blood-brain barrier – Page 2 – American ME and CFS Society

Severe Neuro-COVID is associated with peripheral immune signatures, autoimmunity and neurodegeneration: a prospective cross-sectional study

Abstract:

Growing evidence links COVID-19 with acute and long-term neurological dysfunction. However, the pathophysiological mechanisms resulting in central nervous system involvement remain unclear, posing both diagnostic and therapeutic challenges. Here we show outcomes of a cross-sectional clinical study (NCT04472013) including clinical and imaging data and corresponding multidimensional characterization of immune mediators in the cerebrospinal fluid (CSF) and plasma of patients belonging to different Neuro-COVID severity classes.

The most prominent signs of severe Neuro-COVID are blood-brain barrier (BBB) impairment, elevated microglia activation markers and a polyclonal B cell response targeting self-antigens and non-self-antigens. COVID-19 patients show decreased regional brain volumes associating with specific CSF parameters, however, COVID-19 patients characterized by plasma cytokine storm are presenting with a non-inflammatory CSF profile. Post-acute COVID-19 syndrome strongly associates with a distinctive set of CSF and plasma mediators. Collectively, we identify several potentially actionable targets to prevent or intervene with the neurological consequences of SARS-CoV-2 infection.

Source: Etter MM, Martins TA, Kulsvehagen L, Pössnecker E, Duchemin W, Hogan S, Sanabria-Diaz G, Müller J, Chiappini A, Rychen J, Eberhard N, Guzman R, Mariani L, Melie-Garcia L, Keller E, Jelcic I, Pargger H, Siegemund M, Kuhle J, Oechtering J, Eich C, Tzankov A, Matter MS, Uzun S, Yaldizli Ö, Lieb JM, Psychogios MN, Leuzinger K, Hirsch HH, Granziera C, Pröbstel AK, Hutter G. Severe Neuro-COVID is associated with peripheral immune signatures, autoimmunity and neurodegeneration: a prospective cross-sectional study. Nat Commun. 2022 Nov 9;13(1):6777. doi: 10.1038/s41467-022-34068-0. PMID: 36351919; PMCID: PMC9645766. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9645766/ (Full text)

Microvascular Injury in the Brains of Patients with Covid-19

To the Editor:

We conducted postmortem high-resolution magnetic resonance imaging (magnetic resonance microscopy) of the brains of patients with coronavirus disease 2019 (Covid-19) (median age, 50 years) and histopathological examination that focused on microvascular changes in the olfactory bulb and brain stem. (See the Materials and Methods section in the Supplementary Appendix, available with the full text of this letter at NEJM.org.) Images were obtained from the brains of 13 patients with the use of an 11.7-Tesla scanner at a resolution of 25 μm for the olfactory bulb and at a resolution of 100 μm for the brain. Abnormalities were seen in the brains of 10 patients.

We examined the brains of patients that showed abnormalities by means of multiplex fluorescence imaging (in 5 patients) and by means of chromogenic immunostaining (in 10 patients). We performed conventional histopathological examination of the brains of 18 patients. Fourteen patients had chronic illnesses, including diabetes and hypertension, and 11 had been found dead or had died suddenly and unexpectedly. Of the 16 patients with available medical histories, 1 had delirium, 5 had mild respiratory symptoms, 4 had acute respiratory distress syndrome, 2 had pulmonary embolism, and the symptoms were not known in 3.

Read the rest of this letter HERE.

Source: Lee MH, Perl DP, Nair G, Li W, Maric D, Murray H, Dodd SJ, Koretsky AP, Watts JA, Cheung V, Masliah E, Horkayne-Szakaly I, Jones R, Stram MN, Moncur J, Hefti M, Folkerth RD, Nath A. Microvascular Injury in the Brains of Patients with Covid-19. N Engl J Med. 2021 Feb 4;384(5):481-483. doi: 10.1056/NEJMc2033369. Epub 2020 Dec 30. PMID: 33378608; PMCID: PMC7787217. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787217/ (Full text)

Molecular Mechanisms of Neuroinflammation in ME/CFS and Long COVID to Sustain Disease and Promote Relapses

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease now well-documented as having arisen commonly from a viral infection, but also from other external stressors, like exposure to agricultural chemicals, other types of infection, surgery, or other severe stress events. Research has shown these events produce a systemic molecular inflammatory response and chronic immune activation and dysregulation. What has been more difficult to establish is the hierarchy of the physiological responses that give rise to the myriad of symptoms that ME/CFS patients experience, and why they do not resolve and are generally life-long.

The severity of the symptoms frequently fluctuates through relapse recovery periods, with brain-centered symptoms of neuroinflammation, loss of homeostatic control, “brain fog” affecting cognitive ability, lack of refreshing sleep, and poor response to even small stresses. How these brain effects develop with ME/CFS from the initiating external effector, whether virus or other cause, is poorly understood and that is what our paper aims to address.

We propose the hypothesis that following the initial stressor event, the subsequent systemic pathology moves to the brain via neurovascular pathways or through a dysfunctional blood-brain barrier (BBB), resulting in chronic neuroinflammation and leading to a sustained illness with chronic relapse recovery cycles. Signaling through recognized pathways from the brain back to body physiology is likely part of the process by which the illness cycle in the peripheral system is sustained and why healing does not occur. By contrast, Long COVID (Post-COVID-19 condition) is a very recent ME/CFS-like illness arising from the single pandemic virus, SARS-CoV-2.

We believe the ME/CFS-like ongoing effects of Long COVID are arising by very similar mechanisms involving neuroinflammation, but likely with some unique signaling, resulting from the pathology of the initial SARS-CoV-2 infection. The fact that there are very similar symptoms in both ongoing diseases, despite the diversity in the nature of the initial stressors, supports the concept of a similar dysfunctional CNS component common to both.

Source: Tate W, Walker M, Sweetman E, Helliwell A, Peppercorn K, Edgar C, Blair A, Chatterjee A. Molecular Mechanisms of Neuroinflammation in ME/CFS and Long COVID to Sustain Disease and Promote Relapses. Front Neurol. 2022 May 25;13:877772. doi: 10.3389/fneur.2022.877772. PMID: 35693009; PMCID: PMC9174654. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174654/ (Full text)

The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure

Abstract:

Although myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has a specific and distinctive profile of clinical features, the disease remains an enigma because causal explanation of the pathobiological matrix is lacking. Several potential disease mechanisms have been identified, including immune abnormalities, inflammatory activation, mitochondrial alterations, endothelial and muscular disturbances, cardiovascular anomalies, and dysfunction of the peripheral and central nervous systems. Yet, it remains unclear whether and how these pathways may be related and orchestrated.

Here we explore the hypothesis that a common denominator of the pathobiological processes in ME/CFS may be central nervous system dysfunction due to impaired or pathologically reactive neuroglia (astrocytes, microglia and oligodendrocytes). We will test this hypothesis by reviewing, in reference to the current literature, the two most salient and widely accepted features of ME/CFS, and by investigating how these might be linked to dysfunctional neuroglia.

From this review we conclude that the multifaceted pathobiology of ME/CFS may be attributable in a unifying manner to neuroglial dysfunction. Because the two key features – post exertional malaise and decreased cerebral blood flow – are also recognized in a subset of patients with post-acute sequelae COVID, we suggest that our findings may also be pertinent to this entity.

Source: Renz-Polster H, Tremblay ME, Bienzle D, Fischer JE. The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure. Front Cell Neurosci. 2022 May 9;16:888232. doi: 10.3389/fncel.2022.888232. PMID: 35614970; PMCID: PMC9124899. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9124899/ (Full text)

Is chronic fatigue syndrome caused by a rare brain infection of a common, normally benign virus?

Abstract:

Chronic fatigue syndrome (CFS) is a disabling disease of unknown aetiology. A variety of factors have been suggested as possible causes. Although the symptoms and clinical findings are heterogeneous, the syndrome is sufficiently distinct, at least in relation to the more obvious cases, that a common explanation seems likely. In this paper, it is proposed that the disease is caused by a ubiquitous, but normally benign virus, e.g., one of the circoviruses.

Circoviruses are chronically present in a majority of people, but are rarely tested for diagnostically. Normally these viruses do not penetrate the blood-brain barrier, but exceptions have been reported, and related viruses cause disease in the central nervous system of animals.

The flu-like illness that often precedes the onset of CFS may either suppress immune function, causing an increased viremia, and/or lower the blood-brain barrier. In both cases the result may be that a virus already present in the blood enters the brain. It is well known that zoonotic viruses typically are more malignant than viruses with a long history of host-virus evolution. Similarly, a virus reaching an unfamiliar organ may cause particular problems.

Source: Grinde B. Is chronic fatigue syndrome caused by a rare brain infection of a common, normally benign virus? Med Hypotheses. 2008 Aug;71(2):270-4. doi: 10.1016/j.mehy.2008.03.014. Epub 2008 Apr 25. https://www.ncbi.nlm.nih.gov/pubmed/18440157

Chronic fatigue syndrome: neurological findings may be related to blood–brain barrier permeability

Abstract:

Despite volumes of international research, the etiology of chronic fatigue syndrome (CFS) remains elusive. There is, however, considerable evidence that CFS is a disorder involving the central nervous system (CNS).

It is our hypothesis that altered permeability of the blood-brain barrier (BBB) may contribute to ongoing signs and symptoms found in CFS. To support this hypothesis we have examined agents that can increase the blood-brain barrier permeability (BBBP) and those that may be involved in CFS.

The factors which can compromise the normal BBBP in CFS include viruses, cytokines, 5-hydroxytryptamine, peroxynitrite, nitric oxide, stress, glutathione depletion, essential fatty acid deficiency, and N-methyl-D-aspartate overactivity. It is possible that breakdown of normal BBBP leads to CNS cellular dysfunction and disruptions of neuronal transmission in CFS. Abnormal changes in BBBP have been linked to a number of disorders involving the CNS; based on review of the literature we conclude that the BBB integrity in CFS warrants investigation.

Source: Bested AC, Saunders PR, Logan AC. Chronic fatigue syndrome: neurological findings may be related to blood–brain barrier permeability. Med Hypotheses. 2001 Aug;57(2):231-7. http://www.ncbi.nlm.nih.gov/pubmed/11461179