Table 1.

Hypotheses and Studies that SARS-CoV-2 Promotes the Development of Parkinson’s Disease.

Study Supports: Cause/Unmasking/Not Support	In Vitro/In Vivo/Clinical	Primary Conclusions
Cause	Clinical	Three published single-case reports describing patients with COVID-19 developing clinical parkinsonism within 2–5 weeks of contracting SARS-CoV-2. As seen with West Nile virus and Western Equine Encephalitis virus, α-synuclein expression increases during viral infection of CNS, suggesting that SARS-CoV-2 infection could predispose individuals to the development of PD later in life. Brundin et al. [148]
Cause	Clinical	A case study of an elderly diabetic woman with parkinsonism with akinetic mutism following non-dyselectrolytemic osmotic demyelination syndrome, which was precipitated by COVID-19 infection induced hyperglycemic hyper-osmolar state. She was placed on levodopa/carbidopa and pramipexole, and after two months of follow-up her features of parkinsonism improved significantly, but with only mild improvement of the features associated with akinetic mutism. Ghosh et al. [205]
Cause	Clinical	A previously healthy 31-year-old man tested positive for COVID-19 and developed acute necrotizing encephalopathy (ANEC), with presenting features of parkinsonism and myorhythmia. Myorhythmia can also occur alongside other movement disorders, such as dystonia and parkinsonism, due to disrupted basal gangliathalamo-frontal cortical circuits. The exact pathogenesis of ANEC is not entirely clear, but systemic inflammatory insult and hypercytokinemia have been postulated to trigger necrotic brain lesions in patients with ANEC. Ong et al. [206]
Cause	In vitro	Identification that the SARS-CoV-2 nucleocapsid protein (N-protein) induces the aggregation of αSYN in a test tube. In the presence of N-protein, the onset of α-synuclein aggregation into amyloid fibrils is strongly accelerated, indicating that N-protein facilitates the formation of a critical nucleus for aggregation. These experiments suggest that SARS-CoV-2 infection and PD might originate from a molecular interaction between virus protein and α-synuclein. Semerdzhiev et al. [78]
Cause	Clinical	Three patients developed parkinsonism while infected with COVID-19, all of whom required levodopa-carbidopa therapy for recovery despite having no prodromal PD symptoms prior to COVID-19 infection. The authors concluded that parkinsonism could be a post-COVID-19 sequelae. Rao et al. [182]
Cause	In vivo	Authors infected macaques with SARS-CoV-2 and demonstrated brain inflammation and post-mortem studies uncovered Lewy bodies were not present in controls. They conclude that this data is a serious warning for potential COVID-19-related neurodegeneration (particularly PD given the presence of hallmark Lewy bodies) even after asymptomatic or mild infection. Philippens et al. [151]
Cause	Clinical	Two cases of patients with COVID-19 encephalopathy who developed parkinsonism without a history of prodromal PD symptoms. FDG-PT/CT imaging showed distinct areas of hypo- and hyper-metabolism in comparison to 48 healthy controls. Authors state that while they cannot dismiss symptom development due to unmasking, given the patients’ lack of prior PD prodromal symptoms and motor features prior to infection, rapid onset of parkinsonism after encephalitis, and lack of improvement after discontinuing neuroleptics and initiating levodopa, that is unlikely. Morassi et al. [207]
Unmasking	Clinical	Single case report of patient who developed parkinsonism within days of COVID-19 symptom onset. Makhoul and Jankovic [144]
Not Support	Clinical	CSF PCR for SARS-CoV-2 was negative for 100% (76/76) in samples analyzed that were assessed previously and were positive for SARS-CoV-2. Jarius et al. [73]
Not Support/Cause	In vivo	RNA viruses upregulate αSYN in neurons, which subsequently can activate the interferon-mediated-anti-viral defense mechanism in innate immunity. However, long term consequences could lead to chronic inflammation with the development or progression of PD. Rosen et al. [208]