**4. Neuro-COVID: neurological consequences of COVID-19 disease**

Reports of neurological complications during COVID-19 infection and their persistence after the recovery have accumulated since the early outbreak. These impairments are broadly categorized as Neuro-COVID. Early investigation in China estimated that 36% of the COVID-positive patients had neurological disturbances [83]. Case test studies from France, performed in March–April 2020, also highlighted the occurrence of encephalopathy, state of confusion, and agitation as well as corticospinal tract symptoms in COVID-19 patients admitted to the hospital due to Acute Respiratory Distress Syndrome (ARDS) [84]. Since then, numerous reports and case studies from across different countries have confirmed the prevalence of mild-to-severe neurological and neuropsychiatric in the CoV-2-infected individuals. The neurological impact correlated with the severity of the infection and distributed across the categories of CNS pathologies, peripheral nervous system (PNS) diseases, and/or skeletal muscular disturbances. A cohort-based longitudinal study by the UK Biobank involving multimodal brain imaging before and after the CoV-2 infections

showed emergence of virus-related abnormalities in specific brain regions and cognitive decline upon infection [2]. Using diffusion imaging-based changes as a readout for brain tissue damage upon infection, they observed detrimental effects in regions including the olfactory-limbic areas, the anterior olfactory nucleus, olfactory tubercle, and the anterior piriform cortex. Profound decrease in the gray matter thickness and contrast was also observed in parahippocampal gyrus and lateral orbitofrontal cortex of the patients. Brain abnormalities were more pronounced in hospitalized patients; however, cognitive decline associated with damage to crus II lobule of the cerebellum was found in majority of the individuals who turned positive for the CoV-2 in this longitudinal study [2]. As virus takes the olfactory route, chemosensory impairments are often seen in a large number of infective cases. These impairments, primarily, anosmia and ageusia, have not only served as the robust predictors of the CoV-2 infection, but also affected quality of life of the patients, recovered individuals, and healthcare workers [85, 86]. We will focus on different aspects that influence the severity and durability of the Neuro-COVID symptoms in the following subsections.

#### **4.1 Effect of age and comorbidities on the neurological sequalae**

The neurological symptoms tend to vary between older (>60 years of age) and younger (<18 years of age) cohorts. While delirium, myalgia, and fatigue were predominant in older cohorts, the younger cohorts primarily reported smell and taste issues, frequent headaches, and infrequently, seizures [66]. This also hinted toward the possibility of comorbidities playing a role in increasing the severity of the effect of the viral infection and tropism. Patients with preexisting neurological conditions had a higher occurrence of hospitalization, in-hospital mortality, enhanced delirium states, and more overall complications upon suffering from COVID-19 [87, 88]. In fact, social isolation and loneliness associated with the pandemic-induced quarantine added to the mental toll of elderly patients [89]. Symptoms worsened with quarantine in 67.5% patients suffering from Parkinson's disease in a Spanish cohort study [90]. Acute encephalopathy due to infection was more commonly observed in older patients with comorbidities and associated with greater critical care and 30-day mortality chances [87, 91]. Across different levels of the neurological impairments upon CoV-2 infection, age has been shown to be positively correlated with the disease severity [92]. Comorbid conditions including de-myelinating disease, acute encephalopathy, and cerebrovascular disease (CVD) were all positively correlated with the severity of the COVID-19 disease [93]. Patients suffering from Alzheimer's, Parkinson's, and other neurodegenerative disorders are at higher risk from infection and can suffer from greater respiratory, olfactory, and cognitive impairments than others [89, 94]. Elderly individuals also suffer from compromised immunity and increased signs of inflammation (increased cytokines, hormonal changes, decrease in growth factors production) leading to physical and mental frailty [92]. Such multiple dysregulations can lead to age-dependent morbid effects of CoV-2 infection.

#### **4.2 Chemosensory and cognitive impairments: neuro-COVID to Long COVID**

Among many neurological impairments, olfactory functioning changes in COVID-19 has highest odds ratio in non-hospitalized cases [86, 95]. These have also become common in healthcare workers. In a study comprising 700 workers, by utilizing a chemosensory perception test, over 80% displayed olfactory and gustatory impairments and ~48% had lowered trigeminal sensitivity. The reduced sensitivity

#### *Neurotropic SARS-CoV-2: Causalities and Realities DOI: http://dx.doi.org/10.5772/intechopen.108573*

remained in over 40% of the individuals with olfactory and gustatory impairments and ~23% in those with trigeminal issues [85]. "COVID & Cognition" cross-sectional study continually aims to understand the cognitive deficits in Long COVID [96]. Long COVID comprises long-lasting symptoms and difficulties arising due to COVID-19. Post-acute COVID persists between 3 and 12 weeks while chronic COVID is when the symptoms persist beyond 12 weeks [72]. Cognitive deficits are expected based on the loss of gray matter in specific regions prevalent in COVID-19. A small cohort study of hospitalized patients displayed gray volume reductions in the hippocampus, right amygdala, and left cingulate cortex. Cognitive deficits are thereby likely to occur, and the extent of it depends on the location and mechanism of the neural damage [97]. A multi-domain impact of the infection on human cognition was also observed in a large population, questionnaire-based study using British Intelligence tests. The cognitive deficits in reasoning, problem-solving, spatial planning, and target detection tasks were substantial and persisted post-infection suggesting that cognitive deficits are indeed prevalent in Long COVID [98]. Cognitive blunting, from mild-to-severe, also referred to as "brain fog" has also been observed in Long COVID. Fluorodeoxyglucose-PET study from two COVID-19 patients with confirmed brain fog and cognitive deficits confirmed abnormal hypometabolic regions in anterior cingulate cortex. Hypometabolisms are also observed in other neurological disorders and psychiatric diseases [99]. The prevalence of chemosensory deficits suggests that they can act as predictors of the COVID-19 infection, which has been elaborated upon, in the next section. The advancements in precisely determining neurocognitive deficits along with sensory impairments non-invasively are also explained.
