Cognitive impact of COVID-19: looking beyond the short term

Abstract

COVID-19 is primarily a respiratory disease but up to two thirds of hospitalised patients show evidence of central nervous system (CNS) damage, predominantly ischaemic, in some cases haemorrhagic and occasionally encephalitic. It is unclear how much of the ischaemic damage is mediated by direct or inflammatory effects of virus on the CNS vasculature and how much is secondary to extracranial cardiorespiratory disease. Limited data suggest that the causative SARS-CoV-2 virus may enter the CNS via the nasal mucosa and olfactory fibres, or by haematogenous spread, and is capable of infecting endothelial cells, pericytes and probably neurons. Extracranially, SARS-CoV-2 targets endothelial cells and pericytes, causing endothelial cell dysfunction, vascular leakage and immune activation, sometimes leading to disseminated intravascular coagulation. It remains to be confirmed whether endothelial cells and pericytes in the cerebral vasculature are similarly targeted. Several aspects of COVID-19 are likely to impact on cognition. Cerebral white matter is particularly vulnerable to ischaemic damage in COVID-19 and is also critically important for cognitive function. There is accumulating evidence that cerebral hypoperfusion accelerates amyloid-β (Aβ) accumulation and is linked to tau and TDP-43 pathology, and by inducing phosphorylation of α-synuclein at serine-129, ischaemia may also increase the risk of development of Lewy body disease. Current therapies for COVID-19 are understandably focused on supporting respiratory function, preventing thrombosis and reducing immune activation. Since angiotensin-converting enzyme (ACE)-2 is a receptor for SARS-CoV-2, and ACE inhibitors and angiotensin receptor blockers are predicted to increase ACE-2 expression, it was initially feared that their use might exacerbate COVID-19. Recent meta-analyses have instead suggested that these medications are protective. This is perhaps because SARS-CoV-2 entry may deplete ACE-2, tipping the balance towards angiotensin II-ACE-1-mediated classical RAS activation: exacerbating hypoperfusion and promoting inflammation. It may be relevant that APOE ε4 individuals, who seem to be at increased risk of COVID-19, also have lowest ACE-2 activity. COVID-19 is likely to leave an unexpected legacy of long-term neurological complications in a significant number of survivors. Cognitive follow-up of COVID-19 patients will be important, especially in patients who develop cerebrovascular and neurological complications during the acute illness.

Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment

“…The negative effects of COVID-19 on the CNS may have a long-term impact that could possibly increase the likelihood of developing AD-like dementia [1, 2, 4, 5, 112]. Here, we investigated the potential mechanisms for this effect.…”

“…For example, after the severe acute respiratory syndrome (SARS-CoV-1) outbreak in 2002 and the Middle East respiratory syndrome (MERS) outbreak in 2012, both caused by human coronaviruses (HCoVs), 20% of recovered patients reported ongoing memory impairment [3]. Evidence now supports similar complications after COVID-19, which due to the global pandemic, is poised to potentially lead to a surge in cases of Alzheimer’s-like dementia or other forms of neurocognitive impairment in the near future [4, 5].…”

Long-term neurological manifestations of COVID-19: prevalence and predictive factors

“…The complex interaction between physical and brain resilience and long-term disability after hospitalization has been indeed already demonstrated for other infectious diseases, such as community-acquired pneumonia 16 . In fact, we need to acknowledge that the experience of hospitalization due to COVID-19 infection in frail elderly should is an important confounding factor-as it can influence the relationship between long-term manifestations and psychosocial long-term disturbances 17-19 .…”

Epidemiology and organ specific sequelae of post-acute COVID19: A narrative review

“…There is cumulative evidence that COVID-19 affects brain function and could exacerbate neurodegenerative and neuroimmune disorders [79][80][81]. CNS and peripheral neural system (PNS) symptoms have been attributed to SARS-CoV-2 neurotropism, post-viral immune-mediated process, or neurological manifestations of systemic and non-specific inflammatory effects [82,83].…”

“…The CNS damage is not specific to SARS-CoV-2, as several post-acute and long-term neurologic manifestations have been reported during pandemics with influenza and other coronaviruses (SARS, MERS) (Table 3). Direct neuro-invasion, neuronal injury secondary to tissue hypoxia or inflammation, local cytokine network dysregulation, and compromised blood brain barrier integrity with resulting transmigration of infected immune cells have been postulated as pathophysiological mechanisms underlying longterm neurological sequalae after coronavirus infections [81,91].…”