Early on in the COVID-19 pandemic were reports of anosmia (inability to smell) that raised concern among the neurology community. In a recent analysis published in the Journal of Parkinson’s Disease, we demonstrated a prevalence of olfactory impairment in 75% of patients infected by the SARS-CoV-2 virus based on studies using quantitative olfactory analysis (Beauchamp, 2020). The olfactory system (machinery need to smell) represents an area of vulnerability of the central nervous system as there are neurons that project directly from the brain into the nose that are unprotected by the blood-brain barrier. Certain viruses, also known as neurotropic viruses, are known to enter the brain through the olfactory pathway. Not only is a loss in the sense of smell an indicator of nervous system involvement and a ‘red flag’ for neuroscientists, it has been reported as one of the first non-motor symptoms of pre-clinical Parkinson’s disease (PD).  

PD and parkinsonism have been linked previously to viral infections, with the most relevant historical connection following the 1918 Spanish Flu. During the Spanish Flu pandemic, there was a concurrent neurological condition of encephalitis lethargica, also known as sleeping sickness. It is hypothesized that this neurological insult lead to an increase in parkinsonism, with people born between 1888-1924 having a 2-3-fold risk of developing Parkinson’s disease, peaking 5 years after recovery from the viral infection (Ravenholt, 1982).

Although there is no evidence that viruses are causative of PD, there is a proposed ‘dual-hit hypothesis’ in which a pathogen entering the brain can result in a neuronal insult that results in a neuroinflammatory response. It is thought that the inflammation  primes the brain in such a way that subsequent neuronal insults, such as aging or exposure to toxins, will be pathogenic and lead to neurodegeneration (Hawkes, 2007).  

Although evidence is limited to date, several key findings support concern for an increased risk of PD and other neurodegenerative diseases subsequent to COVID-19. Firstly, the high prevalence of anosmia suggests neurological symptoms are a prominent feature of the disease, in as many as 3 in 4 cases. Secondly, there have been viral particles detected in the cerebrospinal fluid and brain of people infected with the SARS-CoV-2 virus, suggesting neurotropism of the virus. Thirdly, it has been demonstrated that dopaminergic neurons are permissive to SARS-CoV-2, which is of great concern given the vulnerability and specific loss of dopaminergic neurons in PD. Furthermore, there are increasing reports of neuroinflammation, micro-haemorrhages, and hypoxia – all three of which represent substantial neurological insults and are known risk factors for the development of neurodegenerative diseases. Finally, of grave concern, there have been two case reports of parkinsonism linked to SARS-CoV-2 infection, in a 45-year-old man (Cohen, 2020) and a 35-year-old woman whose respiratory response to COVID-19 was so mild she was not hospitalized (Faber, 2020).

These findings should still be considered preliminary, and there needs to be further investigation of the neurological consequences of COVID-19 in the acute phase, as well as long-term monitoring of convalescent patients. Given the historical links between viruses and PD, as well as two cases of parkinsonism in young, otherwise healthy individuals, it is imperative there is vigilance across the neurology community, as well as increased investment in research of diagnostics, monitoring,  and disease-modifying therapies of PD in order to arm clinicians with the best tools to handle a potential influx of PD over the coming decades.   

References:

Beauchamp LC, Finkelstein DI, Bush AI, Evans AH, Barnham KJ (2020) Parkinsonism as a Third Wave of the COVID-19 Pandemic? Journal of Parkinson's disease:  Doi 10.3233/JPD-202211

Cohen ME, Eichel R, Steiner-Birmanns B, Janah A, Ioshpa M, Bar-Shalom R, Paul JJ, Gaber H, Skrahina V, Bornstein NMet al (2020) A case of probable Parkinson's disease after SARS-CoV-2 infection. The Lancet Neurology 19: 804-805 Doi 10.1016/S1474-4422(20)30305-7

Faber I, Brandao PRP, Menegatti F, de Carvalho Bispo DD, Maluf FB, Cardoso F (2020) Coronavirus Disease 2019 and Parkinsonism: A Non-post-encephalitic Case. Movement disorders : official journal of the Movement Disorder Society:  Doi 10.1002/mds.28277

Hawkes CH, Del Tredici K, Braak H (2007) Parkinson's disease: a dual-hit hypothesis. Neuropathology and applied neurobiology 33: 599-614 Doi 10.1111/j.1365-2990.2007.00874.x

Ravenholt RT, Foege WH (1982) 1918 influenza, encephalitis lethargica, parkinsonism. Lancet 2: 860-864 Doi 10.1016/s0140-6736(82)90820-0

This blog was selected for a WPC Research Spotlight. The authors were interviewed about their work in March 2021.

You may view the interview here:

Professor David Finkelstein presented at the WPC 2016 and 2019. He is a Professor at the Florey Institute of Neuroscience and Mental Health, University of Melbourne, Australia.

Dr. Leah C. Beauchamp is a Postdoctoral researcher at the Florey Institute of Neuroscience and Mental Health, Parkville, Australia

Professor Kevin J. Barnham teaches at the Florey Institute of Neuroscience and Mental Health, University of Melbourne, Australia

Ideas and opinions expressed in this post reflect that of the authors solely. They do not reflect the opinions or positions of the World Parkinson Coalition®