Alterations in brain functioning, especially in regions associated with cognition, can result from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and are predicted to result in various psychiatric diseases. Recent studies have shown that SARS-CoV-2 infection and coronavirus disease 2019 (COVID-19) can directly or indirectly affect the central nervous system (CNS). Therefore, diseases associated with sequelae of COVID-19, or ‘long COVID’, also include serious long-term mental and cognitive changes, including the condition recently termed ‘brain fog’. Hypoxia in the microenvironment of select brain areas may benefit the reproductive capacity of the virus. It is possible that in areas of cerebral hypoxia, neuronal cell energy metabolism may become compromised after integration of the viral genome, resulting in mitochondrial dysfunction. Because of their need for constant high metabolism, cerebral tissues require an immediate and constant supply of oxygen. In hypoxic conditions, neurons with the highest oxygen demand become dysfunctional. The resulting cognitive impairment benefits viral spread, as infected individuals exhibit behaviors that reduce protection against infection. The effects of compromised mitochondrial function may also be an evolutionary advantage for SARS-CoV-2 in terms of host interaction. A high viral load in patients with COVID-19 that involves the CNS results in the compromise of neurons with high-level energy metabolism. Therefore, we propose that selective neuronal mitochondrial targeting in SARS-CoV-2 infection affects cognitive processes to induce ‘brain fog’ and results in behavioral changes that favor viral propagation. Cognitive changes associated with COVID-19 will have increasing significance for patient diagnosis, prognosis, and long-term care.

Persistent comorbidities occur in patients who initially recover from acute coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ‘Long COVID’ involves the central nervous system (CNS), resulting in neuropsychiatric symptoms and signs, including cognitive impairment or ‘brain fog’ and chronic fatigue syndrome. There are similarities in these persistent complications between SARS-CoV-2 and the Ebola, Zika, and influenza A viruses. Normal CNS neuronal mitochondrial function requires high oxygen levels for oxidative phosphorylation and ATP production. Recent studies have shown that the SARS-CoV-2 virus can hijack mitochondrial function. Persistent changes in cognitive functioning have also been reported with other viral infections. SARS-CoV-2 infection may result in long-term effects on immune processes within the CNS by causing microglial dysfunction. This short opinion aims to discuss the hypothesis that the pathogenesis of long-term neuropsychiatric COVID-19 involves microglia, mitochondria, and persistent neuroinflammation.

Blood-brain barrier (BBB) permeability can cause neuroinflammation and cognitive impairment. Caveolin-1 (Cav-1) critically regulates BBB permeability, but its influence on the BBB and consequent neurological outcomes in respiratory viral infections is unknown. We used Cav-1-deficient mice with genetically encoded fluorescent endothelial tight junctions to determine how Cav-1 influences BBB permeability, neuroinflammation, and cognitive impairment following respiratory infection with mouse adapted (MA10) SARS-CoV-2 as a model for COVID-19. We found that SARS-CoV-2 infection increased brain endothelial Cav-1 and increased transcellular BBB permeability to albumin, decreased paracellular BBB Claudin-5 tight junctions, and caused T lymphocyte infiltration in the hippocampus, a region important for learning and memory. Concordantly, we observed learning and memory deficits in SARS-CoV-2 infected mice. Importantly, genetic deficiency in Cav-1 attenuated transcellular BBB permeability and paracellular BBB tight junction losses, T lymphocyte infiltration, and gliosis induced by SARS-CoV-2 infection. Moreover, Cav-1 KO mice were protected from the learning and memory deficits caused by SARS-CoV-2 infection. These results establish the contribution of Cav-1 to BBB permeability and behavioral dysfunction induced by SARS-CoV-2 neuroinflammation.

The recent surge of COVID-19 cases has raised concerns about its potential long-term effects on cognitive function. This review explores the growing body of research investigating the link between COVID-19 infection and cognitive impairment. Studies employing observational, longitudinal, and case–control designs reveal a concerning prevalence of cognitive impairment in survivors, affecting domains like attention, memory, executive function, and processing speed. The persistence of these deficits for months after the initial infection highlights the potential for long-term consequences. While the precise mechanisms remain under investigation, potential contributing factors include neuroinflammation, hypoxia, and psychological effects. Limitations within the current research landscape necessitate further investigation into the long-term trajectory of cognitive decline, the potential for intervention and recovery, and the role of vaccination in mitigating these effects. Understanding the multifaceted nature of this issue is crucial for developing effective strategies to ensure optimal cognitive health outcomes for COVID-19 survivors.

Cognitive changes associated with PASC may not be uniform across populations. We conducted individual-level pooled analyses and meta-analyses of cognitive assessments from eight prospective cohorts, comprising 2,105 patients and 1,432 controls from Argentina, Canada, Chile, Greece, India, Italy, Russia, and the UK. The meta-analysis found no differences by country of origin. The profile and severity of cognitive impairment varied by age, with mild attentional impairment observed in young and middle-aged adults, but memory, language, and executive function impairment in older adults. The risk of moderate to severe impairment doubled in older adults. Moderately severe or severe impairment was significantly associated with infection diagnoses (chi-square = 26.57, p ≤ 0.0001) and the severity of anosmia (chi-square = 31.81, p ≤ 0.0001). We found distinct age-related phenotypes of cognitive impairment in patients recovering from COVID-19. We identified the severity of acute illness and the presence of olfactory dysfunction as the primary predictors of dementia-like impairment in older adults.

Numerous studies report cognitive impairment in COVID-19 patients from the acute to post-acute phases, linked to blood inflammation affecting blood-brain barrier (BBB) permeability and causing leakage of glial and neuronal proteins. However, a clear classification of these cognitive deficits and molecular blood events over time is still lacking. This narrative review summarizes the neuropsychological consequences of COVID-19 and evidence of altered cytokines and BBB disruption as potential mediators of cognitive impairment across post-infection phases. Post-COVID-19 cognitive dysfunction appears to follow a temporal course, evolving from acute focal deficits in attention, working memory, and executive function to more persistent multidomain impairments. We reviewed key cytokines released into the blood during COVID-19 infection, including antiviral (IFNγ, CXCL1, CXCL10), inflammatory (IL-1β, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, GM-CSF, TNFα), and monocyte chemoattractants (MCP1/CCL2, MCP3/CCL7, MIP-1α/CCL3, GM-CSF, G-CSF). This analysis shows that several inflammatory and viral cytokines remain elevated beyond the acute phase and are associated with cognitive deficits, including IL-6, IL-13, IL-8, IL-1β, TNFα, and MCP1 in long-term post-COVID-19 patients. In addition, we examined studies analyzing changes over time in neurovascular unit proteins as biomarkers of BBB disruption, including extracellular matrix proteins (PPIA, MMP-9), astrocytes (S100β, GFAP), and neurons (NFL). These proteins are elevated in acute COVID-19 but generally return to control levels within six months, suggesting BBB restoration. However, in patients followed for over a year, BBB disruption persists only in those with cognitive impairment and is associated with systemic inflammation, with TGFβ as a related biomarker. Although cognitive sequelae can persist for over 12 months after SARS-CoV-2 infection, further studies are needed to investigate long-term neurocognitive outcomes and their link to sustained proinflammatory cytokine elevation and brain impact.

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