Effect of COVID-19 on Alzheimer's and dementia measured through ocular indications

Screening for early detection of Alzheimer's disease (AD) through a comprehensive eye exam appears to be promising and could potentially provide a more sensitive, inexpensive way to visualize early signs of AD for early detection in large populations. Optical coherence tomography (OCT), as well as retinal imaging techniques such as Doppler and fluorescence lifetime imaging ophthalmoscopy (FLIO), can detect signs of early AD such as vascular changes or accumulations of Tau proteins and beta-amyloid proteins. In the age of COVID-19, this screening opportunity is threatened by increased no-show rates leading to decreased early detection of AD. Through the combination of COVID-19 neuroinflammation potentially augmenting AD neurodegeneration, as well as missed opportunity in the use of early ophthalmic detection, the pandemic may have significantly worsened the trajectory of AD. © 2023 Elsevier Inc. All rights reserved.

COVID-19 and Alzheimer's Disease: Neuroinflammation, Oxidative Stress, Ferroptosis, and Mechanisms Involved.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by marked cognitive decline, memory loss, and spatio-temporal troubles and, in severe cases, lack of recognition of family members. Neurological symptoms, cognitive disturbances, and the inflammatory frame due to COVID-19, together with long-term effects, have fueled renewed interest in AD based on similar damage. COVID-19 also caused the acceleration of AD symptom onset. In this regard, the morbidity and mortality of COVID-19 were reported to be increased in patients with AD due to multiple pathological changes such as excessive expression of the viral receptor angiotensin-converting enzyme 2 (ACE2), comorbidities such as diabetes, hypertension, or drug-drug interactions in patients receiving polypharmacy and the high presence of proinflammatory molecules. Furthermore, the release of cytokines, neuroinflammation, oxidative stress, and ferroptosis in both diseases showed common underlying mechanisms, which together worsen the clinical picture and prognosis of these patients.

Neuroinflammation: 2022 update.

Besides important progress in the understanding of the pathological substrate of COVID-19-associated brain disease, major insights into mechanisms of neurodegeneration in human disease have been provided in neuropathological studies published in 2021. Recently developed techniques, which allow the simultaneous detection of a large battery of different molecules within single cells, have proven useful in the analysis of disease mechanisms in experimental and human neuroinflammatory conditions. They have elucidated protective and detrimental effects of activated microglia, which act in a stage and context-dependent manner in the induction and propagation of neurodegeneration. In addition, they emphasize the importance of synaptic damage and of selective neuronal vulnerability in the respective diseases. The results provide important new insights with high clinical relevance.

Neurodegeneration: 2022 update.

Here, we review a collection of recent manuscripts and research trends on the neuropathology of neurodegeneration that are considered by the author to be among the potentially most impactful. To the greatest extent possible, we chose to focus on histopathological studies that are most relevant to experimental and diagnostic neuropathology. While there has been an abundance of important recent discoveries and developments in neurodegenerative disease research, there was a deliberate effort here to provide balance to prevent disease categories and experimental approaches from overshadowing the others. The result is a diverse series of outstanding studies, together showing the landscape of progress across neurodegenerative disorders. One is a stereological study examining dystrophic microglia in aging. We highlight the first large genetic study of primary age-related tauopathy, showing convergence and divergence from classical Alzheimer's disease. There were further advances in the neuropathological criteria and staging of chronic traumatic encephalopathy. Links suggesting a causal role for TMEM106B in TDP-43 proteinopathy emerged. Attempts to subtype Alzheimer's disease on the molecular level were made. Evidence for a role for the VEGF family in cognitive impairment was advanced. Comparison of gene expression profiles from myeloid cells in peripheral blood and brain tissues from Parkinson's disease patients revealed pathways that may lead to new mechanistic insights and biomarkers. A large autopsy series identified an increased frequency of central nervous system developmental malformations in Huntington's disease. A robust and reliable system for assessing Lewy body pathology was proposed. Finally, we continue to be plagued by the COVID-19 pandemic, with lingering concerns of a long-term link with neurodegeneration.

Neurodegeneration: 2021 update.

This article reviews a collection of manuscripts in the field of neurodegenerative disease chosen from what are considered by the author to be among the 10 most important and potentially impactful topics or research trends of 2020 relevant to the field of experimental and diagnostic neuropathology. A deliberate effort was made to provide balance among disease categories covered. The result is a varied selection that includes not just individual papers but also research topics and trends. The association of COVID-19 with longer-term neurological symptoms has launched a research trend fueled by speculation that the SARS-CoV-2 might trigger neurodegenerative changes. The onslaught of transcriptomic studies has begun to give way to proteomics, with three transformative studies published examining glial contributions to Alzheimer disease, cerebral atherosclerosis in cognitive decline, and the complex sequence of post-translational modifications of the tau protein. Plasma biomarkers for Alzheimer disease have continued to make rapid advances, especially around highly sensitive assays capable of detecting different forms of abnormal hyperphosphorylated tau in peripheral blood. Two studies using cryo-electron microscopy showed the power of the approach by continuing to elucidate the diversity of filamentous tau inclusions, and a third study gave the first glimpse of α-synuclein aggregates at near atomic resolution. Another study continued to delineate how different α-synuclein conformers ("strains") target specific brain regions and lead to neurodegeneration. In Huntington's disease, we saw compelling molecular data showing how cells adapt to endoplasmic reticulum stress through the unfolded protein response. Finally, the role of astrocytes in chronic traumatic encephalopathy has emerged as a critical area of interest.

Assessment of early and long-COVID related retinal neurodegeneration with optical coherence tomography.

PURPOSE: The aim of this study is to investigate short-term and long-term effects of coronovirus 19 disease (COVID-19) at inner and outer retinal layers of patients recovered from COVID-19 with Spectral Domain Optical Coherence Tomography (SD-OCT) and compare these to healthy subjects. METHODS: Twenty-seven patients recovered from COVID-19, and age- and gender-matched 27 healthy controls were included in this study. Macular and peripapillary retinal nerve fiber layer (RNFL), ganglion cell-inner plexiform layer (GCIPL), inner nuclear layer (INL), outer plexiform layer (OPL) and outer nuclear layer (ONL) were analyzed with SD-OCT 1 month (V1 visit) and 12 months (V2 visit) after negative result of reverse transcriptase-polymerase chain reaction test. RESULTS: Macular RNFL thickness in outer ring was thinner at V1 and V2 visits than healthy control (p = 0.049 and p = 0.005). Central and inferonasal quadrants of peripapillary RNFL thicknesses were reduced at V1 and V2 visits compared to controls (p = 0.001 and p = 0.024 for V1 visit; p = 0.001 and p = 0.006 for V2 visit). Thinning in ONL thickness in inner ring was observed at V1 and V2 visits than healthy subjects (p = 0.006 and p = 0.001). CONCLUSION: Subclinical localized changes in macular and peripapillary RNFL and outer nuclear layer were demonstrated in early and 12-months follow-up after COVID-19 recovery.

Long-Term Effects of SARS-CoV-2 in the Brain: Clinical Consequences and Molecular Mechanisms.

Numerous investigations have demonstrated significant and long-lasting neurological manifestations of COVID-19. It has been suggested that as many as four out of five patients who sustained COVID-19 will show one or several neurological symptoms that can last months after the infection has run its course. Neurological symptoms are most common in people who are less than 60 years of age, while encephalopathy is more common in those over 60. Biological mechanisms for these neurological symptoms need to be investigated and may include both direct and indirect effects of the virus on the brain and spinal cord. Individuals with Alzheimer's disease (AD) and related dementia, as well as persons with Down syndrome (DS), are especially vulnerable to COVID-19, but the biological reasons for this are not clear. Investigating the neurological consequences of COVID-19 is an urgent emerging medical need, since close to 700 million people worldwide have now had COVID-19 at least once. It is likely that there will be a new burden on healthcare and the economy dealing with the long-term neurological consequences of severe SARS-CoV-2 infections and long COVID, even in younger generations. Interestingly, neurological symptoms after an acute infection are strikingly similar to the symptoms observed after a mild traumatic brain injury (mTBI) or concussion, including dizziness, balance issues, anosmia, and headaches. The possible convergence of biological pathways involved in both will be discussed. The current review is focused on the most commonly described neurological symptoms, as well as the possible molecular mechanisms involved.

Climate Change in Western Australia and Its Impact on Human Health

Climate change is real and here. Climate change has a wide range of effects on the environment – increasing global temperatures and extreme weather events, which in turn are impacting human health. Changes in weather and man-made pollution affect the quality of the air we breathe, the water we drink and the food we eat, resulting in a serious threat to our planet and our health. By examining the current literature, using a systematic review process, we explore the current and potential impact that climate change has on human health with particular relevance to the Western Australian population. There is overwhelming evidence for climate change and how it is affecting the people of planet Earth. The environmental impact will affect human health and may result in increases in cardiovascular respiratory, neurological disorders (including neurodegeneration), vector-borne illnesses (malaria, COVID-19, Ross River Virus) and lead to a detriment in the mental health of Western Australians. Natural diseases and crises complicate healthcare. The COVD-19 pandemic revealed inadequacies in healthcare systems—shortage of healthcare workers and resources—which will compromise the ability to manage climate change induced diseases. Bushfires and raised environmental temperatures, which are particular problems for Western Australia, can impact upon climate change. Mental health may be affected through illness, drought and food insecurity. Those socially disadvantaged, individuals in remote regions and First Nations peoples will be vulnerable. An urgent response to climate change is necessary. Western Australia is particularly vulnerable to the deleterious impacts of climate change.

Curcumin as a natural systemic disease modulator

In the prevention and treatment of various diseases, a variety of preparations based on medicinal plants are now generally acknowledged and well-documented. The main advantages of traditional medicine in underdeveloped nations are safety and affordability. As diferuloylmethane, curcumin is a naturally occurring polyphenol that is mostly produced in the rhizomes of plant roots. Curcumin has a long history of usage in conventional medicine, although its therapeutic effects and health advantages are still little understood. The therapeutic benefits of curcumin include the treatment of malignancies, neurodegenerative, ocular, and COVID diseases as well as inflammatory and digestive disorders, rheumatic and skin issues, and tumors. Apoptosis-related genes, cytokines, enzymes, and other targets have all been found in certain studies to be modulated by curcumin. Furthermore, little is known about the biological mechanisms that underlie these activities. We will examine some of the known molecular targets and biological processes of curcumin in this chapter. The processes through which curcumin functions in neuroprotection and/or mental health disorders will be covered in this chapter. We will also talk about curcumin's protective role in how bone may impact neurological function. © 2023 Nova Science Publishers, Inc.

SARS-CoV-2 Infection to Premature Neuronal Aging and Neurodegenerative Diseases: Is there any Connection with Hypoxia?

The pandemic of coronavirus disease-2019 [COVID-19], caused by SARS-CoV-2, has become a global concern as it leads to a spectrum of mild to severe symptoms and increases death tolls around the world. Severe COVID-19 results in acute respiratory distress syndrome, hypoxia, and multi-organ dysfunction. However, the long-term effects of post-COVID-19 infection are still unknown. Based on the emerging evidence, there is a high possibility that COVID-19 infection accelerates premature neuronal aging and increases the risk of age-related neurodegenerative diseases in mild to severely infected patients during the post-COVID period. Several studies correlate COVID-19 infection with neuronal effects, though the mechanism through which they contribute to the aggravation of neuroinflammation and neurodegeneration is still under investigation. SARS-CoV-2 predominantly targets pulmonary tissues and interferes with gas exchange, leading to systemic hypoxia. The neurons in the brain require a constant supply of oxygen for their proper functioning, suggesting that they are more vulnerable to any alteration in oxygen saturation level that results in neuronal injury with or without neuroinflammation. We hypothesize that hypoxia is one of the major clinical manifestations of severe SARS-CoV-2 infection; it directly or indirectly contributes to premature neuronal aging, neuroinflammation, and neurodegeneration by altering the expression of various genes responsible for the survival of the cells. This review focuses on the interplay between COVID-19 infection, hypoxia, premature neuronal aging, and neurodegenerative diseases and provides a novel insight into the molecular mechanisms of neurodegeneration.

Correlation of covid-19 and Guillain-Barré syndrome: A Mechanistic Perspective.

Aims: Coronaviruses, SARS-CoV-2 particles are spherical and have proteins called spikes that stick out on the surface. COVID-19 most commonly affects the respiratory system, but various clinical manifestations on coronavirus have revealed their potential neurotropism. The neuroinvasive affinity of Coronavirus infections has been reported nearly for all the ß Coronavirus infections, including MERS-CoV, SARS-CoV, HCoV-OC43 and HEV. Coronavirus invasion occurs through hypoxia injury, immune injury, ACE2, and direct infection. The pathophysiology of SARS-CoV-2 and other human Coronaviruses reveals the possible mechanisms of neurodegeneration. Methods: A systematic literature review carried out from various search engines like Scopus, PubMed, Medline, and Elsevier for investigating the therapeutic perspective of association between Covid-19 and Guillain-Barré syndrome. Results: SARS-CoV-2 uses angiotensin-converting enzyme 2 as its entry receptor and enters the central nervous system through a Blood-brain barrier constituted of inflammatory mediators, direct infection of the endothelial cells, or endothelial injury. Guillain-Barré syndrome is an autoimmune disease that injures and attacks the nerves in the peripheral nervous system. Studies suggest that the virus can infect peripheral neurons to cause direct damage through various mechanisms, including direct damage by cytokine-related injury, ACE2 receptors, and the sequelae of hypoxia. Conclusion: we have discussed the possible mechanisms between neuroinvasion of SARs-cov2 and Guillain-barre syndrome.

[Interleukin-11 in Pathologies of the Nervous System].

The study of the role of cytokines in various pathological conditions of the body is a topical area in modern biomedicine. Understanding the physiological roles played by cytokines will aid in finding applications for them as pharmacological agents in clinical practice. Interleukin 11 (IL-11) was discovered in 1990 in fibrocyte-like bone marrow stromal cells, but there has been increased interest in this cytokine in recent years. IL-11 has been shown to correct inflammatory pathways in the epithelial tissues of the respiratory system, where the main events occur during SARS-CoV-2 infection. Further research in this direction will probably support the use of this cytokine in clinical practice. The cytokine plays a significant role in the central nervous system; local expression by nerve cells has been shown. Studies show the involvement of IL-11 in the mechanisms of development of a number of pathologies of the nervous system, and therefore it seems relevant to generalize and analyze the experimental data obtained in this direction. This review summarizes information that shows the involvement of IL-11 in the mechanisms of development of brain pathologies. In the near future this cytokine will likely find clinical application for the correction of mechanisms that are involved in the formation of pathological conditions of the nervous system.

A functional role for alpha-synuclein in neuroimmune responses.

Alpha-synuclein is a neuronal protein with unclear function but is associated with the pathogenesis of Parkinson's disease and other synucleinopathies. In this review, we discuss the emerging functional role of alpha-synuclein in support of the unique immune responses in the nervous system. Recent data now show that alpha-synuclein functions to support interferon signaling within neurons and is released from neurons to support chemoattraction and activation of local glial cells and infiltrating immune cells. Inflammatory activation and interferon signaling also induce post-translational modifications of alpha-synuclein that are commonly associated with Parkinson's disease pathogenesis. Taken together, emerging data implicate complex interactions between alpha-synuclein and host immune responses that may contribute to the pathogenesis of Parkinson's disease. Additional study of the function of alpha-synuclein in the brain's immune response may provide disease-modifying therapeutic targets for Parkinson's disease in the future.

Shared miRNA landscapes of COVID-19 and neurodegeneration confirm neuroinflammation as an important overlapping feature.

Introduction: Development and worsening of most common neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis, have been associated with COVID-19 However, the mechanisms associated with neurological symptoms in COVID-19 patients and neurodegenerative sequelae are not clear. The interplay between gene expression and metabolite production in CNS is driven by miRNAs. These small non-coding molecules are dysregulated in most common neurodegenerative diseases and COVID-19. Methods: We have performed a thorough literature screening and database mining to search for shared miRNA landscapes of SARS-CoV-2 infection and neurodegeneration. Differentially expressed miRNAs in COVID-19 patients were searched using PubMed, while differentially expressed miRNAs in patients with five most common neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis) were searched using the Human microRNA Disease Database. Target genes of the overlapping miRNAs, identified with the miRTarBase, were used for the pathway enrichment analysis performed with Kyoto Encyclopedia of Genes and Genomes and Reactome. Results: In total, 98 common miRNAs were found. Additionally, two of them (hsa-miR-34a and hsa-miR-132) were highlighted as promising biomarkers of neurodegeneration, as they are dysregulated in all five most common neurodegenerative diseases and COVID-19. Additionally, hsa-miR-155 was upregulated in four COVID-19 studies and found to be dysregulated in neurodegeneration processes as well. Screening for miRNA targets identified 746 unique genes with strong evidence for interaction. Target enrichment analysis highlighted most significant KEGG and Reactome pathways being involved in signaling, cancer, transcription and infection. However, the more specific identified pathways confirmed neuroinflammation as being the most important shared feature. Discussion: Our pathway based approach has identified overlapping miRNAs in COVID-19 and neurodegenerative diseases that may have a valuable potential for neurodegeneration prediction in COVID-19 patients. Additionally, identified miRNAs can be further explored as potential drug targets or agents to modify signaling in shared pathways. Graphical AbstractShared miRNA molecules among the five investigated neurodegenerative diseases and COVID-19 were identified. The two overlapping miRNAs, hsa-miR-34a and has-miR-132, present potential biomarkers of neurodegenerative sequelae after COVID-19. Furthermore, 98 common miRNAs between all five neurodegenerative diseases together and COVID-19 were identified. A KEGG and Reactome pathway enrichment analyses was performed on the list of shared miRNA target genes and finally top 20 pathways were evaluated for their potential for identification of new drug targets. A common feature of identified overlapping miRNAs and pathways is neuroinflammation. AD, Alzheimer's disease; ALS, amyotrophic lateral sclerosis; COVID-19, coronavirus disease 2019; HD, Huntington's disease; KEGG, Kyoto Encyclopedia of Genes and Genomes; MS, multiple sclerosis; PD, Parkinson's disease.

Gastrointestinal, Respiratory, and Olfactory Neurotropism of Sars-Cov2 as a Possible Trigger of Parkinson's Disease: Is a Multi-Hit Multi-Step Process on the Cards.

Since the first emergence of COVID-19 on the global stage, there has been a wealth of evidence to suggest that SARS-Cov2 is not merely a pulmonary pathogen. This virus is unique in its ability to disrupt cellular pathways related to protein homeostasis, mitochondrial function, stress response, and aging. Such effects raise concerns about the long-term fate of survivors of COVID-19 infection, particularly regarding neurodegenerative diseases. The concept of interaction between environmental factors and alpha-synuclein formation in the olfactory bulb and vagal autonomic terminals with subsequent caudo-cranial migration has received much attention in the context of PD pathogenesis. Anosmia and gastrointestinal symptoms are two well-known symptoms of COVID-19, with evidence of an olfactory bulb and vagal infiltration by SARS-CoV2. This raises the possibility of the spread of the viral particles to the brain along multiple cranial nerve routes. Neurotropism, coupled with the ability of the SARS-Cov2 virion to induce abnormal protein folding and stress responses in the central nervous system, in presence of an inflammatory milieu, reinforced by hypoxia, coagulopathy, and endothelial dysfunction, reverberates the intriguing possibility of activation of a neurodegenerative cascade leading to the development of pathological alpha-synuclein aggregates and thus, triggering the development of PD in survivors of COVID19. This review attempts to summarize and critically appraise existing evidence from basic science research and clinical reports of links between COVID-19 and PD and explores the prospect of a multi-hit pathophysiological process, induced by SARS-Cov2 infection, ultimately converging on perturbed cellular protein homeostasis, which although is intriguing, presently lacks robust evidence for confirmation.

Parkinson disease following COVID-19: Report of six cases.

BACKGROUND AND PURPOSE: Core clinical manifestations of COVID-19 include influenza-like and respiratory symptoms. However, it is now evident that neurological involvement may occur during SARS-CoV-2 infection, covering an extensive spectrum of phenotypical manifestations. A major challenge arising from this pandemic is represented by detecting emerging neurological complications following recovery from SARS-CoV-2 infection. To date, a few post-COVID-19-infected subjects diagnosed with Parkinson disease (PD) have been described, raising the possibility of a connection between the infection and neurodegenerative processes. Here, we describe a case series of six subjects who developed PD after COVID-19. METHODS: Patients were observed at Scientific Institute for Research and Health Care Mondino Foundation Hospital, Pavia (Italy), and San Paolo University Hospital of Milan (Italy) between March 2021 and June 2022. In all subjects, SARS-CoV-2 infection was confirmed by means of reverse transcriptase polymerase chain reaction from a nasopharyngeal swab. Subjects underwent an accurate neurological evaluation, and neuroimaging studies were performed. RESULTS: We describe six subjects who developed PD with an average time window after SARS-CoV-2 infection of 4-7 weeks. Apparently, no relationship with COVID-19 severity emerged, and no overt structural brain abnormalities were found. All subjects experienced unilateral resting tremor at onset and showed a satisfactory response to dopaminergic treatment. CONCLUSIONS: Immune responses to SARS-CoV-2 infection have been shown to shape the individual susceptibility to develop long-term consequences. We hypothesize that, in these subjects, COVID-19 has unmasked a latent neurodegenerative process. Characterization of the neuroinflammatory signatures in larger cohorts is warranted, which might provide novel insights into the pathogenesis of PD.

Interleukin-11 in Pathologies of the Nervous System.

The study of the role of cytokines in various pathological conditions of the body is a topical area in modern biomedicine. Understanding the physiological roles played by cytokines will aid in finding applications for them as pharmacological agents in clinical practice. Interleukin 11 (IL-11) was discovered in 1990 in fibrocyte-like bone marrow stromal cells, but there has been increased interest in this cytokine in recent years. IL-11 has been shown to correct inflammatory pathways in the epithelial tissues of the respiratory system, where the main events occur during SARS-CoV-2 infection. Further research in this direction will probably support the use of this cytokine in clinical practice. The cytokine plays a significant role in the central nervous system; local expression by nerve cells has been shown. Studies show the involvement of IL-11 in the mechanisms of development of a number of pathologies of the nervous system, and therefore it seems relevant to generalize and analyze the experimental data obtained in this direction. This review summarizes information that shows the involvement of IL-11 in the mechanisms of development of brain pathologies. In the near future this cytokine will likely find clinical application for the correction of mechanisms that are involved in the formation of pathological conditions of the nervous system.

Role of Necroptosis in Central Nervous System Diseases.

Necroptosis is a type of precisely regulated necrotic cell death activated in caspase-deficient conditions. Multiple factors initiate the necroptotic signaling pathway, including toll-like receptor 3/4, tumor necrosis factor (TNF), dsRNA viruses, and T cell receptors. Presently, TNF-induced necroptosis via the phosphorylation of three key proteins, receptor-interacting protein kinase 1, receptor-interacting protein kinase 3, and mixed lineage kinase domain-like protein, is the best-characterized process. Necroptosis induced by Z-DNA-binding protein 1 (ZBP-1) and toll/interleukin-1 receptor (TIR)-domain-containing adapter-inducing interferon (TRIF) plays a significant role in infectious diseases, such as influenza A virus, Zika virus, and herpesvirus infection. An increasing number of studies have demonstrated the close association of necroptosis with multiple diseases, and disrupting necroptosis has been confirmed to be effective for treating (or managing) these diseases. The central nervous system (CNS) exhibits unique physiological structures and immune characteristics. Necroptosis may occur without the sequential activation of signal proteins, and the necroptosis of supporting cells has more important implications in disease development. Additionally, necroptotic signals can be activated in the absence of necroptosis. Here, we summarize the role of necroptosis and its signal proteins in CNS diseases and characterize typical necroptosis regulators to provide a basis for the further development of therapeutic strategies for treating such diseases. In the present review, relevant information has been consolidated from recent studies (from 2010 until the present), excluding the patents in this field.

A Potential Role of the Spike Protein in Neurodegenerative Diseases: A Narrative Review.

Human prion protein and prion-like protein misfolding are widely recognized as playing a causal role in many neurodegenerative diseases. Based on in vitro and in vivo experimental evidence relating to prion and prion-like disease, we extrapolate from the compelling evidence that the spike glycoprotein of SARS-CoV-2 contains extended amino acid sequences characteristic of a prion-like protein to infer its potential to cause neurodegenerative disease. We propose that vaccine-induced spike protein synthesis can facilitate the accumulation of toxic prion-like fibrils in neurons. We outline various pathways through which these proteins could be expected to distribute throughout the body. We review both cellular pathologies and the expression of disease that could become more frequent in those who have undergone mRNA vaccination. Specifically, we describe the spike protein's contributions, via its prion-like properties, to neuroinflammation and neurodegenerative diseases; to clotting disorders within the vasculature; to further disease risk due to suppressed prion protein regulation in the context of widely prevalent insulin resistance; and to other health complications. We explain why these prion-like characteristics are more relevant to vaccine-related mRNA-induced spike proteins than natural infection with SARS-CoV-2. We note with an optimism an apparent loss of prion-like properties among the current Omicron variants. We acknowledge that the chain of pathological events described throughout this paper is only hypothetical and not yet verified. We also acknowledge that the evidence we usher in, while grounded in the research literature, is currently largely circumstantial, not direct. Finally, we describe the implications of our findings for the general public, and we briefly discuss public health recommendations we feel need urgent consideration. An earlier version of this article was previously posted to the Authorea preprint server on August 16, 2022.

Exploring the Role of ACE2 as a Connecting Link between COVID-19 and Parkinson's Disease.

Coronavirus disease 2019 (COVID-19) is frequently accompanied by neurological manifestations such as headache, delirium, and epileptic seizures, whereas ageusia and anosmia may appear before respiratory symptoms. Among the various neurological COVID-19-related comorbidities, Parkinson's disease (PD) has gained increasing attention. Some cases of PD disease have been linked to COVID-19, and both motor and non-motor symptoms in Parkinson's disease patients frequently worsen following SARS-CoV-2 infection. Although it is still unclear whether PD increases the susceptibility to SARS-CoV-2 infection or whether COVID-19 increases the risk of or unmasks future cases of PD, emerging evidence sheds more light on the molecular mechanisms underlying the relationship between these two diseases. Among them, angiotensin-converting enzyme 2 (ACE2), a significant component of the renin-angiotensin system (RAS), seems to play a pivotal role. ACE2 is required for the entry of SARS-CoV-2 to the human host cells, and ACE2 dysregulation is implicated in the severity of COVID-19-related acute respiratory distress syndrome (ARDS). ACE2 imbalance is implicated in core shared pathophysiological mechanisms between PD and COVID-19, including aberrant inflammatory responses, oxidative stress, mitochondrial dysfunction, and immune dysregulation. ACE2 may also be implicated in alpha-synuclein-induced dopaminergic degeneration, gut-brain axis dysregulation, blood-brain axis disruption, autonomic dysfunction, depression, anxiety, and hyposmia, which are key features of PD.