COVID-19 and Neurocognitive Disorders

Elizabeta B. Mukaetova-Ladinska; Golo Kronenberg; Ruma Raha-Chowdhury


Curr Opin Psychiatry. 2021;34(2):149-156. 

In This Article

Neuropathological Mechanism of Central Nervous System Damage in COVID-19 Infection and Their Relevance to Neurocognitive Disorder

Many viral infections can cause serious damage to the structure and function of the central nervous system (CNS), including severe encephalitis due to coronaviruses (CoVs), toxic encephalopathy caused by severe systemic viral infection (e.g. SARS-CoV and SARS-CoV-2) and severe acute demyelinating lesions developing after viral infection.[21] Some viruses (including the SARS-CoV-2) are neurotropic and can invade nervous tissues and cause infections of immune-functioning macrophages, microglia or astrocytes in the CNS.[22] Acute viral infection is also an important cause of this disease, exemplified by a respiratory infection caused by CoVs.[23] Patients with COVID-19 often suffer from severe hypoxia and viremia, which has the potential to cause toxic encephalopathy. Its clinical symptoms are complex and diverse: patients with a mild course of the disease may develop headache, dysphoria, mental disorder and delirium, whereas those seriously affected may experience loss of consciousness, coma and paralysis.[24,25]

Hypoxic Brain Injury

Severe pneumonia can result in systemic hypoxia leading to brain damage. The contributing factors include peripheral vasodilatation, hypercarbia, hypoxia and anaerobic metabolism with accumulation of toxic compounds. These can result in neuronal swelling and brain oedema, which ultimately result in neurological damage.[26,27]

Blood Circulation Pathway

Proteins of various viruses can often be detected in nervous system tissue samples (such as cerebrospinal fluid or brain), suggesting that viruses can directly invade the nervous system and cause neuronal damage.[28] A typical virus enters the CNS through the blood circulation, with the virus multiplying in the vasculature and choroid plexus.[29] The virus is subsequently released into the blood stream to reproduce in mononuclear macrophages throughout the body. The secondary release into the blood may increase the permeability of the blood–brain barrier through the produced cytokines, thereby promoting the virus to enter the brain and cause viral encephalitis.[28] The low detectable SARS-CoV-2 viral load in the brain tissue postmortem[30] argues for blood-derived viruses presence in some of them.

Neuronal Pathway

The neuronal pathway is an important vehicle for neurotropic viruses to enter the CNS. Viruses can migrate by infecting sensory or motor nerve endings, achieving retrograde or anterograde neuronal transport through the motor proteins, dynein and kinesins.[31] One of the important examples of a neuronal pathway is that of olfactory neuron transport. The unique anatomical organization of olfactory nerves and the olfactory bulb in the nasal cavity and in main olfactory bulb in forebrain effectively makes it a channel between the nasal epithelium and the CNS.[28] As a consequence, SARS-CoV-2 can enter the brain through the olfactory tract in the early stages of infection.[32] Anosmia and chemosensory dysfunction were reported as both one of the first clinical symptoms and being at least 10-fold more common in COVID-19 infection.[33] Although the neuroimaging reports are not conclusive, anosmia has been linked to atrophy[34] or hypometabolism of the olfactory bulb (Niesen et al., unpublished data), as well as transient morphological changes in the olfactory bulb.[35] These observed clinical and neuroradiological changes may be in particularly important for the early detection of post-COVID-19 NCDs, as olfactory dysfunction has been now associated with amnestic mild cognitive impairment in HIV adults.[36]

One of the dopaminergic pathways also originates in the olfactory bulb and it makes it, thus, another candidate for SARS-CoV-2 entry and propagation into the CNS. Dopaminergic receptors modulate the innate immune response to a viral infection (i.e. HIV,[37] Ebola virus,[38]) and some viruses, such as the Japanese Encephalitis Virus (JEV), utilize the dopaminergic signal transduction pathway to increase neuronal susceptibility to infection.[39] It is, thus, not surprising that these viruses (i.e. JEV) are found in dopaminergic rich areas, such as thalamus and the midbrain (reviewed in[40]) and therapies targeting dopamine receptors are also being investigated to mitigate viral infections.[38] SARS-CoV-2 may utilize the same pathway to gain entry in the human body[41] and also influence the autoimmune innate response.