Parkinson’s disease (PD) is a progressive neurodegenerative disease. Many motor and non-motor symptoms characterize it. Among the motor symptoms – muscle stiffness, tremor, immobility, imbalance. Non-motor disorders include sleep disorders, constipation, sweating, low blood pressure, fatigue, and cognitive dysfunction.
For years or even decades before the appearance of classic motor symptoms, the PD process is associated with characteristic preceding symptoms. Pathology in PD includes the loss of dopamine neurons in the midbrain, neuroinflammation, and the development in many areas of the brain of intra-neuronal protein clusters-aggregates rich in α-synuclein and called Levi’s bodies.
Parkinson’s disease is the second most common neurodegenerative disease, affecting 2-3% of the population over 65. genetic studies show that PD is a family disease in ~ 5% of cases, and in some families, hereditary PD manifests itself in ~ 25% of cases.
Aging is the most significant risk factor for Parkinson’s disease. Analysis of genes associated with PD risk revealed multiple cellular dysfunctions, including immune system regulation and protein homeostasis. Biomarker studies also support chronic systemic inflammation in PD, and immune system disorders are associated with an increased PD risk. Although it is unknown what triggers Parkinson’s disease, bacterial and viral infections have been implicated in some cases.
Parkinson’s disease in patients with SARS-CoV-2 coronavirus
Spanish, Israeli, and Brazilian scientists have described cases where patients with COVID-19 developed clinical Parkinson’s disease, in isolation or other neurological disorders, within 2-5 weeks after infection with the SARS-CoV-2 coronavirus.
The patients were 35, 45, and 58 y.o. All three had severe respiratory infections that required hospitalization. Two patients had reduced Parkinson’s disease symptoms after taking traditional dopaminergic drugs, and the third patient recovered spontaneously.
In all cases, brain imaging revealed a decrease in the nigrostriatal dopaminergic nerve pathway activity responsible for motor activity. Dopaminergic neurons in this pathway release dopamine. In PD, these neurons die.
None of the patients had a family history of Parkinson’s disease or a history of symptoms before Parkinson’s disease. one patient underwent genetic testing that revealed no risk of PD.
These cases do not prove a causal relationship between SARS-CoV-2 infection and the development of Parkinson’s disease. The described patients were possibly predisposed to PD, and the SARS-CoV-2 viral infection only accelerated the neurodegenerative process. However, the rapid onset of severe motor symptoms shortly after a viral infection still indicates a causal relationship. Also, none of the patients had pre-PD symptoms before COVID-19 illness.
There are no descriptions of neuropathology in patients who developed acute Parkinson’s disease after SARS-CoV-2 infection. However, a study describing the neuropathology of 43 non-Parkinson’s disease patients who died from COVID-19 found evidence of microglial activation and invasion of cytotoxic T cells (T-killers that destroy damaged cells) into the brain stem. These neuropathological signs are also associated with Parkinson’s disease. Microglia are resident macrophages of the central nervous system. Their function is to protect the central nervous system from pathogens. But excessive activation of microglia can cause neuronal death.
Three possible mechanisms for the rapid development of Parkinson’s disease after SARS-CoV-2 infection
The mechanisms described below can work either individually or together.
First, in the severe form of COVID-19, combined with the condition of hypercoagulation – blood clot-vascular strokes have been reported to develop in many organs, including the brain. It might directly damage the nigrostriatal pathway, similar to what is observed in vascular Parkinson’s disease. However, in the study mentioned above on 43 deceased patients, no bleeding or thrombosis of the brain’s small vessels was reported.
Second, inflammatory diseases increase the risk of Parkinson’s disease. Severe COVID-19 may cause severe systemic inflammation can cause neuroinflammation and the death of dopamine neurons. Dopamine neurons in the midbrain are thought to be particularly sensitive to systemic inflammation. Several studies have shown elevated levels of the pro-inflammatory cytokine IL-6 in COVID-19, and one report suggested that the kynurenic pathway of tryptophan metabolism, which regulates inflammation and immunity, is disrupted. Both of these mechanisms are associated with BP.
Third, SARS-CoV-2 may be a neurotropic virus, as viral RNA has been found in the brains of some patients who have died from COVID-19. Besides, neuropathological studies using immuno-staining of aggregated α-synuclein have shown that the PD process begins in the olfactory system or the intestinal nerves and then spreads along the nerve pathways to other areas of the brain. Indeed, hyposmia (decreased sense of smell) and constipation are harbingers of PD, and α – synuclein aggregates may contribute to their pathophysiology. Strikingly, hyposmia and dysgeusia (taste disorder) are common in COVID-19, and SARS-CoV-2 can infect the gastrointestinal tract, suggesting that this way, the virus gains direct access to areas of the brain associated with PD. The airway is also innervated by the vagus nerve – another portal for the virus to enter the brain. In addition, dopamine neurons in the midbrain express high levels of the ACE2 receptor necessary for the SARS-CoV-2 virus to enter the cell. This may make dopamine neurons vulnerable to a SARS-CoV-2 attack.
An exciting possibility is that damage to SARS-CoV-2 neurons leads to increased regulation of neuronal α-synuclein. This increase in α-synuclein was observed after infection with West Nile virus and Western equine encephalitis virus, and animals lacking neuronal α-synuclein were more susceptible to viral encephalitis compared to animals that have this protein. These findings suggest that α-synuclein expression increases during the nervous system’s viral infection and acts as a virus restriction factor. In COVID-19, it is possible that persistently elevated levels of intraneuronal α-synuclein lead to the formation of aggregates similar to those in the brain in PD, which may be accompanied by neuronal death.
If the latter theory is correct, then SARS-CoV-2 may predispose to PD development later in life. Experimental studies and data obtained in families with increased expression of α-synuclein genes show that persistently elevated levels of α-synuclein contribute to the accumulation of this protein. Along with this, long-term systemic inflammation or neuroinflammation due to COVID-19 may contribute to PD development.
Conclusion
Although acute Parkinson’s disease in combination with COVID-19 is rare, the widespread of SARS-CoV-2 in society can lead to a large proportion of patients being predisposed to develop Parkinson’s disease later in life, mostly because they will also be affected by normal aging processes. Therefore, it is essential to closely monitor large cohorts of patients with COVID-19 and monitor them for PD signs. If patients with SARS-CoV-2 have an increased risk of developing Parkinson’s disease and other related neurodegenerative diseases, it is critical to identify treatments that reduce this risk. The link between COVID-19 and PD also implies that achieving collective immunity by naturally infecting a large part of the population can have disastrous long-term consequences.
Source:
Is COVID-19 a Perfect Storm for Parkinson’s Disease?
