Lack of an active treatment strategy and vaccine makes SARS-CoV-2 infection an immense threat to humankind. The COVID-19 pandemic arrived when the world was already facing other rising health problems, one of the most serious of which is the epidemic of neurodegenerative diseases and dementia. Now there are some signs of stabilization of COVID-19 spread, at least in some countries and hope for the development of a vaccine. Therefore, it is time to understand how the COVID-19 pandemic interferes with another challenge – the epidemic of neurodegenerative diseases. How do these two threats to human health affect each other and what can physicians and researchers do to alleviate their consequences?
The collision between these diseases requires the answers to many questions. For example, are patients with neurodegenerative diseases at higher risk of COVID-19? What are their risk factors, and do their clinical manifestations differ from the general population? Are common signaling pathways involved in both the two types of diseases? In this Editorial, I will discuss some of these questions and the questions that require further investigation for our understanding of the interplay between COVID-19 and neurodegenerative diseases.
An epidemic of neurodegenerative diseases
As the population continues to age, the world is facing an epidemic of devastating neurodegenerative diseases that take a tremendous economic and emotional toll on families and society. There is currently no efficient therapy for age-related neurodegenerative diseases and no efficient diagnostic methods for their early identification. We are witnessing something completely exceptional in human history: an explosion of people living well past their reproductive years. The incidence of Alzheimer's disease (AD) and other dementias, together with Parkinson's disease (PD) and other movement disorders, rise exponentially from the age of about 60. As a result, by the time a person reaches their mid-eighties, the chance of displaying symptoms of at least one of these diseases is close to 50% [1].
AD is an age-related, non-reversible disorder associated with memory loss and confusion. As it progresses, AD gradually leads to behavior and personality deviations, a deterioration in cognitive abilities, ultimately leading to a severe loss of mental function [2]. PD, the second most common neurodegenerative disease after AD, is a form of motor system disorder caused by the loss of dopaminergic cells [2, 3].
COVID-19 pandemic
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) originated in the autumn of 2019 in Wuhan, China, and quickly spread in many countries. Fast dissemination of the infection is explained by a high rate of virus transmission measured by the reproductive number, which for SARS-CoV-2 is between 3.6 and 4 demonstrating higher infectivity than other viruses (for example, for influenza it is 1.4 to 1.6) [4].
Neurological manifestation of COVID-19
Emerging evidence indicates that SARS-CoV-2 can cause neurological complications. The main clinical manifestations of COVID‐19 infection affect the lungs; however, several associated neurological features and signs often accompany pulmonary symptoms. Most often, they affect the kidney, gastrointestinal tract, skin, and may also be expressed as other neurological manifestations [5, 6]. During recent months, there has been a growing number of COVID-19 patients presenting with severe neurological manifestations most probably related to COVID-19, such as stroke, polyneuritis, and encephalopathy [5 -7]. The appearance of this wide spectrum of neurological signs may be explained by an invasion of the virus into nervous tissues causing damage to neural cells. The variety and diversity of neurological manifestations point to the involvement of both the central and peripheral nervous systems in COVID-19 infection [5].
How COVID-19 affects patients with neurodegenerative diseases
There are concerns about the vulnerability of patients living with chronic diseases to COVID-19, including patients with PD and other neurological conditions. Here, we will pay more attention to the connection between COVID-19 and movement disorders, predominately PD. To date, there have been more studies of this association and clearer (although putative) mechanisms suggested than for other movement disorders, which explains the selection of PD as a disorder to focus on. Hopefully, the association between COVID-19 and other neurodegenerative diseases will be clarified soon.
Interestingly, a hypothesis concerning a link between coronavirus infection and risk of PD was put forward a long time before the COVID-19 pandemic. The impetus for the investigation of this association was the finding that, although coronavirus is a respiratory pathogen in humans, it has a high affinity for the basal ganglia. A selective affinity of coronavirus MHV-A59 for the basal ganglia was described in mice by Fishman et al. in 1985 [8]. Infected mice had a hunched posture, locomotion difficulties, neuronal loss, and gliosis in the substantia nigra (SN). In 1992, Fazzini and collaborators [9] found that PD patients had an elevated cerebrospinal fluid antibody response to coronaviruses MHV-JHM and MHV-A59 when compared to a control group of individuals, pointing to their infection with coronaviruses. MHV-JHM is a neurotrophic virus with a selective affinity for the SN.
The impact of COVID-19 on clinical features of PD is poorly understood, and some recent reports are contradictory. Currently, there is no strong and consistent evidence that movement disorder patients are at a significantly increased risk of coronavirus infection, compared to individuals of comparable age and with similar comorbidities [10]. However, patients with a chronic neurological disease are, in general, more susceptible to the effects of any severe infection, especially of respiratory origin. A recent study by Cilia and coauthors [11] demonstrated deteriorated motor and nonmotor symptoms in the COVID-19 group. Among nonmotor symptoms, COVID-19 most significantly aggravated fatigue and urinary issues but only marginally affected cognitive dysfunction [11]. The worsening of symptoms in PD patients infected by COVID-19 may be explained by direct infection-related mechanisms and compromised pharmacokinetics of dopaminergic therapy. Deterioration of motor and nonmotor symptoms during mild-to-moderate COVID-19 illness does not depend on age and disease duration [11]. Pharmacodynamics alterations in the SN and striatum, such as interactions between the dopaminergic and renin-angiotensin systems in the SN and striatum may also contribute [11, 12].
In an unselected large cohort study conducted in Lombardy, Italy, the COVID-19 risk and mortality did not differ in PD patients from the general population; however, symptoms were milder in PD patients. The authors hypothesized that a milder disease course might be explained by a protective role of vitamin D supplementation given to PD patients, which may reduce concentrations of proinflammatory cytokines [13, 14]. Poor COVID-19 outcome in PD patients in this population was associated with older age and longer disease duration.
PD is more common in the elderly, and PD can compromise the respiratory system, as reflected by the increased risk of pneumonia present in patients with advanced PD. Although documented reports are lacking, it is conceivable that having a diagnosis of PD is a risk factor for worse respiratory complications or even an unfavorable outcome after a COVID-19 infection.
Biochemical mechanisms linking COVID-19 and PD
SARS-Cov2 affects several biochemical mechanisms and pathways that play a crucial role in PD pathogenesis. After binding of SARS-Cov2 to angiotensin-converting enzyme 2 (ACE2) the virus may enter epithelial cells of blood vessels and other organs. After internalization, the virus impairs cell organelles (mitochondria, lysosomes) important in PD pathogenesis. The damage to these organelles raises the intracellular level of reactive oxygen species (ROS) and increases protein misfolding and aggregation. These processes play a key role in PD pathogenesis. Furthermore, binding of SARS-Cov2 to ACE2 increases the intracellular level of angiotensin 2, which causes vasoconstriction and promotes brain degeneration [15].
Other important alterations in response to viral infection, the role of which is not completely understood, are transcriptional changes caused by the virus. Downregulation of mitochondrial organization affecting respiration processes, upregulation of the cytokine/ inflammatory processes, and changes in the autophagy processes occur in SARS-CoV-2 infected cells [16, 17]. Mitochondria playing a key role in PD pathogenesis are especially vulnerable to changes in gene expression since their biogenesis is a result of delicate coordination between nuclear and mitochondrial genomes [18, 19].
Questions that need further investigation
The COVID-19 pandemic raises many issues related to PD patients, for example:
1) How do drugs used for PD treatment affect the response to SARS-CoV-2? How does SARS-CoV-2 infection change the response to PD treatment?
2) Is the SN a site of susceptibility for the virus? SN is a basal ganglia structure in the midbrain that plays a central role in movement. The loss of dopaminergic neurons in SN is a key characteristic of PD. Takahashi and coauthors [20] investigated the infection of the H1N1 influenza virus and found the accumulation of the viral antigen in SN. The authors suggested that influenza A viruses could be one of the causative agents for parkinsonism. These findings are in line with the observation by Mattock and colleagues that individuals born during the 1918-1928 influenza pandemic had a higher risk of developing idiopathic PD [21].
3) How does α-synuclein – the main component of Lewy bodies, which are the hallmark of PD– interfere with pathological processes following viral infection? α-Synuclein plays a dual role in neurodegeneration. On the one hand, it forms toxic oligomers and inclusion bodies in PD and other neurodegenerative diseases [22, 23]. On the other hand, it may have a protective effect in neurodegeneration [24], by inhibiting pro-inflammatory responses [25] and facilitating immune reactions against infections [26].
Expression of α-synuclein in neurons inhibits viral RNA replication [27] and may be involved in immune defense responses [28] and prevent neuroinvasion [29]. According to a recent hypothesis, overexpression of α-synuclein in PD patients might alleviate the consequences of coronavirus infection by inhibiting the spread of the virus from the peripheral nervous system to the CNS [30]. On the other hand, coronavirus infection can prompt cytotoxic aggregation of proteins, including α-synuclein as was shown in animal models [31, 32]. Dopaminergic neurons may have high vulnerability because of their elevated bioenergetic demands and impaired proteostasis due to the large axon size [32]. Importantly, α-synuclein expression can be induced following viral infection [7] contributing to α-synuclein aggregation [33].
4) What is the role of the aryl hydrocarbon receptor (AhR) in COVID-19 infection and PD pathology? There are several signaling pathways and biochemical regulators used in the course of COVID-19 infection and PD pathogenesis. One of them is a transcription factor AhR that transcriptionally regulates parkin (PRKN) - a ubiquitin E3 ligase that catalyzes ubiquitination of α-synuclein and several other proteins [34]. The treatments designed to induce PRKN expression by AhR agonist ligands may be a new approach to treat or delay PD. On the other hand, AhR is one of the central players in CoV signaling. CoV induces up-regulation of several AhR-dependent downstream effectors, which causes a "Systemic AhR Activation Syndrome" [35]. Therefore, Ahr is located on the crossroad of signaling pathways used both in PD pathology and in COVID-19 infection. The activity and regulation of this transcription factor should be thoroughly investigated as a potential target for treatment.
One of an alternative mechanisms by which COVID-19 virus may generate long term neuronal alterations could be related to an autoimmune response against α-synuclein, which plays a role in immune regulation and protection against viral infections [36].
Several recent case reports [37-39] describe the development of acute parkinsonism following COVID-19. However, underlying cellular and molecular mechanisms are not completely understood and do not prove a causal relationship between these pathologies. According to one hypothesis, the viral infection may only speed up an ongoing processes of neurodegeneration around a critical time point [40].
Acknowledgments
Support from VA Merit Review grants 1I01BX000361, and the Glaucoma Foundation grantQB42308 is acknowledged.
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