Tag: neuroinflammation

Central and peripheral kynurenine pathway metabolites in COVID-19: Implications for neurological and immunological responses

Abstract:

Long-term symptoms such as pain, fatigue, and cognitive impairments are commonly observed in individuals affected by coronavirus disease 2019 (COVID-19). Metabolites of the kynurenine pathway have been proposed to account for cognitive impairment in COVID-19 patients.

Here, cerebrospinal fluid (CSF) and plasma levels of kynurenine pathway metabolites in 53 COVID-19 patients and 12 non-inflammatory neurological disease controls in Sweden were measured with an ultra-performance liquid chromatography-tandem mass spectrometry system (UPLC-MS/MS) and correlated with immunological markers and neurological markers. Single cell transcriptomic data from a previous study of 130 COVID-19 patients was used to investigate the expression of key genes in the kynurenine pathway.

The present study reveals that the neuroactive kynurenine pathway metabolites quinolinic acid (QUIN) and kynurenic acid (KYNA) are increased in CSF in patients with acute COVID-19. In addition, CSF levels of kynurenine, ratio of kynurenine/tryptophan (rKT) and QUIN correlate with neurodegenerative markers.

Furthermore, tryptophan is significantly decreased in plasma but not in the CSF. In addition, the kynurenine pathway is strongly activated in the plasma and correlates with the peripheral immunological marker neopterin. Single-cell transcriptomics revealed upregulated gene expressions of the rate-limiting enzyme indoleamine 2,3- dioxygenase1 (IDO1) in CD14+ and CD16+ monocytes that correlated with type II-interferon response exclusively in COVID-19 patients.

In summary, our study confirms significant activation of the peripheral kynurenine pathway in patients with acute COVID-19 and, notably, this is the first study to identify elevated levels of kynurenine metabolites in the central nervous system associated with the disease. Our findings suggest that peripheral inflammation, potentially linked to overexpression of IDO1 in monocytes, activates the kynurenine pathway. Increased plasma kynurenine, crossing the blood-brain barrier, serves as a source for elevated brain KYNA and neurotoxic QUIN.

We conclude that blocking peripheral-to-central kynurenine transport could be a promising strategy to protect against neurotoxic effects of QUIN in COVID-19 patients.

Source: Li X, Edén A, Malwade S, Cunningham JL, Bergquist J, Weidenfors JA, Sellgren CM, Engberg G, Piehl F, Gisslen M, Kumlien E, Virhammar J, Orhan F, Rostami E, Schwieler L, Erhardt S. Central and peripheral kynurenine pathway metabolites in COVID-19: Implications for neurological and immunological responses. Brain Behav Immun. 2024 Nov 28:S0889-1591(24)00720-7. doi: 10.1016/j.bbi.2024.11.031. Epub ahead of print. PMID: 39615604. https://www.sciencedirect.com/science/article/abs/pii/S0889159124007207

Upregulation of olfactory receptors and neuronal-associated genes highlights complex immune and neuronal dysregulation in Long COVID patients

Abstract:

A substantial portion of patients infected with SARS-CoV-2 experience prolonged complications, known as Long COVID (LC). A subset of these patients exhibits the most debilitating symptoms, similar to those defined in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). We performed bulk RNA sequencing (RNAseq) on the whole blood of LC with ME/CFS, at least 12 months post-onset of the acute disease, and compared them with controls.

We found that LC patients had a distinct transcriptional profile compared to controls. Key findings include the upregulation of genes involved in immune dysregulation and neuronal development, such as Fezf2, BRINP2, HOXC12, MEIS2, ZFHX3, and RELN. These genes are linked to neuroinflammatory responses, cognitive impairments, and hematopoietic disturbances, suggesting ongoing neurological and immune disturbances in LC patients. RELN, encoding the Reelin protein, was notably elevated in LC patients, potentially serving as a biomarker for LC pathogenesis due to its role in inflammation and neuronal function.

Immune cell analysis showed altered profiles in LC patients, with increased activated memory CD4 + T cells and neutrophils, and decreased regulatory T cells and NK cells, reflecting immune dysregulation. Changes in cytokine and chemokine expression further underscore the chronic inflammatory state in LC patients. Notably, a unique upregulation of olfactory receptors (ORs) suggest alternative roles for ORs in non-olfactory tissues. Pathway analysis revealed upregulation in ribosomal RNA processing, amino acid metabolism, protein synthesis, cell proliferation, DNA repair, and mitochondrial pathways, indicating heightened metabolic and immune demands. Conversely, downregulated pathways, such as VEGF signaling and TP53 activity, point to impaired tissue repair and cellular stress responses.

Overall, our study underscores the complex interplay between immune and neuronal dysfunction in LC patients, providing insights into potential diagnostic biomarkers and therapeutic targets. Future research is needed to fully understand the roles and interactions of these genes in LC pathophysiology.

Source: Shahbaz S, Rezaeifar M, Syed H, Redmond D, Terveart JWC, Osman M, Elahi S. Upregulation of olfactory receptors and neuronal-associated genes highlights complex immune and neuronal dysregulation in Long COVID patients. Brain Behav Immun. 2024 Nov 28:S0889-1591(24)00721-9. doi: 10.1016/j.bbi.2024.11.032. Epub ahead of print. PMID: 39615603. https://www.sciencedirect.com/science/article/pii/S0889159124007219 (Full text)

Impact of age and sex on neuroinflammation following SARS-CoV-2 infection in a murine model

Abstract:

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19, is known to infect people of all ages and both sexes. Senior populations have the greatest risk of severe COVID-19, and sexual dimorphism in clinical outcomes has been reported. Neurological symptoms are widely observed in COVID-19 patients, with many survivors exhibiting persistent neurological and cognitive impairment. The present study aims to investigate the impact of age and sex on the neuroinflammatory response to SARS-CoV-2 infection using a mouse model. Wild-type C57BL/6J mice were intranasally inoculated with SARS-CoV-2 lineage B.1.351, a variant known to infect mice.

Older male mice exhibited a significantly greater weight loss and higher viral loads in the lung at 3 days post infection. Notably, no viral RNA was detected in the brains of infected mice. Nevertheless, expression of IL-6, TNF-α, and CCL-2 in the lung and brain increased with viral infection. RNA-seq transcriptomic analysis of brains showed that SARS-CoV-2 infection caused significant changes in gene expression profiles, implicating innate immunity, defense response to virus, and cerebrovascular and neuronal functions.

These findings demonstrate that SARS-CoV-2 infection triggers a neuroinflammatory response, despite the lack of detectable virus in the brain. Aberrant activation of innate immune response, disruption of blood-brain barrier and endothelial cell integrity, and suppression of neuronal activity and axonogenesis underlie the impact of SARS-CoV-2 infection on the brain. Understanding the role of these affected pathways in SARS-CoV-2 pathogenesis helps identify appropriate points of therapeutic interventions to alleviate neurological dysfunction observed during COVID-19.

Source: Krishna VD, Chang A, Korthas H, Var SR, Low WC, Li L, Cheeran MC. Impact of age and sex on neuroinflammation following SARS-CoV-2 infection in a murine model. bioRxiv [Preprint]. 2023 Aug 14:2023.08.11.552998. doi: 10.1101/2023.08.11.552998. Update in: Front Microbiol. 2024 Jul 15;15:1404312. doi: 10.3389/fmicb.2024.1404312. PMID: 37645925; PMCID: PMC10462071. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10462071/ (Full text)

Brain temperature and free water increases after mild COVID-19 infection

Abstract:

The pathophysiology underlying the post-acute sequelae of COVID-19 remains understudied and poorly understood, particularly in healthy adults with a history of mild infection. Chronic neuroinflammation may underlie these enduring symptoms, but studying neuroinflammatory phenomena in vivo is challenging, especially without a comparable pre-COVID-19 dataset.

In this study, we present a unique dataset of 10 otherwise healthy individuals scanned before and after experiencing mild COVID-19. Two emerging MR-based methods were used to map pre- to post-COVID-19 brain temperature and free water changes. Post-COVID-19 brain temperature and free water increases, which are indirect biomarkers of neuroinflammation, were found in structures functionally associated with olfactory, cognitive, and memory processing.

The largest pre- to post-COVID brain temperature increase was observed in the left olfactory tubercle (p = 0.007, 95% CI [0.48, 3.01]), with a mean increase of 1.75 °C. Notably, the olfactory tubercle is also the region of the primary olfactory cortex where participants with chronic olfactory dysfunction showed the most pronounced increases as compared to those without lingering olfactory dysfunction (adjusted pFDR = 0.0189, 95% CI [1.42, 5.27]). These preliminary insights suggest a potential link between neuroinflammation and chronic cognitive and olfactory dysfunction following mild COVID-19, although further investigations are needed to improve our understanding of what underlies these phenomena.

Source: Sharma AA, Nenert R, Goodman AM, Szaflarski JP. Brain temperature and free water increases after mild COVID-19 infection. Sci Rep. 2024 Mar 28;14(1):7450. doi: 10.1038/s41598-024-57561-6. PMID: 38548815; PMCID: PMC10978935. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10978935/ (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)

Unravelling shared mechanisms: insights from recent ME/CFS research to illuminate long COVID pathologies

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic illness often triggered by an initiating acute event, mainly viral infections. The transition from acute to chronic disease remains unknown, but interest in this phenomenon has escalated since the COVID-19 pandemic and the post-COVID-19 illness, termed ‘long COVID’ (LC). Both ME/CFS and LC share many clinical similarities.

Here, we present recent findings in ME/CFS research focussing on proposed disease pathologies shared with LC. Understanding these disease pathologies and how they influence each other is key to developing effective therapeutics and diagnostic tests. Given that ME/CFS typically has a longer disease duration compared with LC, with symptoms and pathologies evolving over time, ME/CFS may provide insights into the future progression of LC.

Source: Annesley SJ, Missailidis D, Heng B, Josev EK, Armstrong CW. Unravelling shared mechanisms: insights from recent ME/CFS research to illuminate long COVID pathologies. Trends Mol Med. 2024 Mar 4:S1471-4914(24)00028-5. doi: 10.1016/j.molmed.2024.02.003. Epub ahead of print. PMID: 38443223. https://www.sciencedirect.com/science/article/pii/S1471491424000285 (Full text)

Neuroinflammatory imaging markers in white matter: insights into the cerebral consequences of post-acute sequelae of COVID-19 (PASC)

Abstract:

Symptoms of coronavirus disease 2019 (COVID-19) can persist for months or years after infection, a condition called Post-Acute Sequelae of COVID-19 (PASC). Whole-brain white matter and cortical gray matter health were assessed using multi-shell diffusion tensor imaging. Correlational tractography was utilized to dissect the nature and extent of white matter changes.

In this study of 42 male essential workers, the most common symptoms of Neurological PASC (n = 24) included fatigue (n = 19) and headache (n = 17). Participants with neurological PASC demonstrated alterations to whole-brain white matter health when compared to controls made up of uninfected, asymptomatic, or mildly infected controls (n = 18). Large differences were evident between PASC and controls in measures of fractional anisotropy (Cohen’s D=-0.54, P = 0.001) and cortical isotropic diffusion (Cohen’s D = 0.50, P = 0.002).

Symptoms were associated with white matter fractional anisotropy (fatigue: rho = -0.62, P < 0.001; headache: rho = -0.66, P < 0.001), as well as nine other measures of white and gray matter health. Brain fog was associated with improved cerebral functioning including improved white matter isotropic diffusion and quantitative anisotropy.

This study identified changes across measures of white and gray matter connectivity, neuroinflammation, and cerebral atrophy that were interrelated and associated with differences in symptoms of PASC. These results provide insights into the long-term cerebral implications of COVID-19.

Source: Sean Clouston, Chuan Huang, Jia Ying et al. Neuroinflammatory imaging markers in white matter: insights into the cerebral consequences of post-acute sequelae of COVID-19 (PASC), 19 January 2024, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-3760289/v1] https://www.researchsquare.com/article/rs-3760289/v1 (Full text)

Brain FADE syndrome: the final common pathway of chronic inflammation in neurological disease

Abstract:

Importance: While the understanding of inflammation in the pathogenesis of many neurological diseases is now accepted, this special commentary addresses the need to study chronic inflammation in the propagation of cognitive Fog, Asthenia, and Depression Related to Inflammation which we name Brain FADE syndrome. Patients with Brain FADE syndrome fall in the void between neurology and psychiatry because the depression, fatigue, and fog seen in these patients are not idiopathic, but instead due to organic, inflammation involved in neurological disease initiation.

Observations: A review of randomized clinical trials in stroke, multiple sclerosis, Parkinson’s disease, COVID, traumatic brain injury, and Alzheimer’s disease reveal a paucity of studies with any component of Brain FADE syndrome as a primary endpoint. Furthermore, despite the relatively well-accepted notion that inflammation is a critical driving factor in these disease pathologies, none have connected chronic inflammation to depression, fatigue, or fog despite over half of the patients suffering from them.

Conclusions and relevance: Brain FADE Syndrome is important and prevalent in the neurological diseases we examined. Classical “psychiatric medications” are insufficient to address Brain FADE Syndrome and a novel approach that utilizes sequential targeting of innate and adaptive immune responses should be studied.

Source: Khalid A. Hanafy, Tudor G. Jovin. Brain FADE syndrome: the final common pathway of chronic inflammation in neurological disease. Front. Immunol., 17 January 2024, Sec. Inflammation, Volume 15 – 2024 | https://doi.org/10.3389/fimmu.2024.1332776 https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1332776/full (Full text)

The molecular fingerprint of neuroinflammation in COVID-19: A comprehensive discussion on molecular mechanisms of neuroinflammation due to SARS-COV2 antigens

Abstract:

Background and objective: Severe acute respiratory syndrome coronavirus 2 attacks the neural system directly and indirectly via various systems, such as the nasal cavity, olfactory system, and facial nerves. Considering the high energy requirement, lack of antioxidant defenses, and high amounts of metal ions in the brain, oxidative damage is very harmful to the brain. Various neuropathic pain conditions, neurological disorders, and neuropsychiatric complications were reported in Coronavirus disease 2019, prolonged Coronavirus disease 2019, and after Coronavirus disease 2019 immunization. This manuscript offers a distinctive outlook on the interconnectedness between neurology and neuropsychiatry through its meticulous analysis of complications.

Discussion: After recovering from Coronavirus disease 2019, approximately half of the patients reported developing Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Long Coronavirus disease 2019 imaging reports illustrated the hypometabolism in various parts of the brain, such as olfactory bulbs, limbic/paralimbic domains, the brainstem, and the cerebellum. Ninety imaging and neuropathological studies of Coronavirus disease 2019 have shown evidence of white matter, brainstem, frontotemporal, and oculofrontal lesions. Emotional functions, such as pleasant, long/short-term memory, movement, cognition and cognition in decision-making are controlled by these regions. The neuroinflammation and the mechanisms of defense are well presented in the discussion. The role of microglia activation, Inducible NO synthase, Cyclooxygenases ½, Reactive oxygen species, neurotoxic toxins and pro-inflammatory cytokines, such as Interleukin-1 beta, Interleukin-6 and Tumor Necrosis Factor-alpha are highlighted in neuronal dysfunction and death. Nuclear factor kappa-light-chain-enhancer of activated B cells, Mitogen-activated protein kinase, Activator Protein 1, and Interferon regulatory factors are the main pathways involved in microglia activation in Coronavirus disease 2019 neuroinflammation.

Conclusion: The neurological aspect of Coronavirus disease 2019 should be highlighted. Neurological, psychological, and behavioral aspects of Coronavirus disease 2019, prolonged Coronavirus disease 2019, and Coronavirus disease 2019 vaccines can be the upcoming issues. We need a global awareness where this aspect of the disease should be more considered in health research.

Source: Zayeri ZD, Torabizadeh M, Kargar M, Kazemi H. The molecular fingerprint of neuroinflammation in COVID-19: A comprehensive discussion on molecular mechanisms of neuroinflammation due to SARS-COV2 antigens. Behav Brain Res. 2024 Jan 20;462:114868. doi: 10.1016/j.bbr.2024.114868. Epub ahead of print. PMID: 38246395. https://www.sciencedirect.com/science/article/abs/pii/S016643282400024X

Brain-regional characteristics and neuroinflammation in ME/CFS patients from neuroimaging: A systematic review and meta-analysis

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition characterized by an elusive etiology and pathophysiology. This study aims to evaluate the pathological role of neuroinflammation in ME/CFS by conducting an exhaustive analysis of 65 observational studies.

Four neuroimaging techniques, including magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), electroencephalography (EEG), and positron emission tomography (PET), were employed to comparatively assess brain regional structure, metabolite profiles, electrical activity, and glial activity in 1529 ME/CFS patients (277 males, 1252 females) and 1715 controls (469 males, 1246 females). Clinical characteristics, including sex, age, and fatigue severity, were consistent with established epidemiological patterns.

Regional alterations were most frequently identified in the cerebral cortex, with a notable focus on the frontal cortex. However, our meta-analysis data revealed a significant hypoactivity in the insular and thalamic regions, contrary to observed frequencies. These abnormalities, occurring in pivotal network hubs bridging reason and emotion, disrupt connections with the limbic system, contributing to the hallmark symptoms of ME/CFS.

Furthermore, we discuss the regions where neuroinflammatory features are frequently observed and address critical neuroimaging limitations, including issues related to inter-rater reliability. This systematic review serves as a valuable guide for defining regions of interest (ROI) in future neuroimaging investigations of ME/CFS

Source: Lee JS, Sato W, Son CG. Brain-regional characteristics and neuroinflammation in ME/CFS patients from neuroimaging: A systematic review and meta-analysis. Autoimmun Rev. 2023 Nov 26:103484. doi: 10.1016/j.autrev.2023.103484. Epub ahead of print. PMID: 38016575. https://www.sciencedirect.com/science/article/pii/S1568997223002185 (Full text)