significantly impair individuals’ quality of life and result in higher
healthcare costs.3
7298 JIANG ET AL.
RESEARCH IN CONTEXT
1. Systematic review: We have applied all aspects of a systematic review in the writing process. The expert panel of electrophysiological
professional interest area, which is connected to Alzheimer Association has previously published a review on pathological slowing of
resting-state electroencephalographic (EEG) in Alzheimer’s disease and related dementias (ADRD) patients. After we identified the
research questions on the connection between coronavirus disease 2019 (COVID-19) and EEG, we conducted the key words search
from multiple sources, for example, PubMed, Google scholar, NIH, CDC, and literature software. We set the criteria for the present
review on EEG signatures of Long COVID literature to curate relevant references specific to EEG studies in COVID-19 positive indi-
viduals. Additionally, we enhanced our expert panel of electrophysiological experts of ADRD and COVID-19 by inviting additional
experts in neurophysiology and astrocyte reactivity and neuroinflammation. Additional references were identified by the authors on
the expert panel especially new publications through 2024. Aimed to cover all related EEG and Long-COVID studies, the review was
also benefited from co-authors’ research on COVID-19 and EEG, publication recommendations, and personal communications from
the experts.
2. Interpretation: Similar slowing of resting brain activity to that of COVID-19 is typically seen in patients with mild cognitive
impairments. Our review presents new evidence and supports the idea that cognitive deficits due to COVID-19 and ADRD
are driven by overlapping pathologies, also reflected by similar neurophysiological abnormalities. Both neural inflammation and
cytokine/complement activation in COVID-19, amyloid and tau pathologies in ADRD contribute to astrocyte over reactivity, leading
to synaptic dysfunction in neurodegenerative diseases. Astrocytes are likely a primary target of COVID-19 because of the close inter-
action with the vasculature. Evidence presented here suggests that astrocytes are indeed injured/activated by COVID-19 infection
or infection with similar viruses resulting in neuroinflammation. Parallel changes in astrocyte reactivity are found in ADRD and are
suspected to cause synapse loss and neurodegeneration. What we have learned in the ADRD field may give us clues to how reactive
astrocytes contribute to the neural morbidities seen in COVID-19, for example, astrocyte reactivity leads to the production of Com-
plement C3 and loss of glutamate transport, both of which can damage synapses. Postsynaptic current and synchrony of oscillations is
what EEG measures.
3. Future directions: (1) Determine the value of EEG monitoring of COVID-19 severity and prediction of long-term consequences and
cognitive decline risk. (2) Investigate EEG measurements as proxy for synaptic dysfunction due to astrocyte-microglia reactivity
and pathology. (3) Establish specific EEG features closely associated with COVID-19 disease and cognitive dysfunctions. (4) Identify
common EEG features in both COVID-19 and ADRD. (5) Evaluate EEG network features as neural biomarkers for clinical trials of phar-
macological and nonpharmacological interventions in COVID-19 patients. (6) Assess variations of COVID-19 related EEG indicators
in diverse populations.
2.1 Neurological and cognitive symptoms of Long
COVID
Neurological symptoms are a significant part of Long COVID, and
understanding the underlying mechanisms is crucial for better diagno-
sis and treatment. In a meta-analysis of 18 studies on 10,530 patients
3 months after COVID-19 onset, overall prevalence of neurological
symptoms was 32% for brain fog, 28% for memory problems, and 22%
for attention disorder.4Another report with clinical observations of
neurological complications in 236,379 patients in the 6 months after a
COVID-19 diagnosis found that 33.62% of patients had demonstrated
clinically significant neurological or psychiatric dysfunction.5
Neurological symptoms of Long COVID reflect the COVID-19 neu-
roinvasion and include headache, tremors, problems with attention and
concentration, sluggish cognitive function, dysfunction in the periph-
eral nerves, and mental health problems.6,7 Beyond these typical
brain fog symptoms, systematic evidence suggests frequent associa-
tions with depression4and post-traumatic stress disorder (PTSD).8
Together, these symptoms can be characterized as “brain fog.” The
American Medical Association defines brain fog as some persistent
neurological symptoms, including slowed cognition, concentration dif-
ficulties, confusion, and forgetfulness.9Most people with Long COVID
report instances of severe fatigue and brain fog several months after
their initial infection.10 Those symptoms may fluctuate or relapse over
time.11
The relationship between SARS-CoV-2 infection and cognitive
impairment is another important topic.12 Long-term effects of COVID-
19 on cognition are illustrated by a recent case study, reporting a
62-year-old woman suffering from persistent cognitive deficits 8
months after COVID-19 infection with no preinfection history of
cognitive impairment. At follow-up observation, the individual showed
symptoms of memory loss, confusion, slowed motor function, and diffi-
culty in language production and comprehension.13 Similarly, a recent
study examining cognitive functioning in adults following a COVID-19
infection found that those with persistent unresolved symptoms
exhibited larger deficits than those with quickly resolved symptoms
and those in the non-COVID-19 control group.14 Those deficits
included poor memory and reasoning, as well as increased brain fog.
JIANG ET AL.7299
These studies present a model for potential neurophysiological and
neurological dysfunctions due to COVID-19 neuroinvasion.13,15–17
As research has progressed throughout the pandemic, a grow-
ing number of studies have reported cases of Long COVID patients
suffering from similar impairments in focus and attention, memory
retrieval, executive functioning, language production, and visuospa-
tial abilities.1,17–20 This cognitive impairment did not occur only in the
acute disease phase and in severe cases.21,22 Possible causes of emer-
gence of ADRD included microglial inflammation,23 ischemic changes
associated with COVID-19,24 and endothelial lesions that can impair
the clearance of brain metabolites including beta-amyloid peptides,
which are involved in AD.25 Structurally, there was reduced brain
grey and white matter in individuals with brain fog and in recovered
patients, along with cortical thinning in frontal and temporal lobes.26 In
brain organoids, astrocytic subclusters with enrichment for genes that
are implicated in neurodegenerative diseases revealed differentially
expressed genes (DEGs) related to upregulation of pathways found
commonly in Alzheimer’s disease (AD) and Parkinson’s disease (PD)
in response to SARS-CoV-2.27 Furthermore, patients with COVID-19
encephalopathy have higher plasma neurofilament light chain (pNfL)
and plasma glial fibrillary acidic protein (pGFAP) concentrations which
indicate neuronal dysfunction and CNS injury in their blood, like many
other types of dementias.28
2.2 Long COVID and EEG activity
EEG markers may be of interest for the clinical research carried
out in patients with cognitive impairment, as they are noninvasive,
repeatable without significant learning effects, globally available, and
cost-effective.29 Scalp-recorded EEG recordings allow the investiga-
tion of underlying cortical neural activities, including ionic current
flows and related voltages, with a great time resolution (less than 1
msec).30 It is also well known that EEG markers provide evidence of
nonspecific alterations in neuronal network activities caused by under-
lying neurodegenerative or vascular changes31–33 in the early stages of
cognitive impairments.34,35 Furthermore, topographical and spectral
features of EEG measured at rest reflect neurophysiological oscilla-
tory mechanisms underpinning the (dys)regulation of vigilance, mood,
and cognition. The ability to measure these features at rest (i.e., while
the individual is sitting with their eyes open or closed) is a particular
strength, as it allows for the study of brain function and connectivity in
healthy individuals and in those with ADRD alike.36
Previous studies have reported that rsEEG rhythms are abnormal
in patients suffering from persistent or Long COVID brain fog; specif-
ically, individuals exhibit topographically focal or diffuse “slowing” of
rsEEG rhythms.16,37 This slowing can be quantified by the spectral
analysis of rsEEG rhythms as diffuse power density increase in rsEEG
activity at low frequencies, such as delta (<4Hz)andtheta(4–7Hz)fre-
quency bands, and power density decrease at alpha (8–12 Hz) and beta
(13–30 Hz) frequencies. In the healthy aging brain, rsEEG activity at
alpha frequencies reflects spontaneous synchronization of cortical and
thalamic neurons as a main neurophysiological mechanism regulating
global cortical arousal states and vigilance.34,36
2.2.1 Epileptiform-like activity
In severe cases of COVID-19, EEG has been found to be a valuable
method to assess early neurological changes, including encephalopa-
thy, seizures, and status epilepticus.38 In COVID-19 patients, EEG
displays several abnormalities including epileptiform activity and gen-
eralized slowing, especially in frontal regions, despite normal brain
MRI.39–41 During the early phase of the pandemic, two meta-analyses
reported abnormal background EEG activity in COVID-19 patients,
showing EEG pathologies between 69% and 96% of patients.39,41 In
these reports, epileptiform activity was observed in lower proportions
(20% and 23% respectively). EEG seizures in COVID-19 patients were
associated with higher mortality rates.42 However, this finding may be
related to the fact that patients with diagnosis of previously existing
epilepsy or comorbid conditions tend to display higher rates of EEG
abnormalities.39,42,43
In summary, Long COVID involves complex interactions between
cognitive functions, structural and molecular mechanisms, and neuro-
physiological alterations related to underlying activities of neuronal
networks. While much remains to be explored, these recent findings
provide valuable insights for future research and suggest potential
assessment, monitoring, and therapeutic strategies using EEG record-
ings.
3METHODOLOGY OF THE REVIEW
Two reviews of EEG findings in COVID-19 patients in 2020 and
2021 demonstrated slowing of EEG waveforms with COVID-19.39,44
The expert panel of electrophysiological professional interest area
(EPIA) associated with Alzheimer Association has previously published
a review on slowing of resting-state EEG features for clinical trials in
AD/ADRD. After formulating the research question regarding COVID-
19 and EEG, we conducted key word searches from multiple sources,
for example, PubMed, Google Scholar, National Institutes of Health
(NIH), Centers for Disease Control and Prevention (CDC), and litera-
ture software. Keywords used in the search were: “resting EEG,” “back-
ground frequency,” “Alzheimer’s disease and related dementia”, “Neu-
rovascular,” “COVID-19 and EEG,” “Long COVID and EEG,” COVID-
19, SARS-CoV-2, encephalopathy, angiotensin-converting enzyme 2
(ACE2), astrocytes, Inflammatory cytokine storm, “Cognitive Decline,”
and “Long COVID OR coronavirus OR SARS AND EEG.”
After setting the criteria for the present review on EEG signatures
of Long COVID, a literature search was performed to curate relevant
references specific to EEG studies in COVID-19 positive individuals.
Two authors (Y.J. and J.N.) reviewed each article to determine rele-
vance to EEG and cognitive decline and brain fog. New citations of
several encompassing reviews on COVID-19 or cognitive decline were
identified and reviewed for further follow up of sources.17,18,20,45,46
From this, additional studies were identified pertaining to the effect of
COVID-19 on cognitive decline, with a specific focus on EEG correlates.
After further review of these articles, those deemed relevant, novel,
and impactful in relation to EEG correlation in persons with (Long)
COVID-19 were included (Figure 1).
7300 JIANG ET AL.
FIGURE 1 Diagram detailing the process of systematic literature
review. *Reasons for exclusion of references were duplicates, absence
of electroencephalogram (EEG), and lack of access. **Reasons for
full-text article exclusion were lack of EEG finding reports, focus on
adolescent subjects, and descriptive articles on EEG collection
Meanwhile, we enhanced our expert panel of electrophysiological
experts on AD/ADRD and COVID-19 by inviting additional specialists
in neurophysiology, astrocyte reactivity, and neuroinflammation. We
also internally debated various hypotheses about underlying patholog-
ical changes related to neurophysiological findings. Additional refer-
ences were identified by the authors on the expert panel, especially
new publications through 2024. Aiming to cover all related EEG and
long-COVID studies, we also benefited from co-authors’ research on
COVID-19 and EEG, publication recommendations, and personal com-
munications from the experts. Figure 2shows the interconnectedness
of literatures of COVID-19 and those in AD/ADRD.
We identified two caveats of this methodology, including (1) the
broad diagnostic criteria in the enrollment of patients with Long
COVID brain fog after testing negative (e.g., type, duration, and
severity of the symptoms) from the reviewed studies and (2) the het-
erogeneous procedures used during rsEEG data analysis (e.g., removal
of artifacts) and for computing the rsEEG spectral measures. Ideally,
future studies should aim at standardizing these criteria.
4EEG STUDIES IN COVID-19 PATIENTS
4.1 rsEEG activity in acute COVID-19
Several studies discussed characteristics of abnormal rsEEG activity
recorded in COVID-19 patients ranging from acute individual case
reports47 to larger longitudinal studies.48 Results showed disrupted
brain activity,38,49 but normal EEG activity was also reported.50 The
EEG abnormalities observed were correlated with severity of the gen-
FIGURE 2 Overlap in coronavirus disease 2019 (COVID-19) and
Alzheimer’s disease and related dementias (ADRD) literatures. A
diagram demonstrating the significant overlap and
interconnectedness of the literature in dementia and COVID-19
literature. Larger circles indicate a bigger impact of a paper in the field
based on citations (created by LitMaps)
eral health condition, COVID-19 assessment, length of surveillance,
and any pre-existing neurological problems like epilepsy.39 Slowed or
aberrant electrical brain activity, mainly in the frontal lobe, was the
most frequent EEG finding.41,51,52
EEG abnormalities seen in COVID-19 individuals could indicate
potential brain damage that may persist after acute infection. In
this context, frontal lobe-specific EEG abnormalities may be quali-
fied as a possible biomarker if consistently observed in COVID-19
encephalopathy.53 Some previous studies performed a visual anal-
ysis of ongoing EEG waveforms in critically ill COVID-19 patients
with long-lasting neurological symptoms, including encephalopathy,
for example, confusion, fluctuating alertness, or delayed awakening
after stopping sedation in the intensive care unit.54 In the following
paragraphs, we compare the EEG activity recorded during and months
after COVID-19.
Acute COVID-19 causes characteristic rsEEG patterns (Table 1)
with a generalized “slowing” in the rsEEG activity.39,48,54,55 In these
studies, most acute COVID-19 patients (60%–90%) were character-
ized by abnormal rsEEG activity, such as dominant background rsEEG
delta-theta rhythms (<7 Hz) or intermittent delta (<4 Hz) rhyth-
mic activity instead of typical posterior dominance in rsEEG alpha
rhythms, and nonconvulsive epileptiform activity or alpha (8–12 Hz)
coma in a minority of cases.39,48,54–56 Concerning frequency features,
abnormal power densities at rsEEG delta, theta, and alpha rhythms
JIANG ET AL.7301
TAB L E 1 Acute COVID-19 EEG studies
Authors and title of the studies Study type
Affected brain
site
Neurological
abnormalities EEG findings EEG markers
Antony and Haneef (2020),
Systematic review of EEG
findings in 617 patients
diagnosed with COVID-19
Literature review Frontal - stroke
- headache
- seizure
- altered mental status
- speech difficulties
- diffuse slowing (68%)
- focal slowing (17%)
- slow posterior dominant rhythm (2.3%)
- absent posterior dominant rhythm (10.2%)
- background attenuation/suppression (1.3%)
- discontinuous EEG/burst suppression (2.1%)
- asymmetry (2.1%)
- decreased reactivity (3.2%)
- frontal epileptiform
discharges
- frontal monomorphic
biphasic slow waves
- periodic discharges with
triphasic morphology
- generalized rhythmic delta
activity
Haykal, M. A., and Menkes, D. L.
(2023), The clinical
neurophysiology of
COVID-19-direct infection,
long-term sequelae and
para-immunization responses: A
literature review
Literature review Frontal - nonspecific
encephalopathy
- generalized periodic discharges
- generalized slowing
- epileptiform discharges
- alpha coma pattern
Koutroumanidis et al. (2021),
Alpha coma EEG pattern in
patients with severe COVID-19
related encephalopathy
Observational
study
Frontal - headache
- dizziness
- impaired
consciousness
- seizure
- encephalopathic features
- generalized slowing
- general low voltage
- spontaneous fluctuations
- anterior theta
- anterior delta
- bilateral delta bursts
- alpha coma
Pati et al. (2020), Quantitative
EEG markers to prognosticate
critically ill patients with
COVID-19: A retrospective
cohort study
Retrospective
cohort study
Unspecified Unspecified
encephalopathy
- low voltage - low spectral delta-theta
power
- low theta-alpha activity
Pellinen et al. (2020), Continuous
EEG findings in patients with
COVID-19 infection admitted to
a New York academic hospital
system
Retrospective
study
Unspecified - coma
- encephalopathy
- seizure
- seizures
- generalized slowing
- periodic discharges
- nonperiodic epileptiform discharges
- generalized rhythmic delta
activity
Petrescu et al. (2020),
Electroencephalogram (EEG) in
COVID-19: A systematic
retrospective study
Retrospective
study
Left temporal - headache
- confusion
- sporadic triphasic waves
- multifocal or generalized periodic discharges
- left temporal sharp contoured waves
- generalized rhythmic delta
activity
- diffuse delta and theta
slowing
Vespignani et al. (2020), Report
on electroencephalographic
findings in critically ill patients
with COVID-19
Report Frontal - altered mental status
- headache
- loss of consciousness
- poor arousal
- poor responsiveness
- periodic discharges
- generalized slowing
- high amplitude frontal
monomorphic delta waves
- diffuse nonspecific theta
and alpha activity
- theta consistent with
sedation
7302 JIANG ET AL.
were reported in severe cases of acute COVID-19.56,57 Regard-
ing spatial characteristics, frontal rsEEG abnormalities were often
prominent.39,54–57
More severe rsEEG alterations (summarized in Tables 1–2)
in COVID-19 patients were associated with prior pathological
conditions.56 Both seizure and epileptiform activity were seen in those
with history of epilepsy or seizures, while those with a prior history
of cognitive impairment exhibited stronger changes relative to those
with normal cognitive history.48 Unfortunately, there is no systematic
comparison between these findings and abnormalities reported in
patients with other brain disorders. However, multiple studies have
shown that acute infections impact CNS function, leading to seizures,
epileptiform activity, and alpha coma (AC) patterns.48,54–56 AC is a
distinctive EEG pattern observed in unconscious patients in a state
of clinical coma. It is a predominant, generalized, and symmetrical
rhythm within the alpha frequency band (8–13 Hz) associated with
brain stem lesions. Patients may transition to theta coma caused by
cortical dysfunctions.58
4.2 rsEEG findings in Long COVID
EEG studies highlighting the features of rsEEG abnormalities in
Long COVID patients showed interesting results summarized in
Tab l e 2.15,17,40,59,60 Background “slowing” of rsEEG rhythms was a
common finding.15,17 Specifically, the posterior dominance in rsEEG
alpha rhythms (typical in noninfected individuals) was observed in only
42% of patients with Long COVID, while the others are character-
ized by dominant power in theta (42%) or theta-delta (14%) bands.15
Furthermore, hemispherical asymmetries in rsEEG amplitude were
abnormally high at delta, theta, alpha, and beta bands in Long COVID
patients.17,61 Abnormally high rsEEG delta rhythms on widespread
scalp regions were the most common abnormality in Long COVID
patients.15,17,40,61 Notably, Brutto et al. (2021) reported that individ-
uals with a history of mild COVID-19 infection are 18 times more
likely to develop long term brain disorder and cognitive decline than
controls based on 6-month follow-up rsEEG.17 Both verbal memory
deficits and frontal executive functioning issues were also correlated
with rsEEG abnormalities in Long COVID patients 2 months after the
infection.40
5EEG SLOWING IN COVID-19
Some abnormalities in rsEEG activity reported in Long COVID patients
were observed in patients with ADRD. For example, abnormally high
rsEEG delta-theta power density over widespread scalp regions was
reported in AD patients, in comparison to healthy controls.62,63 Fur-
thermore, early AD patients typically showed a shift to lower fre-
quency in rsEEG rhythms29 and altered task-evoked EEG potentials,
which led to gradual loss of cognitive functions, especially working
memory and executive functions, as well as slower reaction times.64
Such slowing of rsEEG rhythms is thought to reflect a thalamocorti-
cal “disconnection mode” during disease progression from preclinical
to clinical stages of ADRD.29 Along these lines, similar abnormally
prominent rsEEG activity was reported in patients with MCI, partially
induced by vascular or metabolic dysfunctions, for example, high blood
pressure and type 2 diabetes.63 Overall, a continuum of alterations in
rsEEG was associated with pathological aging, generally characterized
by reduced alpha and beta power and increased delta and theta power
in ADRD compared to healthy controls, with some variation across
brain regions. There were also reductions in the frequency and power
density of the posterior dominant rhythm in AD.
5.1 COVID-19 EEG abnormality and known AD
pathologies
It is not entirely clear how COVID-19 contributes to a shift to lower
frequencies in the rsEEG activity, parallel to that observed in ADRD
patients.65 New magnetoencephalographic (MEG) evidence supports
the link between “slowing” in the brain rhythms and cellular mech-
anisms of impaired cerebral excitatory and inhibitory (E/I) synaptic
functions associated with tau and A-beta (Aβ) in AD patients.66,67 In
these seminal studies, increased excitatory activity was related to high
tau levels, while increased inhibitory time-constants correlated with
higher Aβdepositions.66 Linking these effects to the abnormal rsEEG
activity seen in Long COVID patients, it can be speculated that similar
accumulation of amyloid and tau may co-occur with the neuroinflam-
matory, autoimmune, hypoxia, and cerebrovascular alterations that are
often observed in ADRD patients.67
Understanding a potential relationship between COVID-19 and the
amyloid and tau pathologies could also be insightful. Studies show
that COVID-19 patients having neurological symptoms had amyloid
pathologies. For instance, patients with amyloidosis are at a higher risk
for severe COVID-19 infection and mortality.68 Furthermore, total-tau
and neurofilament light (NfL) chain in cerebrospinal fluid (CSF) were
elevated in one in four COVID-19 patients with acute neurological syn-
dromes compared to non-COVID-19 control patients.69 Both in vivo
and in vitro studies showed that amyloid precursor protein promotes
the entry of SARS-CoV-2 virus into cells and further aggravates AD
pathology.70
At the molecular level, microarray and RNAseq dataset analy-
sis suggest common enriched genes in COVID-19 and AD. These
include hub genes, specific miRNA targets associated with COVID-
19 and AD, and several enriched cell-signaling pathways, such as
PI3K-AKT, Neurotrophin, Rap1, and Ras, which may induce amy-
loid precursor protein and tau hyperphosphorylation associated with
neurodegeneration.71,72 The structure of SARS-CoV-2 includes four
proteins: spike, envelope, membrane, and nucleocapsid proteins,
which form amyloid fibrils intracellularly or extracellularly (spike
protein).73 Besides direct viral induction of Aβ, indirect connec-
tions between COVID-19 and Aβare also reported. For example,
COVID-19 as a respiratory disease causes hypoxia that has been
linked with increased Aβburden and dementia.74 Alternative indirect
COVID-19-Aβburden connection mechanisms were also reported,
including inflammation,75 blood-brain barrier breakdown,76,77 glucose
metabolism dysregulation,78 and commonly associated genetic risk
JIANG ET AL.7303
TAB L E 2 Postacute Long COVID studies
Authors and title of the studies Study type Affected brain site Neurological abnormalities EEG findings EEG markers
Cecchetti et al. (2022), Cognitive,
EEG, and MRI features of
COVID-19 survivors: A 10-month
study
Longitudinal study - Bilateral frontal
- Central temporal
- chronic malaise
- diffuse myalgia
- sleep disturbances
- migraine-like headaches
- ageusia
- anosmia
- frontal slow waves - high individual alpha
frequency
- cortical current source
density
- high delta linear lagged
connectivity
- delta oscillations
Brutto et al. (2021), Cognitive
decline among individuals with
history of mild symptomatic
SARS-CoV-2 infection: A
longitudinal prospective study
nested to a population cohort
Longitudinal
prospective study
- Right temporal
- Frontal
- anosmia
- ageusia
- headache
- generalized
background slowing
- focal slowing
- epileptiform
discharges
- sporadic sharp waves
- posterior dominant
alpha rhythm
- rhythmic delta waves
Furlanis et al. (2023), Cognitive
deficit in post-acute COVID-19: An
opportunity for EEG evaluation?
Cross-sectional
study
- Bilateral frontal
-temporal
-hyposmia
- myalgia
- headache
- dizziness
- tinnitus
- epileptiform
discharges
- generalized slowing
- seizures
diffuse theta-delta
slowing
Kopanska et al. (2022), Attempted
brain wave modeling in
participants under severe chronic
stress using quantitative
electroencephalogram
Longitudinal
comparative study
- Frontal
- Parietal
- chronic stress - high frequency right
hemispheric waves
- low level sensorimotor
rhythm
- reduced alpha
- decreased theta
Saez-Landete et al. (2021),
Retrospective Analysis of EEG in
Patients With COVID-19: EEG
Recording in Acute and Follow-up
Phase
Longitudinal
Retrospective
Analysis
- Frontal
-Temporal
- low awareness
- disorientation
- mood disturbance
- confusion
- inattention
- absence of posterior
dominant rhythm
- reduced voltage
- reduced alpha
- reduced theta
Babiloni et al. (2024), Resting-state
EEG rhythms are abnormal in post
COVID-19 patients with brain fog
Cross-sectional
study
- Occipital
- Parietal
- chronic fatigue
- postexertional malaise
- myalgia
- headaches
- confusion
- lowered posterior
resting state dominant
rhythm
- reduced alpha 2
- reduced alpha 3
7304 JIANG ET AL.
factors such as apolipoprotein E4 (APOE4).79 For example, one study
reported increased proinflammatory cytokines in the CSF of COVID-
19 patients, which negatively correlated with decreased CSF soluble
amyloid precursor protein.80 Intriguingly,SARS-CoV-2 induced Aβbur-
den can serve dual functions, both in a protective role and by activating
Aβexpression and toxicity underlying AD progression.81–83 More
knowledge needs to be gained to understand the unprecedented con-
dition that we will be facing in the next few decades. Taken together,
these preliminary findings suggest that the links between amyloid,
tau pathology, and COVID-19 may explain the slowing EEG waves in
COVID-patients.
5.2 Hypoxia, heart rate variability, and rsEEG
activity in Long COVID
Hypoxia, which is associated with ADRD, including AD and cere-
brovascular dementia,84 is another possible cause of abnormalities in
rsEEG activity and neurological symptoms in Long COVID patients.
Hypoxia serves as a vital connection between lung and heart deficits
that are linked to cerebrovascular dysfunction in the brain. Here, we
present well established evidence that hypoxia contributes to rsEEG
activity and likely to Long COVID. COVID-19 infection impacts brain
blood perfusion and oxygenation by several mechanisms. SARS-CoV-
2 neuroinvasion through the cerebral vasculature may affect regional
brain blood flow and metabolism, thus affecting the synchronization
of oscillatory activity in cortical and thalamic neurons, which under-
lie dominant rsEEG alpha rhythms and regulation of cortical arousal
and vigilance.29,85,86 Lower oxygen saturation levels have been linked
with more severe rsEEG abnormalities, indicating that higher lev-
els of hypoxemia could contribute to brain dysfunction. Related EEG
abnormalities include mostly diffuse and focal slowing, and absence of
posterior dominant rhythm.87
COVID-19 is associated with respiratory symptoms and often
requires treatment via ventilation in severe cases connected to acute
respiratory distress syndrome (ARDS). ARDS can induce hypoxia,
which results in hypoxic encephalopathy, particularly in older individ-
uals with high vulnerability to oxidative stress.45 Respiratory damage
can even give rise to silent hypoxia, defined as a condition where an
individual has alarmingly lower oxygen saturation levels than antici-
pated (∼50%–80% saturation, while the anticipated saturation level is
95% or higher) in the absence of any breathing difficulty.88 As illus-
trated by Rahman et al. (2021), silent hypoxia has been associated
with several COVID-19 related symptoms.89 Silent hypoxia can result
in overexpression of ACE2 receptors thereby increasing the risk of
damage through COVID-19 infection. The condition can also further
contribute to the mechanism of the “cytokine storm” by recruiting dif-
ferent mediators of inflammation. Moreover, silent hypoxia can cause
serious endothelial damage through nuclear factor kappa B (NF-kB)
transcription factor activation. Finally,silent hypoxia can signal a differ-
ent immune-metabolism pathway and cause secondary organ damage.
All these factors lead to the critical condition of COVID-19 patients
along with an increased mortality rate.89
Hypoxia could result from abnormal heart-brain connections as
well. The heart provides oxygen for the brain through cardiovascular
blood flow that is regulated by the balance of two branches of auto-
nomic activity (symptomatic and parasympathetic/vagal nerves). The
autonomic activity is proxied by heart-rate variability (HRV), which
has been reported to change in COVID-19 patients. For example, in a
recent study, resting HRV predicted survival in patients aged 70 and
older.90 COVID-19 was shown to be related to decreased HRV,91 sug-
gesting COVID-19 may link with autonomic dysfunction. Autonomic
dysfunction may be reflected by orthostatic intolerance, which has
been experienced by some COVID-19 patients.92 Orthostatic intoler-
ance or autonomic dysfunction can be associated with hypoperfusion
in the brain and may contribute to hypoxia and cognitive symptoms
(e.g., brain fog). Besides HRV, the change of cardiovascular activity can
also result from COVID-19 infection in the heart itself.93,94 Changes
in cardiac tissue will affect the pumping activity and eventually link
to hypoperfusion of the brain. Allostatic interoceptive overload, com-
monly observed in dementia via autonomic-cardiac-brain interaction,
could also represent a complex and multilevel mechanism involved in
COVID-19.
An EEG signature in some COVID-19 patients who are slow to
recover consciousness includes burst suppression.95 Burst suppres-
sion is an EEG pattern during which active and isoelectric (flat) periods
alternate. The characteristics of burst suppression suggest that it can
be a dynamic process, affecting nearly the entire cortex, and that
it is associated with a decreased cerebral metabolic rate of oxygen
consumption. Electrophysiological modeling has shown that burst sup-
pression is likely a signature of a neurometabolic state that preserves
basic cellular function “during states of lowered energy availability.”
These brain states likely serve as a neuroprotective mechanism. Pro-
longed coma and recovery accompanied with hypoxia and markedly
reduced brain metabolism with similar EEG patterns are present in
certain patients after cardiac arrest and in certain anoxia-tolerant
vertebrates.95 In some severe COVID-19 encephalopathy patients, an
AC pattern may be observed. The predominant, generalized, and sym-
metrical rhythm within the alpha frequency band58 is rare in other
encephalopathies but has a relatively high incidence in COVID-19
encephalopathy, which may imply neurotropism with a predilection for
the brainstem ascending reticular system.54
Hypoxia related EEG patterns in COVID-19 patients may mimic
those seen in sleep apneas (OSA). In a study of men with obstructive
sleep apnea (OSA), severity of hypoxia was significantly associated with
EEG slowing and reduced power across all frequency bands, predomi-
nantly in rapid eye movement (REM) sleep, and with beta power during
non-REM (NREM) sleep.96 Reduced P300 amplitudes in severe OSA
(SOSA) patients suggest impaired attentional resources during stim-
ulus evaluation processes, while prolonged P300 latency is linked to
altered stimulus classification and cognitive processing speed.97 The
alterations in brain electrical activity in regions associated with emo-
tional regulation, long-term memory, and the default mode network
may be caused by chronic global hypoxic state.98
Previous studies indicate that transient experimental hypoxia
induces abnormal posterior resting state delta and alpha rhythms in
JIANG ET AL.7305
healthy volunteers.99 A study comparing EEGs of subjects who inhaled
an acute hypoxic mixture at sea level or who reached a high-altitude
area under chronic hypoxia, showed that severe hypoxia caused more
obvious abnormalities on EEGs, and that acute hypoxia caused more
obvious abnormalities but faster recovery than chronic hypoxia.100,101
Other studies indicate that during systemic hypoxia, the spectralpower
of rsEEG with closed eyes increases, except for in the alpha band.101 In
the alpha band, a rapid decrease in power is observed, which is greater
at mild desaturation,102 especially in the first 150 s of hypoxia.103
Regarding event-related potentials (ERPs), significant reduction can be
observed in the amplitude of the visual mismatch negativity (MMN)
under hypoxic conditions.104 Acute hypoxia has been found to impair
neural activity in motor executive and inhibitory processing, cause a
reduction in the peak amplitudes of Go-P300 and No-go-P300, and
delay peak latency of Go-P300105 and P300 latency,106 withno change
in earlier components (i.e., P200 or N100).107 Thus, cognitive ERPs
can be sensitive to hypoxia induced cognitive impairments. Regard-
ing modality, auditory responses are believed to be less sensitive to
hypoxia compared to visual responses, resulting in relatively less slow-
ing with auditory stimuli.107 Regarding topography of hypoxic changes
in the brain, a MEG study localized an increase in beta-1 activity
to the right superior frontal gyrus, indicating a relationship between
prefrontal activation and performance deficits.108 Further research is
needed to understand the relationship between EEG/MEG alterations
and hypoxic conditions directly resulting from COVID-19.
COVID-19 can lead to CNS hypometabolism as well. Brain
hypometabolism, measured by positron emission tomography (PET),
has been observed in Long COVID patients with persistent memory
impairment.109 Furthermore, Martini et al. (2022) reported a diffuse
brain hypometabolism in COVID-19 patients followed longitudinally,
which recovered after 5 months along with blood saturation and
inflammatory biomarker levels, and cognitive status.110 In these
patients, EEG monitoring showed general “slowing” of frontal rsEEG
rhythms, along with a spread in frontal hypometabolism.16 Arica-Polat
et al. (2022) reported that cognitive impairment due to COVID-19
infection may be caused by ACE receptor density in the pial, hippocam-
pal, and amygdala areas.111 Furthermore, individuals with severe
dementia having a milder COVID-19 infection could be explained by
gray matter atrophy in those brain areas.
Building on emerging evidence of EEG abnormality in COVID-19,
the expanded Expert Panel endorsed the present narrative review to
clarify the likely relationships between EEG abnormalities related to
Long COVID (Figure 3). Next, the hypotheses of possible overlapping
pathophysiological and neurophysiological mechanisms underlying
Long COVID and ADRD are examined.
6POSSIBLE NEUROPHYSIOLOGICAL
ABNORMALITIES IN LONG COVID: PARALLEL TO
ADRD
Recent studies have discussed how Long COVID infection can affect
neuronal activity and cognitive status, though the exact pathophysi-
ological mechanisms leading to the neurological and psychiatric con-
sequences of Long COVID have not been determined conclusively.112
Early in the pandemic, it was debated whether the SARS-Co-V2 virus
can directly infect central (CNS) and peripheral (PNS) nervous systems,
or if the “neurotoxicity” may result from indirect immune-mediated
mechanisms.110 The CNS was found to be substantially involved
in COVID-19 based on several neurological and pathophysiological
symptoms,113 although there are varying degrees of CNS involvement
in the acute phase of COVID-19 patients.87 Patients with transient
COVID-19 effects may have a substantially preserved neuronal func-
tion illustrated by normal background rsEEG alpha activity; in con-
trast, those with more severe prognoses exhibited significant rsEEG
abnormalities.87 A few causative neurobiological and neurophysiolog-
ical mechanisms for Long COVID and abnormal rsEEG activity are
outlined below. These mechanisms will be also discussed in relation to
ADRD for the similarities in the rsEEG abnormalities in Long COVID
and ADRD.
6.1 Neuronal abnormalities in Long COVID and
ADRD arising from neuroinflammation and chronic
glial reactivity
One of the most likely mechanisms of COVID-19 neuroinvasion
explaining the “slowing” of rsEEG activity is the inflammatory
response to the SARS-COVID-19 virus, leading to cytokine-mediated
neuroinflammation.114 Binding of coronavirus spike proteins to ACE2
in the bloodstream115 can affect ACE2 expression throughout cere-
bral vasculature, resulting in vascular inflammation and possibly the
disruption of the blood-brain barrier (BBB). Infiltration of bloodborne
particles into the brain is a well-known trigger for the activation of
microglia and astrocytes associated with elevated neuroinflammatory
signaling.116 Moreover, inflammation-mediated disruption of the BBB
can make astrocytes and other resident brain cells directly accessible
to SARS-CoV-2 viral particles.
Astrocytes are metabolic liaisons between cerebral vessels and neu-
rons. Nearly every cerebral vessel is sheathed by specialized processes
called astrocyte endfeet (circles in Figure 4). Other astrocyte processes
cradle many, if not most, excitatoryconnections in the brain. Astrocytes
can uptake viral particles directly through coronavirus coreceptors
(e.g., CD147 or DPP4), or through interactions with other perivas-
cular cells like pericytes. Not surprisingly, astrocytic injury has been
reported to occur early in acute phases of COVID-19 infection.117
Once injured (or activated), astrocytes can release a wide array of
cytokines and chemokines. Astrocytes were suggested to play a major
role in the generation of an inflammatory cytokine storm response fol-
lowing infection with a murine coronavirus that mirrors COVID-19.
Viral infection of astrocytes has been linked to encephalitis and other
acute inflammation-related morbidities.118
Astrocyte reactivity is a prominent feature of AD and most ADRDs
(e.g. in response toxic Ab and Tau species) where it is suspected
as a proximal cause of neuroinflammation, cerebrovascular dysfunc-
tion, impaired synapse function, and neuronal hyperexcitability.119,120
7306 JIANG ET AL.
FIGURE 3 Electroencephalographic (EEG) abnormality in healthy versus coronavirus disease 2019 (COVID-19) positive individuals. Scalp
EEG signals measure synchronized postsynaptic current and neurovascular network activity. EEG abnormalities observed in COVID-19 patients
display increased slow-wave and epileptiform-like EEG signals in mostly frontal sites, as seen in Table 1(acute) and Table 2(Long COVID). Cognitive
and neurological dysfunctions reported in COVID-19 patients resemble those with mild cognitive impairment due to neurodegenerative diseases.
Like AD and ADRDs, changes in COVID-19-associated astrocytic
inflammatory signatures are regulated by canonical NF-kB signal
transduction.121,122 Interestingly, neurotropism and neurotoxicity are
higher after COVID-19 infection in neurons and astrocytes express-
ing the AD risk gene APOE4,123 suggesting that astrocytes may be
a source of confluence for pathophysiologic changes observed in
individuals with COVID-19 and dementia. As outlined above, reac-
tive astrocytes may contribute to neurologic dysfunction arising with
COVID-19 and dementias through the initiation and/or maintenance
of harmful neuroinflammatory responses. Below, we consider how
reactive astrocyte signaling and neuroinflammation can directly affect
synapses (and EEG patterns) based on findings from the AD/ADRD
literature.
6.1.1 Astrocytes, complement C3 factors, and
synapse loss
The complement cascade (Figure 4) is a critical defense mechanism
against invading pathogens (both outside and inside the CNS) but
can cause extensive damage to host tissues when chronically engaged
and/or dysregulated.124 As compared to controls, the brain tissues of
patients who died from COVID-19 have shown a significant increase
in multiple complement components including C1q, C4d, C5b-9, and
C3. These effects have been shown to occur with vascular endothe-
lial cells and are associated with the extravasation of fibrinogen and
apparent leakage of the BBB.125 These findings implicate both the clas-
sical and alternative complement pathways and suggest that C3b and
the C5b-9 terminal complement complex (membrane attack complex,
MAC) may act in concert with neuroinflammatory and immune fac-
tors to contribute to the neurological sequelae seen in patients with
COVID-19.
Among their many functions in brain tissue, the complement system
plays an important role in eliminating unnecessary or dysfunctional
synaptic structures. The essential players in synapse elimination are
C1q, coming primarily from neurons, and C3, derived primarily from
astrocytes. Under neuroinflammatory conditions (and elevated com-
plement signaling), the release of C3 from reactive astrocytes is
converted to proteolytic fragments upon interaction with C1q from
nearby neurons. These C3 fragments, especially C3b, opsonize inactive
or dysfunctional synapses leading to microglial mediated phagocytic
clearance. C3 has been proposed as a primary mechanism for synapse
loss and dysfunction in AD.126 C3 is robustly elevated in reactive astro-
cytes in aging and most ADRDs and is strongly induced in astrocytes
by exposure to pathogenic Aβpeptides.127 In mouse models of AD-like
pathology, C3 and C1q tend to localize with synapses to a much greater
extent than what is observed in age-matched wild-type littermates.
Moreover, genetic knockdown of C3 has been shown to preserve
synaptic density and improve neural function in amyloidogenic mice.
Whether COVID 19 mediates synapse loss and/or neurodegeneration
through a similar release of C3 from reactive astrocytes remains to be
determined.
In addition to releasing C3 and other synapse-related proteins,
reactive astrocytes in ADRDs also lose properties that help protect
or maintain healthy synapses. One of the fundamental protective
roles of astrocytes is the uptake of glutamate from synapses via
high-capacity glutamate transporters, like EAAT2 (GLT1 in rodents)
and EAAT1 (GLAST in rodents). Glutamate transport from the synapse
into the astrocyte not only preserves excitatory/inhibitory balance and
protects against exocytotic damage, but it also regulates the delivery
of energy substrates (e.g. lactate) to neurons.120 Potent neuroinflam-
matory mediators, including cytokines (e.g., interleukin 1 beta [IL-1β]
and tumor necrosis factor alpha [TNFα]) and Aβpeptides arising with
neuroinflammation and/or ADRDs lead to the downregulation of
JIANG ET AL.7307
FIGURE 4 Complex brain pathophysiology and pathology of coronavirus disease 2019 (COVID-19) infection and Alzheimer’s disease and
related dementias (ADRDs). COVID-19 is a viral pathogen that systemically induces blood immune cell activation, glycocalyx damage, blood
clotting, vascular damage and dysfunction observed in heart attack and stroke. This causes blood component infiltration, hypoperfusion and glia
cell activation in brain tissue. The circles illustrate endfeet of astrocyte in modulation of synaptic functions. Alternatively, this viral particle could
directly enter and trigger parenchymal astrocyte and microglia activation. Proinflammatory cytotoxic cytokines and complements produced from
both blood and glia cells cause neuroinflammation and neuronal injury. Dysregulation of glutamate, calcium signaling, and oxidative stress further
complicates physiological function of synapses and neurons. This complex pathophysiology is similarly found in AD and ADRDs where vascular
pathology and neuronal loss are commonly observed. Hypoxia, oxygen, and heart-brain dysfunction contribute to EEG signals. Consequently, signs
and symptoms of confusion, inability to concentrate, learning and memory impairment are concurrently found with reduced
electroencephalographic (EEG) signals and abnormal EEG synchrony in cortical, subcortical, and deep brain regions.
astrocytic glutamate transporters,128–131 resulting in delayed gluta-
mate clearance, dendritic degeneration, and synapse hyperexcitability.
Glutamate transporter levels are regulated by classic inflamma-
tory pathways, like NFκB, and closely intertwined Ca2+dependent
pathways like calcineurin/NFAT (nuclear factor of activated T cells).
Astrocytes pre-exposed to a variety of cytokines and other inflam-
matory mediators lead to hyperactivated Ca2+-signaling,132 which
may, in turn, stop the development of synchronized neuronal calcium
oscillations133 and/or promote deficits in Ca2+dependent synaptic
plasticity.134 Hyperactivation of astrocytic calcineurin and NFATs is a
common feature of several ADRDs including AD,135,136 vascular cogni-
tive impairment and dementia,137,138 and traumatic brain injury.139,140
Targeted blockade of calcineurin/NFAT signaling in astrocytes pre-
vents downregulation of glutamate transporters in primary astrocyte
culture models of neuroinflammation, and in mouse models of amyloid
pathology, leading to improved glutamate uptake, reduced neuronal
7308 JIANG ET AL.
hyperexcitability, increased synaptic strength and dendritic integrity,
and improved cognitive function.130,131,135 However, the role of astro-
cytic calcium signaling or glutamate dysregulation as contributing
factors in COVID-19 related neurologic dysfunction and degeneration
has yet to be investigated.
6.1.2 Abnormal EEG reflects synaptic dysfunction
It has been well established that EEG signals measure synchronized
postsynaptic neural activity and neuron networks that reflect altered
synaptic functions underlying cognitive changes.141 Abnormal EEG
signals arise mainly from postsynaptic currents and not action poten-
tials in the brain. Synaptic losses were observed early on in both the
temporal and parietal cortexes of brains of patients with MCIs and
AD.142
Decades of literature has shown cognitive event-related EEG poten-
tials (averaged EEG activity related to a cognitive event such as
attention or memory retrieval) correlate to various cognitive functions
in healthy humans and dysfunctions in aging and mental disorders141
including ADRD.31 However, cognitive EEG studies in COVID-19
patients appear to be a missing piece.
6.2 Autoimmune response in Long COVID and
ADRD
A second potential common mechanism of COVID-19 neuroinva-
sion and ADRD explaining the “slowing” of rsEEG activity may
be an autoimmune driven response. Some factors such as proin-
flammatory cytokines and chemokines, damage-associated molec-
ular patterns (DAMPs), molecular mimicry, cross-reactive antibod-
ies, and auto-antibodies may contribute to autoimmune dysregula-
tion in Long COVID patients. The analysis of a COVID-19 positive
patient showed neurological improvement to steroid treatment, indi-
cating that the viral mechanism could be tied to an autoimmune
neuroinflammation.143 A cytokine storm induced by COVID-19 caused
neuroinflammatory encephalitis via immune effector cell-associated
neurotoxicity syndrome (ICANS).18,45 ICANS presents with general-
ized EEG “slowing” as well as clinical manifestations including confu-
sion, short-term memory impairment, expressive deficits, and behavior
disturbances including impulsivity, emotional lability, abulia, and aki-
netic mutism.18,45
It has also been revealed that autoimmune disease related
encephalitis, due to antibodies acting against the N-methyl-D-
aspartate (NMDA) receptors, can lead to diverse neurological and
psychiatric symptoms.144 Similarly, COVID-19 patients showed
dysregulated autoantibody levels correlating with the virus sever-
ity, including antibodies against the dopamine-1 receptor, NMDA
receptor, brain-derived neurotrophic factor, myelin oligodendrocyte
glycoprotein (MOG), and acetylcholine receptor when compared with
healthy controls.145 Overall, the complex pathophysiology seen in
Figure 4is similarly found in AD and ADRDs where vascular pathology
and neuronal loss are commonly observed. Consequently, signs and
symptoms of confusion, inability to concentrate, and learning and
memory impairment are concurrently found with reduced EEG signals
and abnormal EEG synchrony in cortical, subcortical, and deep brain
regions.
6.3 Cerebrovascular injury and atrophy in
COVID-19 and ADRD are linked to abnormal EEG
Cerebrovascular injury and atrophy are signals of relative long-term
brain damage and have been linked to abnormal rsEEG activity in
COVID-19 and ADRD. A UK Biobank study investigating brain scans
before and after COVID-19 infection compared with matched con-
trols with no previous infection showed significant loss of gray matter
with (1) greater reduction in global brain size, (2) greater reduction in
the orbitofrontal cortex and para-hippocampal gyrus, and (3) greater
changes in regions that are functionally connected to the primary olfac-
tory cortex.146 In another study exploring if the spatial distribution
of the anatomical events follows a cortical or subcortical pattern, the
authors found the epicenters of this spread may be the cerebellum
and putamen.147 Furthermore, white matter events were identified
most frequently in the corticospinal tract and corpus callosum. The
corticospinal tract is the main pathway connecting subcortical brain
regions such as the thalamus and basal ganglia. Along with this, the
corpus callosum has an important role in interhemispheric communi-
cation, which can lead to a disconnection syndrome and a wide variety
of neurocognitive deficits.147
To summarize the contrasts and commonalities in COVID-19 and
AD/ADRD, we built a model from pathology,EEG, and cognitive impair-
ment (Figure 5). Evidence in Section 6suggests that astrocytes are
indeed injured/activated by COVID-19 infection, or infection with
similar viruses, resulting in neuroinflammation. Parallel changes in
astrocyte reactivity are found in ADRDs. In ADRD, astrocyte reac-
tivity is suspected to cause synaptic hyperactivity, synapse loss, and
neurodegeneration. Astrocyte reactivity leads to the production of
complement C3 and loss of glutamate transport, both of which can
damage synapses. EEG measures postsynaptic activity in neuronal net-
works that reflect synaptic injury underpinning cognitive dysfunction.
What we have learned in the ADRD field gives us clues to how reactive
astrocytes and neuroinflammation contribute to the neural morbidities
seen in COVID-19.
7UNRESOLVED ISSUES AND POTENTIAL EEG
NEURAL BIOMARKERS FOR INTERVENTION
Some substantial open questions remain. One question is whether
there is converging evidence on spatial and frequency features of
abnormal rsEEG rhythms in Long COVID patients. Another question is
whether these abnormal features are specific to Long COVID patients
or reminiscent of those with vigilance and cognitive deficits due to
other pathological processes. Indeed, some abnormalities in rsEEG
JIANG ET AL.7309
FIGURE 5 Proposed model: Parallel pathology underlying shared electroencephalographic (EEG) abnormality, and cognitive dysfunction in
coronavirus disease 2019 (COVID-19) and Alzheimer’s disease/Alzheimer’s disease and related dementias (AD/ADRD). (A) Similar pathologies
between COVID-19 and ADRD. Both neural inflammation and cytokine/complement activation in COVID-19, amyloid and tau pathologies in
ADRD contribute to astrocyte over-reactivity, leading to synaptic dysfunction in neurodegenerative diseases. Astrocytes are likely a primary
target of COVID because of the close interaction with the vasculature. Evidence in Section 6suggests that astrocytes are indeed injured/activated
7310 JIANG ET AL.
by COVID infection or infection with similar viruses resulting in neuroinflammation. Parallel changes in astrocyte reactivity are found in ADRDs. In
ADRD, astrocyte reactivity is suspected to cause synapse loss and neurodegeneration. What we have learned in the ADRD field may give us clues
to how reactive astrocytes contribute to the neural morbidities seen in COVID 19, for example, astrocyte reactivity leads to the production of
Complement C3 and loss of glutamate transport, both of which can damage synapses. (B) EEG signals represent synchronized postsynaptic neural
activity and neurovascular coupling networks measured at the scalp. Common abnormalities observed include increased slow-wave EEG signals
and network hyperexcitability in EEG of both COVID-19 and ADRD patients. Although cognitive event-related potentials (e.g., searching for a car
as working memory target) exhibit consistent brainwave patterns in Young heathy individuals versus those with mild cognitive impairment (MCI),
cognitive EEG has not yet been explored in COVID-19 patients. (C) Highlights of key cognitive dysfunctions, e.g., poorer frontal executive
functions, decision-making, reduced attention focus, and short-term memory, along with slowed reaction times, reported in both COVID-19 and
MCI patients. Decades of literature documents that cognitive event-related potentials underserve various cognitive functions. Although attention,
memory, and frontal decision-making dysfunctions are common in both COVID-19 and ADRD patients, COVID-19 patients commonly report more
brain or mental fog, while spatial and visual disorientation, predominantly affecting the posterior brain regions, are more frequently observed in
dementia patients
delta, theta, and alpha rhythms have been reported in patients with
cognitive deficits due to AD or cerebrovascular diseases. The cause of
brain fog in Long COVID has not been fully understood.148,149 Similar
symptoms have been observed in people living with other brain condi-
tions (e.g., stroke, epilepsy) without previous COVID-19 infection.1,150
Several important issues are currently unresolved or understudied in
COVID-19 related EEG indicators.
7.1 Fatigue, severity of Long COVID, and
contribution to EEG signals
Fatigue, which is frequent in older adults and ADRD patients, is one
of the most consistently reported symptoms of COVID-19, both ini-
tially and after infection.10 The exact source of this persistent fatigue
is disputed, but it is proposed that fatigue suffered by those infected
with COVID-19 is related to the inflammatory nature of the virus.
Chronic fatigue is linked to many diseases, including autoimmune
diseases like rheumatoid arthritis.151 It is proposed that long-term,
low-grade inflammation maintains consistent fatigue by creating an
imbalance between cellular energy availability and behavioral energy
expenditure.152 It is contribution to EEG signals is no clear. The inflam-
matory cytokine storms that the body undergoes during infection
of COVID-19 create a consistent energy expenditure of the immune
system, causing the infected individual to experience fatigue.
Challenges regarding mixed EEG index of severity of symptoms of
Long COVID were found in aging individuals, along with severe effects
found in younger individuals in the acute phase of the virus.153,154
Intermittent frontal rhythmic dischargers were reported as an EEG
biomarker of acute SARS-CoV-2 infection in children.155 Valsamis
et al. (2023) reported more severe effects of EEG slowing in acute
COVID-19 subjects below age 70.154 The average power spectrum
was significantly enhanced in the delta band and attenuated in the
alpha and beta bands compared to aged-matched control patients in
the intensive care unit (ICU) with a negative COVID-19 polymerase
chain reaction (PCR) test.154 These observations raise several ques-
tions, including the main mechanisms contributing to CNS symptoms
in COVID-19 infection, which might be different in young and older
patients (e.g., magnitude of cytokine storm). Another debate is whether
preexisting cognitive impairment does not cause higher morbidity
rates in COVID-19 individuals, but rather those with preexistingcogni-
tive impairment are more likely to suffer from other comorbidities that
cause more severe cases of COVID-19.156
Cognitive functions and anxiety were significantly affected by an
acute omicron infection in 2023, which demonstrates its association
with nervous system symptoms (gray matter thickness/subcortical
nuclear volume). Yet, there is evidence that cognitive deficits subside
after some time in mild COVID-19 patients.157 However, measuring
associations between mild COVID-19 infection and long-term cogni-
tive deficits is challenging due to the scarcity of longitudinal data, as
infection is unpredictable and reinfection rates are high.158
7.2 EEG monitoring in COVID-19 recovery and
treatment
There are various methods of treatment for COVID-19. Many of
the remedies for COVID-19 include antiviral medications or a mon-
oclonal antibody intravenous treatment. More serious cases of indi-
viduals hospitalized with COVID-19 warrant treatment focused on
different elements of the virus, including immunotherapy drugs like
tocilizumab.52 In the case of an individual hospitalized with COVID-
19, presenting with excessive aphasia and inattentiveness, progressing
to severe encephalopathy, treatment with tocilizumab resolved neu-
rological symptoms within 2 days.59 Initial EEG after hospitalization
revealed background slowing and sharp frontal waves, while the 2-
month follow-up EEG post-treatment with tocilizumab showed no
remarkable abnormalities.59 The fact that tocilizumab disrupts the
inflammatory cytokine storm response demonstrates a potential treat-
ment for neurological symptoms of COVID-19. In the case of a 77-year-
old female presenting with neurological deficits following COVID-19
infection, intravenous methylprednisolone treatment resulted in a
gradual improvement of speech and cognition as well as a reduction of
the background slowing of the EEG signal.16 These cases of COVID-19
successfully treated using drugs offer hope.
Pharmacological treatments of COVID-19 tend to be a broad
approach to treat the illness rather than specifically targeting the cog-
nitive symptoms that result from the infection. Though not in broad
clinical practice, a proposed method of treatment to specifically target
these neurological deficits is quantitative EEG (QEEG) neurofeedback
JIANG ET AL.7311
therapy. This method of coaching individuals to influence their own
EEG frequencies has been utilized to mitigate some behavioral symp-
toms of other conditions.59 QEEG may be a useful tool to monitor
the recovery of brain functioning as it is easily applicable and repeat-
able over time, even in large cohorts of subjects with COVID-19, from
asymptomatic to critical illness. In using a treatment method that
specifically targets cognitive function, there may be greater poten-
tial to remedy neurological symptoms of COVID-19 and ameliorate
the effects of long-term brain fog. However, research is needed to
directly test this hypothesis, and EEG studies could provide objective
measurements of the integrative functional state of the brain.
7.3 Modulation of COVID-19 related abnormal
EEG by age, sex, and education
Age is a primary risk factor for both ADRD and COVID-19. Age and
sex made significant differences in the survival rates for COVID-19 in
Wuhan China. Deceased patients are typically older than recovered
patients,159 recovered patients are more likely to be male. Resting-
state EEG alpha rhythms in MCI patients are also differently affected
by age and sex, as well as education attainment.160 Posterior alpha
sources are more abnormal in male MCI patients due to AD.66,161 The
psychiatric manifestations are varied between many identifying fac-
tors, such as presence of a pre-existing psychiatric disorder, critical
illness, intensive care, and systemic inflammation.162
Fear of the disease has an interesting age effect. COVID-19 related
stress is expressed differently across sexes and is not consistent across
varied populations.163 Contrary to expectations, some evidence sug-
gest that younger individuals are more susceptible to stress, and
psychological manifestations compared to older generations.164 Sim-
ilar increases of worry and risk perception are observed in women
from low-income settings.165 In contrast, there were no noticeable sex
differences in instances of anxiety, depression, and stress.166 Proso-
cial activity and cooperation are important factors influencing the
adequate responses to the pandemic.165,167,168 Forced lockdowns left
many aging people without social structure and support, resulting in
more significant cognitive decline.169 This exemplifies the detriment of
isolation on individuals because of the COVID-19 pandemic.
The sex or gender differences in electrophysiology of COVID-19
infection or underlying mechanisms are not well investigated, how-
ever it is well known that gender distribution of cognitive symptoms
was clearly visible.170 In a study including patients with COVID-19
infection and associated neurological symptoms, post-COVID-19 syn-
drome was found to be more common in women than men, with the
most common symptoms being headache and cognitive impairment. In
addition, PTSD was more prevalent in women during the COVID-19
pandemic. In a longitudinal study on PTSD, greater Late Positive Poten-
tial (LPP) EEG response predicted PTSD, indicating that this might be
useful as a marker for prevention and treatment. To continue, assess-
ing anxiety symptoms and pretrauma LPP to emotional stimuli may
be helpful for identifying vulnerable individuals before the onset of
symptoms.171 Furthermore, prior research suggests that gender is an
important factor in hypoxia resilience. There is identifiable brain wave
suppression for both men and women with hypoxic exposure,and there
are significant differences in this suppression between genders, such as
significant decreases in theta and gamma frequency power for women
compared to men.172
Several rsEEG studies investigated the effect of the sex factor in
ADRD patients, which offers insights of future COVID-19 related EEG
studies in men and women. One study showed higher values of pos-
terior delta and theta power in females over male patients (56–79
years).173 Additionally, another study showed that in AD patients, the
male sex combined with early disease onset and increased severity of
behavioral impairment predicted mortality.174 A third study showed
that, in those patients, mortality was predicted by the combination of
the male sex with the following conditions: older age, poor cognitive
function, low rsEEG alpha and beta power density, and temporopari-
etal atrophy.175 These findings agree with previous evidence showing
that brains of women over men may benefit from a sort of neuropro-
tection related to larger normalized volumes of the hippocampus, basal
ganglia, and thalamus.176 This neuroprotective effect may depend on
both constitutional and environmental factors and might interact with
the AD-related amyloid and tau neuropathology and/or the cortical
neurodegeneration,177,178 stabilizing the rsEEG alpha source activities
in the normal elderly and prodromal AD females.160 Finally, sex differ-
ences in astrocyte and complement C3 have not yet been examined in
the context of COVID-19 EEG evaluation.
Educational level may also be related to healthcare access,179 par-
ticularly for older people who experienced difficulties in accessing
such services due to a lack of familiarity or skill with digital applica-
tions. Educational level is strictly related to the concept of cognitive
reserve, allowing those individuals with high education attainment and
whose life is typically characterized by many occasions and opportuni-
ties to learn new knowledge and exercise cognitive functions in their
job and social environment to be resilient concerning their cognitive
status along physiological and pathological aging.180,181 The neuro-
protective effect of education becomes compensatory while ADRD
neuropathological processes occur, as revealed by more resilient cog-
nitive neural systems to the neuropathological and neurodegenerative
burden.181 Previous results on rsEEG biomarkers in cognitively intact
adults showed that early AD amyloidosis contrast the beneficial effects
of cognitive reserve on neurophysiological oscillatory mechanisms
at alpha frequencies86 and connectivity between the thalamus and
visual cortical networks.182 The functional compensatory mechanisms
unrelated to brain structure alterations were observed also at the pro-
dromal stage of the disease.29 Whether education will have protective
effect for cognitive impairment due to Long COVID is not known.
7.4 Racial disparities in COVID-19 EEG
Many bio-social factors influence COVID-19 symptoms like ADRD,
for example, genetics of an individual brain, and cognitive reserve.
The effects of COVID-19 on the brain have not only been related to
general cognitive function, but also psychiatric symptoms. Both the
7312 JIANG ET AL.
neurological consequences of the virus and the stresses of solitude dur-
ing lockdown can contribute to increased cognitive decline, particularly
in those with predementia.169 Recovered individuals post-COVID-19
infection have reported worse mental health issues, including anxi-
ety, depression, and PTSD for up to 10 months after infection.40 The
continued cognitive impairment coupled with persistent psychiatric
symptoms could indicate a link between the effects of COVID-19 on
the brain in various areas of function. EEG abnormalities include high
individual alpha frequency, cortical current source density, high delta
linear lagged connectivity, and delta oscillations.
The expectation for severe psychiatric symptoms associated with
COVID-19 infection would be that the stress of hospitalization and
treatment causes higher rates of mental illness. However, this is not
always the case. In a study that compared hospitalized and home-
treated COVID-19 infected individuals, members in both groups
showed symptoms of PTSD postinfection recovery,illustrating that the
stress of ventilation and sedation in hospital treatment cannot be the
only cause of psychiatric symptoms of COVID-19.40 Suicidal thoughts
were also more prevalent in home-isolated individuals compared to
hospitalized individuals. In addition, depression screening showed that
home-isolated individuals had scores over twice as high as those who
were hospitalized, indicating severe depressive symptoms.183 Compar-
ison of home versus hospital treated individuals highlights the impact
of isolation on mental health of those infected with COVID-19.
Environmental stress associated with COVID-19 can increase multi-
level allostatic overload, which in turn increases the risk of developing
AD184 and other dementias.185 Having to face the uncertainty of the
infection in isolation contributes to fear and worsening mental state
without the support of direct medical intervention that is seen in
hospital treatment.183
To the best of our effort, we could not find any studies specifically
focusing on EEG markers of COVID-19 in Black or African American
participants. Lack of research is surprising since it is well documented
that the pandemic disproportionately affected Black or African Ameri-
can individuals. African American/Black and Hispanic populations have
been reported to experience higher rates of COVID-19 infection and
mortality.Differences in exposure risk and healthcare access could lead
to higher mortality and infection rates.186 Among the EEG research
community, which strives to gather good quality data, there is uninten-
tional bias, which can include avoidance of recruitment and retention
of Black and African American participants due to common hair types
(e.g., curlier) and hairstyles (e.g., braids).187
As stated in a recent special issue in diversity in neuroscience
research, there is growing evidence of racial disparities within the
field.188 The systemic lack of data from Black and African American
participants significantly limits the generalizability of findings. This is
especially concerning considering in the context of dementia as Black
and African American individuals are twice as likely as White indi-
viduals to have ADRD.189 Complex mechanisms can be involved. For
example, the associations between APOE4 and ADRD are weaker in
populations of African descent than in other populations.190 However,
we believe that the COVID-19 pandemic and reverberating negative
effects represent a unique opportunity for EEG researchers to commit
additional efforts to recruit and retain sizable diverse samples. We also
require novel EEG solutions that can better accommodate different
hair types. While these are being developed, gaps still exist, particularly
for dense EEG topographies (e.g., 64- and 128-channel systems).191
Neuroimaging studies have documented racial and ethnic dispari-
ties in brain health in mid- and late life. For example,a recent MRI study
found that, compared to White and Latinx adults, Black adults showed
an accelerated pattern of brain aging (i.e., cortical thickness and white
matter hyperintensity volume) in middle age.192 Similar studies using
EEG markers can significantly add to this evidence base and thus
further highlight the impacts of social, physical, and economic adversi-
ties that are often faced by individuals from excluded populations.192
Unsurprisingly, these effects are purported to be higher in popu-
lations with negative social determinants of health and who face
inequities.37,193 Unlike expensive neuroimaging methods, EEG record-
ings are affordable and can be done wirelessly and remotely,194,195
which indicates it to be a good candidate for reducing health disparity
in rural and underprivileged populations around the world.
8FUTURE DIRECTIONS AND CONCLUSION
With an aging population worldwide, the persistence of neurologi-
cal effects such as brain fog with Long COVID represents a massive
societal and biomedical challenge. In particular, the potential role of
Long COVID as a risk factor for ADRD in older populations warrants
further investigation. Growing research has focused on elucidating
common neurophysiological substrates underlying vigilance and cog-
nitive symptoms in Long COVID and ADRD risk. EEG is ideal to address
these questions, as it is cost-effective, minimally invasive, and widely
accessible.
9FUTURE DIRECTIONS
Future studies should capture both similarities and differences in
the pathophysiology of cerebral oscillations in COVID-19 and ADRD.
There are multiple unresolved issues that are important to explore
including: (1) Determine the value of EEG monitoring of COVID-
19 severity and prediction of long-term consequences and cognitive
decline risk. (2) Investigate EEG measurements as proxy for synap-
tic dysfunction due to astrocyte-microglia reactivity and pathology. (3)
Establish specific EEG features closely associated with COVID-19 dis-
ease and cognitive dysfunctions. (4) Identify common EEG features
in both COVID-19 and ADRD. (5) Evaluate EEG network features as
neural biomarkers for clinical trials of pharmacological and nonphar-
macological interventions in COVID-19 patients. (6) Assess variations
of COVID-19 related EEG indicators in diverse populations.
10 CONCLUSION
In this review, we try to communicate three take-home messages. First,
EEG abnormalities have potential for identifying neurological compli-
cations and assisting clinical assessment and cognitive decline risk in
JIANG ET AL.7313
Long COVID patients. Second, identifying overlapping pathophysiol-
ogy, such as neuroinflammatory mechanisms and astrocyte reactivity,
will advance our understanding of critical pathways of both ADRD and
COVID-19 underlying cognitive and functional decline. Third, what we
have learned in the neurophysiology and ADRD field provides insights
as to how reactive astrocytes may contribute to the neurovascular
comorbidities seen in COVID-19. Also, it elucidates research questions
regarding cognitive EEG and MCI in Long COVID that have not yet
been adequately investigated.
In conclusion, some individuals with COVID-19 display abnormal
intrinsic brain activity and cognitive impairments that resemble those
seen in neurodegenerative diseases, particularly ADRD. The evidence
presented indicates that COVID-19 and ADRD pathologies share com-
mon impacts on synaptic and neurovascular dysfunctions involving
astrocyte reactivity and neuroinflammation. Furthermore, cognitive
symptoms due to COVID-19 are underpinned by neurophysiological
abnormalities typically seen in ADRD, which can be detected by routine
EEG exams.
ACKNOWLEDGMENTS
This manuscript was facilitated by the Alzheimer’s Association Inter-
national Society to Advance Alzheimer’s Research and Treatment
(ISTAART), through the Electrophysiology Professional Interest
Area (EPIA). The views and opinions expressed by authors in this
publication represent those of the authors and do not necessarily
reflect those of the EPIA membership, ISTAART or the Alzheimer’s
Association. The following authors serve as current or past members
of the EPIA executive committee: Drs. Claudio Babiloni, Mihály Hajós,
Bahar Güntekin, Görsev Yener, Xianghong Arakaki, Agustin Ibanez,
Francesca R Farina, Susanna Lopez, and Yang Jiang. EPIA is committed
to (1) exploiting EEG biomarkers for improving the understanding
of neurophysiological mechanisms underlying Alzheimer’s disease
and age-related brain disorders at various spatial and temporal
scales and (2) promoting clinical applications. The authors thank
Thomas Dolan for medical illustration of Figure 5and Mariena Pas-
sidomo for proof-reading and editing assistance. The review was
partially supported by United States National Institute of Health
(NIH), National Institute of Aging (NIA) Funding P01AG078116,
P30AG072946, R01AG063857, R01AG057234, R01AG054484,
R56AG060608, and 1R21AG046637; United States Department of
Veterans Affairs Funding 5I21RX003173; Alzheimer’s Association
grants SG-20-725707, AAR-F2-1848281, and HAT-07-60437; by
Funding from ANID/FONDECYT Regular (1210195 and 1210176
and 1220995); ANID/FONDAP/15150012; ANID/PIA/ANILLOS
ACT210096; FONDEF ID20I10152, ID22I10029; ANID/FONDAP
15150012; Takeda CW2680521 and the MULTI-PARTNER CON-
SORTIUM TO EXPAND DEMENTIA RESEARCH IN LATIN AMERICA.
Rainwater Charitable foundation – Tau Consortium, and Global Brain
Health Institute); HORIZON 2021, H2021-MSCA-DN-2021 (Marie
Skłodowska-Curie Doctoral Networks) grant 101071485; PNRR-
MAD-2022-12376415 and Italian Ministry of University, Scientific
and Technological Research funding 2010SH7H3F. The contents
of this publication are solely the responsibility of the authors and
do not represent the official views of these Institutions. The fun-
ders played no role in preparation of the manuscript or decision to
publish.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest. Author disclosures are
available in the Supporting information.
ORCID
Yang J ia ng https://orcid.org/0000-0003-4589-0097
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