Can SARS-CoV-2 Infection Lead To Neurodegeneration And Parkinson’s Disease? Part 1

Abstract: 

The SARS-CoV-2 pandemic has affected the daily life of the worldwide population since 2020. Links between the newly discovered viral infection and the pathogenesis of neurodegenerative diseases have been investigated in different studies. 

With the development of society, people are paying more and more attention to the importance of health problems, especially viral infections. Viral infections can have many negative effects on our bodies, but what many people may not have thought about is that viral infections can also have an impact on our memory. While this may sound scary, don't worry too much because in most cases there are steps we can take to prevent and avoid this effect.

First, we need to understand the mechanism by which viral infection affects memory. Generally speaking, viruses invade our bodies through multiple pathways, including respiratory tract, digestive tract, blood, etc. When a viral infection attacks our body, our immune system is activated and begins to fight off the viral infection. During this process, our bodies produce some hormones, such as adrenaline and cortisol, which have a certain impact on our cognition and memory.

We know that adrenaline and cortisol increase our arousal and alertness so that we can fight off viral infections, but if this state of arousal persists for an extended period, it can hurt our brains. People who are chronically stressed may experience problems such as long-term memory loss and reduced working memory, which is why many people experience fatigue and lack of energy after infection.

However, we don't need to worry too much about these issues. First, we can help our bodies cope with viral infections by focusing on getting enough sleep and exercise to stay in good shape. Secondly, we can use some relaxation techniques, such as deep breathing, meditation, etc., to help us control our emotions and mental state and reduce stress and tension.

Finally, we need to understand the fact that a healthy body is the foundation of a healthy brain. As long as we maintain good physical condition, we can enjoy better memory, cognition, and quality of life. Therefore, we should pay attention to a healthy diet, eat more foods rich in vitamins, minerals, and antioxidants, and reduce the intake of sugary and high-fat foods, thereby minimizing the risk of viral infection while protecting our body and brain.

In short, viral infection has a certain impact on our memory, but as long as we actively take preventive measures and maintain good physical condition, we can reduce the impact of viral infection on our brain health, allowing us to have better memory and enjoy a better life. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory because Cistanche deserticola is a traditional Chinese medicinal material that has many unique effects, one of which is to improve memory. The efficacy of Cistanche deserticola comes from the multiple active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc. These ingredients can promote brain health through a variety of pathways.

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This review aims to summarize the literature concerning COVID-19 and Parkinson's disease (PD) to give an overview of the interface between viral infection and neurodegeneration on this current topic. 

We will highlight SARS-CoV2 neurotropism, neuropathology, and the suspected pathophysiological links between the infection and neurodegeneration as well as the psychosocial impact of the pandemic on patients with PD. 

Some evidence discussed in this review suggests that the SARS-CoV-2 pandemic might be followed by a higher incidence of neurodegenerative diseases in the future. However, the data generated so far are not sufficient to confirm that COVID-19 can trigger or accelerate neurodegenerative diseases.

Keywords: 

Parkinson's disease; COVID-19; SARS-CoV-2; neurodegeneration; Alzheimer's disease; viral infection.

1. Introduction

This review aims to summarize the data on the link between COVID-19, other viral infections, and Parkinson's disease. 

Therefore, different mechanisms of the SARS-CoV-2 virus affecting cerebral functions and inducing neurodegeneration have to be considered. First, a direct neurotoxic effect of the virus resulting from neuroinvasion is possible as well as secondary effects due to systemic inflammatory alterations. 

In the first section, we present the knowledge on SARS-CoV-2 neurotropism, neuropathology, neuroinflammation, and changes in levels of biomarkers that have been observed during infection. 

This is followed by a brief overview of the connection between other viral infections and neurodegenerative diseases. In the third chapter, we highlight the link between COVID-19 and neurodegeneration focusing on Parkinson's disease (PD) and cognitive dysfunction/Alzheimer's disease (AD). 

At last, we discuss how the pandemic has influenced symptoms and psychosocial aspects in PD patients underlining the tremendous impact that the infection has had especially on people with preexisting neurological conditions and disabilities.

2. Methods

Literature research for this review was done in PubMed using the search terms "COVID-19", "SARS-CoV-2", "Parkinson's disease", "Alzheimer's disease", "neurodegeneration", "viral infection" and "infection" in different combinations. 

Only articles published in English in international peer-reviewed journals were included in the selection process. Articles were selected by screening the abstracts for eligibility; publications contributing relevant data to the core content of this review were included.

3. Chapter 1

3.1. SARS-CoV-2 Neurotropism

SARS-CoV-2, the cause of the current pandemic, belongs to the well-known family of Coronaviridae. Previously defined Coronaviridae (HCov-OC43, HCov-229E, SARS-CoV, MERS-Cov) were detected in human brain samples, which proves their neurotropism and their ability to cause persistent infections of the central nervous system (CNS) [1–3]. 

As early as 1999 it was shown in vitro that neuroblastoma, neuroglioma, and glial cells were susceptible to infection with human Coronaviridae and that the infection could persist for at least 130 days of culture time [2]. In animal models, this persistent infection led to neuronal loss and long-term sequelae such as reduced activity and hippocampal neuronal volumes as signs of a neurodegenerative phenotype [4–6]. 

There is an ongoing debate about whether SARS-CoV-2 can enter and persist in cerebral structures. Indeed, some data support the theory of SARS-CoV-2 neurotropism that will be outlined in the following paragraphs. The ACE-2-receptor was identified as one of SARS-CoV-20 s most common entry receptors [7]. However, it is not highly expressed in the brain compared to other tissues [7]. 

Its expression in the CNS was shown on glial cells (astrocytes), capillary endothelium, monocytes/macrophages, and neurons [8,9]. A comparably high expression of ACE-2-receptor was detected in brainstem areas leading to the hypothesis that SARS-CoV-2 invasion might impair brainstem structures involved in regulating cardiovascular functions [10]. 

An infection of ACE-2-receptor transgenic mice also led to the expression of viral antigens in neurons especially in the thalamus, cerebrum, and brainstem, while the cerebellum remained uninfected [5]. The affected brain areas showed neuronal loss and microglial activation in the absence of other inflammatory signs [5]. In contrast, there is increasing evidence that the ACE-2 receptor may not be the primary way of invasion into the CNS. 

Instead, other receptors such as neuropilin 1 (NRP-1) could contribute substantially to the invasion of SARS-CoV-2 into cerebral structures [11–13]. NRP-1 was found to be highly expressed in neurons and astrocytes [12]. 

Three main routes are speculated to lead to SARS-CoV-2 invasion into the CNS that are presented below [10,11,14–18]. The first possible way of viral invasion is the transneural way starting in the nasal epithelium and the olfactory nerves and progressing into the brain via axonal transport [5,14,19]. 

This route of neurotropism was shown for SARS-CoV and HCov-OC43 after intranasal infection [4,20]. In transgenic ACE-2-receptor-expressing mice, intranasal infection with SARS-CoV resulted in neuronal loss [3,20]. Additionally, the mouse equivalent of the human coronavirus, the mouse hepatitis virus, entered the brain via the olfactory nerve after intranasal inoculation [21]. 

Supporting this idea of neurotropism is the fact that COVID-19 frequently causes olfactory dysfunction (OD). A wide variation in the incidence of OD associated with COVID-19 (5–98%) was observed mostly due to missing objective testing [22]. 

An Iranian study using objective smell testing in 60 COVID-19 patients revealed that 98% demonstrated smell loss, but only 35% were subjectively aware of their OD, which underlines the importance of objective testing for this symptom [23,24]. Gustation dysfunctions are also common in COVID-19 and can be confused with olfactory problems [25]. OD appears to be a very early symptom in the course of COVID-19 [26]. 

In general, two mechanisms can lead to OD: First, an obstruction of the olfactory cleft by swelling or rhinorrhea, which could not be detected in COVID-19 patients [24,25,27]. Secondly, defects of sensorineural transmission can impair the sense of smell [25]. 

A detailed imaging study using CT and MRI on COVID-19 patients with prolonged OD (minimum 1 month) revealed decreased volumes of the olfactory bulb (43.5%) and shallow olfactory sulci (60.9%) as evidence for this underlying pathology of OD in COVID-19 [27]. 

However, ACE-2 receptors are absent in olfactory sensory neurons and can only be found in supporting cells such as sustentacular cells and horizontal basal cells (reserve stem cells) in the olfactory and respiratory epithelium [22,28]. 

It has to be acknowledged that OD is generally a common symptom in the elderly, as it occurs in 10% of people over 65 years and in 62–80% over 80 years old [24]. OD is also known to be a common symptom in early PD and AD [24]. 

Interestingly, OD in COVID-19 occurs more often in younger patients and is inversely correlated with death [29]. This supports the contrasting hypothesis that OD is a sign of defense against the virus to prevent it from reaching cerebral structures rather than allowing entry into the CNS [30]. Alternative transneural ways of CNS invasion by SARS-CoV-2 via the trigeminal or vagal nerve have also been discussed [10,11]. 

The second proposed route of viral invasion into the CNS is the hematogenous pathway with subsequent crossing of the blood-brain barrier or infection of the choroid plexus [10,11,14,15]. This was described for various other viruses, e.g., HIV, HSV, HCMV, and enteroviruses [6]. 

The endothelial cells in blood vessels and choroid plexus could be the target of invasion in this route of infection, as they were shown to express the ACE-2 receptor [8,11]. Additionally, the SARS-CoV-2 spike protein can cross and impair the blood-brain barrier itself by inducing an inflammatory response within the microvascular endothelium [31,32]. 

Another mechanism supporting this route of invasion could be an increase in the blood-brain barrier permeability due to elevated IL-6 levels that are present in acute COVID-19 disease [14,33]. 

The third possible pathway of neurotropism for SARS-CoV-2 is the so-called "Trojan horse mechanism" which describes the viral infection of immune cells (neutrophils, macrophages, monocytes, CD4+ -lymphocytes) that reach the CNS via the bloodstream and then migrate into cerebral structures by diapedesis [10–12,15–18]. 

Once they are in the cerebral tissue, the virus or viral particles could be released by those immune cells [12].

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