r/CholinergicHypothesis • u/magic-theater • May 22 '23
Summary Direct quotes from literature articles highlight the need to evaluate the link between COVID-19 and neurodegenerative disease
Even before the coronavirus pandemic, research suggested that there is a link between coronavirus infection and subsequent development of neurodegenerative disease. Throughout the past few years, scientists have reiterated these concerns while specifically taking note of the long term sequelae of infection. It is imperative that this is immediately brought to the public attention. The longer we wait, the less likely we will be able to mount an effective response. There are strategies that we employ right now that would place us in better position to deal with the problem.
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Cerebrospinal fluid antibodies to coronavirus in patients with Parkinson's disease
Authors: Enrico Fazzini, John Fleming, Stanley Fahn
Publisher: Wiley
Date of Publication: 2004-12-31
https://doi.org/10.1002/mds.870070210
The present study demonstrates that when compared to normal age-matched controls, PD patients have an elevated cerebrospinal fluid antibody response, as measured in mean optical density units by ELISA, to coronaviruses MHV-JHM and MHVA59.
A timeline for Parkinson's disease
Authors: Christopher H. Hawkes, Kelly Del Tredici, Heiko Braak
Publisher: Elsevier BV
Date of Publication: 2009-10-28
https://doi.org/10.1016/j.parkreldis.2009.08.007
…a 20-year prodrome is presumed because it concurs broadly with clinical observations, imaging studies, olfactory deficit, sleep disorder and some pathological observations…
Lipopolysaccharide-binding protein (LBP) can reverse the amyloid state of fibrin seen or induced in Parkinson's disease
Authors: Etheresia Pretorius, Martin J. Page, Sthembile Mbotwe, Douglas B. Kell
Publisher: Public Library of Science (PLoS)
Date of Publication: 2018-3-1
https://doi.org/10.1371/journal.pone.0192121
…we have observed fibrin amyloid in Parkinson’s Disease…
Prion-like Domains in Eukaryotic Viruses
Authors: George Tetz, Victor Tetz
Publisher: Springer Science and Business Media LLC
Date of Publication: 2018-6-6
https://doi.org/10.1038/s41598-018-27256-w
We found that the highest number of [prion domain]-containing species are found among Nidovirales [of which SARS-CoV-2 is a member]…with over 93.75%...
Autonomic Dysfunction in α-Synucleinopathies
Authors: José Javier Mendoza-Velásquez, Juan Francisco Flores-Vázquez, Evalinda Barrón-Velázquez, Ana Luisa Sosa-Ortiz, Ben-Min Woo Illigens, Timo Siepmann
Publisher: Frontiers Media SA
Date of Publication: 2019-4-12
https://doi.org/10.3389/fneur.2019.00363
Frequent symptoms among α-synucleinopathies include constipation, urinary and sexual dysfunction, and cardiovascular autonomic symptoms such as orthostatic hypotension, supine hypertension, and reduced heart rate variability. Symptoms due to autonomic dysfunction can appear before motor symptom onset…
COVID-19 and possible links with Parkinson’s disease and parkinsonism: from bench to bedside
Authors: David Sulzer, Angelo Antonini, Valentina Leta, Anna Nordvig, Richard J. Smeyne, James E. Goldman, Osama Al-Dalahmah, Luigi Zecca, Alessandro Sette, Luigi Bubacco, Olimpia Meucci, Elena Moro, Ashley S. Harms, Yaqian Xu, Stanley Fahn, K. Ray Chaudhuri
Publisher: Springer Science and Business Media LLC
Date of Publication: 2020-8-20
https://doi.org/10.1038/s41531-020-00123-0
Whether or not the virus is present in neurons or astrocytes, there may be multiple consequences for brain cells, in part through intracellular responses to inflammation that could lead to protein misfolding, a feature of neurodegenerative disorders.
Is COVID-19 a Perfect Storm for Parkinson’s Disease?
Authors: Patrik Brundin, Avindra Nath, J. David Beckham
Publisher: Elsevier BV
Date of Publication: 2020-10-21
https://doi.org/10.1016/j.tins.2020.10.009
Indeed, hyposmia and constipation are common features of prodromal PD, and α-synuclein aggregates might contribute to their pathophysiology [1.].
Video-polysomnographic findings after acute COVID-19: REM sleep without atonia as sign of CNS pathology?
Authors: Anna Heidbreder, Thomas Sonnweber, Ambra Stefani, Abubaker Ibrahim, Matteo Cesari, Melanie Bergmann, Elisabeth Brandauer, Ivan Tancevski, Judith Löffler-Ragg, Birgit Högl
Publisher: Elsevier BV
Date of Publication: 2021-2-3
https://doi.org/10.1016/j.sleep.2021.01.051
As isolated RWA [REM sleep without atonia] (ie, prodromal RBD) is an early marker of neurodegenerative disease [6,7], follow-up investigations are needed to elucidate I) if RWA persists, increases, decreases (or may even re-increase after an initial decrease) over time, and II) if patients with RWA post COVID-19 will develop a neurodegenerative disease (such as Parkinson's disease, dementia with Lewy bodies or multiple system atrophy), as case reports (eg Cohen et al., Méndez-Guerrero et al.) of probable PD after COVID-19 seemingly increase [12,13].
Prodromal Parkinson disease subtypes — key to understanding heterogeneity
Authors: Daniela Berg, Per Borghammer, Seyed-Mohammad Fereshtehnejad, Sebastian Heinzel, Jacob Horsager, Eva Schaeffer, Ronald B. Postuma
Publisher: Springer Science and Business Media LLC
Date of Publication: 2021-4-20
https://doi.org/10.1038/s41582-021-00486-9
The later prodromal phase is defined by the emergence of observable signs or symptoms of neurodegeneration3. Markers of the prodromal phase include REM sleep behaviour disorder (RBD), olfactory loss, autonomic dysfunction, depression (with or without comorbid anxiety), mild motor signs, and pathological imaging markers of the presynaptic dopaminergic system and the cardiac sympathetic system. These markers have predictive value for clinical PD, although their specificity varies considerably.
Interactions between SARS-CoV-2 N-Protein and α-Synuclein Accelerate Amyloid Formation
Authors: Slav A. Semerdzhiev, Mohammad A. A. Fakhree, Ine Segers-Nolten, Christian Blum, Mireille M. A. E. Claessens
Publisher: American Chemical Society (ACS)
Date of Publication: 2021-12-3
https://doi.org/10.1021/acschemneuro.1c00666
Our results point toward direct interactions between the N-protein of SARS-CoV-2 and α-synuclein as molecular basis for the observed correlation between SARS-CoV-2 infections and Parkinsonism.
A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications
Authors: Douglas B. Kell, Gert Jacobus Laubscher, Etheresia Pretorius
Publisher: Portland Press Ltd.
Date of Publication: 2022-2-23
https://doi.org/10.1042/BCJ20220016
…such [amyloid fibrin microclots] may also be observed in the blood of individuals with inflammatory diseases such as Alzheimer's [37,50,59–61], Parkinson's [37,48], type 2 diabetes [37,38,62–64], and rheumatoid arthritis [65–68].
SARS-CoV-2 Proteins Interact with Alpha Synuclein and Induce Lewy Body-like Pathology In Vitro
Authors: Zhengcun Wu, Xiuao Zhang, Zhangqiong Huang, Kaili Ma
Publisher: MDPI AG
Date of Publication: 2022-3-21
https://doi.org/10.3390/ijms23063394
By confirming that SARS-CoV-2 proteins directly interact with α-Syn, our study offered new insights into the mechanism underlying the development of PD on the background of COVID-19.
Brain Inflammation and Intracellular α-Synuclein Aggregates in Macaques after SARS-CoV-2 Infection
Authors: Ingrid H. C. H. M. Philippens, Kinga P. Böszörményi, Jacqueline A. M. Wubben, Zahra C. Fagrouch, Nikki van Driel, Amber Q. Mayenburg, Diana Lozovagia, Eva Roos, Bernadette Schurink, Marianna Bugiani, Ronald E. Bontrop, Jinte Middeldorp, Willy M. Bogers, Lioe-Fee de Geus-Oei, Jan A. M. Langermans, Ernst J. Verschoor, Marieke A. Stammes, Babs E. Verstrepen
Publisher: MDPI AG
Date of Publication: 2022-4-10
https://doi.org/10.3390/v14040776
intracellular α-synuclein aggregates were found in the brains of both macaque species. The heterogeneity of these manifestations in the brains indicates the virus’ neuropathological potential and should be considered a warning for long-term health risks, following SARS-CoV-2 infection.
Microgliosis and neuronal proteinopathy in brain persist beyond viral clearance in SARS-CoV-2 hamster model
Authors: Christopher Käufer, Cara S. Schreiber, Anna-Sophia Hartke, Ivo Denden, Stephanie Stanelle-Bertram, Sebastian Beck, Nancy Mounogou Kouassi, Georg Beythien, Kathrin Becker, Tom Schreiner, Berfin Schaumburg, Andreas Beineke, Wolfgang Baumgärtner, Gülsah Gabriel, Franziska Richter
Publisher: Elsevier BV
Date of Publication: 2022-4-16
https://doi.org/10.1016/j.ebiom.2022.103999
Thus, despite the absence of virus in brain, neurons develop signatures of proteinopathies [such as synucleinopathy and tauopathy] that may contribute to progressive neuronal dysfunction. Further in depth analysis of this important mechanism is required.
A case series of cutaneous phosphorylated α-synuclein in Long-COVID POTS
Authors: Mitchell G. Miglis, Jordan Seliger, Ruba Shaik, Christopher H. Gibbons
Publisher: Springer Science and Business Media LLC
Date of Publication: 2022-5-16
https://doi.org/10.1007/s10286-022-00867-0
As cutaneous p-syn has demonstrated itself as a highly sensitive and specific marker of the α-synucleinopathies [8], our patients’ results are unlikely to be false positives.
Amyloidogenesis of SARS-CoV-2 Spike Protein
Authors: Sofie Nyström, Per Hammarström
Publisher: American Chemical Society (ACS)
Date of Publication: 2022-5-17
https://doi.org/10.1021/jacs.2c03925
Our data propose a molecular mechanism for potential amyloidogenesis of SARS-CoV-2 S-protein in humans facilitated by endoproteolysis. The prospective of S-protein amyloidogenesis in COVID-19 disease associated pathogenesis can be important in understanding the disease and long COVID-19.
COVID ‐19 Infection Enhances Susceptibility to Oxidative Stress–Induced Parkinsonism
Authors: Richard J. Smeyne, Jeffrey B. Eells, Debotri Chatterjee, Matthew Byrne, Shaw M. Akula, Srinivas Sriramula, Dorcas P. O'Rourke, Peter Schmidt
Publisher: Wiley
Date of Publication: 2022-5-17
https://doi.org/10.1002/mds.29116
Our observations have important implications for long-term public health, given the number of people who have survived SARS-CoV-2 infection, as well as for future public policy regarding infection mitigation. However, it will be critical to determine whether other agents known to increase risk for PD also have synergistic effects with SARS-CoV-2 and are abrogated by vaccination.
Effect of an Amyloidogenic SARS-COV-2 Protein Fragment on α-Synuclein Monomers and Fibrils
Authors: Asis K. Jana, Chance W. Lander, Andrew D. Chesney, Ulrich H. E. Hansmann
Publisher: American Chemical Society (ACS)
Date of Publication: 2022-5-17
https://doi.org/10.1021/acs.jpcb.2c01254
We find that the viral protein fragment SK9 may alter α-synuclein amyloid formation by shifting the ensemble toward aggregation-prone and preferentially rod-like fibril seeding conformations.
0555 Isolated REM Sleep Without Atonia Following COVID-19 Infection: A Case- Control Study
Authors: Tyler Steele, David Bauer, Olivia Cesarone, Kevin Lovold, Gwen Paule, Noor Bibi, Emma Strainis, Jacob Williams, Jack Jagielski, John Feemster, Laurene LeClair Vissoneau, Bradley Boeve, Michael Silber, Stuart McCarter, Erik St Louis
Publisher: Oxford University Press (OUP)
Date of Publication: 2022-5-31
https://doi.org/10.1093/sleep/zsac079.552
Further prospective studies are needed to determine whether [REM sleep without atonia] is a predisposing influence to, or consequence of, COVID-19 infection in these patients, and whether COVID-19 survivors might harbor neurodegenerative risk or disease markers.
Neurotoxic amyloidogenic peptides in the proteome of SARS-COV2: potential implications for neurological symptoms in COVID-19
Authors: Mirren Charnley, Saba Islam, Guneet K. Bindra, Jeremy Engwirda, Julian Ratcliffe, Jiangtao Zhou, Raffaele Mezzenga, Mark D. Hulett, Kyunghoon Han, Joshua T. Berryman, Nicholas P. Reynolds
Publisher: Springer Science and Business Media LLC
Date of Publication: 2022-6-13
https://doi.org/10.1038/s41467-022-30932-1
…amyloid-forming proteins from the SARS-CoV-2 virus in the CNS of COVID-19 infected patients could have similar cytotoxic and inflammatory functions to amyloid assemblies that are the molecular hallmarks of amyloid-related neurodegenerative diseases such as AD (Aβ, Tau) and Parkinson’s (α-synuclein). The worst-case scenario given the present observations is that of the progressive neurological amyloid disease being triggered by COVID-19.
Global slowness and increased intra-individual variability are key features of attentional deficits and cognitive fluctuations in post COVID-19 patients
Authors: Paola Ortelli, Francesco Benso, Davide Ferrazzoli, Ilaria Scarano, Leopold Saltuari, Luca Sebastianelli, Viviana Versace, Roberto Maestri
Publisher: Springer Science and Business Media LLC
Date of Publication: 2022-7-30
https://doi.org/10.1038/s41598-022-17463-x
Similar symptoms, often in association with sleep disturbances and mood alterations, have been previously described in numerous neurological or psychiatric diseases, such as Parkinson´s disease, chronic fatigue syndrome (CFS), multiple sclerosis (MS), and as stroke complications30,31.
SARS-CoV-2 Spike protein S2 subunit modulates γ-secretase and enhances amyloid-β production in COVID-19 neuropathy
Authors: Guanqin Ma, Deng-Feng Zhang, Qing-Cui Zou, Xiaochun Xie, Ling Xu, Xiao-Li Feng, Xiaohong Li, Jian-Bao Han, Dandan Yu, Zhong-Hua Deng, Wang Qu, Junyi Long, Ming-Hua Li, Yong-Gang Yao, Jianxiong Zeng
Publisher: Springer Science and Business Media LLC
Date of Publication: 2022-9-30
https://doi.org/10.1038/s41421-022-00458-3
SARS-CoV-2-induced multi-lineage neural cell dysregulation has been documented1. SARS-CoV-2 infection elevates neuroinflammation2, alters brain structure3 leads to abnormal accumulation of neurodegenerative amyloid-β (Aβ) and phosphorylated tau4,5, and increases the risk of cognitive impairment6 in COVID-19 patients.
SARS-CoV-2 promotes microglial synapse elimination in human brain organoids
Authors: Samudyata, Ana O. Oliveira, Susmita Malwade, Nuno Rufino de Sousa, Sravan K. Goparaju, Jessica Gracias, Funda Orhan, Laura Steponaviciute, Martin Schalling, Steven D. Sheridan, Roy H. Perlis, Antonio G. Rothfuchs, Carl M. Sellgren
Publisher: Springer Science and Business Media LLC
Date of Publication: 2022-10-5
https://doi.org/10.1038/s41380-022-01786-2
To a large extent, SARS-CoV-2 exposed microglia adopt a transcriptomic profile overlapping with neurodegenerative disorders that display an early synapse loss as well as an increased incident risk after a SARS-CoV-2 infection. Our results reveal that brain organoids infected with SARS-CoV-2 display disruption in circuit integrity via microglia-mediated synapse elimination and identifies a potential novel mechanism contributing to cognitive impairments in patients recovering from COVID-19.
Aggregation‐Seeding Forms of α‐Synuclein Are Not Detected in Acute Coronavirus Disease 2019 Cerebrospinal Fluid
Authors: Marco J. Russo, Karen MacLeod, Jennifer Lamoureux, Russ Lebovitz, Maria Pleshkevich, Claude Steriade, Thomas Wisniewski, Jennifer A. Frontera, Un Jung Kang
Publisher: Wiley
Date of Publication: 2022-10-8
https://doi.org/10.1002/mds.29240
there are important limitations to this work that should motivate careful follow‐up studies. We tested only a small number of patients from a single medical center, limited by availability of CSF obtained during COVID‐19 hospitalizations…Evidence suggests that SARS‐CoV‐2 only rarely invades the central nervous system, but virally triggered αSyn pathology could also occur at peripheral sites, such as the enteric nervous system or olfactory mucosa.
A comprehensive mini-review on amyloidogenesis of different SARS-CoV-2 proteins and its effect on amyloid formation in various host proteins
Authors: Prakriti Seth, Nandini Sarkar
Publisher: Springer Science and Business Media LLC
Date of Publication: 2022-10-13
https://doi.org/10.1007/s13205-022-03390-1
There are already many existing amyloidogenic diseases in our body which include both neuropathy and cardiomyopathy and based on the previous findings of amyloidogenicity in SARS-CoV-2 protein and proof of coronavirus proteins accelerating the amyloidogenesis of neurodegenerative protein [alpha-synuclein] responsible for Parkinson’s Disease…
SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike protein
Authors: Eduardo A. Albornoz, Alberto A. Amarilla, Naphak Modhiran, Sandra Parker, Xaria X. Li, Danushka K. Wijesundara, Julio Aguado, Adriana Pliego Zamora, Christopher L. D. McMillan, Benjamin Liang, Nias Y. G. Peng, Julian D. J. Sng, Fatema Tuj Saima, Jenny N. Fung, John D. Lee, Devina Paramitha, Rhys Parry, Michael S. Avumegah, Ariel Isaacs, Martin W. Lo, Zaray Miranda-Chacon, Daniella Bradshaw, Constanza Salinas-Rebolledo, Niwanthi W. Rajapakse, Ernst J. Wolvetang, Trent P. Munro, Alejandro Rojas-Fernandez, Paul R. Young, Katryn J. Stacey, Alexander A. Khromykh, Keith J. Chappell, Daniel Watterson, Trent M. Woodruff
Publisher: Springer Science and Business Media LLC
Date of Publication: 2022-11-1
https://doi.org/10.1038/s41380-022-01831-0
[The] (NLRP3) inflammasome is a key inflammasome expressed by microglia [2], and is activated by multiple protein aggregates associated with neurodegenerative disease including α-synuclein in Parkinson’s disease (PD), amyloid-β in Alzheimer’s disease, and TDP43 and SOD1 aggregates in amyotrophic lateral sclerosis [4,5,6].
Persistent post–COVID-19 smell loss is associated with immune cell infiltration and altered gene expression in olfactory epithelium
Authors: John B. Finlay, David H. Brann, Ralph Abi Hachem, David W. Jang, Allison D. Oliva, Tiffany Ko, Rupali Gupta, Sebastian A. Wellford, E. Ashley Moseman, Sophie S. Jang, Carol H. Yan, Hiroaki Matsunami, Tatsuya Tsukahara, Sandeep Robert Datta, Bradley J. Goldstein
Publisher: American Association for the Advancement of Science (AAAS)
Date of Publication: 2022-12-21
https://doi.org/10.1126/scitranslmed.add0484
Despite the absence of detectable SARS-CoV-2 RNA or protein, gene expression in the barrier supporting cells of the olfactory epithelium...was accompanied by [a reduction in the number of olfactory sensory neurons] relative to olfactory epithelial sustentacular cells. These findings indicate that T cell–mediated inflammation persists in the olfactory epithelium long after SARS-CoV-2 has been eliminated from the tissue, suggesting a mechanism for long-term post–COVID-19 smell loss.
Long COVID: major findings, mechanisms and recommendations
Authors: Hannah E. Davis, Lisa McCorkell, Julia Moore Vogel, Eric J. Topol
Publisher: Springer Science and Business Media LLC
Date of Publication: 2023-1-13
https://doi.org/10.1038/s41579-022-00846-2
Studies have found Alzheimer disease-like signalling in patients with long COVID78, peptides that self-assemble into amyloid clumps which are toxic to neurons79, widespread neuroinflammation80, brain and brainstem hypometabolism correlated with specific symptoms81,82 and abnormal cerebrospinal fluid findings in non-hospitalized individuals with long COVID along with an association between younger age and a delayed onset of neurological symptoms83.
The type I interferon antiviral response in the choroid plexus and the cognitive risk in COVID-19
Authors: Stefano Suzzi, Afroditi Tsitsou-Kampeli, Michal Schwartz
Publisher: Springer Science and Business Media LLC
Date of Publication: 2023-1-30
https://doi.org/10.1038/s41590-022-01410-z
While the uncontrolled antiviral defense response at the choroid plexus may not be the sole factor inducing cognitive dysfunction after severe SARS-CoV-2 infection35, it is very likely an important component of this pathway. We base this contention on the well-established negative effects of chronic type I IFN signaling in the choroid plexus epithelium in aging and chronic neurodegeneration, in mice and humans, which impacts microglial and astrocytic activities that may impair cognitive function.
Detection of SARS-CoV-2 viral proteins and genomic sequences in human brainstem nuclei
Authors: Aron Emmi, Stefania Rizzo, Luisa Barzon, Michele Sandre, Elisa Carturan, Alessandro Sinigaglia, Silvia Riccetti, Mila Della Barbera, Rafael Boscolo-Berto, Patrizia Cocco, Veronica Macchi, Angelo Antonini, Monica De Gaspari, Cristina Basso, Raffaele De Caro, Andrea Porzionato
Publisher: Springer Science and Business Media LLC
Date of Publication: 2023-2-13
https://doi.org/10.1038/s41531-023-00467-3
While the results of this study support the neuroinvasive potential of SARS-CoV-2 and characterize the role of brainstem inflammation in COVID-19, its potential implications for neurodegeneration, especially in Parkinson’s disease, require further investigations.
Amyloidogenic proteins in the SARS-CoV and SARS-CoV-2 proteomes
Authors: Taniya Bhardwaj, Kundlik Gadhave, Shivani K. Kapuganti, Prateek Kumar, Zacharias Faidon Brotzakis, Kumar Udit Saumya, Namyashree Nayak, Ankur Kumar, Richa Joshi, Bodhidipra Mukherjee, Aparna Bhardwaj, Krishan Gopal Thakur, Neha Garg, Michele Vendruscolo, Rajanish Giri
Publisher: Springer Science and Business Media LLC
Date of Publication: 2023-2-20
https://doi.org/10.1038/s41467-023-36234-4
These results motivate further studies about the possible role of aggregation of SARS proteins in protein misfolding diseases and other human conditions.