Creutzfeldt-Jakob Disease with Initial Typical Parkinsonism Precipitated by COVID-19? A Case Report (preprint)

Background Creutzfeldt-Jakob disease (CJD) is a rare and fatal neurodegenerative disease caused by the accumulation of PrPSc. While COVID-19-induced sporadic CJD (sCJD) with parkinsonism as the initial symptom is extremely uncommon, this report aims to raise awareness of sCJD cases that present with parkinsonism that are not associated with genetic mutations or pathological α-synuclein (α-Syn) accumulation. Case presentation This report presents the case of a 72-year-old man with probable sporadic Creutzfeldt-Jakob disease (sCJD) who initially showed symptoms of parkinsonism, which worsened rapidly after contracting COVID-19. Despite a history of responsive tremor and bradykinesia, his condition deteriorated following the viral infection, leading to rapid consciousness decline and diffuse myoclonus. Diagnostic tests, including brain MRI, cerebrospinal fluid analysis, and EEG, pointed towards prion disease. PrPSc, a marker for CJD, was detected in both the cerebrospinal fluid and skin samples using RT-QuIC, further confirming the diagnosis. Notably, skin analysis revealed PrPSc but no pathological α-synuclein deposits, ruling out typical Parkinson's disease.  Conclussion This case underscores the importance of considering sCJD in patients with parkinsonism, especially if they experience sudden neuropsychiatric symptoms, especially if they do not exhibit pathological α-Syn accumulation or have genetic mutations.

Olfactory and Cognitive Decrements in 1991 Gulf War Veterans (preprint)

Background Prominent symptoms of Gulf War illness (GWI), the disorder related to military service in the 1991 Gulf War (GW), include fatigue, pain, and cognitive dysfunction. Although anosmia is not a typical GWI symptom, anecdotally some veterans reported losing their sense smell shortly after the war. Because olfactory deficit is a prodromal symptom of neurodegenerative diseases like Parkinson’s and Alzheimer’s disease, and because we previously reported suggestive evidence that deployed GW veterans may be at increased risk for Mild Cognitive Impairment (MCI) and dementia, the current study examined the relationship between olfactory and cognitive function in deployed GW veterans.Methods Eighty deployed GW veterans (mean age: 59.9 ± 7.0; 4 female) were tested remotely with the University of Pennsylvania Smell Identification Test (UPSIT) and the Montreal Cognitive Assessment (MoCA). Veterans also completed self-report questionnaires about their health and deployment-related exposures and experiences. UPSIT and MoCA data from age-matched healthy controls (HC) were downloaded from the Parkinson’s Progression Markers Initiative (PPMI) study for comparison.Results GW veterans had a mean UPSIT score of 27.8 ± 6.3 (range 9–37) and a mean MoCA score of 25.3 ± 2.8 (range 19–30). According to age- and sex-specific normative data, 31% of GW veterans (vs. 8% PPMI HCs) had UPSIT scores below the 10th percentile. Nearly half (45%) of GW veterans (vs. 8% PPMI HCs) had MoCA scores below the cut-off for identifying MCI. Among GW veterans, but not PPMI HCs, there was a positive correlation between UPSIT and MoCA scores (Spearman’s ρ = 0.39, p < 0.001). There was no significant difference in UPSIT or MoCA scores between GW veterans with and without history of COVID and with and without Kansas GWI exclusionary conditions.Conclusions We found evidence of olfactory and cognitive deficits and a significant correlation between UPSIT and MoCA scores in a cohort of 80 deployed GW veterans. Because impaired olfactory function has been associated with increased risk for MCI and dementia, it may be prudent to screen aging, deployed GW veterans with smell identification tests so that hypo- and anosmic veterans can be followed longitudinally and offered targeted neuroprotective therapies as they become available.

COVID-19 infection enhances susceptibility to oxidative-stress induced parkinsonism (preprint)

Background: Viral induction of neurological syndromes has been a concern since parkinsonian-like features were observed in patients diagnosed with encephalitis lethargica subsequent to the 1918 influenza pandemic. Given the similarities in the systemic responses following SARS-CoV-2 infection with those observed after pandemic influenza, there is a question if a similar syndrome of post-encephalic parkinsonism could follow COVID-19 infection. Objectives: To determine if prior infection with SARS-CoV-2 increased sensitivity to a mitochondrial toxin known to induce parkinsonism. Methods: hACE2 mice were infected with SARS-CoV-2 to induce mild to moderate disease. After 31 days recovery, mice were administered a non-lesion inducing dose of the parkinsonian toxin MPTP. Subsequent neuroinflammation and SNpc dopaminergic neuron loss was determined and compared to SARS-CoV-2 or MPTP alone. Results: hACE2 mice infected with SARS-CoV-2 or MPTP showed no SNpc DA neuron loss following MPTP. In mice infected and recovered from SARS-CoV-2 infection, MPTP induced a 23% or 19% greater loss of SNpc dopaminergic neurons than SARS-CoV-2 or MPTP, respectively (p < 0.05). Examination of microglial activation showed a significant increase in the number of activated microglia in the SARS-CoV-2 + MPTP group compared to SARS-CoV-2 or MPTP alone. Conclusions: Our observations have important implications for long-term public health, given the number of people that have survived SARS-CoV-2 infection as well as for future public policy regarding infection mitigation. However, it will be critical to determine if other agents known to increase risk of PD also have synergistic effects with SARS-CoV-2 and if are abrogated by vaccination.

Cascading from SARS-CoV-2 to Parkinson's Disease through Protein-Protein Interactions.

Extensive extrapulmonary damages in a dozen of organs/systems, including the central nervous system (CNS), are reported in patients of the coronavirus disease 2019 (COVID-19). Three cases of Parkinson's disease (PD) have been reported as a direct consequence of COVID-19. In spite of the scarce data for establishing a definitive link between COVID-19 and PD, some hypotheses have been proposed to explain the cases reported. They, however, do not fit well with the clinical findings reported for COVID-19 patients, in general, and for the PD cases reported, in particular. Given the importance of this potential connection, we present here a molecular-level mechanistic hypothesis that explains well these findings and will serve to explore the potential CNS damage in COVID-19 patients. The model explaining the cascade effects from COVID-19 to CNS is developed by using bioinformatic tools. It includes the post-translational modification of host proteins in the lungs by viral proteins, the transport of modified host proteins via exosomes out the lungs, and the disruption of protein-protein interaction in the CNS by these modified host proteins. Our hypothesis is supported by finding 44 proteins significantly expressed in the CNS which are associated with PD and whose interactions can be perturbed by 24 host proteins significantly expressed in the lungs. These 24 perturbators are found to interact with viral proteins and to form part of the cargoes of exosomes in human tissues. The joint set of perturbators and PD-vulnerable proteins form a tightly connected network with significantly more connections than expected by selecting a random cluster of proteins of similar size from the human proteome. The molecular-level mechanistic hypothesis presented here provides several routes for the cascading of effects from the lungs of COVID-19 patients to PD. In particular, the disruption of autophagy/ubiquitination processes appears as an important mechanism that triggers the generation of large amounts of exosomes containing perturbators in their cargo, which would insult several PD-vulnerable proteins, potentially triggering Parkinsonism in COVID-19 patients.

INFLUENCE OF NOVEL CORONAVIRUS DISEASE (COVID-19) ON PARKINSONS DISEASE: SYSTEMATIC REVIEW (preprint)

Background: The novel Coronavirus (COVID 19) infection has affected the population with various medical issues including the underlying neurological comorbidities such as Parkinson disease. COVID 19 is found to bind with the host angiotensin-converting enzyme 2 (ACE2) receptors for viral entry. ACE2 receptors are normally expressed in various body surfaces as well as in the neurons and glial cells where they act as an entry port to SARS-CoV-2 infection to invade the central nervous system (CNS). ACE2 are also highly expressed in dopamine neurons which might worsen the outcome in terms of motor symptoms in PD with the treatment course. It may lead to an indirect response via immune-mediated cytokine storms and propagate through CNS leading to damage. Parkinsons disease has also been noticed due to certain post viral infections apart from COVID-19 such as, HSV, Influenza virus A, Measles virus, Cytomegalovirus and Mumps (Olsen et al, 2018). We aim to provide a thorough review on neurological outcomes and impact of COVID-19 in Parkinson disease. Methods: A systematic review was conducted to analyze the impact of COVID 19 in patients with Parkinson disease (> 21 yo). Systematic literature search was done using PubMed, Science Direct, Google Scholar and Cochrane databases. PRISMA guidelines were followed summarized in Fig. 3 for study acquisition. Results: Of the Parkinsons patients that were tested positive for SARS-CoV 2, worsening of motor symptoms were reported along with other COVID 19 symptoms (Fig. 4 and 5). These symptoms include bradykinesia, tremors, gait disturbances, delirium and dementia and severe spasms of arms and legs. Encephalopathy was also one of the main symptoms presented in two of the studies. Increased mortality rates were identified for those who were hospitalized due to COVID-19 and PD when compared to other patients. Conclusion: Parkinsons disease may experience substantial worsening of motor and non motor symptoms during COVID 19. Due to the novelty of the virus, studies were reported from recent years and further extensive studies are needed to explore more about the disease severity and neurological outcomes when compared to other non-PD patients. Authors identify this as a limitation for this paper. Additional studies are needed to understand the role of ACE2 in increasing vulnerability to viruses and role of ACE inhibitors as treatment modality.

Cascading from SARS-CoV-2 to Parkinson's Disease through Protein-Protein Interactions (preprint)

Background : Extensive extrapulmonary damages in a dozen of organs/systems, including the central nervous system (CNS), are reported in patients of the coronavirus disease 2019 (COVID-19). Three cases of Parkinson's disease (PD) have been reported as a direct consequence of COVID-19. In spite of the scarce data for establishing a definitive link between COVID-19 and PD some hypothesis have been proposed to explain the cases reported. They, however, do not fit well with the clinical findings reported for COVID-19 patients in general and for the PD cases reported in particular. Given the importance of this potential connection we present here a molecular-level mechanism that explain well these findings and will serve to explore the potential CNS damage in COVID-19 patients. Methods : A model explaining the cascade effects from COVID-19 to CNS is developed by using bioinformatic tools. It includes the post-translational modification of host proteins in the lungs by viral proteins, the transport of modified host proteins via exosomes out the lungs, and the disruption of protein-protein interaction in the CNS by these modified host proteins. Results : We found 44 proteins significantly expressed in the CNS which are associated with PD and whose interactions can be perturbed by 24 host proteins significantly expressed in the lungs. These 24 perturbators are found to interact with viral proteins and to form part of the cargoes of exosomes in human tissues. The joint set of perturbators and PD-vulnerable proteins form a tightly connected network with significantly more connections than expected by selecting a random cluster of proteins of similar size from the human proteome. Conclusions : The molecular-level mechanism presented here provides several routes for the cascading of effects from the lungs of COVID-19 patients to PD. In particular, the disruption of autophagy/ubiquitination processes appears as an important mechanism that triggers the generation of large amounts of exosomes containing perturbators in their cargo, which would insult several PD-vulnerable proteins, potentially triggering Parkinsonism in COVID-19 patients.

Cascading from SARS-CoV-2 to Parkinson's Disease through Protein-Protein Interactions (preprint)

Background: Extensive extrapulmonary damages in a dozen of organs/systems, including the central nervous system (CNS), are reported in patients of the coronavirus disease 2019 (COVID-19). Three cases of Parkinson's disease (PD) have been reported as a direct consequence of COVID-19. In spite of the scarce data for establishing a definitive link between COVID-19 and PD some hypothesis have been proposed to explain the cases reported. They, however, do not fit well with the clinical findings reported for COVID-19 patients in general and for the PD cases reported in particular. Given the importance of this potential connection we present here a molecular-level mechanism that explain well these findings and will serve to explore the potential CNS damage in COVID-19 patients.Methods: A model explaining the cascade effects from COVID-19 to CNS is developed by using bioinformatic tools. It includes the post-translational modification of host proteins in the lungs by viral proteins, the transport of modified host proteins via exosomes out the lungs, and the disruption of protein-protein interaction in the CNS by these modified host proteins.Results: We found 44 proteins significantly expressed in the CNS which are associated with PD and whose interactions can be perturbed by 24 host proteins significantly expressed in the lungs. These 24 perturbators are found to interact with viral proteins and to form part of the cargoes of exosomes in human tissues. The joint set of perturbators and PD-vulnerable proteins form a tightly connected network with significantly more connections than expected by selecting a random cluster of proteins of similar size from the human proteome.Conclusions: The molecular-level mechanism presented here provides several routes for the cascading of effects from the lungs of COVID-19 patients to PD. In particular, the disruption of autophagy/ubiquitination processes appears as an important mechanism that triggers the generation of large amounts of exosomes containing perturbators in their cargo, which would insult several PD-vulnerable proteins, potentially triggering Parkinsonism in COVID-19 patients.

Clinical Characteristics of Coronavirus disease 2019 (COVID-19) Among Patients at a Movement Disorders Center (preprint)

It is not established whether SARS-CoV-2 (COVID-19) patients with movement disorders, are at greater risk for more serious outcomes than the larger COVID-19 population beyond the susceptibility associated with greater age. We reviewed electronic health records and conducted telephone interviews to collect the demographics and clinical outcomes of patients seen at our Movement Disorders Center who tested positive for COVID-19 from 8 March 2020 through 6 June 2020. Thirty-six patients were identified, 23 men and 13 women, median age of 74.5 years. They primarily carried diagnoses of idiopathic Parkinson disease (n=22; 61%) and atypical parkinsonism (n=7; 19%) with the balance having other diagnoses. Twenty-seven patients (75%) exhibited alteration in mental status and fifteen (42%) had abnormalities of movement as common manifestations of COVID-19; in 61% and 31%, these were the presenting symptoms of the disease. 67% of patients in our cohort required hospitalization, and the mortality rate was 39%.. These data demonstrate that in patients with movement disorders, the likelihood of hospitalization and death after contracting COVID-19 was substantially greater than in the general population. Patients with movement disorders frequently presented with altered mental status, generalized weakness, or worsening mobility but not anosmia.