**4.2 Systemic inflammation and acute respiratory distress syndrome**

During the COVID-19 disease process, cytokine storm causes severe systemic inflammation [14]. Increased interleukin-1 (IL-1) and other mediators in the systemic circulation are major factors in systemic inflammation associated with COVID-19 [40, 41]. Increased proinflammation causes a vasculitic process, impaired capillary permeability and diffuse vascular thrombosis. This process causes damage to the blood-brain barrier. In addition, microglial inflammation is activated [42]. Neurological symptoms occur as a result of all these mechanisms. In the early period, delirium and seizures have been described [3]. Besides, increased inflammation may be associated with cerebrovascular diseases. As a result, a cerebral hypoxic-ischemic process is induced [5]. The possible causal elements of inflammatory factors on cognitive symptoms associated with COVID-19 disease are figured (**Figure 2**).

It is known that there is a relationship between cognitive disorders and increased inflammation. In a study evaluating Alzheimer's patients and the control group, a correlation was detected between cognitive impairment and increased systemic inflammation [43]. Long-term cognitive dysfunction is more common in patients with severe inflammatory disease. In addition, neurocognitive dysfunction associated with inflammation is higher in patients with neurodegenerative disease [44, 45].

The relationship between C-reactive protein (CRP) level and cognitive dysfunction was investigated in patients with COVID-19 disease. A positive correlation was determined between increased CRP level and cognitive impairment [46].


#### **Table 1.**

*The pathophysiological mechanisms of neurocognitive dysfunction in COVID-19 disease.*

*COVID-19 Pandemic and Neurocognitive Process: New Scenarios for Understanding… DOI: http://dx.doi.org/10.5772/intechopen.106687*

These results were evaluated in another study. The relationship between CRP levels and cognitive impairment was confirmed. In the same study, the relationship between cognitive dysfunction and CRP level was also demonstrated over a long period. Disease-related respiratory failure and hypercapnia are the causes of increased IL-1 levels. These results are associated with cognitive impairment [47].

In a study from China with a large patient population, hospitalization was indicated in 19% of COVID-19 patients. In addition, ARDS was detected as a major indication for hospitalization associated with COVID-19 disease [48]. Post-ARDS cognitive impairment is not only associated with COVID-19 disease. Other diseases can also cause cognitive impairment after ARDS [49]. Neurocognitive impairment after ARDS is associated with hypoxia, induced hyperinflammation, and hemodynamic instability. Meta-analyses and studies have reported that neurocognitive dysfunction after ARDS has a high incidence. The incidence of neurocognitive dysfunction is 70−100% at the time of hospital discharge, 46−80% one year after discharge and 20% five years after discharge [49]. In addition, mechanical ventilation without ARDS is associated with long-term cognitive dysfunction and poor quality of life. Sedative treatments for mechanical ventilation are also associated with long-term cognitive impairment [50]. The evidence for the isolation of the virus directly from the cerebrospinal fluid (CSF) is insufficient [14]. There is a relationship between all these pathophysiological mechanisms. These mechanisms are complex and they create cognitive dysfunction.

#### **4.3 Direct neurotropism**

The investigations are limited about the direct invasion of the SARS-CoV-2 virus to central nervous system. However, it is thought that SARS-CoV-2 may invade neuronal tissue similar to other coronaviruses [51, 52]. Rare investigations have reported evidence of SARS-CoV-2 in the CSF examination [30, 53]. There are some mechanisms for the invasion of the virus (SARS-CoV-2) into the central nervous system However; these mechanisms are not definitive evidence. All mechanisms are explained in 3 main pathways.

The first pathway is direct retrograde neuronal transmission via olfactory neurons. It is known that the sense of smell and taste associated with SARS-CoV-2 is reduced. This is the first symptom of the disease in some COVID-19 patients. The smell impairment is explained by direct invasion of the mucosal epithelium and olfactory nerves [54]. Direct invasion is associated with angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) receptors. SARS-CoV-2 has a high affinity for ACE2 receptors [55]. Experimental studies about SARS-CoV confirmed neuronal transmission to the brain via the olfactory bulb. Structural and/or functional changes associated with COVID-19 have been reported in several areas of the brain (entorhinal cortex and hippocampus). Neuronal dysfunction associated with this process has been demonstrated [24].

The second pathway is hematogenous spreading. Some researchers report that the virus may cause cognitive disorders by direct hematogenous spread via the cerebrovascular pathway [5]. There is some data that SARS-CoV-2 has been detected in the blood samples of some COVID-19 patients. Functional (ACE2) receptors of SARS-CoV-2 are higher in endothelial cells and pericytes [56, 57]. The interaction of the virus with these receptors is the first step towards neuronal dysfunction. Delayed neurotropic features of SARS-CoV-2 induce major etiopathogenetic mechanisms for cognitive deficits and neurological symptoms [3]. Induced interleukins, tumour necrosis factor (TNF) and other inflammatory cytokines associated with SARS-CoV-2 may disrupt the endothelial structure of the blood-brain barrier [58]. This process contributes to a major neuroinvasion.

The third pathway is immune-mediated neuronal spreading. In a SARS-CoVrelated study published in 2005, it was demonstrated that viral particles were detected in monocytes and lymphocytes [59]. Immune system cells may cause direct brain damage via ACE-2 receptors [60]. However, direct immune cell infiltration was not detected in the brain with pathological investigation after autopsy [60].
