[Paper] The Impact of COVID-19 on Cognition: Looking beyond the Short-Term Perspective.

[Paper] The Impact of COVID-19 on Cognition: Looking beyond the Short-Term Perspective.


COVID-19 is primarily a respiratory disease, but up to two-thirds of hospitalized patients show evidence of central nervous system CNS injury, primarily ischemic, in some cases hemorrhagic, and occasionally encephalitis. It is unknown how much of the ischemic damage is mediated by direct or inflammatory effects of the virus on the CNS vasculature and how much is secondary to extracranial cardiopulmonary disease. Limited data suggest that the causative SARS-CoV-2 virus may enter the CNS via the nasal mucosa and olfactory fibers or by hematogenous spread, potentially infecting endothelial cells, pericytes, and possibly neurons. Extracranially, SARS-CoV-2 targets endothelial and pericyte cells and is associated with endothelial cell dysfunction, vascular leakage
out, and immune activation, sometimes leading to disseminated intravascular coagulation. Whether endothelial and pericyte cells of the cerebral vasculature are similarly targeted remains to be confirmed. Several aspects of COVID-19 are likely to affect cognition. Cerebral white matter is particularly vulnerable to ischemic damage in COVID-19 and is also critical for cognitive function. Evidence is accumulating that cerebral hypoperfusion accelerates amyloid-β (Aβ) accumulation and is associated with tau and TDP43 pathology, and by inducing α-synuclein phosphorylation at serine-129, ischemia also may increase the risk of developing Lewy body disease. Current therapies for COVID-19 are, of course, focused on aiding respiratory function, preventing thrombosis, and reducing immune activity. Angiotensin-converting enzyme (ACE)-2 is the receptor for SARS-CoV-2, and ACE inhibitors and angiotensin receptor blockers are predicted to increase ACE-2 expression. Therefore, there was initial concern that their use might exacerbate COVID-19. A recent meta-analysis suggests that these drugs are prophylactic instead. This is presumably because SARS-CoV-2 entry depletes ACE-2, tipping the balance toward angiotensin II-ACE-1-mediated classical RAS activation, exacerbating hypoperfusion and promoting inflammation. APOEε4 individuals, who appear to be at high risk for COVID-19, also appear to have the lowest ACE activity; COVID-19 is likely to leave an unexpected legacy of long-term neurological complications in a significant number of survivors; cognitive tracking of COVID 19 patients is particularly important during acute illness, as cerebrovascular and neurological complications during acute illness.

Keywords:. COVID-19, SARS-CoV-2, stroke, white matter ischemia, angiotensin converting enzyme-2, angiotensin variant
Conversion enzyme inhibitors, angiotensin receptor blockers, cognitive impairment, dementia


COVID-19, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is primarily a respiratory illness but has the ability to damage other organs, including the brain. Like the severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MER) viruses, SARS-CoV-2 targets the brain, and a growing number of case reports and cohort studies have shown significant neurological deficits in COVID-19 patients. Central nervous system CNS disorders, including nonspecific encephalopathy (headache, confusion, disorientation), were first reported in 53 (25%) of 214 hospitalized patients in Wuhan, China. More recent studies in Europe have reported higher rates of CNS involvement, 69% of 58 inpatients in a French study and 31% of 125 patients with altered mental status including psychosis and neurocognitive changes in a recent UK study。 A recent report describes a gravity-disorder syndrome in 33% of 43 discharged patients, consisting of inattention, disorientation, or unorganized movements in response to commands. In addition, neuroradiological evidence of microstructural damage and disruption of functional brain integrity at 3-month follow-up in recovered COVID-19 patients indicates potential long-term neurological consequences in severely ill COVID-19 patients. Acute cerebrovascular disease (CVD), typically manifesting as ischemic stroke but sometimes as intracerebral hemorrhage (ICH), emerges as an important clinical feature in COVID-19 (reviewed). There have been several case reports of encephalitis with brainstem involvement. CNS involvement with neurologic manifestations is more frequent in older, more severely ill COVID-19 patients. Based on the lowest prevalence of neurological complications in SARS and MERS, Elul et al. An estimated 4.8 million of the COVID-19 cases reported in 1805-9671 developed CNS complications. Human coronaviruses are known to target the central nervous system and cause damage through direct neurotoxicity or activation of host immune responses. The propensity of SARS-CoV2 to cause cerebrovascular damage not only through its cumulative destructive effects of multifocal cerebral ischemia or hemorrhage, but also through chronic post-infection complications of CVD, including endothelial and blood-brain barrier (BBB) dysfunction in the brain and up-regulation of inflammation-inducing cytokines, which significantly increases the risk of chronic brain injury. Neurodegeneration associated with long-term cognitive decline and hippocampal atrophy has previously been reported to be complicated by systemic inflammation associated with severe sepsis. Acute respiratory distress syndrome (ARDS), a common clinical presentation in COVID-19 patients, has also been associated with cognitive decline and neurodegeneration. Long-term follow-up of COVID-19 patients, including detailed cognitive assessment, may be important in determining the extent and prevalence of long-term neurological and psychiatric consequences of COVID-19, especially in patients who develop cerebrovascular and neurological complications during acute illness. This review discusses the pathophysiological processes and risk factors shared by COVID-19 and dementia, with a particular focus on the role of cerebrovascular disease and the involvement of the renin-angiotensin system (RAS) (Table 1). We will examine whether SARSCoV-2 infection may increase the risk of developing dementia later in life, especially in patients with underlying cerebrovascular disease and high-risk comorbidities such as diabetes and hypertension.

Cerebrovascular disease (CVD) is a severe COVIDCommonly seen in -19

Unlike SARS and MERS, COVID-19 patients are at considerable risk of developing acute CVD.
In a Spanish cohort of patients with COVID-19, in which previous studies have shown that CVD affects 2~6% of hospitalized patients, 23 of 1683 (1.4%) developed CVD, 74% of 23 with cerebral ischemia and 23% with ICH. A much higher incidence of CVD has been reported in COVID-19 patients with neurological complications. Acute CVD was diagnosed in 77% of 56 patients admitted to an Italian neurological ward. In a recent UK-wide survey of 153 COVID-19 cases with neurological and/or psychiatric disorders, the majority of patients (62% of 125) had cerebrovascular events, compared to 31% with brain damage, 74% of CVD patients had ischemic stroke, 12% had ICH, and 1% had CNS vasculitis CNS vasculitis. A common theme in most of these studies is the predominance of CVD in older patients with more severe disease and comorbidities, including hypertension, diabetes, and underlying cerebrovascular disease. However, macrovascular stroke has also been reported in young adults with COVID-19. The pathophysiology of CVD in COVID-19 is not yet fully understood (Figure 1). Inflammation-induced disseminated intravascular coagulation syndrome (DIC), often complicated by pulmonary embolism, is likely a major contributor to most acute CVD events in COVID-19 with a high proportion of patients having neurovascular complications, especially reported in young healthy adults COVID-19 has been reported in young healthy adults in particular. A recent review highlighted a number of pathways, including focal endothelial cell dysfunction, vascular leakage, and unregulated immune activation, that contribute to DIC formation in ARDS in COVID-19 patients. Activation of the kallikrein-bradykinin system leads to decreased blood flow, leukocyte mobilization, upregulation of adhesion molecules mediating platelet and neutrophil activation, and increased inflammation and immune surveillance, which may contribute to vascular injury (and lung injury) in COVID-19 patients. SARSCoV-2 has also been shown to target and infect endothelial cells in the vascular bed of multiple tissues, but whether endothelial cells in the cerebral vasculature are similarly targeted remains to be confirmed. Most studies to date have implicated vascular dysfunction and ischemic damage in the major neurological complications associated with COVID-19. Autopsy neuropathology of 18 COVID-19 cases revealed that all had acute hypoxic ischemic brain injury affecting the cerebrum and cerebellum, with rare foci of perivascular inflammation in the brains of two patients, but no convincing evidence of the virus within the CNS. MRI of autopsy brains of deceased COVID-19 patients within 24 hours of death revealed white matter changes, including hemorrhagic foci, in two cases and evidence of posterior reversible encephalopathy syndrome in another. Plasma markers of neuronal and stellate cell damage (neurofilament light chain protein and glial fibrillary acidic protein) were elevated in COVID-19 patients and were associated with disease severity. The authors concluded that further studies are needed to assess the relationship between ischemic brain damage and inflammatory processes. The major unresolved questions are how much damage is mediated by the direct effects of the virus on the parenchyma or vasculature of the CNS (damage that is expected to persist after the virus is removed from the CNS), how much indirect CNS vascular damage is mediated by immune activation, and how much hypoxic-ischemic damage is secondary to extracranial effects of the virus on the respiratory and cardiovascular systems.

Table 1: Pathophysiological processes contributing to increased risk of chronic neurological diseases, including dementia, in COVID-19 patients.

Figure 1: Mechanisms of Cerebrovascular Injury in COVID-19

Neuronal Process = neurite, Exudate = exudate, Thrombus = thrombus, Pericyte = pericyte , Endothelium = endothelium
Astrocyte Process = Astrocyte Process

SARS-CoV-2 infects the human brain

SARS-CoV-2 antigen and RNA have been detected in brain tissue in postmortem studies in humans, primarily in the medulla and lower cranial nerves. SARS-CoV-2 was detected in cerebrospinal fluid from patients with viral encephalitis and was observed in nerve and capillary endothelial cells in COVID-19 brain tissue at autopsy. These findings need to be confirmed in further studies, especially considering the high Ct values used for PCR detection of viral RNA and the difficulty of electron microscopic interpretation of virus-like particles. Retrograde axonal transport through the olfactory bulb with olfactory loss is a potential pathway for neural invasion, but it is likely that the cerebral vasculature plays a more important role in viral entry into the CNS. The major SARS-CoV-2 receptor, ACE-2, is highly expressed by endothelial and pericytes throughout the body, and analysis of publicly available databases indicates that ACE-2 is also expressed in the brain. Despite the apparently low levels of ACE-2 mRNA in the brain, SARSCov-2 infects induced pluripotent stem cell-derived human neural stem and progenitor cells, neurospheres, and cortical neurons with brain organelles (all of which express ACE-2). These data suggest that mRNA levels do not necessarily reflect ACE-2 protein or enzyme activity in the brain, but point out that some of the information is published only on preprint servers, and peer review may lead to revised conclusions. We and others have immunohistochemically detected ACE-2 within the cerebral vasculature in human postmortem brains, and a study previously published by the Betsholtz lab indicates that ACE-2 is also abundant in brain pericytes. In addition to ACE-2, other docking receptors for SARS-CoV-2 have been identified, including bacigin (BSG, CD147) and neuropilin (NRP1), which are highly expressed in endothelial and pericytes. These receptors may play important roles in the mechanisms of viral entry and disease pathogenesis, either in parallel with ACE2 or separately. Brain endothelial activation in a range of disease states, including AD, is associated with increased expression of integrins and selectins involved in the adhesion, mooring, and passage of immune cells through the BBB. Translated with (free version)

This leads to infiltration of brain tissue by immune cells, including neutrophils, monocytes, and lymphocytes, contributing to the etiology of this disease. In view of endothelial activation in COVID-19 and inflammatory cell infiltration in lungs and other tissues, cerebral endothelial activation and infiltration by immune cells may also contribute to neuropathy in many patients, although this also remains unclear.

Pericytes are wall cells located within the basement membrane of microvessels that communicate with endothelial cells to maintain the integrity of the BBB and regulate essential vascular functions: blood flow and neurovascular conjugation, endothelial cell transcytosis, and angiogenesis. Transcriptional analysis of mouse heart and brain indicates that pericytes express high levels of ACE-2 and are therefore likely targets of SARS-CoV-2. Lung biopsies of four hospitalized patients with Covid-19 showed a dramatic decrease in pericyte coverage of alveolar capillaries in addition to capillary wall thickening. In COVID-19, pericyte degeneration and the resulting disruption of endothelial signaling and homeostasis are likely important contributors to vascular instability. Mice deficient in pericytes
(Pdgfrbret/ret) have elevated levels of von Willebrand factor, which promotes platelet aggregation and coagulation, suggesting that pericyte loss contributes to the pro-angiogenic response in COVID-19 patients. These studies suggest pericyte dysfunction as a mediator of pathophysiology in COVID-19. It is not yet known whether pericytes in the brain degenerate or become dysfunctional in COVID-19 patients with neurological symptoms.

Recent studies have provided further evidence of the neural invasive potential of SARS-CoV-2. The authors demonstrated ACE-2-dependent infection of neurons within human brain organs and hypoxia-like metabolic changes and damage in adjacent uninfected cells. Expression of humanized ACE-2 in the brains of mice experimentally infected with SARS-CoV-2 caused vascular remodeling throughout the cortex and greatly increased mortality. The authors examined brain tissue from three COVID-19 patients and reported that SARS-CoV-2 spike protein could be detected immunohistochemically within the walls of small vessel cortex adjacent to microinfarcts. Immunopositivity for spike protein was also reported in some cortical neurons. However, these findings need to be confirmed.

The type of cerebral ischemic damage seen in COVID-19 is a major contributor to cognitive decline and dementia

In COVID-19, pre-existing dementia is one of the most significant risk factors, or comorbidities. A retrospective evaluation of UK health records in the UK OpenSAFELY platform showed a hazard ratio of 2.16 (fully adjusted model) associated with pre-existing dementia/stroke. In a regional study of UK biobanks, an odds ratio of 3.07 was associated with dementia. The reasons for the increased risk and mortality in patients with pre-existing dementia are well explored. It is probably not widely recognized that the type of brain damage seen in COVID-19 is itself a major cause of cognitive decline and dementia.

Ischemic brain injury is the defining pathological process of vascular dementia (VaD), and stroke is a major risk factor for dementia. Occlusion of cerebral blood vessels, a major complication of thromboembolic DIC, can result in a wide range of neurological deficits, including cognitive impairment or dementia. It is estimated that approximately 20% of stroke-related dementia cases are single or multiple infarcts as a result of thromboembolism involving the major cerebral arteries. In severely ill COVID-19 patients, acute large cerebral vessel occlusion associated with increased coagulability may increase the risk of dementia to some degree.

Small vessel disease (SVD) accounts for approximately 20% of all strokes, but is the most common cause of vascular cognitive impairment in approximately 80% of cases of stroke-related dementia. Neuroimaging abnormalities of the white matter and atherosclerosis of the cerebral microvasculature associated with SVD are present in approximately 50% of all patients with dementia. Comorbidities of SVD include hypertension and diabetes (both also risk factors for severe COVID-19). Hypercoagulability and disseminated intravascular coagulation syndrome, which affect many patients with severe COVID-19, are more likely to reduce perfusion through small intracerebral vessels than large vessels. SARS-COV-2 induces endothelial dysfunction and infects the vascular bed of multiple tissues. Cerebral white matter is particularly vulnerable to changes in cerebral blood flow, as would be expected in association with diffuse small vessel dysfunction, as reported in COVID-19. Subcortical white matter integrity is critical to the maintenance of cognitive function, and one of the consequences of white matter damage in COVID-19 is likely to be cognitive impairment. This was underscored by neuroradiological demonstration that damage to white matter and disruption of functional integrity in brain regions such as the hippocampus were associated with memory loss at 3-month follow-up in recovered COVID-19 patients. Although the pathophysiology of SVD is not fully understood, damage to endothelial and pericyte cells and BBB leakage contribute to SVD-related brain damage that is likely exacerbated in severe COVID-19. Endothelial dysfunction and pericyte loss are associated with cerebral influx and accumulation of toxic components in plasma, such as fibrinogen, causing oligodendrocyte damage and myelin loss. Activation of the fibrinogen-mediated osteogenic protein signaling pathway prevents oligodendrocyte progenitor cell maturation and limits oligodendrocyte maturation and myelin remodeling. Immune cell infiltration through the damaged BBB may also contribute to white matter damage and cognitive decline in dementia and possibly COVID-19 . In addition, endothelial dysfunction and loss of pericytes likely impairs clearance of brain metabolites, including amyloid β-peptide, which is toxic when present in excess. Impaired drainage of metabolites, including Aβ, has been implicated in the development of cerebral amyloid angiopathy and Alzheimer's disease, and ineffective drainage of solutes is probably responsible for the enlargement of the perivascular space in patients with SVD. Several other factors may influence cerebral perfusion during systemic infection. Increased blood viscosity tends to delay capillary passage and limit oxygen supply. Damage to the glycocalyx, the carbohydrate-rich matrix on the lumenal side of the capillaries, may impair perfusion and exacerbate ischemia. Many of the detrimental changes in small vessels in systemic infections are exacerbated by the same risk factors that predispose to severe COVID-19 such as aging, hypertension, diabetes, and obesity.

Postmortem and neuroimaging studies have shown that up to two-thirds of AD patients have ischemic damage to cerebral white matter. Although cerebral amyloid vasculopathy may contribute to the impairment, in most cases ischemia-related damage is thought to result from a combination of atherosclerotic SVD and nonstructural vascular dysfunction. A series of recent neuroimaging studies have shown that ischemic white matter damage occurs very early in AD, accelerating disease progression and contributing to cognitive decline. These clinical findings suggest that cerebral ischemia promotes amyloid β accumulation by combining dysregulated processing of amyloid β precursor protein (APP) with impaired amyloid β clearance, and that amyloid β peptides may be involved in pericyte and vascular smooth muscle cell
This is supported by experimental studies showing that it mediates vasoconstriction by inducing contraction [95]. Studies on microvascular endothelial cell monolayers, human APP transgenic mouse models, and human postmortem brain tissue have shown that amyloid β-peptide also impairs BBB function, in part by downregulating expression of tight junction proteins. Pericyte degeneration in AD is associated with BBB degradation. Loss of pericytes accelerates Aβ pathology and induces tau pathology and cognitive decline in human APP mice. In human brain tissue from AD patients, decreased levels of the pericyte marker, platelet-derived growth factor-β (PDGFRβ), were associated with increased levels of amyloid-β and decreased brain perfusion. Amyloid β peptide is toxic to human brain pericytes in culture [105], and analysis of cerebrospinal fluid shows that levels of soluble PDGFRβ, a marker of pericyte damage and BBB leakage, are elevated in the elderly in association with the earliest detectable changes in cognitive performance.

There is growing evidence that cerebral hypoperfusion is also associated with tau pathology. Clinically normal adults with positron emission tomography (PET) evidence of cerebral amyloid-β accumulation were significantly more likely to show evidence of tau accumulation in patients who also had an elevated cardiovascular disease risk score. In patients with mild cognitive impairment, increased cerebrovascular load was associated with increased PET-Tau signaling and worse cognitive performance, independent of Aβ-PET. Several experimental studies have shown that modeling cerebral hypoperfusion increases tau phosphorylation: adult Wistar rats [108], transgenic mice with Aβ and tau accumulation, and rat and human brain sections exposed to oxygen and glucose deprivation. In a recent autopsy study, elevated levels of soluble tau and insoluble phosphotau in AD were associated with decreased levels of the endothelial tight junction proteins claudin-5 and occludin. Tau overexpressing mice were shown to have abnormal vascular morphology and increased vascular density. Recent studies have shown that in young (2~3 months) mice expressing mutant Tau, neurovascular conjugation is impaired prior to neurodegeneration. Thus, there are clinical and experimental data suggesting a bidirectional relationship between cerebrovascular dysfunction and pathological tau. There is evidence from recent studies that TDP-43 pathology is likewise associated with cerebrovascular dysfunction, including pericyte loss and
microvascular disease. Finally, cerebral ischemia induces phosphorylation of α-synuclein at serine-129; this is a disease-related modification of α-synuclein Lewy bodies and neurites in Parkinson's disease, and dementia with Lewy bodies and is significantly associated with AD pathology in these Lewy body diseases.

Both cerebral ischemia and systemic inflammation induce endothelial activation, increasing integrin and selectin expression and causing leukocyte adhesion to the brain parenchyma and transendothelial migration. Endothelial activation with leukocyte mobilization has also been shown in AD. Leukocytes enter the brain via postcapillary venules in the parenchyma and, to a lesser extent, into the soft meninges and choroid plexus vessels. Activated neutrophils in cerebral vessels and parenchyma were found to contribute to gliosis and cognitive deficits in human APP mice. In APP/PS1 mice, respiratory infection increased brain infiltration by interferon-γ- and interleukin-17-producing T cells and natural killer T cells and increased gliosis and amyloid-β deposition. Monocytes are the most common type of peripheral immune cells that migrate into the brain via the BBB in AD. CCL2, the major ligand for CCR2, is expressed on monocytes and is upregulated in AD microvessels and plays a role in amyloid β clearance. Whether endothelial activation predicts not only acute but also longer neurological complications (including dementia) in COVID-19 remains to be determined.


A) Ang-II is formed by ACE-1-mediated cleavage of Ang-I, and the binding of Ang-II to AT1R in blood vessels not only induces vasoconstriction but also affects vascular permeability and neurovascular conjugation, promoting neuroinflammation and oxidative stress within the central nervous system. Under normal circumstances, these effects are counteracted by ACE-2 activity, leading to production of Ang-1-9 and Ang-(1-7) and activation of MasR.

B) Binding of SARS-CoV-2 virus and internalization or cleavage of membrane-bound ACE-2 after cell entry leads to downregulation of regulatory RAS and overactivation of classical RAS in COVID-19, causing vascular dysfunction, inflammation, oxidative stress, and CNS damage.

Angiotensin-converting enzyme-2-mediated entry of SARS-CoV-2 into human cells and activation of the classical renin-angiotensin system

SARS-CoV-2 cell adhesion and invasion are initiated by viral binding to angiotensin-converting enzyme-2 (ACE-2). Therefore, ACE-2 expression at the cell surface is likely an important determinant of viral affinity and pathobiology in COVID-19. ACE-2 is expressed in stem cell-derived neurons, neurons in the brain, and glial cells, and may allow virus entry and spread through the cribriform plate by retrograde axonal transport along the olfactory nerve or from sensory fibers passing from the lung to the brain stem via vagal and nodal ganglia. ACE-2 is also expressed in the temporal lobe and hippocampal brain regions involved in cognition and memory and affected by AD [122]. In human ACE-2 transgenic mice infected with SARS-CoV-1 and SARS-CoV-2, neuronal uptake and expansion in the brain was demonstrated. However, as noted above, ACE-2 is also highly expressed on endothelial and pericytes, and hematogenous spread followed by endothelial uptake or influx of infected peripheral immune cells is a further possible route of virus entry into the brain.

During SARS-Cov-1 infection, ACE-2 is cleaved from the cell surface by ADAM-17 during virus entry. Although highly likely, it remains to be determined whether SARS-Cov-2 results in a similar loss of plasma membrane-associated ACE-2. ACE-2 is usually an important effector of the regulatory RAS that counteracts the actions of the classical RAS and reduces the risk of cardiovascular disease, stroke, and dementia (Figure 2). ACE-2 is reduced in Alzheimer's disease (AD), and cognitive decline is more pronounced in ACE-2 knockout mice. The loss of ACE-2 due to SARS-CoV-2 invasion (as in SARS) would increase the risk of cerebrovascular and neurological damage in COVID-19 patients due to angiotensin II-mediated classical RAS activation. This mechanism has also been proposed to explain other vascular and pulmonary manifestations of COVID-19. Internalization of ACE2 as a consequence of angiotensin II-induced activation of angiotensin receptor type 1 (AT1R) may further exacerbate the damage. The available harboring host of ACE-2 may be an important determinant of clinical outcome in COVID-19. Studies in rodents have shown that ACE-2 expression declines with age and in males. In contrast, estrogen may upregulate ACE-2 and help protect premenopausal women from the severe complications of COVID-19. COVID-19's
Most comorbidities that increase the risk of complications (e.g., hypertension, obesity, diabetes) may be associated with classical RAS overactivity. Indeed, ethnicity and genetic variation may also influence baseline ACE-2 levels and provide a biological explanation for why some ethnic groups are at higher risk for COVID-19. The hypothesis is that blockade of angiotensin II (Ang-II) signaling or Ang-II synthesis, respectively, downregulates the classical RAS and upregulates ACE-2 This would explain why angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme-1 inhibitors (ACE-I) reduce mortality in patients with COVID-19.

RAS imbalance contributes to acute ARDS and occurs in the majority of COVID-19 patients who develop viral pneumonia. Patients with ARDS exhibit classical RAS hyperactivity and decreased ACE-2. Increased Ang-II-mediated AT1R signaling, which causes inflammation [154], is likely a contributing factor to the inflammatory storm in severe COVID-19. Lung tissue damage in ARDS can be reduced by administration of ARBs and ACEIs, as well as recombinant ACE-2. ACE-2 catalyzes the formation of Ang-(1-7), which binds to mass receptors, and activation of ACE2 and mass receptors by Ang-(1-7) attenuates lung injury in ARDS. expression and prevents lung injury.
Recombinant soluble ACE-2 (rsACE-2) has shown therapeutic promise in severe COVID-19 infection, and administration was reported to reduce viral titer and serum Ang-II by altering the balance between the classical and regulatory portions of the renin-angiotensin system (RAS) in COVID-19 Ang-II is a key component of ACE-1. Ang-II is formed by ACE-1-mediated cleavage of Ang-I, and the binding of Ang-II to AT1R in blood vessels not only induces vasoconstriction but also affects vascular permeability and neurovascular conjugation, promoting neuroinflammation and oxidative stress within the central nervous system. Under normal circumstances, these effects are counteracted by ACE-2 activity,
Ang-1-9 and Ang-(1-7) production and activation of MasR. Internal migration or cleavage of membrane-bound ACE-2 after SARS-CoV-2 virus binding and cell entry causes downregulation of regulatory RAS and overactivation of classical RAS, promotes vascular dysfunction, inflammation, oxidative stress and CNS damage in COVID-19, and increases serum Ang-(1-7) levels and markedly reduce proinflammatory cytokines. In addition to preventing viral binding, reduction via rsACE-2 at Ang-II may prevent AT1R-mediated ADAM17 cleavage of membrane-bound ACE-2 and restore RAS balance.

Possible neurological effects of increased activation of the classical renin-angiotensin system in COVID-19

The RAS is independently expressed and functions in the brain. Overactivation of the classical RAS with elevated ACE-1 and Ang-II has been demonstrated in postmortem human brain tissue in AD. Ventricular infusion of Ang-II into adult Wistar rats enhanced Aβ production and tau pathology, and ARB and ACEI protected against cognitive decline and disease pathology in a transgenic APP mouse model of AD. The authors previously reported that decreased ACE-2 in brain tissue in AD correlated strongly with increased parenchymal amyloid-β and tau concentrations and ACE-1 activity. We and others have subsequently shown that induction of ACE-2 or administration of Ang-(1-7) or peptide analogues protects against Aβ-related cognitive decline in mice associated with reduced neuroinflammation and oxidative stress. The RAS is an important regulator of vascular function. Ang-II binds to AT1R on vascular smooth muscle cells to induce cerebral arteriolar constriction and on pericytes to cause microvascular constriction. Ang-II also modulates BBB permeability: AT1R signaling induces leakage in endothelial cell culture models of BBB and Ang-II infusion and causes BBB leakage in mice, which can be reversed by adding superoxide scavengers, suggesting a role for oxidative This can be reversed by the addition of superoxide scavengers, suggesting a role for oxidative stress. Several mediators of BBB leakage, including vascular endothelial growth factor and matrix metalloproteinases (MMP)-2 and MMP-9
tors are induced by Ang-II. In mice, Ang-II was shown to impair neurovascular coactivation (i.e., blood flow response to increased neural activity) in the somatosensory cortex and interfere with cerebral autoregulation. The accumulation of ACE-1 in the extracellular matrix around cerebral arterioles (especially in AD patients with cerebral amyloid angiopathy) suggests that locally produced (and circulating) Ang-II is involved in cerebrovascular dysfunction mediated by the overactivation of the classical RAS The accumulation of Ang-II Overactivation of the classical RAS may also reduce clearance of amyloid-β. Intramural periarterial drainage (IPAD) and paravascular glymphatic channels are involved in the removal of amyloid-β from the brain. The function of these drainage pathways depends on the polar expression of aquaporin-4 in astrocyte end feet, which is regulated by pericytes. When pericytes are locally deficient, aquaporin-4 is redistributed into the cell body. RAS was shown to modulate aquaporin-4 expression in astrocytes and Ang-II acted via AT1R to decrease ACE-2 expression in astrocyte cultures. These alterations in pericyte and astrocyte function likely impair amyloid β clearance. Whether this occurs in COVID-19 remains to be determined. Neuroinflammation is strongly implicated in the pathogenesis of AD. Genome-wide association studies have identified risk factors for AD and
Several inflammatory pathway genes have been identified as Activation of complement and inflammasomes likely contributes to cerebrovascular dysfunction, neurotoxicity, and accumulation of amyloid beta and tau in AD. Ang-II activates the complement system and the NLRP3 inflammasome, and it has been proposed that activation of both complement and inflammasome contributes to neurological disease in COVID-19 patients.

Recent in silico studies suggest that activation of Toll-like receptor 4 (TLR4) by SARS-CoV-2 is a major contributor to the inflammatory response of COVID-19. Ang-II upregulates TLR4, a key determinant of Ang-II-mediated vascular remodeling. Blockade of TLR4 signaling delayed the onset of Ang-II-mediated hypertension in rats and was associated with a dramatic increase in ACE-2. Pericytes express high levels of TL4R, which is activated by free long-chain fatty acids. The spike protein of SARS-CoV-2 has been shown to bind linoleic acid, affecting protein conformation and possibly virus binding to ACE-2 (previously reported studies). Thus, it may be relevant that linoleic acid is decreased in both COVID-19 and AD and may affect the progression of both diseases. Ang-II also acts as a molecular switch that modulates the microglial phenotypic switch between M1 (inflammation-induced) and M2 (immunomodulatory) defense phagocytic phenotypes associated with AD pathogenesis. The role of microglia in the neurological manifestations of COVID-19 remains poorly understood. Endothelial activation via Ang-II promotes leukocyte binding and dialysis via the BBB, and these effects are moderated by Ang-1-7. Pericytes also have immunomodulatory properties and localize within the cerebral vasculature, suggesting that pericytes may play a "gatekeeper" role in regulating immune cell infiltration. Pericytes express ACE-2, but whether they are targets of SARSCoV-2 has not yet been established. Because of the central role of pericytes in regulating cerebrovascular function (and possibly immune cell infiltration), virus-induced pericyte injury may impair cerebral perfusion, BBB integrity, and immune regulation. In addition to vascular effects, Ang-II-derived angiotensin peptides, including Ang-IV and Ang-(1-7), have neuromodulatory and neuroprotective activation of Mas (regulatory RAS) receptors and Ang-IV activation of c-Met and insulin regulatory aminopeptidase receptors and limits tissue damage in stroke models. Similarly, ACE-2 activation and/or Ang-(1-7) infusion prevents cognitive decline and disease pathogenesis in animal models of amyloid-β accumulation, independent of changes in blood pressure. Thus, there is a wide range of mechanisms by which reduced regulatory RAS signaling exacerbates brain damage in COVID-19.

Is APOEε4 an established risk factor for AD and vascular dysfunction and is it also a risk factor for COVID-19?

APOE polymorphisms significantly affected the risk of developing AD, with risk increased for APOEε4 and decreased for APOEε2.
The physiological role of the encoded apolipoprotein (apolipoprotein E, ApoE) is not yet fully understood.
Recent studies have shown that possession of APOEε4 is associated with cerebrovascular dysfunction, including BBB leakage and pericyte degeneration, and cerebral amyloid vasculopathy with capillary lesions. A recent UK study reported a higher prevalence of COVID-19 in individuals who are carriers of APOEε4. The authors previously showed that APOEε4 individuals also have the lowest ACE-2 activity. Pericyte expression of APOEε4 was reported to promote BBB leakage due to defective basement membrane formation. Furthermore, possession of APOEε4 is associated with reduced cerebral blood flow and increased subcortical ischemic white matter damage, as well as neuroinflammation in AD. Future
The study aimed to determine the relationship between APOEε4, COVID-19, and cerebrovascular dysfunction and AD
Should be.

Possible up-regulation of ADAM-17 in COVID-19

ACE-2 is cleaved by ADAM-17 when SARS-Cov-1 enters the cell. This may also occur upon SARSCov-2 cell entry, but data are not yet available. Ang-II-mediated activation of ADAM-17 and release of ACE-2 represents a positive feedback loop in which increased Ang-II levels are associated with loss of ACE-2. However, it is It is noteworthy. Thus, upregulation of ADAM-17 may exacerbate vascular dysfunction in COVID-19. ADAM-17 also acts as an α-secretase, cleaving APP and interfering with amyloid β formation. The complex and diverse roles of ADAM-17 in AD and potentially COVID-19 require further study.

Potential future targets for clinical management, clinical trials, and therapeutic interventions in COVID-19 patients

In severe COVID-19, patients present with pneumonia, and the most severely ill patients develop ARDS with features of septic shock and multiorgan failure, requiring oxygen therapy and/or mechanical ventilation. Infection-induced inflammatory and vascular changes associated with coagulopathy and thrombosis, including venous thromboembolism (VTE), DIC, and thromboembolic microvascular complications, are common complications of severe COVID-19, as indicated by reports of VTE in 25% to 27% of hospitalized patients. The International Society of Thrombosis and Haemostasis (ISTH) recommends measurement of d-dimer, prothrombin time, partial thromboplastin time, and platelet count in COVID-19 hospitalized patients. In a retrospective study conducted in Wuhan, China, early in the pandemic, patients who received low molecular weight heparin and
The mortality rate was found to be lower in patients who were Patients with clinically managed severe COVID-19 are now routinely treated with low-dose subcutaneous heparin and/or thromboprophylaxis, unless they are at high risk for bleeding. In severe COVID-19, lymphopenia with marked loss of regulatory T and B cells and natural killer cells, decreased monocytes, eosinophils and basophils, and increased neutrophils is typical. Concentrations of proinflammatory cytokines are also elevated, sometimes manifesting
markedly (so-called cytokine storm). Plasma and plasma exchange during recovery improves survival in severe disease,
Immunomodulatory therapies such as tocilizumab, a monoclonal antibody against the IL-6 receptor, and sarilumab, an IL-6 receptor antagonist, have provided preventive effects and are currently in clinical trials. Neutralizing antibodies targeting other proinflammatory cytokines (IL-1, IL-17) may also provide protection, as may potential inhibitors of complement system activation. Intravenous transplantation of mesenchymal stem cells was shown to improve outcomes in seven COVID-19 patients with pneumonia in Beijing, China. Mesenchymal stem cells, given their immunomodulatory and anti-inflammatory properties, as well as their ability to attenuate BBB damage and neuroinflammation after cerebral ischemia,
Brain damage in severe COVID-19 may also improve.

The role of systemic or inhaled corticosteroids in COVID-19 patients continues to be debated. While previous studies have shown a lack of benefit from corticosteroids, a randomized clinical trial reported by the RECOVERY Collaborative Research Group (Oxford, UK) found that systemic dexamethasone reduced mortality in severely ill COVID-19 patients. Inhaled steroids have previously been shown to reduce inflammation and tissue damage in ARDS. In addition to their inherent anti-inflammatory properties, steroids may have antiviral properties. Ciclesonide, an inhaled corticosteroid, was shown to inhibit MERS-CoV, SARS-CoV, and SARS-CoV-2 replication in vitro. The expression and activity of interferon-β (IFN-β), an endogenous protein with antiviral and anti-inflammatory properties, is impaired in COVID-19. Interferon inhibits SARSCoV-2 replication in vitro. In a Phase II clinical trial, the combination of an antiviral drug and IFN-β reduced the duration of viral elimination and hospitalization. In a Phase II trial of SNG001, an inhaled IFN-β, the British pharmaceutical company Synairgen reported a lower risk of requiring ventilation and an approximately 79% reduction in mortality (these data are not currently published). ACE-2 is the receptor for SARS-CoV-2, which is a receptor for ACEI and
Because ARBs are predicted to increase ACE-2 expression, there was initial concern that the use of these drugs might exacerbate COVID-19. Recent meta-analyses suggest that RAS-targeted agents are instead prophylactic in COVID-19. This may be due to the protective role of ACE-2 in reducing or preventing classical RAS overactivation and minimizing the resulting Ang-II-mediated ischemic and inflammatory damage, as outlined above. Several clinical trials of ARBs such as losartan in COVID-19 patients have been published in the National Institutes of Health (NIH)
have been registered: NCT0435123, NCT04312009, and NCT04311177. The impact of ACE-I discontinuation on COVID-19 (EudraCT numbers 20-001544-26 and 2020-001206-35) was also studied in two studies. Enhancing the regulatory arm of the RAS may improve COVID-19 by protecting ACE-2 and Ang-(1-7); recombinant human Interventional trials with ACE2 (rhACE2) and Ang-(1-7) have also been enrolled (NCT04287686 and NCT043266, respectively), but the rhACE2 trial, which sought to recruit people aged 18~80 in China, has since been discontinued. A further rhACE2 study (2020-001172-15) is on the EU Clinical
Floor Trial Registry. Several other studies attempting to inhibit TMPRSS2 are under review. Studies that may include TL4R blockers and ADAM-17 inhibitors may also merit further study. For a comprehensive review of pharmacological targets currently under consideration as potential interventions and treatments in COVID-19, see the recent review.


Cerebrovascular disease has emerged as a major complication of severe COVID-19 . It causes persistent brain damage and likely increases the risk of stroke and vascular cognitive impairment. Some of the metabolic abnormalities affecting COVID-19 patients may also increase the risk of developing AD. Dementia and COVID-19 share many comorbidities and risk factors, including age, gender, hypertension, diabetes, obesity, and APOEε4 carriage, most of which are associated with overactive RAS, cerebrovascular dysfunction, and neuroinflammation. These comorbid comorbidities and similar mechanisms may also explain the high incidence and increased mortality in patients with dementia. Research is urgently needed to better understand the etiology of COVID-19 neuropathy, some of which is probably hidden and whose prevalence may be substantially underestimated. This understanding is essential to establish the long-term consequences of the disease (including the possible increased risk of dementia in some cases) and to identify means to prevent or ameliorate brain damage.


AD: Alzheimer's disease; ApoE: apolipoprotein E; APP: amyloid-β precursor protein; angiotensin II; ARB: angiotensin receptor blocker; ARDS: acute respiratory distress syndrome; AT1R: angiotensin type 1 receptor; BBB: blood-brain barrier; BSG: Basigin; CNS: central nervous system; CVD: cerebrovascular disease; DIC: disseminated intravascular coagulation; IFN-β: interferon-β; ICH: intracerebral hemorrhage; IL: interleukin; LRP-1: low-density lipoprotein receptor-related protein 1; MMP: matrix metalloproteinase; MER: Middle East respiratory syndrome; NRP1: neuropilin; PDGFRβ: platelet-derived growth factor-β; PET: positron emission tomography; RAS: renin-angiotensin
system; SARS: severe acute respiratory syndrome; SARS-CoV-2: severe acute respiratory syndrome coronavirus-2; SVD: small vessel disease; TLR4: Toll-like receptor 4


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