Tag: neurodegenerative diseases

Immunometabolic changes and potential biomarkers in CFS peripheral immune cells revealed by single-cell RNA sequencing

Abstract:

The pathogenesis of Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains unclear, though increasing evidence suggests inflammatory processes play key roles. In this study, single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) was used to decipher the immunometabolic profile in 4 ME/CFS patients and 4 heathy controls.

We analyzed changes in the composition of major PBMC subpopulations and observed an increased frequency of total T cells and a significant reduction in NKs, monocytes, cDCs and pDCs. Further investigation revealed even more complex changes in the proportions of cell subpopulations within each subpopulation. Gene expression patterns revealed upregulated transcription factors related to immune regulation, as well as genes associated with viral infections and neurodegenerative diseases.

CD4+ and CD8+ T cells in ME/CFS patients show different differentiation states and altered trajectories, indicating a possible suppression of differentiation. Memory B cells in ME/CFS patients are found early in the pseudotime, indicating a unique subtype specific to ME/CFS, with increased differentiation to plasma cells suggesting B cell overactivity. NK cells in ME/CFS patients exhibit reduced cytotoxicity and impaired responses, with reduced expression of perforin and CD107a upon stimulation. Pseudotime analysis showed abnormal development of adaptive immune cells and an enhanced cell-cell communication network converging on monocytes in particular.

Our analysis also identified the estrogen-related receptor alpha (ESRRA)-APP-CD74 signaling pathway as a potential biomarker for ME/CFS in peripheral blood. In addition, data from the GSE214284 database confirmed higher ESRRA expression in the monocyte cell types of male ME/CFS patients. These results suggest a link between immune and neurological symptoms.

The results support a disease model of immune dysfunction ranging from autoimmunity to immunodeficiency and point to amyloidotic neurodegenerative signaling pathways in the pathogenesis of ME/CFS. While the study provides important insights, limitations include the modest sample size and the evaluation of peripheral blood only.

These findings highlight potential targets for diagnostic biomarkers and therapeutic interventions. Further research is needed to validate these biomarkers and explore their clinical applications in managing ME/CFS.

Source: Sun Y, Zhang Z, Qiao Q, Zou Y, Wang L, Wang T, Lou B, Li G, Xu M, Wang Y, Zhang Z, Hou X, Chen L, Zhao R. Immunometabolic changes and potential biomarkers in CFS peripheral immune cells revealed by single-cell RNA sequencing. J Transl Med. 2024 Oct 11;22(1):925. doi: 10.1186/s12967-024-05710-w. PMID: 39394558. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-05710-w (Full text)

Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders

Abstract:

Neuroinflammatory and neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD), traumatic brain injury (TBI) and Amyotrophic lateral sclerosis (ALS) are chronic major health disorders. The exact mechanism of the neuroimmune dysfunctions of these disease pathogeneses is currently not clearly understood.

These disorders show dysregulated neuroimmune and inflammatory responses, including activation of neurons, glial cells, and neurovascular unit damage associated with excessive release of proinflammatory cytokines, chemokines, neurotoxic mediators, and infiltration of peripheral immune cells into the brain, as well as entry of inflammatory mediators through damaged neurovascular endothelial cells, blood-brain barrier and tight junction proteins. Activation of glial cells and immune cells leads to the release of many inflammatory and neurotoxic molecules that cause neuroinflammation and neurodegeneration.

Gulf War Illness (GWI) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are chronic disorders that are also associated with neuroimmune dysfunctions. Currently, there are no effective disease-modifying therapeutic options available for these diseases. Human induced pluripotent stem cell (iPSC)-derived neurons, astrocytes, microglia, endothelial cells and pericytes are currently used for many disease models for drug discovery. This review highlights certain recent trends in neuroinflammatory responses and iPSC-derived brain cell applications in neuroinflammatory disorders.

Source: Cohen J, Mathew A, Dourvetakis KD, Sanchez-Guerrero E, Pangeni RP, Gurusamy N, Aenlle KK, Ravindran G, Twahir A, Isler D, Sosa-Garcia SR, Llizo A, Bested AC, Theoharides TC, Klimas NG, Kempuraj D. Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders. Cells. 2024 Mar 14;13(6):511. doi: 10.3390/cells13060511. PMID: 38534355; PMCID: PMC10969521. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10969521/ (Full text)

Vitamin B12 as an epidrug for regulating peripheral blood biomarkers in long COVID-associated visuoconstructive deficit

Abstract:

Approximately four months after recovering from a mild COVID-19 infection, around 25% of individuals developed visuoconstructive deficit (VCD), which was found to be correlated with an increase in peripheral immune markers and alterations in structural and metabolic brain imaging. Recently, it has been demonstrated that supplemental vitamin B12 regulates hyperinflammation during moderate and severe COVID-19 through methyl-dependent epigenetic mechanisms.

Herein, whole peripheral blood cultures were produced using samples obtained from patients with confirmed persistent VCD, and controls without impairment, between 10 and 16 months after mild COVID-19. This experimental model was used to assess the leukocyte expression patterns of 11 biomarkers previously associated with VCD in long COVID and explore the potential of pharmacological B12 in regulating these genes. The results showed that patients with persistent VCD displayed continued upregulation of CCL11 and LIF compared to controls.

It is worth noting that elevated serum levels of CCL11 have been previously linked to age-related neurodegenerative diseases. Notably, the addition of 1 nM of vitamin B12 to blood cultures from individuals with VCD normalized the mRNA levels of CCL11, upregulated the neuroprotective HGF, and, to a lesser extent, downregulated CSF2 and CXCL10. There was an inverse correlation observed between CCL11 mRNA levels and methylation levels of specific cytosines in its promoter region.

These findings underscore the significance of systemic inflammation in persistent VCD associated with long COVID. Moreover, the study provides evidence suggesting that B12, acting as an epidrug, shows promise as a therapeutic approach for addressing this cognitive impairment.

Source: Larissa Cassiano, Jonas Paula, Daniela Rosa et al. Vitamin B12 as an epidrug for regulating peripheral blood biomarkers in long COVID-associated visuoconstructive deficit, 11 October 2023, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-3158180/v1] https://www.researchsquare.com/article/rs-3158180/v1 (Full text)

Pathophysiology, diagnosis, and management of neuroinflammation in covid-19

Abstract:

Although neurological complications of SARS-CoV-2 infection are relatively rare, their potential long term morbidity and mortality have a significant impact, given the large numbers of infected patients. Covid-19 is now in the differential diagnosis of a number of common neurological syndromes including encephalopathy, encephalitis, acute demyelinating encephalomyelitis, stroke, and Guillain-Barré syndrome.

Physicians should be aware of the pathophysiology underlying these presentations to diagnose and treat patients rapidly and appropriately. Although good evidence has been found for neurovirulence, the neuroinvasive and neurotropic potential of SARS-CoV-2 is limited. The pathophysiology of most complications is immune mediated and vascular, or both. A significant proportion of patients have developed long covid, which can include neuropsychiatric presentations. The mechanisms of long covid remain unclear. The longer term consequences of infection with covid-19 on the brain, particularly in terms of neurodegeneration, will only become apparent with time and long term follow-up.

Source: Brown R L, Benjamin L, Lunn M P, Bharucha T, Zandi M S, Hoskote C et al. Pathophysiology, diagnosis, and management of neuroinflammation in covid-19 BMJ 2023; 382 :e073923 doi:10.1136/bmj-2022-073923 https://www.bmj.com/content/382/bmj-2022-073923.abstract (Full text available as PDF file)

Evaluation of Post–COVID-19 Cognitive Dysfunction: Recommendations for Researchers

Opinion:

SARS-CoV-2 infection is associated with increased rates of postillness cognitive dysfunction, colloquially referred to as “brain fog,”1 that may portend significant consequences for patient functioning and quality of life. Post–COVID-19 cognitive dysfunction is 1 of approximately 200 symptoms of post–COVID-19 condition (PCC), defined by the World Health Organization as developing within 3 months of an initial SARS-CoV-2 infection, lasting at least 2 months, and cannot be explained by an alternative diagnosis. A pooled analysis of 54 studies and 1.2 million individuals found that 3.2% of patients’ self-reported cognitive problems 3 months after symptomatic infection,1 while other studies have shown objective evidence of cognitive dysfunction in approximately 24% of patients nearly 1 year later.2 Accumulating evidence also supports the hypothesis that COVID-19 may increase risk for later neurodegeneration3 and exacerbate preexisting cognitive dysfunction.4 As one of the most common symptoms of PCC and one for which affected individuals may seek accommodations and disability benefits in accordance with the Americans With Disabilities Act, it is imperative that we use more rigorous studies of cognitive outcomes. Accordingly, the following recommendations have been generated by members of the NeuroCOVID International Neuropsychology Taskforce based on initial guidelines.5

Source: Jaqueline H. Becker, PhD; Tracy D. Vannorsdall, PhD; Sara L. Weisenbach, PhD. JAMA Psychiatry. Published online August 16, 2023. doi:10.1001/jamapsychiatry.2023.2820 https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2808155

Identification of the pathogenic relationship between Long COVID and Alzheimer’s disease by bioinformatics methods

Abstract:

Background: The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an unprecedented global health crisis. Although many Corona Virus Disease 2019 (COVID-19) patients have recovered, the long-term consequences of SARS-CoV-2 infection are unclear. Several independent epidemiological surveys and clinical studies have found that SARS-CoV-2 infection and Long COVID are closely related to Alzheimer’s disease (AD). This could lead to long-term medical challenges and social burdens following this health crisis. However, the mechanism between Long COVID and AD is unknown.

Methods: Genes associated with Long COVID were collected from the database. Two sets of AD-related clinical sample datasets were collected in the Gene Expression Omnibus (GEO) database by limiting screening conditions. After identifying the differentially expressed genes (DEGs) of AD, the significant overlapping genes of AD and Long COVID were obtained by taking the intersection. Then, four kinds of analyses were performed, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis, protein-protein interaction (PPI) analysis, identification of hub genes, hub gene verification and transcription factors (TFs) prediction.

Results: A total of 197 common genes were selected for subsequent analysis. GO and KEGG enrichment analysis showed that these genes were mainly enriched in multiple neurodegenerative disease related pathways. In addition, 20 important hub genes were identified using cytoHubba. At the same time, these hub genes were verified in another data set, where 19 hub gene expressions were significantly different in the two diseases and 6 hub genes were significantly different in AD patients of different genders. Finally, we collected 9 TFs that may regulate the expression of these hub genes in the Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining (TRUSST) database and verified them in the current data set.

Conclusion: This work reveals the common pathways and hub genes of AD and Long COVID, providing new ideas for
the pathogenic relationship between these two diseases and further mechanism research.

Source:

Long Covid and Neurodegenerative Disease

Abstract:

Brain fog with compromised ability to concentrate has been the most frequent Long Covid (LC) complaint. This is due to an increased TGF beta/IFN gamma with consequently increased bradykinin (BKN), especially in Caucasian females. Brain and lung blood vessels “leak.” This same ratio is increased in Alzheimer’s disease (AD), but decreased in Parkinson’s disease (PD), because CD4+ and CD8+ T cells are differentially affected by the invading associated viruses, e.g., SARS CoV2, HIV, ….

In Covid-19 CD147 receptors on immune cells are critical in generating the increased TGF beta/IFN gamma and those on endothelial cells, platelets, and erythrocytes are critical to the abnormal microvascular blood flow. ACE2 receptors on pneumocytes and enterocytes enable pulmonary and GI entry, initiating gut dysbiosis.

Epigenetics, methylation, magnesium, vitamin D, the B vitamins, and antioxidants suggest that these issues can be surmounted. Biochemical, physiologic, and epidemiologic data are analyzed to answer these questions. An LC model is presented and discussed in the context of the most recent research. Suggestions to avoid these and other worrisome concerns are included. Other topics discussed include estrogen, the gut microbiome, type 2 diabetes (T2D), and homocysteine.

Source: Chambers, P. Long Covid and Neurodegenerative Disease. Preprints 2023, 2023020027 (doi: 10.20944/preprints202302.0027.v1) https://www.preprints.org/manuscript/202302.0027/v1 (Full text available as PDF file)

 

The relationship between chronic immune response and neurodegenerative damage in long COVID-19

Abstract:

In the past two years, the world has faced the pandemic caused by the severe acute respiratory syndrome 2 coronavirus (SARS-CoV-2), which by August of 2022 has infected around 619 million people and caused the death of 6.55 million individuals globally. Although SARS-CoV-2 mainly affects the respiratory tract level, there are several reports, indicating that other organs such as the heart, kidney, pancreas, and brain can also be damaged.

A characteristic observed in blood serum samples of patients suffering COVID-19 disease in moderate and severe stages, is a significant increase in proinflammatory cytokines such as interferon-α (IFN-α), interleukin-1β (IL-1β), interleukin-2 (IL-2), interleukin-6 (IL-6) and interleukin-18 (IL-18), as well as the presence of autoantibodies against interferon-α (IFN-α), interferon-λ (IFN-λ), C-C motif chemokine ligand 26 (CCL26), CXC motif chemokine ligand 12 (CXCL12), family with sequence similarity 19 (chemokine (C-C motif)-like) member A4 (FAM19A4), and C-C motif chemokine ligand 1 (CCL1). Interestingly, it has been described that the chronic cytokinemia is related to alterations of blood-brain barrier (BBB) permeability and induction of neurotoxicity.

Furthermore, the generation of autoantibodies affects processes such as neurogenesis, neuronal repair, chemotaxis and the optimal microglia function. These observations support the notion that COVID-19 patients who survived the disease present neurological sequelae and neuropsychiatric disorders. The goal of this review is to explore the relationship between inflammatory and humoral immune markers and the major neurological damage manifested in post-COVID-19 patients.

Source: Elizalde-Díaz JP, Miranda-Narváez CL, Martínez-Lazcano JC, Martínez-Martínez E. The relationship between chronic immune response and neurodegenerative damage in long COVID-19. Front Immunol. 2022 Dec 16;13:1039427. doi: 10.3389/fimmu.2022.1039427. PMID: 36591299; PMCID: PMC9800881. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9800881/ (Full text)

Molecular and cellular similarities in the brain of SARS-CoV-2 and Alzheimer’s disease individuals

Abstract:

Infection with the etiological agent of COVID-19, SARS-CoV-2, appears capable of impacting cognition, which some patients with Post-acute Sequelae of SARS-CoV-2 (PASC). To evaluate neuro-pathophysiological consequences of SARS-CoV-2 infection, we examine transcriptional and cellular signatures in the Broadman area 9 (BA9) of the frontal cortex and the hippocampal formation (HF) in SARS-CoV-2, Alzheimer’s disease (AD) and SARS-CoV-2 infected AD individuals, compared to age- and gender-matched neurological cases. Here we show similar alterations of neuroinflammation and blood-brain barrier integrity in SARS-CoV-2, AD, and SARS-CoV-2 infected AD individuals. ‘

Distribution of microglial changes reflected by the increase of Iba-1 reveal nodular morphological alterations in SARS-CoV-2 infected AD individuals. Similarly, HIF-1α is significantly upregulated in the context of SARS-CoV-2 infection in the same brain regions regardless of AD status. The finding may help to inform decision-making regarding therapeutic treatments in patients with neuro-PASC, especially those at increased risk of developing AD.

Source: Griggs E, Trageser K, Naughton S, Yang EJ, Mathew B, Van Hyfte G, Hellmers L, Jette N, Estill M, Shen L, Fischer T, Pasinetti GM. Molecular and cellular similarities in the brain of SARS-CoV-2 and Alzheimer’s disease individuals. bioRxiv [Preprint]. 2022 Nov 23:2022.11.23.517706. doi: 10.1101/2022.11.23.517706. PMID: 36451886; PMCID: PMC9709800. https://www.biorxiv.org/content/10.1101/2022.11.23.517706v1.full (Full text)

SARS-CoV-2, long COVID, prion disease and neurodegeneration

Introduction:

On the last day of the year 2019 a novel Betacoronavirus (2019-nCov), now known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and causing the highly transmissible and lethal pneumonia COVID-19 was first reported in Wuhan, Hubei Province in Central China (Huang et al., ; Fu et al., ; Lu and Sun, ). Since then ongoing research and long-term studies of the sequelae of SARS-CoV-2 infection have indicated that post-infection, recovery from COVID-19 and/or COVID-19 aftermath is associated with long-term physiological and neurological deficits known generically as “long COVID” (Roy et al., ; Ahmad et al., ; Baazaoui and Iqbal, ). Multiple independent epidemiological and clinical studies further indicate that SARS-CoV-2 infection and “long COVID” strongly correlate with the onset of progressive neurological disturbances that include Alzheimer’s disease (AD), prion disease (PrD) and other neurodegenerative disorders. These are apparent: (i) especially in aged and/or senile COVID-19 patients; (ii) in patients experiencing overlapping or inter-current illnesses that include heart disease, diabetes, hypertension, neuropsychiatric and other age-related neurological disorders; and (iii) in those COVID-19 patients who have experienced a particularly virulent and/or a near fatal episode of SARS-CoV-2 infection (Farheen et al., ; Flud et al., ; Fu et al., ). Conversely, increasing numbers of epidemiological studies suggest that elderly people with neurological deficits commonly observed in AD are highly vulnerable to SARS-CoV-2 infection, and especially the development of more severe forms of COVID-19 disease (Chiricosta et al., ; Hsu et al., ; Fu et al., ). The recent finding that the SARS-CoV-2 “S1” spike protein essential for viral infectivity contains prion-like domains associated with immune-evasion and the promotion of protein aggregation and aggregate “seeding” is particularly intriguing (Baazaoui and Iqbal, ; Bernardini et al., ; Tetz and Tetz, ). Based on these and other very recent findings this “Opinion” paper will: (i) address our current understanding of the emerging role of SARS-CoV-2 infection with “long COVID” with special reference to AD and PrD; (ii) will review the latest findings of the SARS-CoV-2 “S1” spike protein and its preferred interaction with the ubiquitous angiotensin converting enzyme-2 (ACE2) receptor (ACE2R); and (iii) will highlight the interplay of the molecular biology and neuropathology of SARS-CoV-2 with the unusual and immune-evasive character of prion neurobiology, AD and PrD.

Read the rest of this article HERE.

Source: Zhao Y, Jaber VR, Lukiw WJ. SARS-CoV-2, long COVID, prion disease and neurodegeneration. Front Neurosci. 2022 Sep 27;16:1002770. doi: 10.3389/fnins.2022.1002770. PMID: 36238082; PMCID: PMC9551214.  Zhao Y, Jaber VR, Lukiw WJ. SARS-CoV-2, long COVID, prion disease and neurodegeneration. Front Neurosci. 2022 Sep 27;16:1002770. doi: 10.3389/fnins.2022.1002770. PMID: 36238082; PMCID: PMC9551214. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9551214/ (Full text)