**1. Introduction**

Since the onset of pandemics, our world has witnessed over 500 million confirmed cases of COVID-19 and over 15 million related (direct and indirect) deaths till date [1]. With the progression of the disease, severe and more complex processes like acute respiratory distress syndrome, cytokine storm, and NETosis may develop [2, 3]. This is the tip of the iceberg. Our knowledge about the disease manifestation is increasing day by day. A wide spectrum of illnesses vary from a simple cold and fever to multisystemic diseases. It has been reported that a hypercoagulable state, damage of renal tubule cells, and heart muscles are also associated with the development of COVID 19 [4–6].

Besides respiratory insufficiency, neurological complications like seizures, loss of consciousness, encephalitis, Guillain-Barre syndrome, acute necrotizing, hemophagocytic lymphohistiocytosis, acute ischemic cerebrovascular syndrome, anosmia, or ageusia as well as neuropsychiatric symptoms like headaches, nausea, dizziness, hallucinations, and depression have emerged as a significant cause for COVID-related morbidity and mortality [6–8]. Of note, these damages may significantly increase the incidence rate of other neurodegenerative diseases and foster dementia (**Figure 1**) [8].

Over the past few decades, different novel viral epidemics, such as influenza, Middle Eastern respiratory syndrome (MERS), and severe acute respiratory syndrome (SARS) have appeared, with the aid of zoonosis [9]. So far, various studies have been done to establish the link between viral infections and neurodegeneration disease. The most eminent of them is the 1918 influenza pandemic (Spanish flu) which coexisted with an increased rate of encephalitis lethargica, followed by postencephalitic Parkinsonism [10]. In recent times, multiple studies have indicated a possible relation between onset and/or worsening progression of PD and viral infections. Although the detailed mechanism of viral infections–induced neurodegeneration is still unclear, the role of the immune system or the direct effect of zoonosis cannot be overruled. Neurodegenerative diseases like PD and Alzheimer's disease (AD) are

#### **Figure 1.**

*Schematic representation of COVID-19-related symptoms. Primary pathogenesis associated with COVID-19 are shown in inner circle (in red). The outer circle (in blue) depicts the neurological manifestation related to COVID-19.*

*COVID-19 and Its Impact on Onset and Progression of Parkinson's and Cognitive Dysfunction DOI: http://dx.doi.org/10.5772/intechopen.105667*

mainly protein aggregation diseases in which specific proteins, such as α-synuclein (α-Syn) in PD and tau and Aβ peptide in AD aggregate together to form amyloids. Once triggered, the aggregation process begins to spread from cell to cell and continues to form and deposit amyloids that in turn hamper the brain function [9–11]. A detailed study on molecular pathogenesis of the acute and delayed neurological manifestations and establishment of the link between SARS-CoV-2 infections and the development of PD will be helpful to design the new therapeutic approach.

### **2. Brain expression of SARS-CoV-2 receptor and molecular pathogenesis**

The beta-coronaviruses are large enveloped non-segmented positive-sense RNA viruses. Like its related family members MERS-CoV (exploits dipeptidyl peptidase 4), and SARS-CoV-1, SARS-CoV-2 utilizes its specific proteins, in particular, Spike (S) protein, to bind to a number of host proteins (virus receptors) that assist in its entry [12]. Distributions of host receptors on various tissues are generally believed to decide the virus tropisms within the host cell. For an efficient host cell entry similar to SARS-CoV-1, SARS-CoV-2 uses angiotensin converting enzyme-2 (ACE2) type 1 transmembrane receptors as the major docking receptor followed by proteolytic processing of the spike protein by transmembrane protease serine 2 (TMPRSS2) [13]. Targeting of different cell types by the viral protein has been partially attributed to the distribution ACE2 receptors on the endothelial and epithelial cells of the respiratory system, as well as on immune cells. Along with that, expression of ACE2 is widely found in lung parenchyma, vasculature, heart, kidney, and the gastrointestinal tract [14, 15]. Expression of ACE2 receptors is widespread within brain structures, such as the central nervous system, in human brain vessels, pericytes and smooth muscle cells in the vascular wall, hypothalamus, and visual tracts, which are associated with the various neurological symptoms in coronavirus disease 2019 (COVID-19) infection [10, 11, 14]. However, data mining study of human brain single-nuclear RNA sequencing (RNA-seq) data has also found the expression of ACE2 receptors in the choroid plexus and neocortical neurons, in less amount [16]. Even presence of non-canonical SARS-CoV-2 receptors in other brain cell types makes them vulnerable to the virus.

Interaction with viral S protein and ACE2 receptors on the vascular endothelial cells leads to disruption of the blood-brain barrier, resulting in consequent cerebral edema and microhemorrhages. In addition to this, SARS-CoV-2 may expend direct neuronal damage due to the affinity of the spike S1 protein toward ACE2 receptors expressed on neurons. In short, the virus can utilize two possible pathways for invasion into the brain, either through retrograde axonal transport (olfactory route) or by crossing the blood-brain barrier [17]. Furthermore, production of SARS-CoV-2-associated cytokines, such as interleukin (IL)-6, IL-17, IL-1b, and tumor necrosis factor (TNF), are able to disrupt the BBB [18] and could facilitate the viral entry. Even in some studies SARS-CoV-2 has been predicted to induce infection in cerebral endothelial cells as well as inflammation in peripheral vessels [19], but direct evidence has not been far provided. Co-morbidity factors like cardiovascular risk factors and/or pre-existing neurological diseases could alone or in combination with cytokines intensify the rate of BBB permeability [18]. Nonetheless, viruses are able to enter the brain by carried by infected immune cells that also act as a reservoir [20]. Neutrophils T cells and Monocytes, may traffic into the brain through the vasculature, whereas the meninges and the choroid plexus [21], could be considered as entry points for infected immune cells. In COVID-19 loss of smell is considered a frequent

neurological manifestation that is consistent with infection of the olfactory system. The internalization of the virus in nerve terminals by endocytosis, transportation retrogradely, and spread trans-synaptically to other regions of brain, has been studied in other coronaviruses [22]. Detection of ACE2and TMPRSS2 in the nasal mucosa at both RNA and protein levels increases the chance of involvement of olfactory neurons in viral transmission. The hypothalamus could contribute to the dysregulation of the immune cells. In COVID-19, upregulation of cytokines like IL-6, IL-1b, and TNF act as the activators of the hypothalamic-pituitary-adrenocortical (HPA) axis. This HPA axis acts as the center of the systemic immune activity regulation and is activated by BBB dysfunction and neurovascular inflammation [23].

However, apart from ACE2, SARS-CoV-2 can utilize neuropilin-1 (NRP1) and basigin (BSG; CD147) as docking receptors, whereas a variety of proteases such as cathepsin B and L,TMPRSS11A/B, and furin (FURIN) have been shown to promote viral cell entry as well as replication within the host cell [24–26]. Exposure of brain tissue to COVID-19-related injuries like hypercoagulable states, inflammation, hypoxia, immune response (cytokine storm), or dyselectrolytemia is thought to play the main role in the cerebral pathomechanism of viral damage and cause all the neurodegenerative conditions like AD and PD [27].

### **3. Molecular link between COVID-19 and Parkinson's**

Parkinson's disease (PD) is a neurodegenerative disorder, defined as α-synucleinopathy that affects 1% of the population aged above 60 years with an annual incidence of 15 per 100,000 populations. It is a disorder of the central nervous system (progressive loss of dopamine neurons) that mainly affects the motor system, particularly, the nigrostriatal pathway. Therefore, the major PD symptoms include tremor, bradykinesia/akinesia, rigidity, and postural instability. The clinical manifestations of PD also include non-motor symptoms (NMS) such as dementia, anxiety, depression, fatigue, and others [28]. The major pathological features of PD include selective loss of dopaminergic neurons in the substantia nigra pars compacta and aggregation of protein (called Lewy neurites and Lewy bodies) consisting mainly of α-syn proteins present in neurons [29, 30].

Alpha-synuclein (α-syn), is a small protein (forms an α-helix-rich tetramer) that comprises of 140 amino acids, and the human *SNCA* gene encodes them. Expression of α-syn takes place in the central nervous system (CNS) and is mainly localized in synapses and nuclei. Although the exact function of α-syn is not clearly explained yet, various studies have shown that maintaining synaptic plasticity, vesicle trafficking, and interaction with synaptic vesicles as well as physiological regulation of vesicle recycling is regulated by α-syn [30–32]. The major biological function of α-syn is employed through the non-amyloid-beta component (NAC), N-terminal, and C-terminal domains. The KTKEGV motif is present in the N-terminus that maintains tetramerization of α-syn, and mutations in this motif lead to neurotoxicity. NAC is a highly hydrophobic domain and was first identified in patients with AD. It forms a β-sheet structure for α-syn aggregation. The C-terminus of α-syn is a proline-rich region domain that helps in interaction with other proteins [30, 33]. Misfolded or unfolded α-syn protein forms fibrillar aggregates that generate insoluble inclusions in the affected neurons and glial cells. Aggregated α-syn can induce other pathological features, such as mitochondrial dysfunction, dysregulation of calcium homeostasis, endoplasmic reticulum (ER) stress, neuroinflammation, Golgi fragmentation,

#### *COVID-19 and Its Impact on Onset and Progression of Parkinson's and Cognitive Dysfunction DOI: http://dx.doi.org/10.5772/intechopen.105667*

lysosomal dysfunction, and impaired protein quality control that lead to neuronal toxicity [30, 33–35]. The non-neuronal cells present in the brain are called Gila cells that play a critical role in maintenance of the neuronal system. Glia cells are comprised of microglia, astrocytes, and oligodendrocytes in the CNS. The glial cells comprise a majority of brain cells, and they regulate neurogenesis and synaptogenesis. Furthermore, glial cells influence the development and function of brain-blood barrier (BBB) by interactions with endothelial cells and neurons to protect the brain from pathogenic attacks [30, 33]. Although the major function of astrocytes and microglia involves the immune response but under pathological conditions, they seem to be activated by specific stimuli. Upon activation, microglia and astrocytes can release pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), IL-2, IL-4, interleukin-6 (IL-6), and also causes reduced levels of neurotrophins, like nerve growth factor and brain-derived neurotrophic factor (BDNF) that lead to the reactive oxidative stress (ROS) production followed by BBB dysfunction. Intercellular crosstalk between these factors induces neuronal cell death and engenders neurodegenerative diseases such as AD or PD [30, 33, 36].

In patients with PD/parkinsonism, the COVID-19 pandemic has had an indirect and negative impact that might be explained by the dopamine-dependent adaptation hypothesis. Due to the pandemic, there is a change in daily life and routine; therefore, flexibility in cognitive (and motor) functions is required to adapt to such changes. Even pharmacodynamic effects, social isolation, stress, and anxiety as well as prolonged immobility have detrimental effects on motor and non-motor symptoms and quality of life in PD. In patients with PD, damage to nigrostriatal dopamine neurons results in lower cognitive as well as motor neuron flexibility. Such patients often experience confusion and increased psychological stress, which can lead to the worsening of parkinsonism symptoms as well as mental illnesses such as anxiety and depression [37]. The development of permanent or transient Parkinsonism followed by a viral might occur through different mechanisms:


There are fundamental clinical and anatomopathological differences present in each of these instances [37, 38].

The onset of transient parkinsonism has been associated with many viral infections including West Nile Virus, Japanese Encephalitis, Western Equine virus, Coxsackie virus, Epstein Barr virus, HIV, and currently SARS- CoV-2. Expression of high level ACE2 receptor on the midbrain dopamine neurons could facilitate entry of SARS-CoV-2 that can alter the expression of alpha-synuclein [39–41]. Since elevated alpha-synuclein levels can promote aggregation of the protein, this could predispose an infected patient to PD down the line. Various experimental models also suggest that SARS-CoV-2 may interact with different proteins in age-related pathways (lipid

metabolism, proteostasis, mitochondrial function, and stress responses) [37, 40]. Dysfunction of these pathways could lead to alpha-synuclein aggregation and selective neurodegeneration. Even elevated cytokines (the primary mediators of inflammation in SARS-CoV-2) can accelerate the neurodegeneration in PD [41]. Studies revealed that the release of cytokines may activate the resident immune cells in the CNS. Activation of immune cells leads to their infiltration including activated T cells and microglia from the periphery that may kill neurons, astrocytes, and vascular cell types. Elevated levels of pro-inflammatory cytokines, such as TNF and IL-1beta, are also associated with increased risk of PD [41].

A current study has established the possible mechanism of triggering PD followed by COVID-19 infection. Virus-initiated amyloid-formation of α-synuclein acts as the main cell-toxic agent in the death of dopamine-producing neurons in the brain. By interacting with amyloidogenic regions with nucleocapsid protein (that encapsulates the RNA genome inside the virus), SARS-COV-2 speeds up the formation of amyloid fibrils. In the context of Alzheimer's disease, it has been speculated that amyloid fibrils are formed as an immune response to an infection, and neutralizing pathogens. A similar mechanism may play a role in progression of PD. In a current study, test tube experiments have shown that SARS-CoV-2 spike protein (S-protein) has no effect on α-synuclein aggregation, whereas SARS-CoV-2 nucleocapsid protein (N-protein) considerably speeds up the aggregation process That results in formation of multiprotein complexes and eventually amyloid fibrils that disturb the α-synuclein proteostasis and increase the rate of cell death (**Figure 2**) [42, 43].

As the cases of PD rises sharply in the older age group, particularly in those over the age of 80 years, a personalized approach to the clinical management of PD patients affected by COVID-19 is need of the hour. In addition, disturbance of α-synuclein proteostasis might be considered the first step toward nucleation of fibrils. Direct

#### **Figure 2.**

*Schematic representation of neuroinflammation and neurodegeneration due to SARS-CoV-2 infection. A immunological crosstalk between different organs. Created with BioRender.com.*

interaction between the N-protein of SARS-CoV-2 and α-synuclein establishes a molecular link between virus infections and Parkinsonism. This piece of puzzle thus suggests that SARS-CoV-2 infections may have prolonged implications and consider N-protein as an attractive alternative target in designing novel vaccination strategies.
