key: cord-0690840-hpzs0oce authors: Wei, Penghui; Lyu, Wenyuan; Wan, Tiantian; Zheng, Qiang; Tang, Wenxi; Li, Jianjun; Yang, Jian-jun title: COVID-19: a novel risk factor for perioperative neurocognitive disorders date: 2021-06-19 journal: Br J Anaesth DOI: 10.1016/j.bja.2021.06.016 sha: b6fb7a5de9252f36ff0fec7c66dfa804a42c8cf5 doc_id: 690840 cord_uid: hpzs0oce nan reliance on social security. 5 Interestingly, the enhanced expression of angiotensin-converting enzyme-2 (ACE-2) receptors in the central nervous system (CNS) of patients with dementia may make them more susceptible to COVID-19 ( Fig. 1 ). 6, 7 Clinical studies have identified advanced age, major surgery, low educational level, history of alcohol or opioid use, anticholinergic medication and pre-existing cognitive impairment as important risk factors for PND. 3, 8 The COVID-19 pandemic has significantly affected the epidemiological characteristics of many diseases, and COVID-19 must be considered a potential risk factor for acute or chronic neurological complications because the causative virus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is more invasive in the CNS than other coronaviruses. 9,10 Acute neurological symptoms associated with COVID-19, including confusion, headache, hypogeusia, hyposmia, and seizures, provide evidence of direct invasion by SARS-CoV-2 into the CNS. Most COVID-19 patients fully resolve from these acute symptoms after clinical recovery. 7 However, a small observational study showed that 33% of severe COVID-19 patients experienced cognitive and motor dysfunction, including inattention, disorientation, and poorly organized movements in response to command, even after hospital discharge. 11 Long-term neurological disorders have been observed in non-critical COVID-19 patients as well, although results are yet to be completed. 12 Moreover, COVID-19 may promote the initiation and progression of age-related progressive neurodegenerative conditions, such as Alzheimer's disease (AD). Preliminary observations have revealed that COVID-19 causes worsening of behavioural symptoms and potential gradual aggravation of the underlying AD neuropathologies and related dementia, which may take months or years to detect. [13] [14] [15] Support for a relationship between age-related neurodegenerative conditions and COVID-19 has yet to be reported because of the recent origin of the pandemic. Anaesthesia and surgery can disrupt the integrity of the blood-brain barrier (BBB) and facilitate migration of peripheral innate immune molecules into the hippocampus, and SARS-CoV-2 infection may accelerate this process. 16, 17 Neurotoxicity via ACE-2 receptors in the hippocampus can be caused by SARS-CoV-2 via its access to the CNS through retrograde axonal transport along the olfactory bulb and/or disrupted BBB (Fig. 1) . 7,9 SARS-CoV-2-mediated immune responses can also play a critical role in cognitive impairment through indirect CNS involvement. Furthermore, the molecular mechanisms, including significant neuroinflammation, mitochondrial oxidative stress, and accumulation of amyloid beta (Aβ), of SARS-CoV-2-induced cognitive disorders are similar to those of PNDs (Fig. 1) . 7, 8 Surgical trauma can trigger complement signalling activation in the CNS and subsequently activate microglia via CD11b signalling, which further increases SARS-CoV-2-mediated neuroinflammation. 9,18 A recent editorial suggested a correlation between PND and cognitive disorders associated with SARS-CoV-2 due to their overlapping inflammatory response to injury. 12 The authors stated that it may be beneficial to alleviate long-term neurological consequences of COVID-19 by implementing preventive interventions or treatments before surgery and anaesthesia, which could improve pre-existing poor cognitive and functional outcomes for COVID-19 patients. Increasing evidence suggests that mitochondrial dysfunction is involved in both PND and COVID-19. 8, 19 SARS-CoV-2 can enter cells via the ACE-2 receptor and affect mitochondria, causing increased fusion and excess production of reactive oxygen species, thereby damaging mitochondrial DNA and accelerating CNS oxidative stress. 19 Additionally, reports have suggested a critical role of Aβ accumulation in the brain in PND. 20 SARS-CoV-2 neuroinvasion could promote endothelial dysfunction and loss of pericytes (disrupted BBB), which can impair Aβ clearance and lead to excess Aβ generation in the hippocampus. 7,16 SARS-CoV-2 infection could directly induce Aβ generation in the CNS as part of the immune response; however, this hypothesis needs to be tested further. 7 Taken together, COVID-19 may potentially lead to an accelerated cognitive decline associated with anaesthesia and surgical stress through independent and synergistic mechanisms. COVID-19 soon could be recognised as a long-term risk factor for accelerated onset or deterioration of PND in the ageing population undergoing surgery. Future clinical research needs to consider COVID-19 as a potential risk factor for PND in the post-COVID-19 era. Long-term prospective longitudinal studies in elderly patients undergoing surgery and anaesthesia with concomitant or previous COVID-19 diagnosis should be designed to determine the effect of COVID-19 on the pathological progression of PND and other age-related dementias. Fig. 1 Mechanism of neuroinvasion by SARS-CoV-2, and the potential association between of SARS-CoV-2 infection, anaesthesia and surgery, and PND in cognitive impairment. Neuroinvasion by SARS-CoV-2 occurs through retrograde axonal transport along the olfactory bulb and/or disrupted blood-brain barrier. SARS-CoV-2 infection combined with anaesthesia and surgery may lead to significant neuroinflammation, excess mtROS, and amyloid beta accumulation that can cause hippocampus injury. Furthermore, PND may lead to enhanced ACE-2 expression in J o u r n a l P r e -p r o o f Hip Fracture Characteristics and Outcomes During COVID-19: A Large Retrospective National Database Review Should cognitive impairment be an exclusion criterion for hip fracture studies? Predictors of cognitive dysfunction after major noncardiac surgery Neuroinflammation and Perioperative Neurocognitive Disorders Long-term consequences of J o u r n a l P r e -p r o o f postoperative cognitive dysfunction Angiotensin-converting enzyme 2 (ACE2) is upregulated in Alzheimer's disease brain COVID-19 and Alzheimer's Disease Post-Operative Cognitive Dysfunction: An exploration of the inflammatory hypothesis and novel therapies SARS-CoV-2 mediated neuroinflammation and the impact of COVID-19 in neurological disorders Overview of COVID-19 and neurological complications Neurologic Features in Severe SARS-CoV-2 Infection The 'third wave': impending cognitive and functional decline in COVID-19 survivors COVID-19 Epidemic in Argentina: Worsening of Behavioral Symptoms in Elderly Subjects With Dementia Living in the Community COVID-19 as a risk factor for Alzheimer's disease and related dementia: A perspective from Detroit, MI Does SARS-CoV-2 infection cause chronic neurological complications? Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms Perioperative Neurocognitive Disorder: State of the Preclinical Science Neuroinflammation after surgery: from mechanisms to therapeutic targets Impact of COVID-19 on Mitochondrial-Based Immunity in Aging and Age-Related Diseases the hippocampus, making it more susceptible to SARS-CoV-2 infection. SARS-CoV-2 ACE-2, angiotensin-converting enzyme-2 PND, perioperative neurocognitive disorders mtDNA, mitochondrial DNA; mtROS, mitochondrial reactive oxygen species; IL-1β, interleukin-1β IL-6, interleukin-6 The authors declare that they have no conflicts of interest.