Tag: cerebrospinal fluid

Neurologic sequelae of COVID-19 are determined by immunologic imprinting from previous coronaviruses

Abstract:

Coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global public health emergency. Although SARS-CoV-2 is primarily a respiratory pathogen, extra-respiratory organs, including the CNS, can also be affected. Neurologic symptoms have been observed not only during acute SARS-CoV-2 infection, but also at distance from respiratory disease, also known as long-COVID or neurological post-acute sequelae of COVID-19 (neuroPASC). The pathogenesis of neuroPASC is not well understood, but hypotheses include SARS-CoV-2-induced immune dysfunctions, hormonal dysregulations and persistence of SARS-CoV-2 reservoirs.

In this prospective cohort study, we used a high throughput systems serology approach to dissect the humoral response to SARS-CoV-2 (and other common coronaviruses: 229E, HKU1, NL63 and OC43) in the serum and CSF from 112 infected individuals who developed (n = 18) or did not develop (n = 94) neuroPASC. Unique SARS-CoV-2 humoral profiles were observed in the CSF of neuroPASC compared with serum responses. All antibody isotypes (IgG, IgM, IgA) and subclasses (IgA1-2, IgG1-4) were detected in serum, whereas CSF was characterized by focused IgG1 (and absence of IgM).

These data argue in favour of compartmentalized brain-specific responses against SARS-CoV-2 through selective transfer of antibodies from the serum to the CSF across the blood-brain barrier, rather than intrathecal synthesis, where more diversity in antibody classes/subclasses would be expected.

Compared to individuals who did not develop post-acute complications following infection, individuals with neuroPASC had similar demographic features (median age 65 versus 66.5 years, respectively, P = 0.55; females 33% versus 44%, P = 0.52) but exhibited attenuated systemic antibody responses against SARS-CoV-2, characterized by decreased capacity to activate antibody-dependent complement deposition (ADCD), NK cell activation (ADNKA) and to bind Fcγ receptors. However, surprisingly, neuroPASC individuals showed significantly expanded antibody responses to other common coronaviruses, including 229E, HKU1, NL63 and OC43.

This biased humoral activation across coronaviruses was particularly enriched in neuroPASC individuals with poor outcome, suggesting an ‘original antigenic sin’ (or immunologic imprinting), where pre-existing immune responses against related viruses shape the response to the current infection, as a key prognostic marker of neuroPASC disease.

Overall, these findings point to a pathogenic role for compromised anti-SARS-CoV-2 responses in the CSF, likely resulting in incomplete virus clearance from the brain and persistent neuroinflammation, in the development of post-acute neurologic complications of SARS-CoV-2 infection.

Source: Spatola M, Nziza N, Jung W, Deng Y, Yuan D, Dinoto A, Bozzetti S, Chiodega V, Ferrari S, Lauffenburger DA, Mariotto S, Alter G. Neurologic sequelae of COVID-19 are determined by immunologic imprinting from previous coronaviruses. Brain. 2023 Oct 3;146(10):4292-4305. doi: 10.1093/brain/awad155. PMID: 37161609. https://academic.oup.com/brain/article/146/10/4292/7158783 (Full text)

Myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia are indistinguishable by their cerebrospinal fluid proteomes

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and fibromyalgia have overlapping neurologic symptoms particularly disabling fatigue. This has given rise to the question whether they are distinct central nervous system (CNS) entities or is one an extension of the other.

Material and methods: To investigate this, we used unbiased quantitative mass spectrometry-based proteomics to examine the most proximal fluid to the brain, cerebrospinal fluid (CSF). This was to ascertain if the proteome profile of one was the same or different from the other. We examined two separate groups of ME/CFS, one with (n = 15) and one without (n = 15) fibromyalgia.

Results: We quantified a total of 2083 proteins using immunoaffinity depletion, tandem mass tag isobaric labelling and offline two-dimensional liquid chromatography coupled to tandem mass spectrometry, including 1789 that were quantified in all the CSF samples. ANOVA analysis did not yield any proteins with an adjusted p value <.05.

Conclusion: This supports the notion that ME/CFS and fibromyalgia as currently defined are not distinct entities.

Key message: ME/CFS and fibromyalgia as currently defined are not distinct entities. Unbiased quantitative mass spectrometry-based proteomics can be used to discover cerebrospinal fluid proteins that are biomarkers for a condition such as we are studying.

Source: Schutzer SE, Liu T, Tsai CF, Petyuk VA, Schepmoes AA, Wang YT, Weitz KK, Bergquist J, Smith RD, Natelson BH. Myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia are indistinguishable by their cerebrospinal fluid proteomes. Ann Med. 2023 Dec;55(1):2208372. doi: 10.1080/07853890.2023.2208372. Epub 2023 Sep 18. PMID: 37722890. https://www.tandfonline.com/doi/full/10.1080/07853890.2023.2208372 (Full text)

The Link Between Empty Sella Syndrome, Fibromyalgia, and Chronic Fatigue Syndrome: The Role of Increased Cerebrospinal Fluid Pressure

Abstract:

The etiopathogenesis of fibromyalgia (FM) and chronic fatigue syndrome (CFS) is not yet elucidated. Hypothalamo-pituitary-adrenal (HPA) axis dysfunction is reflected in the hormonal disturbances found in FM and CFS. Some study groups have introduced a novel hypothesis that moderate or intermittent intracranial hypertension may be involved in the etiopathogenesis of FM and CFS.

In these conditions, hormonal disturbances may be caused by the mechanical effect of increased cerebrospinal fluid pressure, which hampers blood flow in the pituitary gland. Severe intracranial pressure may compress the pituitary gland, resulting in primary empty sella (ES), potentially leading to pituitary hormone deficiencies.

The aim of this narrative review was to explore whether similar hormonal changes and symptoms exist between primary ES and FM or CFS and to link them to cerebrospinal fluid pressure dysregulation. A thorough search of the PubMed and Web of Science databases and the reference lists of the included studies revealed that several clinical characteristics were more prevalent in primary ES, FM or CFS patients than in controls, including increased cerebrospinal fluid pressure, obesity, female sex, headaches and migraine, fatigue, visual disturbances (visual acuity and eye motility abnormalities), vestibulocochlear disturbances (vertigo and neurosensorial hearing loss), and bodily pain (radicular pain and small-fiber neuropathy).

Furthermore, challenge tests of the pituitary gland showed similar abnormalities in all three conditions: blunted adrenocorticotropic hormone, cortisol, growth hormone, luteinizing hormone, and thyroid stimulating hormone responses and an increased prolactin response. The findings of this narrative review provide further support for the hypothesis that moderately or intermittently increased cerebrospinal fluid pressure is involved in the pathogenesis of FM and CFS and should stimulate further research into the etiopathogenesis of these conditions.

Source: Hulens M, Dankaerts W, Rasschaert R, Bruyninckx F, De Mulder P, Bervoets C. The Link Between Empty Sella Syndrome, Fibromyalgia, and Chronic Fatigue Syndrome: The Role of Increased Cerebrospinal Fluid Pressure. J Pain Res. 2023;16:205-219
https://doi.org/10.2147/JPR.S394321 https://www.dovepress.com/the-link-between-empty-sella-syndrome-fibromyalgia-and-chronic-fatigue-peer-reviewed-fulltext-article-JPR (Full text)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and fibromyalgia are indistinguishable by their cerebrospinal fluid proteomes

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and fibromyalgia have overlapping neurologic symptoms particularly disabling fatigue. This has given rise to the question whether they are distinct central nervous system (CNS) entities or is one an extension of the other. To investigate this, we used unbiased quantitative mass spectrometry-based proteomics to examine the most proximal fluid to the brain, cerebrospinal fluid (CSF). This was to ascertain if the proteome profile of one was the same or different from the other.

We examined two separate groups of ME/CFS, one with (n=15) and one without (n=15) fibromyalgia. We quantified a total of 2,083 proteins using immunoaffinity depletion, tandem mass tag isobaric labeling and offline two-dimensional liquid chromatography coupled to tandem mass spectrometry, including 1,789 that were quantified in all the CSF samples. ANOVA analysis did not yield any proteins with an adjusted p-value < 0.05. This supports the notion that ME/CFS and fibromyalgia as currently defined are not distinct entities.

Source: Steven E. Schutzer, Tao Liu, Chia-Feng Tsai, Vladislav A. Petyuk, Athena A. Schepmoes, Yi-Ting Wang, Karl K. Weitz, Jonas Bergquist, Richard D. Smith, Benjamin H Natelson. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and fibromyalgia are indistinguishable by their cerebrospinal fluid proteomes. bioRxiv 2022.09.14.506792; doi: https://doi.org/10.1101/2022.09.14.506792 https://www.biorxiv.org/content/10.1101/2022.09.14.506792v2.full (Full text)

Rapid improvement in severe long COVID following perispinal etanercept

Abstract:

Background: This study aimed to describe the neurological improvements in a patient with severe long COVID brain dysfunction following perispinal etanercept administration. Perispinal administration of etanercept, a novel method designed to enhance its brain delivery via carriage in the cerebrospinal venous system, has previously been shown to reduce chronic neurological dysfunction after stroke. Etanercept is a recombinant biologic that is capable of ameliorating two components of neuroinflammation: microglial activation and the excess bioactivity of tumor necrosis factor (TNF), a proinflammatory cytokine that is a key neuromodulator in the brain. Optimal synaptic and brain network function require physiological levels of TNF. Neuroinflammation, including brain microglial activation and excess central TNF, can be a consequence of stroke or peripheral infection, including infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19.

Methods: Standardized, validated measures, including the Montreal Cognitive Assessment, Beck Depression Index-II (BDI-II), Fatigue Assessment Scale, Controlled Oral Word Association Test, Trail Making Tests, Timed Finger-to-Nose Test, 20 meter Self-Paced Walk Test, 5 Times Sit-to-Stand Test and Grip Strength measured with a Jamar Dynamometer were used to quantitate changes in cognition, depression, fatigue and neurological function after a single 25mg perispinal etanercept dose in a patient with severe long COVID of 12 months duration.

Results: Following perispinal etanercept administration there was immediate neurological improvement. At 24 hours there were remarkable reductions in chronic post-COVID-19 fatigue and depression, and significant measureable improvements in cognition, executive function, phonemic verbal fluency, balance, gait, upper limb coordination and grip strength. Cognition, depression and fatigue were examined at 29 days; each remained substantially improved.

Conclusion: Perispinal etanercept is a promising treatment for the chronic neurologic dysfunction that may persist after resolution of acute COVID-19, including chronic cognitive dysfunction, fatigue, and depression. These results suggest that long COVID brain neuroinflammation is a potentially reversible pathology and viable treatment target. In view of the increasing unmet medical need, clinical trials of perispinal etanercept for long COVID are urgently necessary. The robust results of the present case suggest that perispinal etanercept clinical trials studying long COVID populations with severe fatigue, depression and cognitive dysfunction may have improved ability to detect a treatment effect. Positron emission tomographic methods that image brain microglial activation and measurements of cerebrospinal fluid proinflammatory cytokines may be useful for patient selection and correlation with treatment effects, as well as provide insight into the underlying pathophysiology.

Source: Tobinick E, Spengler RN, Ignatowski TA, Wassel M, Laborde S. Rapid improvement in severe long COVID following perispinal etanercept. Curr Med Res Opin. 2022 Jul 6:1-23. doi: 10.1080/03007995.2022.2096351. Epub ahead of print. PMID: 35791687.  https://pubmed.ncbi.nlm.nih.gov/35791687/

Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation

Summary:

COVID survivors frequently experience lingering neurological symptoms that resemble cancer therapy-related cognitive impairment, a syndrome for which white-matter microglial reactivity and consequent neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective microglial reactivity in mice and humans.
Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11. Systemic CCL11 administration specifically caused hippocampal microglial reactivity and impaired neurogenesis. Concordantly, humans with lasting cognitive symptoms post-COVID exhibit elevated CCL11 levels. Compared to SARS-CoV-2, mild respiratory influenza in mice caused similar patterns of white matter-selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis and elevated CCL11 at early timepoints, but after influenza only elevated CCL11 and hippocampal pathology persisted. These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.
Source: Anthony Fernández-Castañeda, Peiwen Lu, Anna C. Geraghty, Eric Song, MyoungHwa Lee, Jamie Wood, Michael R. O’Dea, Selena Dutton, Kiarash Shamardani, Kamsi Nwangwu, Rebecca Mancusi, Belgin Yalçın, Kathryn R. Taylor, Lehi AcostaAlvarez, Karen Malacon, Michael B. Keough, Lijun Ni, Pamelyn J. Woo, Daniel Contreras-Esquivel, Angus Martin Shaw Toland, Jeff R. Gehlhausen, Jon Klein, Takehiro Takahashi, Julio Silva, Benjamin Israelow, Carolina Lucas, Tianyang Mao, Mario A. Peña-Hernández, Alexandra Tabachnikova, Robert J. Homer, Laura Tabacof, Jenna Tosto-Mancuso, Erica Breyman, Amy Kontorovich, Dayna McCarthy, Martha Quezado, Hannes Vogel, Marco M. Hefti, Daniel P. Perl, Shane Liddelow, Rebecca Folkerth, David Putrino, Avindra Nath, Akiko Iwasaki, Michelle Monje. Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation.  Cell (2022). Published: June 12, 2022 DOI:https://doi.org/10.1016/j.cell.2022.06.008 https://www.sciencedirect.com/science/article/pii/S0092867422007139 (Full text available as PDF file)

Cerebrospinal Fluid Analysis Post-COVID-19 Is Not Suggestive of Persistent Central Nervous System Infection

Abstract:

This study was undertaken to assess whether SARS-CoV-2 causes a persistent central nervous system infection. SARS-CoV-2-specific antibody index and SARS-CoV-2 RNA were studied in cerebrospinal fluid following COVID-19. Cerebrospinal fluid was assessed between days 1 and 30 (n = 12), between days 31 and 90 (n = 8), or later than 90 days (post-COVID-19, n = 20) after COVID-19 diagnosis. SARS-CoV-2 RNA was absent in all patients, and in none of the 20 patients with post-COVID-19 syndrome were intrathecally produced anti-SARS-CoV-2 antibodies detected. The absence of evidence of SARS-CoV-2 in cerebrospinal fluid argues against a persistent central nervous system infection as a cause of neurological or neuropsychiatric post-COVID-19 syndrome.

Source: Schweitzer F, Goereci Y, Franke C, Silling S, Bösl F, Maier F, Heger E, Deiman B, Prüss H, Onur OA, Klein F, Fink GR, Di Cristanziano V, Warnke C. Cerebrospinal Fluid Analysis Post-COVID-19 Is Not Suggestive of Persistent Central Nervous System Infection. Ann Neurol. 2022 Jan;91(1):150-157. doi: 10.1002/ana.26262. Epub 2021 Nov 22. PMID: 34724243; PMCID: PMC8653324. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8653324/ (Full text)

Informatics Inference of Exercise-Induced Modulation of Brain Pathways Based on Cerebrospinal Fluid Micro-RNAs in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Introduction: The post-exertional malaise of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) was modeled by comparing micro-RNA (miRNA) in cerebrospinal fluid from subjects who had no exercise versus submaximal exercise.

Materials and Methods: Differentially expressed miRNAs were examined by informatics methods to predict potential targets and regulatory pathways affected by exercise.

Results: miR-608, miR-328, miR-200a-5p, miR-93-3p, and miR-92a-3p had higher levels in subjects who rested overnight (nonexercise n=45) compared to subjects who had exercised before their lumbar punctures (n=15). The combination was examined in DIANA MiRpath v3.0, TarBase, Cytoscape, and Ingenuity software® to select the intersection of target mRNAs. DIANA found 33 targets that may be elevated after exercise, including TGFBR1, IGFR1, and CDC42. Adhesion and adherens junctions were the most frequent pathways. Ingenuity selected seven targets that had complementary mechanistic pathways involving GNAQ, ADCY3, RAP1B, and PIK3R3. Potential target cells expressing high levels of these genes included choroid plexus, neurons, and microglia.

Conclusion: The reduction of this combination of miRNAs in cerebrospinal fluid after exercise suggested upregulation of phosphoinositol signaling pathways and altered adhesion during the post-exertional malaise of ME/CFS.

Clinical Trial Registration Nos.: NCT01291758 and NCT00810225.

Source: Narayan V, Shivapurkar N, Baraniuk JN. Informatics Inference of Exercise-Induced Modulation of Brain Pathways Based on Cerebrospinal Fluid Micro-RNAs in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Netw Syst Med. 2020 Nov 18;3(1):142-158. doi: 10.1089/nsm.2019.0009. PMID: 33274349; PMCID: PMC7703497.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703497/ (Full text)

Autoantibodies to beta-adrenergic and muscarinic cholinergic receptors in Myalgic Encephalomyelitis (ME) patients – A validation study in plasma and cerebrospinal fluid from two Swedish cohorts

Abstract:

Myalgic encephalomyelitis (ME) also known as ME/CFS (Chronic Fatigue Syndrome) or ME/SEID (Systemic Exertion Intolerance Disorder), is a disabling and often long-lasting disease that can drastically impair quality of life and physical/social functioning of the patients. Underlying pathological mechanisms are to a large extent unknown, but the presence of autoantibodies, cytokine pattern deviations and the presentation of cognitive and autonomic nervous system related symptoms provide evidence for ME being an immunological disorder with elements of autoimmunity. Increased levels of autoantibodies binding to adrenergic and muscarinic receptors in ME-patients have been reported. It is hypothesized that these autoantibodies have pathological significance and contribute to the ME-specific symptoms, however, these observations need to be validated.

This study was designed to investigate potential differences in adrenergic and muscarinic receptor autoantibody levels in plasma and cerebrospinal fluid (CSF) samples between ME patients and gender and age-matched healthy controls, and to correlate the autoantibody levels to disease severity.

We collected bodyfluids and health-related questionnaires from two Swedish ME cohorts, plasma and CSF from one of the cohorts (n ​= ​24), only plasma from the second cohort (n ​= ​24) together with plasma samples (n ​= ​24) and CSF (n ​= ​6) from healthy controls.

All samples were analysed for IgG autoantibodies directed against Alpha- (α1, α2) and Beta- (β1-3) adrenergic receptors and Muscarinic (M) 1–5 acetylcholine receptors using an ELISA technique. The questionnaires were used as measures of disease severity.

Significant increases in autoantibody levels in ME patients compared to controls were found for M3 and M4 -receptors in both cohorts and β1, β2, M3 and M4-receptors in one cohort. No significant correlations were found between autoantibody levels and disease severity. No significant levels of autoantibodies were detected in the CSF samples. These findings support previous findings that there exists a general pattern of increased antibody levels to adrenergic and muscarinic receptors within the ME patient group. However, the role of increased adrenergic and muscarinic receptor autoantibodies in the pathogenesis of ME is still uncertain and further research is needed to evaluate the clinical significance of these findings.

Source: Annie Bynke; Per Julin; Carl-Gerhard Gottfries; Harald Heidecke; Carmen Scheibenbogen; Jonas Bergquist. Autoantibodies to beta-adrenergic and muscarinic cholinergic receptors in Myalgic Encephalomyelitis (ME) patients – A validation study in plasma and cerebrospinal fluid from two Swedish cohorts. Brain, Behavior, & Immunity – Health, ISSN: 2666-3546, Vol: 7, Page: 100107 https://www.sciencedirect.com/science/article/pii/S2666354620300727 (Full text)

The putative glymphatic signature of chronic fatigue syndrome: A new view on the disease pathogenesis and therapy

Abstract:

The underlying pathophysiology of chronic fatigue syndrome remains incompletely understood and there are no curative treatments for this disorder at present. However, increasing neuroimaging evidence indicates that functional and structural abnormalities exist in the brains of chronic fatigue syndrome patients, suggesting that the central nervous system is involved in this disorder and that at least some chronic fatigue syndrome patients may have an underlying neurological basis for their illness.

In the present paper, we speculate that glymphatic dysfunction, causing toxic build up within the central nervous system, may be responsible for at least some cases of chronic fatigue syndrome. We further postulate that cerebrospinal fluid diversion such as lumboperitoneal shunting may be beneficial to this subgroup of patients by restoring glymphatic transport and waste removal from the brain.

Although recent evidence indicates that at least some chronic fatigue syndrome patients may benefit from cerebrospinal fluid drainage, further studies are needed to confirm this finding and to determine whether this can be attributed to enhancement of glymphatic fluid flow and interstitial fluid clearance. If confirmed, this could offer promising avenues for the future treatment of chronic fatigue syndrome. Clearly, given the relative invasive nature of cerebrospinal fluid diversion, such procedures should be reserved for chronic fatigue syndrome patients who are severely debilitated, or for those with severe headaches. Anyhow, it seems worthwhile to make every effort to identify new therapies for patients who suffer from this devastating disease, especially given that there are currently no effective treatments for this condition.

Source: Wostyn P, De Deyn PP. The putative glymphatic signature of chronic fatigue syndrome: A new view on the disease pathogenesis and therapy. Med Hypotheses. 2018 Sep;118:142-145. doi: 10.1016/j.mehy.2018.07.007. Epub 2018 Jul 6. https://www.ncbi.nlm.nih.gov/pubmed/30037603