COVID-19, perioperative neurocognitive disorder and SARS-CoV-2-induced dysregulation of the renin–angiotensin system and kynurenine metabolism. Comment on Br J Anaesth 2021; 127: e113–e115

Abstract

Editor—Wei and colleagues1Wei P. Lyu W. Wan T. et al.COVID-19: a novel risk factor for perioperative neurocognitive disorders.Br J Anaesth. 2021; 127: E113-E115Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar postulated COVID-19 as a risk factor for perioperative neurocognitive disorders (PNDs). We agree that older individuals experiencing COVID-19 are at special risk, but believe that the proposed mechanisms are incomplete. The authors offered SARS-CoV-2 invasion into the CNS as a mechanism.1Wei P. Lyu W. Wan T. et al.COVID-19: a novel risk factor for perioperative neurocognitive disorders.Br J Anaesth. 2021; 127: E113-E115Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar However, there is limited evidence of SARS-CoV-2 infection of neurones, and brain autopsies of patients with COVID-19 show no neuronal infection.2Solomon I.H. Normandin E. Bhattacharyya S. et al.Neuropathological features of Covid-19.N Engl J Med. 2020; 383: 989-992Crossref PubMed Scopus (457) Google Scholar Direct viral involvement of brain or olfactory nerves was limited to detecting low levels of viral RNA and rare viral antigens in cranial nerves and scattered brainstem cells3Mukerji S.S. Solomon I.H. What can we learn from brain autopsies in COVID-19?.Neurosci Lett. 2021; 742: 135528Crossref PubMed Scopus (60) Google Scholar,4Matschke J. Lütgehetmann M. Hagel C. et al.Neuropathology of patients with COVID-19 in Germany: a post-mortem case series.Lancet Neurol. 2020; 19: 919-929Abstract Full Text Full Text PDF PubMed Scopus (564) Google Scholar; the presence of CNS SARS-CoV-2 was not associated with neuropathological severity.4Matschke J. Lütgehetmann M. Hagel C. et al.Neuropathology of patients with COVID-19 in Germany: a post-mortem case series.Lancet Neurol. 2020; 19: 919-929Abstract Full Text Full Text PDF PubMed Scopus (564) Google Scholar Although translational research supports spike-protein-mediated direct injury of the blood-brain barrier (BBB) without evidence of neuronal infection,5Pellegrini L. Albecka A. Mallery D.L. et al.SARS-CoV-2 infects the brain choroid plexus and disrupts the blood-CSF barrier in human brain organoids.Cell Stem Cell. 2020; 27: 951-961.e5Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar immunohistochemistry using antibodies that recognise the viral spike protein, has been negative in most human cases.3Mukerji S.S. Solomon I.H. What can we learn from brain autopsies in COVID-19?.Neurosci Lett. 2021; 742: 135528Crossref PubMed Scopus (60) Google Scholar Hence, it is important to consider pathological processes distinct from virus or virus-related proteins related to SARS-CoV-2 infection in inducing indirectly BBB injury and neuroinflammation. These have also been associated with Alzheimer's disease (AD) and PND.6Baker H.A. Safavynia S.A. Evered L.A. The ‘third wave’: impending cognitive and functional decline in COVID-19 survivors.Br J Anaesth. 2021; 126: 44-47Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar Based on the finding of increased angiotensin-converting enzyme 2 (ACE2) expression in AD brain,7Ding Q. Shults N.V. Harris B.T. Suzuki Y.J. Angiotensin-converting enzyme 2 (ACE2) is upregulated in Alzheimer’s disease brain.bioRxiv. 2020; (Advance Access published on October 8)https://doi.org/10.1101/2020.10.08.331157Crossref Scopus (0) Google Scholar Wei and colleagues1Wei P. Lyu W. Wan T. et al.COVID-19: a novel risk factor for perioperative neurocognitive disorders.Br J Anaesth. 2021; 127: E113-E115Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar considered patients with AD to have greater risk for SARS-CoV-2-induced CNS infection. However, this is arguable, as the structure and function of ACE2 isoforms upregulated during inflammation are unclear. Recent studies show that interferons and viruses induce ACE2 isoforms that lack angiotensin-II (Ang-II) catalytic activity and differ from full-length SARS-CoV-2 receptors.8Onabajo O.O. Banday A.R. Stanifer M.L. et al.Interferons and viruses induce a novel truncated ACE2 isoform and not the full-length SARS-CoV-2 receptor.Nat Genet. 2020; 52: 1283-1293Crossref PubMed Scopus (138) Google Scholar,9Blume C. Jackson C.L. Spalluto C.M. et al.A novel ACE2 isoform is expressed in human respiratory epithelia and is upregulated in response to interferons and RNA respiratory virus infection.Nat Genet. 2021; 53: 205-214Crossref PubMed Scopus (72) Google Scholar Thus, it is unclear whether interferon-gamma (INF-γ)-induced upregulation of ACE2 as evident in SARS-CoV-2 infection,10Ziegler C.G.K. Allon S.J. Nyquist S.K. et al.SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues.Cell. 2020; 181: 1016-1035.e19Abstract Full Text Full Text PDF PubMed Scopus (1364) Google Scholar and possibly in other inflammatory situations, such as AD,1Wei P. Lyu W. Wan T. et al.COVID-19: a novel risk factor for perioperative neurocognitive disorders.Br J Anaesth. 2021; 127: E113-E115Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar,7Ding Q. Shults N.V. Harris B.T. Suzuki Y.J. Angiotensin-converting enzyme 2 (ACE2) is upregulated in Alzheimer’s disease brain.bioRxiv. 2020; (Advance Access published on October 8)https://doi.org/10.1101/2020.10.08.331157Crossref Scopus (0) Google Scholar increases susceptibility to SARS-CoV-2 infection. Ding and colleagues7Ding Q. Shults N.V. Harris B.T. Suzuki Y.J. Angiotensin-converting enzyme 2 (ACE2) is upregulated in Alzheimer’s disease brain.bioRxiv. 2020; (Advance Access published on October 8)https://doi.org/10.1101/2020.10.08.331157Crossref Scopus (0) Google Scholar found no relationship between ACE2 upregulation and AD severity, whilst elsewhere ACE2 downregulation in brain correlated with increased expression of amyloid beta (Aβ), tau pathology, AD disease progression, and worsened outcomes.11Kehoe P.G. Wong S. AL Mulhim N. Palmer L.E. Miners J.S. Angiotensin-converting enzyme 2 is reduced in Alzheimer’s disease in association with increasing amyloid-β and tau pathology.Alzheimers Res Ther. 2016; 8: 50Crossref PubMed Scopus (112) Google Scholar Downregulation of normal ACE2 and increased expression of ACE2 isoforms lacking catalytic activity could establish hyperactive angiotensin-converting enzyme (ACE)–Ang-II–angiotensin 1 receptor (AT1R) signalling in AD11Kehoe P.G. Wong S. AL Mulhim N. Palmer L.E. Miners J.S. Angiotensin-converting enzyme 2 is reduced in Alzheimer’s disease in association with increasing amyloid-β and tau pathology.Alzheimers Res Ther. 2016; 8: 50Crossref PubMed Scopus (112) Google Scholar and COVID-19.12Jain A. Lamperti M. Upregulation of ACE/ACE2 balance in nasal mucosa: a working hypothesis to explain the absence of nasal inflammatory symptoms in COVID-19 disease.Ear Nose Throat J. 2021; (Advance Access published on June 15)https://doi.org/10.1177/01455613211025747Crossref Scopus (1) Google Scholar To implement preoperative strategies to alleviate neurological consequences of COVID-19, one must propose pathophysiological models that link COVID-19 with AD and PND.6Baker H.A. Safavynia S.A. Evered L.A. The ‘third wave’: impending cognitive and functional decline in COVID-19 survivors.Br J Anaesth. 2021; 126: 44-47Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar We postulate two such pathways that may be triggered by SARS-CoV-2-induced epithelial–endothelial cross-talk12Jain A. Lamperti M. Upregulation of ACE/ACE2 balance in nasal mucosa: a working hypothesis to explain the absence of nasal inflammatory symptoms in COVID-19 disease.Ear Nose Throat J. 2021; (Advance Access published on June 15)https://doi.org/10.1177/01455613211025747Crossref Scopus (1) Google Scholar and inflammation (Fig. 1). SARS-CoV-2 infection in nasal and olfactory epithelium produces ACE2 downregulation with upregulation of pro-inflammatory cytokines, establishing high local expression of ACE and Ang-II.12Jain A. Lamperti M. Upregulation of ACE/ACE2 balance in nasal mucosa: a working hypothesis to explain the absence of nasal inflammatory symptoms in COVID-19 disease.Ear Nose Throat J. 2021; (Advance Access published on June 15)https://doi.org/10.1177/01455613211025747Crossref Scopus (1) Google Scholar From the olfactory epithelium, Ang-II can diffuse transmucosally to produce high concentrations in the olfactory bulb, prefrontal cortex, and hippocampus13Derad I. Willeke K. Pietrowsky R. Born J. Fehm H. Intranasal angiotensin II directly influences central nervous regulation of blood pressure.Am J Hypertens. 1998; 11: 971-977Crossref PubMed Scopus (39) Google Scholar; these are brain regions with high expression of AT1Rs.14Mendelsohn F.A. Quirion R. Saavedra J.M. Aguilera G. Catt K.J. Autoradiographic localization of angiotensin II receptors in rat brain.Proc Natl Acad Sci U S A. 1984; 81: 1575-1579Crossref PubMed Google Scholar Hence, high Ang-II-mediated activity in SARS-CoV-2 could be a mechanism for hippocampal neurotoxicity. Importantly, increased central Ang-II induces amyloidogenesis during stress, and Aβ production is completely abolished by intracerebroventricular administration of losartan.15Zhu D. Shi J. Zhang Y. et al.Central angiotensin II stimulation promotes β amyloid production in Sprague Dawley rats.PLoS One. 2011; 6e16037Crossref PubMed Scopus (93) Google Scholar Similarly, AT1R deficiency decreased Aβ amyloid and amyloid plaque formation in a mouse model of AD.16Liu J. Liu S. Matsumoto Y. et al.Angiotensin type 1a receptor deficiency decreases amyloid β-protein generation and ameliorates brain amyloid pathology.Sci Rep. 2015; 5: 12059Crossref PubMed Scopus (27) Google Scholar Angiotensin-III, a metabolite of Ang-II, is associated with Aβ and tau pathology.17Kehoe P.G. Hibbs E. Palmer L.E. Miners J.S. Angiotensin-III is increased in Alzheimer’s disease in association with amyloid-β and tau pathology.J Alzheimers Dis. 2017; 58: 203-214Crossref PubMed Scopus (28) Google Scholar Increased ACE activity in medial hippocampus, parahippocampal gyrus, frontal cortex, and caudate nucleus correlates with Aβ plaque load.18Miners J.S. Ashby E. Van Helmond Z. et al.Angiotensin-converting enzyme (ACE) levels and activity in Alzheimer’s disease, and relationship of perivascular ACE-1 to cerebral amyloid angiopathy.Neuropathol Appl Neurobiol. 2008; 34: 181-193Crossref PubMed Scopus (122) Google Scholar The ACE/ACE2 ratio increases, whilst a decrease in the Ang-II/Ang (1–7) ratio occurs in AD11Kehoe P.G. Wong S. AL Mulhim N. Palmer L.E. Miners J.S. Angiotensin-converting enzyme 2 is reduced in Alzheimer’s disease in association with increasing amyloid-β and tau pathology.Alzheimers Res Ther. 2016; 8: 50Crossref PubMed Scopus (112) Google Scholar and possibly in the pathogenesis of COVID-19.12Jain A. Lamperti M. Upregulation of ACE/ACE2 balance in nasal mucosa: a working hypothesis to explain the absence of nasal inflammatory symptoms in COVID-19 disease.Ear Nose Throat J. 2021; (Advance Access published on June 15)https://doi.org/10.1177/01455613211025747Crossref Scopus (1) Google Scholar In fact, centrally acting ACE inhibitors reduce dementia and cognitive decline, and enhance memory in mild-to-moderate AD,19Farag E. Liang C. Mascha E.J. et al.Association between use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and postoperative delirium.Anesthesiology. 2020; 133: 119-132Crossref PubMed Scopus (5) Google Scholar and candesartan, an AT1R antagonist, diminishes the incidence of non-fatal stroke.19Farag E. Liang C. Mascha E.J. et al.Association between use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and postoperative delirium.Anesthesiology. 2020; 133: 119-132Crossref PubMed Scopus (5) Google Scholar Increased hippocampal expression of Ang-II and AT1R is linked with hippocampal BBB disruption as early as 6 h after surgery in aged rats, whereas AT1R antagonists restore BBB integrity by suppressing the canonical surgery-induced nuclear factor-кB activation cascade.20Li Z. Mo N. Li L. et al.Surgery-induced hippocampal angiotensin II elevation causes blood-brain barrier disruption via MMP/TIMP in aged rats.Front Cell Neurosci. 2016; 10: 105Crossref PubMed Scopus (36) Google Scholar Importantly, starting ACE inhibitors or AT1R blockers in the early postoperative period was associated with reduced delirium in critical care settings.19Farag E. Liang C. Mascha E.J. et al.Association between use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and postoperative delirium.Anesthesiology. 2020; 133: 119-132Crossref PubMed Scopus (5) Google Scholar Interferon-γ and Ang-II via INF-γ induce indoleamine 2,3-dioxygenase (IDO) activity after SARS-CoV-2 infection.21Lawler N.G. Gray N. Kimhofer T. et al.Systemic perturbations in amine and kynurenine metabolism associated with acute SARS-CoV-2 infection and inflammatory cytokine responses.J Proteome Res. 2021; 20: 2796-2811Crossref PubMed Scopus (43) Google Scholar Increased expression of IDO activity and kynurenine (KYN)/tryptophan (TRP) ratio is evident in nasal epithelium after influenza type A infection.22Jacoby D.B. Choi A.M.K. Influenza virus induces expression of antioxidant genes in human epithelial cells.Free Radic Biol Med. 1994; 16: 821-824Crossref PubMed Scopus (76) Google Scholar Altered KYN metabolism is an early marker of inflammation in SARS-CoV-2 infection, high levels of neurotoxic metabolites (3-hydroxykynurenine [3-HK] and quinolinic acid [QUIN]) with low levels of neuroprotective by-products (kynurenic acid [KYNA]). The xanthurenic acid (XA) of KYN pathways is linked with COVID-19 severity.21Lawler N.G. Gray N. Kimhofer T. et al.Systemic perturbations in amine and kynurenine metabolism associated with acute SARS-CoV-2 infection and inflammatory cytokine responses.J Proteome Res. 2021; 20: 2796-2811Crossref PubMed Scopus (43) Google Scholar In fact, high 3-HK/KYN, 3HK/KYNA, and QUIN/KYNA ratios are evident on metabolomic studies in COVID-19.21Lawler N.G. Gray N. Kimhofer T. et al.Systemic perturbations in amine and kynurenine metabolism associated with acute SARS-CoV-2 infection and inflammatory cytokine responses.J Proteome Res. 2021; 20: 2796-2811Crossref PubMed Scopus (43) Google Scholar High levels of neoptrin and low levels of XA are additional markers of severity.21Lawler N.G. Gray N. Kimhofer T. et al.Systemic perturbations in amine and kynurenine metabolism associated with acute SARS-CoV-2 infection and inflammatory cytokine responses.J Proteome Res. 2021; 20: 2796-2811Crossref PubMed Scopus (43) Google Scholar Severe COVID-19 is associated with reduced quinolinic acid phosphoribosyltransferase expression and reduced production of nicotinamide adenine dinucleotide.23Heer C.D. Sanderson D.J. Voth L.S. et al.Coronavirus infection and PARP expression dysregulate the NAD metabolome: an actionable component of innate immunity.bioRxiv. 2020; (Advance Access published on October 6)http://biorxiv.org/lookup/doi/10.1101/2020.04.17.047480PubMed Google Scholar 3-HK and QUIN are strong competitive agonists of glutamate.24Gulaj E. Pawlak K. Bien B. Pawlak D. Kynurenine and its metabolites in Alzheimer’s disease patients.Adv Med Sci. 2010; 55: 204-211Crossref PubMed Scopus (168) Google Scholar Contrarily, both KYNA and XA inhibit N-methyl-D-aspartate receptors. KYNA also inhibits presynaptic α7 nicotinic receptors in hippocampal neurones, but increases non-α7 nicotinic receptor expression.24Gulaj E. Pawlak K. Bien B. Pawlak D. Kynurenine and its metabolites in Alzheimer’s disease patients.Adv Med Sci. 2010; 55: 204-211Crossref PubMed Scopus (168) Google Scholar 3-HK may cause reactive oxygen species formation leading to microvascular damage, increased BBB permeability, and neurotoxicity. Increased QUIN and 3-HK levels in astrocytes and neurones result from cytokines, such as INF-γ, tumour necrosis factor-α, and interleukin-1β.24Gulaj E. Pawlak K. Bien B. Pawlak D. Kynurenine and its metabolites in Alzheimer’s disease patients.Adv Med Sci. 2010; 55: 204-211Crossref PubMed Scopus (168) Google Scholar Increased QUIN and 3-HK levels can cause nerve conduction abnormalities and neurological toxicity especially in the hippocampus, striatum, and other parts of the neocortex that are sensitive to QUIN.24Gulaj E. Pawlak K. Bien B. Pawlak D. Kynurenine and its metabolites in Alzheimer’s disease patients.Adv Med Sci. 2010; 55: 204-211Crossref PubMed Scopus (168) Google Scholar We hypothesise that SARS-CoV-2 infection produces QUIN and 3-HK from olfactory epithelium that diffuses transmucosally to produce direct neuroexcitatory injury to olfactory bulb neurones, resulting in anosmia. Interestingly, direct glutamate administration at the level of olfactory bulb induces anosmia that recovers spontaneously within 2 weeks,25Marin C. Langdon C. Alobid I. Fuentes M. Bonastre M. Mullol J. Recovery of olfactory function after excitotoxic lesion of the olfactory bulbs is associated with increases in bulbar SIRT1 and SIRT4 expressions.Mol Neurobiol. 2019; 56: 5643-5653Crossref PubMed Scopus (11) Google Scholar the duration of anosmia usually seen in COVID-19.26Klopfenstein T. Kadiane-Oussou N.J. Toko L. et al.Features of anosmia in COVID-19.Med Mal Infect. 2020; 50: 436-439Crossref PubMed Scopus (247) Google Scholar Transmucosal spread of KYN metabolites to higher-order brain structures in the olfactory–hippocampal pathway is a possibility. Systemic KYN metabolites, KYN and 3-HK, in contrast to plasma KYNA, can readily cross the BBB to generate high central QUIN levels and induce neuronal inflammation, oxidative stress, and hippocampal injury. Similar alterations in KYN metabolism are seen in patients with neurovascular diseases.21Lawler N.G. Gray N. Kimhofer T. et al.Systemic perturbations in amine and kynurenine metabolism associated with acute SARS-CoV-2 infection and inflammatory cytokine responses.J Proteome Res. 2021; 20: 2796-2811Crossref PubMed Scopus (43) Google Scholar,24Gulaj E. Pawlak K. Bien B. Pawlak D. Kynurenine and its metabolites in Alzheimer’s disease patients.Adv Med Sci. 2010; 55: 204-211Crossref PubMed Scopus (168) Google Scholar Ageing and AD are also associated with deregulated KYN metabolism. Alteration of KYN metabolism, involving tryptophan depletion along with marked increases in QUIN, but decreases in KYNA and XA plasma levels occurred in both AD and with ageing.24Gulaj E. Pawlak K. Bien B. Pawlak D. Kynurenine and its metabolites in Alzheimer’s disease patients.Adv Med Sci. 2010; 55: 204-211Crossref PubMed Scopus (168) Google Scholar Anaesthesia and surgery are associated with inflammatory changes and alterations in TRP oxidative metabolism, which may contribute to postoperative cognitive dysfunction.27Forrest C.M. Mackay G.M. Oxford L. et al.Kynurenine metabolism predicts cognitive function in patients following cardiac bypass and thoracic surgery: kynurenines and cardiopulmonary bypass.J Neurochem. 2011; 119: 136-152Crossref PubMed Scopus (41) Google Scholar Immune-mediated metabolism of KYN is involved in PND after cardiopulmonary bypass.27Forrest C.M. Mackay G.M. Oxford L. et al.Kynurenine metabolism predicts cognitive function in patients following cardiac bypass and thoracic surgery: kynurenines and cardiopulmonary bypass.J Neurochem. 2011; 119: 136-152Crossref PubMed Scopus (41) Google Scholar In conclusion, dysregulated renin–angiotensin and KYN metabolism pathways in COVID-19 pathogenesis are similar to those in ageing, AD dementia, and PND. Studies confirming the role of these pathways in COVID-19 neurocognitive decline are urgently needed to establish targets for reducing PND in patients who had COVID-19 and are undergoing surgery. This is further highlighted by the evidence from the recent meta-analysis showing reduced risk of cognitive decline in older adults on AT1R blockers and ACE inhibitors with BBB-crossing potential.28Ho J.K. Moriarty F. Manly J.J. et al.Blood-brain barrier crossing renin-angiotensin drugs and cognition in the elderly: a meta-analysis.Hypertension. 2021; 78: 629-643Crossref PubMed Scopus (17) Google Scholar ML is a member of the associate editorial board of the British Journal of Anaesthesia. The other authors have no conflicts to declare. COVID-19: a novel risk factor for perioperative neurocognitive disordersBritish Journal of AnaesthesiaVol. 127Issue 3PreviewEditor—Older patients with current or previous SARS-CoV-2 infection (COVID-19) have been undergoing surgical interventions at an increasing rate during the COVID-19 pandemic and face a high risk of postoperative complications. Most older patients are expected to recover from acute postoperative complications, including most pulmonary and renal complications and delirium. Recently, a national database study on hip fracture characteristics and outcomes during the COVID-19 pandemic in the USA showed that older patients with hip fracture and concomitant COVID-19 experienced significantly higher rates of acute postoperative complications, especially pulmonary complications (22.9%). Full-Text PDF Open Archive