Highlights
There have been well-documented reports about the occurrence of parkinsonism after viral infections.
10 studies including 13 patients reported the development of parkinsonism in individuals who recovered from COVID-19 infection.
The commonest symptom of parkinsonism reported in these individuals was cogwheel rigidity 84.6%.
53.8% of individuals fully recovered and had their symptoms resolved after treatment.

Ali SS, Mumtaz A, Qamar MA, Tebha SS, Parhin A, Butt M, Essar MY. New-onset Parkinsonism as a Covid-19 infection sequela: A systematic review and meta-analysis. Ann Med Surg (Lond). 2022 Aug;80:104281. doi: 10.1016/j.amsu.2022.104281. Epub 2022 Aug 8. PMID: 35971509; PMCID: PMC9359766.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9359766/

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Abstract: Brain network dysfunction is increasingly recognised in Alzheimer’s disease (AD). However, the causes of brain connectivity disruption are still poorly understood. Recently, neuroinflammation has been identified as an important factor in AD pathogenesis. Microglia participate in the construction and maintenance of healthy neuronal networks, but pro-inflammatory microglia can also damage these circuits. We hypothesised that microglial activation is independently associated with brain connectivity disruption in AD. We performed a cross-sectional multimodal imaging study and interrogated the relationship between imaging biomarkers of neuroinflammation, Aβ deposition, brain connectivity and cognition. 42 participants (12 Aβ-positive MCI, 14 Aβ-positive AD and 16 Aβ-negative healthy controls) were recruited. Participants had 11C-PBR28 and 18F-flutemetamol PET to quantify Aβ deposition and microglial activation, T1-weighted, diffusion tensor and resting-state functional MRI to assess structural network and functional network. 11C-PBR28 uptake, structural network integrity and functional network orgnisation were compared across diagnostic groups and the relationship between neuroinflammation and brain network was tested in 26 Aβ-positive patients. Increased 11C-PBR28 uptake, decreased FA, network small-worldness and local efficiency were observed in AD patients. Cortical 11C-PBR28 uptake correlated negatively with structural integrity (standardised β = −0.375, p = 0.037) and network local efficiency (standardised β = −0.468, p < 0.001), independent of cortical thickness and Aβ deposition, while Aβ was not. Network structural integrity, small-worldness and local efficiency, and cortical thickness were positively associated with cognition. Our findings suggest cortical neuroinflammation coincide with structural and functional network disruption independent of Aβ and cortical atrophy. These findings link the brain connectivity change and pathological process in Alzheimer’s disease, and suggest a pathway from neuroinflammation to systemic brain dysfunction.

Leng, F., Hinz, R., Gentleman, S. et al. Neuroinflammation is independently associated with brain network dysfunction in Alzheimer’s disease. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01878-z

https://www.nature.com/articles/s41380-022-01878-z

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Highlights

  • Identified 45 pairs of viral exposures associated with increased risk of NDDs
  • Replicated 22 of the viral exposures/NDD pairings
  • Replicated the previously reported Epstein-Barr and multiple sclerosis association
  • Follow-up shows significantly elevated risk of NDD years after viral exposure

Summary

With recent findings connecting the Epstein-Barr virus to an increased risk of multiple sclerosis and growing concerns regarding the neurological impact of the coronavirus pandemic, we examined potential links between viral exposures and neurodegenerative disease risk. Using time series data from FinnGen for discovery and cross-sectional data from the UK Biobank for replication, we identified 45 viral exposures significantly associated with increased risk of neurodegenerative disease and replicated 22 of these associations. The largest effect association was between viral encephalitis exposure and Alzheimer’s disease. Influenza with pneumonia was significantly associated with five of the six neurodegenerative diseases studied. We also replicated the Epstein-Barr/multiple sclerosis association. Some of these exposures were associated with an increased risk of neurodegeneration up to 15 years after infection. As vaccines are currently available for some of the associated viruses, vaccination may be a way to reduce some risk of neurodegenerative disease.

Levine KS, Leonard HL, Blauwendraat C, Iwaki H, Johnson N, Bandres-Ciga S, Ferrucci L, Faghri F, Singleton AB, Nalls MA. Virus exposure and neurodegenerative disease risk across national biobanks. Neuron. 2023 Jan 11:S0896-6273(22)01147-3. doi: 10.1016/j.neuron.2022.12.029. Epub ahead of print. PMID: 36669485.

https://www.cell.com/neuron/fulltext/S0896-6273(22)01147-3

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Semerdzhiev SA, Fakhree MAA, Segers-Nolten I, Blum C, Claessens MMAE. Interactions between SARS-CoV-2 N-Protein and α-Synuclein Accelerate Amyloid Formation. ACS Chem Neurosci. 2022 Jan 5;13(1):143-150. doi: 10.1021/acschemneuro.1c00666. Epub 2021 Dec 3. PMID: 34860005; PMCID: PMC8739828.

https://pubmed.ncbi.nlm.nih.gov/34860005/

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Abstract: “Apart from common respiratory symptoms, neurological symptoms are prevalent among patients with COVID-19. Research has shown that infection with SARS-CoV-2 accelerated alpha-synuclein aggregation, induced Lewy-body-like pathology, caused dopaminergic neuron senescence, and worsened symptoms in patients with Parkinson’s disease (PD). In addition, SARS-CoV-2 infection can induce neuroinflammation and facilitate subsequent neurodegeneration in long COVID, and increase individual vulnerability to PD or parkinsonism. These findings suggest that a post-COVID-19 parkinsonism might follow the COVID-19 pandemic. In order to prevent a possible post-COVID-19 parkinsonism, this paper reviewed neurological symptoms and related findings of COVID-19 and related infectious diseases (influenza and prion disease) and neurodegenerative disorders (Alzheimer’s disease, PD and amyotrophic lateral sclerosis), and discussed potential mechanisms underlying the neurological symptoms and the relationship between the infectious diseases and the neurodegenerative disorders, as well as the therapeutic and preventive implications in the neurodegenerative disorders. Infections with a relay of microbes (SARS-CoV-2, influenza A viruses, gut bacteria, etc.) and prion-like alpha-synuclein proteins over time may synergize to induce PD. Therefore, a systematic approach that targets these pathogens and the pathogen-induced neuroinflammation and neurodegeneration may provide cures for neurodegenerative disorders. Further, antiviral/antimicrobial drugs, vaccines, immunotherapies and new therapies (e.g., stem cell therapy) need to work together to treat, manage or prevent these disorders. As medical science and technology advances, it is anticipated that better vaccines for SARS-CoV-2 variants, new antiviral/antimicrobial drugs, effective immunotherapies (alpha-synuclein antibodies, vaccines for PD or parkinsonism, etc.), as well as new therapies will be developed and made available in the near future, which will help prevent a possible post-COVID-19 parkinsonism in the 21st century.”

Zhang J. Investigating neurological symptoms of infectious diseases like COVID-19 leading to a deeper understanding of neurodegenerative disorders such as Parkinson’s disease. Front Neurol. 2022 Dec 7;13:968193. doi: 10.3389/fneur.2022.968193. PMID: 36570463; PMCID: PMC9768197.

https://pubmed.ncbi.nlm.nih.gov/36570463/

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Abstract: “Parkinson’s disease (PD) by its common understanding is a late-onset sporadic movement disorder. However, there is a need to recognize not only the fact that PD pathogenesis expands beyond (or perhaps to) the brain but also that many early-onset patients develop motor signs before the age of 50 years. Indeed, studies have shown that it is likely the protein aggregation observed in the brains of patients with PD precedes the motor symptoms by perhaps a decade. Studies on early-onset forms of PD have shown it to be a heterogeneous disease with multiple genetic and environmental factors determining risk of different forms of disease. Genetic and neuropathological evidence suggests that there are α-synuclein centric forms (e.g., SNCA genomic triplication), and forms that are driven by a breakdown in mitochondrial function and specifically in the process of mitophagy and clearance of damaged mitochondria (e.g., PARKIN and PINK1 recessive loss-of-function mutations). Aligning genetic forms with recognized environmental influences will help better define patients, aid prognosis, and hopefully lead to more accurately targeted clinical trial design. Work is now needed to understand the cross-talk between these two pathomechanisms and determine a sense of independence, it is noted that autopsies studies for both have shown the presence or absence of α-synuclein aggregation. The integration of genetic and environmental data is critical to understand the etiology of early-onset forms of PD and determine how the different pathomechanisms crosstalk.”

Kolicheski A, Turcano P, Tamvaka N, McLean PJ, Springer W, Savica R, Ross OA. Early-Onset Parkinson’s Disease: Creating the Right Environment for a Genetic Disorder. J Parkinsons Dis. 2022;12(8):2353-2367. doi: 10.3233/JPD-223380. PMID: 36502340.

https://pubmed.ncbi.nlm.nih.gov/36502340/

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Abstract: 

Importance  The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown.

Objective  To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes.

Design, Setting, and Participants  Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022.

Interventions  Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401).

Main Outcomes and Measures  The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83.

Results  Among 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies.

Conclusions and Relevance  Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months.

Writing Committee for the REMAP-CAP Investigators; Higgins AM, Berry LR, Lorenzi E, Murthy S, McQuilten Z, Mouncey PR, Al-Beidh F, Annane D, Arabi YM, Beane A, van Bentum-Puijk W, Bhimani Z, Bonten MJM, Bradbury CA, Brunkhorst FM, Burrell A, Buzgau A, Buxton M, Charles WN, Cove M, Detry MA, Estcourt LJ, Fagbodun EO, Fitzgerald M, Girard TD, Goligher EC, Goossens H, Haniffa R, Hills T, Horvat CM, Huang DT, Ichihara N, Lamontagne F, Marshall JC, McAuley DF, McGlothlin A, McGuinness SP, McVerry BJ, Neal MD, Nichol AD, Parke RL, Parker JC, Parry-Billings K, Peters SEC, Reyes LF, Rowan KM, Saito H, Santos MS, Saunders CT, Serpa-Neto A, Seymour CW, Shankar-Hari M, Stronach LM, Turgeon AF, Turner AM, van de Veerdonk FL, Zarychanski R, Green C, Lewis RJ, Angus DC, McArthur CJ, Berry S, Derde LPG, Gordon AC, Webb SA, Lawler PR. Long-term (180-Day) Outcomes in Critically Ill Patients With COVID-19 in the REMAP-CAP Randomized Clinical Trial. JAMA. 2023 Jan 3;329(1):39-51. doi: 10.1001/jama.2022.23257. PMID: 36525245. 

https://jamanetwork.com/journals/jama/fullarticle/2799870

 

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Abstract:  

Importance  Some individuals experience persistent symptoms after initial symptomatic SARS-CoV-2 infection (often referred to as Long COVID).

Objective  To estimate the proportion of males and females with COVID-19, younger or older than 20 years of age, who had Long COVID symptoms in 2020 and 2021 and their Long COVID symptom duration.

Design, Setting, and Participants  Bayesian meta-regression and pooling of 54 studies and 2 medical record databases with data for 1.2 million individuals (from 22 countries) who had symptomatic SARS-CoV-2 infection. Of the 54 studies, 44 were published and 10 were collaborating cohorts (conducted in Austria, the Faroe Islands, Germany, Iran, Italy, the Netherlands, Russia, Sweden, Switzerland, and the US). The participant data were derived from the 44 published studies (10 501 hospitalized individuals and 42 891 nonhospitalized individuals), the 10 collaborating cohort studies (10 526 and 1906), and the 2 US electronic medical record databases (250 928 and 846 046). Data collection spanned March 2020 to January 2022.

Exposures  Symptomatic SARS-CoV-2 infection.

Main Outcomes and Measures  Proportion of individuals with at least 1 of the 3 self-reported Long COVID symptom clusters (persistent fatigue with bodily pain or mood swings; cognitive problems; or ongoing respiratory problems) 3 months after SARS-CoV-2 infection in 2020 and 2021, estimated separately for hospitalized and nonhospitalized individuals aged 20 years or older by sex and for both sexes of nonhospitalized individuals younger than 20 years of age.

Results  A total of 1.2 million individuals who had symptomatic SARS-CoV-2 infection were included (mean age, 4-66 years; males, 26%-88%). In the modeled estimates, 6.2% (95% uncertainty interval [UI], 2.4%-13.3%) of individuals who had symptomatic SARS-CoV-2 infection experienced at least 1 of the 3 Long COVID symptom clusters in 2020 and 2021, including 3.2% (95% UI, 0.6%-10.0%) for persistent fatigue with bodily pain or mood swings, 3.7% (95% UI, 0.9%-9.6%) for ongoing respiratory problems, and 2.2% (95% UI, 0.3%-7.6%) for cognitive problems after adjusting for health status before COVID-19, comprising an estimated 51.0% (95% UI, 16.9%-92.4%), 60.4% (95% UI, 18.9%-89.1%), and 35.4% (95% UI, 9.4%-75.1%), respectively, of Long COVID cases. The Long COVID symptom clusters were more common in women aged 20 years or older (10.6% [95% UI, 4.3%-22.2%]) 3 months after symptomatic SARS-CoV-2 infection than in men aged 20 years or older (5.4% [95% UI, 2.2%-11.7%]). Both sexes younger than 20 years of age were estimated to be affected in 2.8% (95% UI, 0.9%-7.0%) of symptomatic SARS-CoV-2 infections. The estimated mean Long COVID symptom cluster duration was 9.0 months (95% UI, 7.0-12.0 months) among hospitalized individuals and 4.0 months (95% UI, 3.6-4.6 months) among nonhospitalized individuals. Among individuals with Long COVID symptoms 3 months after symptomatic SARS-CoV-2 infection, an estimated 15.1% (95% UI, 10.3%-21.1%) continued to experience symptoms at 12 months.

Conclusions and Relevance  This study presents modeled estimates of the proportion of individuals with at least 1 of 3 self-reported Long COVID symptom clusters (persistent fatigue with bodily pain or mood swings; cognitive problems; or ongoing respiratory problems) 3 months after symptomatic SARS-CoV-2 infection.

Global Burden of Disease Long COVID Collaborators. Estimated Global Proportions of Individuals With Persistent Fatigue, Cognitive, and Respiratory Symptom Clusters Following Symptomatic COVID-19 in 2020 and 2021. JAMA. 2022;328(16):1604–1615. doi:10.1001/jama.2022.18931.

https://jamanetwork.com/journals/jama/fullarticle/2797443

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Lim, R.G., Al-Dalahmah, O., Wu, J. et al. Huntington disease oligodendrocyte maturation deficits revealed by single-nucleus RNAseq are rescued by thiamine-biotin supplementation. Nat Commun 13, 7791 (2022). https://doi.org/10.1038/s41467-022-35388-x

https://www.nature.com/articles/s41467-022-35388-x

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Abstract: “Widely available effective drugs to treat coronavirus disease-2019 (COVID-19) are still limited. Various studies suggested the potential contribution of selective serotonin-reuptake inhibitor (SSRI) antidepressants to alleviate the clinical course of COVID-19. Initially, SSRI antidepressant-attributed anti-COVID-19 activity was attributed to their direct agonistic or indirect serotonin-mediated stimulation of sigma-1 receptors (Sig1-R). Thereafter, attention was drawn to the property of SSRI antidepressants to decrease ceramide production, as functional inhibitors of acid sphingomyelinase. Ceramides are cell membrane waxy lipids formed by sphingosine and a fatty acid, playing a major role in receptor signaling and infection. In COVID-19 patients, ceramide production is increased due to acid sphingomyelinase activation. Here, we aimed to review the relationships between bradykinins and the proposed pathways supporting SSRI antidepressant-attributed effectiveness in COVID-19. In COVID-19 patients, bradykinin receptor-B1 stimulation is enhanced following the downregulation of angiotensin-converting enzyme-2, which is responsible for the inactivation of des-Arg9-bradykinin, a bradykinin metabolite, contrasting with the decrease in bradykinin receptor-B2 (BDKRB2) stimulation, which results from the inhibition of cathepsin L, a kininogenase involved in bradykinin production and present at the infection site. Sig1-R stimulation modulates the inflammatory response by regulating cytokine production and counterbalances COVID-19-attributed BDKRB2 inhibition by potentiating its effects on the cytosolic calcium concentration. Moreover, the beneficial effects obtained with acid sphingomyelinase inhibition are parallel to those expected with BDKRB2 stimulation in COVID-19. Altogether, these findings suggest that one ultimate pathway of SSRI antidepressant-attributed anti-COVID-19 activity is the potentiation of BDKRB2 effects shown to be inhibited in COVID-19. In conclusion, SSRI antidepressants are able to interact positively with the pathophysiological mechanisms involved in COVID-19. However, their exact benefits in preventing morbidities or improving the outcome in COVID-19 patients remain unknown.“

Gouda AS, Mégarbane B. Molecular Bases of Serotonin Reuptake Inhibitor Antidepressant-Attributed Effects in COVID-19: A New Insight on the Role of Bradykinins. J Pers Med. 2022 Sep 11;12(9):1487. doi: 10.3390/jpm12091487. PMID: 36143272; PMCID: PMC9502697.

https://pubmed.ncbi.nlm.nih.gov/36143272/

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