In late 2019, the global landscape was forever altered with the emergence of a novel coronavirus variant, SARS-CoV-2, which swiftly gave rise to a severe acute respiratory syndrome, capturing the world’s attention as an unprecedented global health crisis [1,2].
Initially recognized as a respiratory pathogen primarily transmitted through respiratory droplets, SARS-CoV-2’s impact transcended the confines of the lungs, showcasing its ability to affect various organs including the brain, heart, kidneys, liver, skeletal muscle, and skin .
A comprehensive analysis involving over 24,000 COVID-19 patients highlighted fever, cough, fatigue, and hyposmia as the prevailing symptoms . Notably, among the distinctive symptoms of COVID-19, impaired olfaction and gustation surfaced in 85% of patients, while a significant proportion—36.4%—exhibited neurological irregularities like dizziness, headaches, and altered consciousness during their hospitalization .
These clinical observations found support in research involving murine models, revealing the potential of coronaviruses to infiltrate the central nervous system (CNS) , thus validating the neurological symptoms reported.
A lingering impact of the virus was recognized as cognitive dysfunction, echoing beyond the acute phase of the infection. In contrast to the hallmark neurological effects like impaired memory, decision-making, and concentration, a subtler yet pervasive array of cognitive and behavioral deficits emerged—an enigmatic “brain fog” or “mental clouding” .
Acknowledgment of these persistent symptoms prompted the formulation of classification terminologies such as “ongoing symptomatic COVID-19” for manifestations lasting 4 to 12 weeks post-acute onset, and “post-COVID-19 syndrome” for those extending beyond 12 weeks .
The intricacies of these cognitive impairments brought attention to the role of inflammation, substantiated by compelling evidence from cohort studies linking continued systemic inflammation during SARS-CoV-2 infection with subsequent cognitive decline and even hippocampal atrophy.
The influence of inflammation is underscored by the virus’s ability to incite the release of pro-inflammatory cytokines, initiating cascading signaling pathways that culminate in compromised tight junction proteins and a compromised blood-brain barrier (BBB). The breached BBB paves the way for immune cell infiltration and other particles, thereby exacerbating brain injuries [10,11].
This review delves into the realm of cognitive decline induced by COVID-19, with a specific focus on the potential contribution of vascular dysfunction. By examining the intricate interplay between inflammation, the blood-brain barrier, and cognitive deficits, we aim to unravel the mechanisms underpinning the cognitive impairments experienced by COVID-19 patients.
Long-Term Neurological and Cognitive Dysfunction Following COVID-19
Throughout the course of the COVID-19 pandemic, a concerning trend of cognitive abnormalities has emerged as a significant consequence of the disease. The implications of long-term cognitive deficits following COVID-19 have garnered increasing attention due to their prevalence and potential impact on affected individuals. These cognitive impairments, collectively referred to as “Long COVID,” encompass a range of symptoms including memory lapses, diminished concentration, language comprehension difficulties, executive function challenges, and persistent fatigue . Strikingly, these cognitive and psychiatric indications can persist and intensify for months after the initial infection, imposing a notable burden on individuals’ quality of life and daily functioning .
In exploring the underlying mechanisms contributing to these enduring cognitive impairments, several avenues of research have been pursued. One prominent area of investigation is centered around the disruption of the blood-brain barrier (BBB). The integrity of this barrier, which typically shields the brain from harmful substances circulating in the blood, appears compromised in COVID-19 patients, potentially allowing inflammatory molecules to infiltrate the brain tissue. This breach contributes to a state of neuro-inflammation, characterized by an abnormal activation of immune responses within the central nervous system. Synaptic dysfunction, disturbances in the release of vital neurotransmitters, and even neuronal loss have all been identified as potential outcomes of this inflammatory cascade, ultimately leading to cognitive deficits .
The shift in focus from acute clinical outcomes to the long-term repercussions of COVID-19 is of paramount importance for both clinical practitioners and public health officials. No longer limited to the immediate mortality rates or short-term clinical effects observed in hospitalized patients, the attention has broadened to encompass the extensive array of lingering adverse outcomes that persist beyond recovery and hospital discharge. This paradigm shift has been fueled by an accumulating body of evidence that highlights the persistence of neurological and cognitive symptoms in individuals who have previously contracted the SARS-CoV-2 virus.
It is particularly alarming that individuals who had no prior history of neurological issues have begun to exhibit signs of neurodegenerative diseases subsequent to a COVID-19 infection. Startling statistics indicate that as many as 15% of COVID-19 cases develop neurological symptoms for the first time within three months of their infection. These symptoms encompass a range of conditions, such as polyneuro/myopathy, Guillain-Barré syndrome, mild encephalopathy, parkinsonism, and ischemic stroke . Furthermore, even non-hospitalized individuals who recover from COVID-19 exhibit persistent neuro-cognitive symptoms, with working memory and executive function notably affected . Notably, these cognitive impairments have also been observed in patients who experienced only mild COVID-19 symptoms, underscoring the far-reaching consequences of the disease .
The cognitive landscape of post-COVID-19 individuals is characterized by a spectrum of deficits that span various cognitive domains. Impairments in episodic and working memory, attention, concentration, executive function, and consciousness are frequently observed. These deficits are seen to be persistent, casting a shadow over individuals’ cognitive capacities even after the resolution of the acute phase of the illness . A particularly illustrative case report highlights the progression of disease, starting from mild symptoms such as myalgia and memory issues, to severe outcomes like weakness, sensory loss, and profound cognitive decline, culminating in neuroimaging-confirmed ischemic infarction .
While certain symptoms appear more prevalent among specific demographic groups, such as women experiencing fatigue, memory, and concentration difficulties, it’s essential to recognize that cognitive deficits are not confined to any one subgroup. Even individuals with a history of mild symptomatic COVID-19 infections have been found to face more than an 18-fold increased risk of cognitive deficits compared to those without clinical manifestations of the disease . Furthermore, the severity of COVID-19 illness has been shown to directly impact the extent of cognitive impairment, with hospitalized and severely affected patients at higher risk for enduring cognitive and neurological dysfunction .
In conclusion, the long-term neurological and cognitive sequelae of COVID-19 pose a substantial challenge to the affected individuals, their families, and society at large. As we deepen our understanding of the mechanisms underlying these deficits, it becomes increasingly evident that these issues extend beyond acute clinical concerns. The complex interplay of neuro-inflammation, BBB disruption, and synaptic dysfunction underscores the need for targeted therapeutic approaches that can mitigate the cognitive impact of COVID-19 and enhance the prospects for a meaningful recovery.
Vascular Inflammation and Blood-Brain Barrier Disruption in COVID-19
The ongoing battle against the COVID-19 pandemic has unveiled the virus’s multifaceted impact on the human body, stretching beyond respiratory symptoms to encompass various organ systems. One intriguing aspect that has come to light is the intricate interplay between the virus, vascular inflammation, and the integrity of the blood-brain barrier (BBB). Recent research has shed light on how SARS-CoV-2, the virus responsible for COVID-19, interacts with the central nervous system through cranial nerves and the BBB, ultimately influencing neurological function.
The BBB, a complex physiological structure primarily composed of brain endothelial cells connected by tight junction (TJ) proteins, plays a pivotal role in maintaining the sanctity of the brain’s microenvironment. This barrier acts as a selective gateway between the circulating blood and the brain parenchyma, preventing the free passage of molecules and pathogens. To breach this barrier, SARS-CoV-2 must navigate the intricate network of brain endothelial cells, pericytes, astrocytes, neural cells, and microglia, collectively forming the neurovascular units (NVUs). These components together create a dynamic fortress that protects the brain from the intrusion of foreign entities.
In normal circumstances, the TJ proteins, including ZO scaffolding proteins, claudin-5, and occludin, along with junctional adhesion molecules, create a formidable defense, tightly regulating the passage of molecules. However, studies have shown that SARS-CoV-2’s impact goes beyond mere neuroinvasion; it can disrupt the integrity of the BBB, leading to potential penetration of the virus into the brain. Hyper-inflammatory responses triggered by COVID-19 infection are strongly implicated in compromising BBB integrity. It has been observed that human brain microvascular endothelial cells exhibit altered expression of TJ proteins, coupled with increased permeability of the BBB following SARS-CoV-2 infection.
One key player in this disruption is the surge of pro-inflammatory cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), in response to the viral infection. These cytokines have been found to directly impact the functionality of TJ proteins, causing their alteration and subsequent weakening of the BBB. Notably, IL-1β has been implicated in promoting the disruption of TJ proteins through the upregulation of matrix metalloproteinase-9 (MMP-9), a process mediated by the activation of extracellular signal-regulated kinases. The cytokine-induced disturbance of various junctional proteins, including VE-cadherin, ZO-1, β-catenin, and gap junction, creates gaps in the BBB, allowing the passage of inflammatory and immune cells.
The compromised BBB exacerbates the infiltration of immune cells and viral particles into the central nervous system (CNS), triggering a cascade of events. Proinflammatory cytokines within the CNS activate additional immune responses, further intensifying the inflammatory milieu. Furthermore, vascular endothelial growth factor (VEGF) released by astrocytes as a result of this inflammatory response contributes to the disruption of TJ proteins within brain capillary endothelial cells, further destabilizing the BBB.
Understanding the intricate interplay between SARS-CoV-2, vascular inflammation, and BBB disruption is vital for comprehending the potential neurological consequences of COVID-19. As research advances, targeting these mechanisms could offer new avenues for therapeutic interventions aimed at preserving BBB integrity and mitigating the neurological impact of the virus. Ultimately, unveiling the mysteries of how the virus interacts with the brain could provide critical insights not only for COVID-19 but also for other neuroinflammatory conditions.
Vascular Dysfunction, Brain Inflammation, and Cognitive Impairment in COVID-19
The intricate relationship between vascular function, brain inflammation, and cognitive impairment has become a significant area of interest in the context of COVID-19. The blood-brain barrier (BBB), a protective barrier formed by endothelial cells lining capillaries in the circulatory system, typically prevents the entry of viruses like SARS-CoV-2 into the brain parenchyma.
However, in the case of SARS-CoV-2 infection, a hyper-inflammatory response induced by the virus leads to the dysfunction of critical BBB components such as VE-cadherin, ZO-1, and β-catenin. This disruption results in increased permeability of the BBB, facilitating the penetration of the virus into cerebral tissue . Once the virus gains access to the brain, it triggers neuro-inflammation by activating microglia and macrophages. This activation leads to the release of local pro-inflammatory cytokines, exacerbating the overall inflammatory response.
Notably, the integrity of the BBB is compromised due to the overwhelming presence of pro-inflammatory cytokines in the circulation. This vulnerability makes the brain susceptible to threats such as ischemia, hypoxia, thrombosis, and invasion by various pathogens [104,105]. Emerging research suggests a correlation between the extent of neurological dysfunction, BBB impairment, and the severity of cognitive deficits in COVID-19 patients. Studies indicate that BBB permeability is disrupted in a significant percentage of COVID-19 cases with neurological manifestations . This suggests that SARS-CoV-2 directly contributes to BBB dysfunction.
Intriguingly, studies conducted on diabetic rats have shed light on the relationship between BBB integrity and cognitive decline. Elevated expression of pro-inflammatory cytokines like TNF-α and IL-6 triggers BBB disruption in the brain, ultimately leading to cognitive impairment . Furthermore, research suggests that the breakdown of the BBB plays a role in APOE4-associated cognitive decline, independent of Alzheimer’s disease pathology .
A distinctive feature of SARS-CoV-2 infection is its contribution to the accumulation of neurodegenerative markers like β-amyloid (Aβ) plaques and phosphorylated tau. This accumulation is linked to increased neuro-inflammation, alterations in brain structure, and abnormal aggregation of these neurodegenerative factors, all of which heighten the risk of cognitive deficits in COVID-19 patients [110,111]. Microglia, the innate immune cells of the central nervous system (CNS), play a crucial role in neurodegeneration. Activated microglia release pro-inflammatory cytokines and reactive species, contributing to neural damage progression [112,113].
Furthermore, the viral spike protein’s interaction with ACE2 receptors, which regulate blood pressure, can disrupt the angiotensin system, affecting normal blood pressure control. Oxygen deprivation in brain tissue due to primary pneumonia and pulmonary infection contributes to hypoxic conditions and metabolic disturbances, further impacting cognitive function .
The cytokine storm phenomenon, characterized by elevated levels of pro-inflammatory cytokines, including IL-2, IL-6, IL-1β, and TNF, is associated with acute respiratory distress syndrome (ARDS) in severe COVID-19 cases. Notably, these cytokines, especially IL-6, TNF-α, and IL-1β, have been shown to have a significant impact on working memory and attention, processes often impaired in cases of delirium. This underscores the role of these cytokines in COVID-19-associated cognitive impairments .
Both acute and chronic cognitive symptoms of COVID-19 are attributed to prolonged neuro-inflammation and persistent hypoxia . Chemokines, small molecules known for regulating leukocyte attraction and modulating immune responses, also play a crucial role in CNS development and function. CCL11, for instance, promotes angiogenesis, cell migration, and oxidative stress, and elevated levels have been observed in long COVID cases with cognitive symptoms, as well as in conditions like Alzheimer’s disease and schizophrenia [123,124,126,127].
A comprehensive study using a mouse model of mild SARS-CoV-2 infection has revealed persistent white matter microglial reactivity and elevated CCL11 levels. This phenomenon was also observed in human brain tissue from SARS-CoV-2-infected individuals with cognitive impairments. The study links prolonged elevated CCL11 levels with astrocyte-mediated microglial activation and consequent cognitive dysfunction in COVID-19 patients [128,129]. Furthermore, cerebral hypoxia has been suggested to contribute to the cognitive and degenerative changes associated with conditions like Alzheimer’s disease .
In conclusion, the intricate interplay between vascular dysfunction, brain inflammation, and cognitive impairment in COVID-19 highlights the multifaceted nature of the disease’s impact on the central nervous system. Exploring these mechanisms is vital for a comprehensive understanding of COVID-19-associated cognitive deficits and the development of targeted therapeutic strategies.
reference link : https://www.mdpi.com/2079-7737/12/8/1106