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.

Keywords: Angiotensin receptor blockers; Angiotensin-converting enzyme inhibitors; Angiotensin-converting enzyme-2; COVID-19; Cognitive impairment; Dementia; SARS-CoV-2; Stroke; White matter ischaemia.

Fig. 1

Mechanisms of cerebrovascular damage in COVID-19. a The virus reaches the central nervous system through inhalation (1) and lung infection followed by haematogenous spread (2), or through the nasal mucosa and olfactory nerve fibres (3). b A high proportion of COVID-19 patients with severe disease develop cerebrovascular disease. In addition to hypoxic-ischaemic brain damage from compromised respiratory and cardiovascular function, the virus may cause large-vessel stroke, multiple small infarcts and foci of haemorrhage, and diffuse ischaemic white matter damage and oedema. Putative mechanisms are illustrated in the diagram. c Already, considerable progress has been made in preventing or ameliorating cerebrovascular damage in COVID-19. Some of the approaches are listed here

Fig. 2

Altered balance between the classical and regulatory parts of the renin-angiotensin system (RAS) in COVID-19. a Ang-II is formed by the ACE-1-mediated cleavage of Ang-I. The binding of Ang-II to AT1R within the vasculature not only induces vasoconstriction but also affects vascular permeability and neurovascular coupling and promotes neuroinflammation and oxidative stress within the CNS. Under normal circumstances, these actions are counteracted by ACE-2 activity, which leads to the production of Ang-1-9 and Ang-(1-7) and the activation of MasR. b Internalisation or cleavage of membrane-bound ACE-2 following the binding and cell entry of SARS-CoV-2 virus leads to downregulation of the regulatory RAS and overaction of the classical RAS, driving vascular dysfunction, inflammation, oxidative stress and CNS injury in COVID-19