Viruses and Parkinson's Disease:
There are a number of viruses (influenza A, corona viruses, Epstein-Barr virus, varicella zoster, hepatitis C virus, HIV, Japanese encephalitis virus, or West Nile virus) that can lead to Parkinson's like symptoms known as parkinsonism. Studies as far back as to the effects of the Spanish flu epidemic of 1918 showed that survivors had double the chance of developing Parkinson’s disease (PD) later in life. The mechanisms are not well understood and are typically observational.
References:- The role of viruses in neurodegenerative and neurobehavioral diseases (2014)
DOI: 10.2174/187152731307141015122638 - Occupational risk factors in Parkinson's disease (1999)
Researchers at the University of British Columbia Hospital Movement Disorders Clinic noticed that teachers and health care workers accounted for an inordinately large proportion of their Parkinson's patients. Researchers hypothesized that an increased exposure to viral respiratory infections, including influenza, predisposed these workers to the development of Parkinson's disease. Employing a case-control design, they found that Parkinson's Disease was associated with being a teacher as well as working in the health care field.
DOI: 10.1007/BF03404523
COVID-19 virus:
The year 2020 is known for the COVID-19 pandemic. While most survived, many were left with permanent ailments such as loss of smell, difficulty speaking, difficulty texting, slowed movement, tremors, eye movement abnormalities, impaired cognitive performance and impared lung function. It was the neurodegenerative Parkinsonism related hypophonia (slowness of speech), anosmia (loss of sense of smell), tremors and bradykinesia (slowness of movement) that began to forge a COVID-19 associated link to Parkinson's. There are studies linking Sars-CoV-2, the virus that causes COVID-19, with neurological deficits. It is assumed that the pathology is inflammation related and the fact that COVID-19 cases experience high levels of pro-inflammatory cytokines supports the argument. It has also been hypothesized that it is possible that SARS-CoV-2 infection may prompt protein misfolding and aggregation due to altered function including potential mitochondrial dysfunction, loss of proteostasis, autophagy dysfunction, inflammation, and endoplasmic reticulum stress. Other researchers have proposed the "multiple hit hypothesis", by which the combination of toxic stress and an inhibition of neuroprotective responses can lead to neuronal death.
COVID-19/Sars-CoV-2 Therapeutics:- Monoclonal Antibodies: (lab synthesized proteins that mimic the immune system antibodies)
- Eli Lilly: Bamlanivimab - not for those requiring oxygen
- Regeneron: Casirivimab (REGN10933)/Imdevimab (REGN10987) - not for those requiring oxygen
- mRNA platform:
These vaccines have Emergency Use Authorization (EUA) from the FDA.
Safety study: COVID-19 Vaccination for Persons with Parkinson's Disease: Light at the End of the Tunnel? (Bloem et al. 2021) - AstraZeneca/Oxford vaccine: AZD1222 - co-invented by the University of Oxford and its spin-out company, Vaccitech Based on a weakened version of a common cold virus (adenovirus) and contains the genetic material of the SARS-CoV-2 virus spike protein.
- Johnson and Johnson vaccine - single shot
- Immediate and long-term consequences of COVID-19 infections for the development of neurological disease
DOI: 10.1186/s13195-020-00640-3 - A case of probable Parkinson's disease after SARS-CoV-2 infection
- Cerebrospinal fluid antibodies to coronavirus in patients with Parkinson's disease (1992)
"Although coronavirus is recognized primarily as a respiratory pathogen in humans, its affinity for the basal ganglia led us to investigate its possible role in human Parkinson's disease."
DOI: 10.1002/mds.870070210 - Induction of microglia activation after infection with the non-neurotropic A/CA/04/2009 H1N1 influenza virus (2015)
DOI: 10.1371/journal.pone.0124047 - Multiple hit hypotheses for dopamine neuron loss in Parkinson's disease (2007)
DOI: 10.1016/j.tins.2007.03.009 - COVID-19 and possible links with Parkinson’s disease and parkinsonism: from bench to bedside (2020)
"A significant number of those diagnosed with COVID-19 have reported a broad spectrum of neurological consequences"
"SARS-CoV-2 appears to display high binding affinity to sialic acid residues, providing an additional candidate for binding. Sialic acid residues are found on plasma membrane proteins of many cell types, including neurons, and are very highly expressed in the upper respiratory tract."
"While there is, at this time, little evidence that SARS-CoV-2 enters the brain parenchyma, there are multiple means by which the virus might be able to do so."
"COVID-19 virus is unlikely to exhibit direct neurotropism, but rather appears to cause inflammatory-mediated brain responses86."
"Because SARS-CoV-2 proteins can interact with host proteins involved in pathways that are altered during aging, including potential mitochondrial dysfunction, loss of proteostasis, autophagy dysfunction, inflammation, and endoplasmic reticulum stress, it is possible that SARS-CoV-2 infection may prompt protein misfolding and aggregation"
"Of particular relevance for PD, recent studies have suggested that the aggregation-prone protein, alpha-synuclein, plays a role in the innate immune response to viral infection"
Epstein-Barr virus (EBV) encephalitis:
EBV patients have been observed to have Parkinson's like symptoms in as many as 36% of cases.
References:- Parkinson-like syndrome as the major presenting symptom of Epstein–Barr virus encephalitis
DOI: 10.1186/s13195-020-00640-3 - Acute manifestations and neurologic sequelae of Epstein-Barr virus encephalitis in children (1996)
DOI: 10.1186/s13195-020-00640-3 - Reversible parkinsonism due to involvement of substantia nigra in Epstein‐Barr virus encephalitis (2011)
DOI: 10.1002/mds.23935
Influenza A:
(Hong Kong H3N2 flu of 1968) On histopathological examination, viral antigens were discovered in the neurons of the hippocampus and the dopaminergic neurons of the substantia nigra. The researchers concluded that the substantia nigra could be a major target for neurovirulent forms of influenza A virus in humans as well; possibly causing Parkinson's disease.
References:- The substantia nigra is a major target for neurovirulent influenza A virus (1995)
"Results suggest that neurovirulent influenza A viruses could be one of the causative agents for postencephalitic parkinsonism."
DOI: 10.1084/jem.181.6.2161
Asian Avian Influenza:
(HPA1 H5N1, H7N7) usually contracted direct or close contact with sick or dead poultry that were infected with the virus. A study found that shortly after H5N1 infection in the CNS, the animals appeared transiently bradykinetic with a distinguishable tremor. A 2009 study showed a significant loss of dopaminergic neurons in the substantia nigra pars compacta 60 days after infection.
References:- Parkinsonism and neurological manifestations of influenza throughout the 20th and 21st centuries (2010)
"Studies of animals infected by H5N1 in the wild, including birds and waterfowl, revealed a disease complex that included behaviors consisting of abnormal postures, imbalance, and the inability to initiate movement; symptoms that appeared to mimic those seen in Parkinson’s disease."
DOI: 10.1016/j.parkreldis.2010.06.012 - Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration (Jang et al. 2009)
"In regions infected by H5N1 virus, we observe activation of microglia and alpha-synuclein phosphorylation and aggregation that persists long after resolution of the infection."
DOI: 10.1073/pnas.0900096106 - Avian influenza and the brain--comments on the occasion of resurrection of the Spanish flu virus (2005)
"these avian influenza subtypes have the propensity to invade the brain along cranial nerves to target brainstem and diencephalic nuclei following intranasal instillation in mice and ferrets."
DOI: 10.1016/j.brainresbull.2005.11.022 - Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration (2009)
"we show the virus is gone from the brain in 21 days but there is a long-lasting activation of microglia and a significant loss of SNpc dopaminergic neurons"
"We have also shown that H5N1 influenza infection of the CNS can induce not only parkinsonian symptoms but also a significant increase in phosphorylation and aggregation of alpha synuclein, which likely results in the observed SNpc dopaminergic neuron degeneration"
DOI: 10.1073/pnas.0900096106
West Nile Virus:
(WNV encephalitis) acute viral infection of the substantia nigra pars compacta occurs in some patients, resulting in clinical Parkinsonian symptoms including cog-wheel rigidity, bradykinesia, and wide-based gait.
References:- Alpha-Synuclein, a Novel Viral Restriction FactorHiding in Plain Sight (2013)
"Extrapyramidal disorders are frequently observed, and features of Parkinsonism may be seen."
Paper also presents the hypothesis that alpha-synuclein is part of an anti-virus neuronal immune system and that when "repeated virus-induced changes in a-syn expression in neurons over time may place genetically susceptible individuals at risk for the development of PD". Supporting this argument is that the "olfactory bulb and the GI neurons are common sites of viral neuroinvasion into the CNS" and that an experiment with "a-syn knockout mice exhibited markedly increased virus-induced weight loss, mortality, and caspase 3-dependent neuronal injury".
DOI: 10.1089/dna.2016.3488 - Transient parkinsonism in west nile virus encephalitis (2003)
Case study of two patients
DOI: 10.1016/S0002-9343(03)00291-2
Hepatitus C:
A study of data from the Taiwan National Health Insurance Research Database revealed that participants with hepatitis C had a 30% greater risk of developing Parkinson’s disease than the controls.
References:- Hepatitis C virus infection as a risk factor for Parkinson disease: A nationwide cohort study (Tsai et al. 2015)
10.1212/WNL.0000000000002307
Other Viruses:
herpes simplex 1, Epstein-Barr, varicella zoster, hepatitis C, and influenza A virus can increase the risk of developing Parkinson's disease in the long-term. In 1958 it was reported that 0.3% of H1N1 "Asian Flu" patients reported neurological issues.
References:- Parkinsonism and neurological manifestations of influenza throughout the 20th and 21st centuries (2010)
A historical study of epidemics and pandemics and the reported neurological manifestations.
DOI: 10.1016/j.parkreldis.2010.06.012 - Neurological and Hepatic Disorders Associated with Influenza (1958)
