Parallel electrophysiological abnormalities due to COVID-19 infection and to Alzheimer's disease and related dementia

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 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. 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 neurological 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 typically 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 elucidates research questions regarding cognitive EEG and mild cognitive impairment in Long COVID that have not yet been adequately investigated.

Keywords: ACE2; Alzheimer's disease and related dementia; COVID‐19; Long COVID; SARS‐CoV‐2; astrocytes; background frequency; brain fog; coronavirus and EEG; encephalopathy; inflammatory cytokine storm; long COVID; resting EEG.

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

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)

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.

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.

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 6 suggests that astrocytes are indeed injured/activated 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