scholarly journals Vascular pathology in multiple sclerosis: reframing pathogenesis around the blood-brain barrier

2017 ◽  
Vol 89 (1) ◽  
pp. 42-52 ◽  
Author(s):  
Jonathan I Spencer ◽  
Jack S Bell ◽  
Gabriele C DeLuca
Keyword(s):  
Multiple Sclerosis ◽  
Immune Response ◽  
Blood Brain Barrier ◽  
Immune Cell ◽  
Neurological Diseases ◽  
Specific Immune Response ◽  
Brain Barrier ◽  
Vascular Pathology ◽  
Current Evidence ◽  
Blood Brain

Blood-brain barrier (BBB) disruption has long been recognised as an important early feature of multiple sclerosis (MS) pathology. Traditionally, this has been seen as a by-product of the myelin-specific immune response. Here, we consider whether vascular changes instead play a central role in disease pathogenesis, rather than representing a secondary effect of neuroinflammation or neurodegeneration. Importantly, this is not necessarily mutually exclusive from current hypotheses. Vascular pathology in a genetically predisposed individual, influenced by environmental factors such as pathogens, hypovitaminosis D and smoking, may be a critical initiator of a series of events including hypoxia, protein deposition and immune cell egress that allows the development of a CNS-specific immune response and the classical pathological and clinical hallmarks of disease. We review the changes that occur in BBB function and cerebral perfusion in patients with MS and highlight genetic and environmental risk factors that, in addition to modulating immune function, may also converge to act on the vasculature. Further context is provided by contrasting these changes with other neurological diseases in which there is also BBB malfunction, and highlighting current disease-modifying therapies that may also have an effect on the BBB. Indeed, in reframing current evidence in this model, the vasculature could become an important therapeutic target in MS.

Cerebrospinal fluid and serum nitric oxide metabolites in patients with multiple sclerosis

1998 ◽  
Vol 4 (1) ◽  
pp. 27-30 ◽  
Author(s):  
G Giovannoni
Keyword(s):  
Nitric Oxide ◽  
Multiple Sclerosis ◽  
Cerebrospinal Fluid ◽  
Blood Brain Barrier ◽  
Neurological Diseases ◽  
Brain Barrier ◽  
Barrier Dysfunction ◽  
Blood Brain ◽  
Nitric Oxide Metabolites ◽  
Nitrate And Nitrite

Nitric oxide is hypothesised to play a role in the immunopathogenesis of multiple sclerosis. Raised cerebrospinal fluid and serum levels of the nitric oxide metabolites nitrate and nitrite have been described in patients with multiple sclerosis. Cerebrospinal fluid and serum nitrate and nitrite were measured in patients with multiple sclerosis, inflammatory and non-inflammatory neurological diseases, and correlated with the albumin quotient, an index of blood-brain-barrier dysfunction. Patients undergoing diagnostic lumbar and vene puncture were prospectively recruited, clinical data were obtained from the hospital records, and the CSF and serum nitrate and nitrite levels were measured by the nitrate reductase and Griess reaction methods. Nitrate and nitrite, were raised in the CSF and serum of patients with multiple sclerosis and other inflammatory neurological diseases compared to patients with non-inflammatory neurological disorders (median nitrate and nitrite: cerebrospinal fluid=10.3 μM vs 15.4 μMvs 6.6 μM, P50.001, and serum=49.0 μM vs 46.4 μM vs 38.8 μM, P=0.02, respectively). CSF nitrate and nitrite levels correlated with the albumin quotient (n=59, r=0.42, P50.001). This study provides further evidence for a role of nitric oxide in the immunopathogenesis of multiple sclerosis and supports a role for nitric oxide as a possible mediator of inflammatory blood-brain-barrier dysfunction.

scholarly journals A Leaky Blood–Brain Barrier to Fibrinogen Contributes to Oxidative Damage in Alzheimer’s Disease

Antioxidants ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 102
Author(s):  
James G. McLarnon
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Brain Barrier ◽  
Immune Cell ◽  
Neurovascular Unit ◽  
Amyloid Β ◽  
Brain Barrier ◽  
Vascular Pathology ◽  
Immune Reactivity ◽  
Blood Brain

The intactness of blood–brain barrier (BBB) is compromised in Alzheimer’s disease (AD). Importantly, evidence suggests that the perturbation and abnormalities appearing in BBB can manifest early in the progression of the disease. The disruption of BBB allows extravasation of the plasma protein, fibrinogen, to enter brain parenchyma, eliciting immune reactivity and response. The presence of amyloid-β (Aβ) peptide leads to the formation of abnormal aggregates of fibrin resistant to degradation. Furthermore, Aβ deposits act on the contact system of blood coagulation, altering levels of thrombin, fibrin clots and neuroinflammation. The neurovascular unit (NVU) comprises an ensemble of brain cells which interact with infiltrating fibrinogen. In particular, interaction of resident immune cell microglia with fibrinogen, fibrin and Aβ results in the production of reactive oxygen species (ROS), a neurotoxic effector in AD brain. Overall, fibrinogen infiltration through a leaky BBB in AD animal models and in human AD tissue is associated with manifold abnormalities including persistent fibrin aggregation and clots, microglial-mediated production of ROS and diminished viability of neurons and synaptic connectivity. An objective of this review is to better understand how processes associated with BBB leakiness to fibrinogen link vascular pathology with neuronal and synaptic damage in AD.

Neurofilament levels are associated with blood–brain barrier integrity, lymphocyte extravasation, and risk factors following the first demyelinating event in multiple sclerosis

2020 ◽  
pp. 135245852091237 ◽  
Author(s):  
Tomas Uher ◽  
Mason McComb ◽  
Shery Galkin ◽  
Barbora Srpova ◽  
Johanna Oechtering ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Sclerosis ◽  
Blood Brain Barrier ◽  
Immune Cell ◽  
Disease Onset ◽  
Cell Subset ◽  
Immunoglobulin M ◽  
Brain Barrier ◽  
Cns Inflammation ◽  
Blood Brain

Background: Increased blood brain barrier (BBB) permeability, CNS inflammation and neuroaxonal damage are pathological hallmarks in early multiple sclerosis (MS). Objective: To investigate the associations of neurofilament light chain (NfL) levels with measures of BBB integrity and central nervous system (CNS) inflammation in MS during the first demyelinating event. Methods: Blood and cerebrospinal fluid (CSF) were obtained from 142 MS (McDonald 2017) treatment-naive patients from the SET study (63% female; age: 29.7 ± 7.9 years) following the disease onset. NfL, albumin, immunoglobulin G (IgG), and immunoglobulin M (IgM) levels were measured in CSF and blood samples. Albumin quotient was computed as a marker of BBB integrity. Immune cell subset counts in CSF were measured using flow cytometry. MS risk factors, such as Human leukocyte antigen DRB1 locus gene ( HLA DRB1)*1501, anti-Epstein–Barr virus (EBV) antibodies, and 25-hydroxy vitamin D3, were also measured. Results: Higher serum NfL (sNfL) levels were associated with higher albumin quotient ( p < 0.001), CSF CD80+ ( p = 0.012), and CD80+ CD19+ ( p = 0.015) cell frequency. sNfL levels were also associated with contrast-enhancing and T2 lesions on brain magnetic resonance imaging (MRI; all p ⩽ 0.001). Albumin quotient was not associated with any of the MS risk factors assessed. sNfL levels were associated with anti-EBV viral capsid antigen (VCA) IgG levels ( p = 0.0026). Conclusion: sNfL levels during the first demyelinating event of MS are associated with greater impairment of BBB integrity, immune cell extravasation, and brain lesion activity on MRI.

scholarly journals The liver and muscle secreted Hfe2-protein maintains blood brain barrier integrity

2021 ◽  
Author(s):  
Xue Fan Wang ◽  
Robin Vigouroux ◽  
Yuriy Baglaenko ◽  
Angeliki Nikolakopoulou ◽  
Dene Ringuette ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Blood Brain Barrier ◽  
Immune Cell ◽  
Three Dimensional ◽  
Light Sheet ◽  
Brain Barrier ◽  
Behavioral Deficits ◽  
Central Nervous System Damage ◽  
Blood Brain ◽  
Blood Brain Barrier Integrity

Abstract Liver failure causes blood-brain-barrier (BBB) breakdown leading to central nervous system damage, however the mechanisms whereby the liver influences BBB-integrity remain elusive. One possibility is that the liver secretes an as-yet to be identified molecule(s) that circulate in the serum to directly promote BBB integrity. We developed light-sheet imaging for three-dimensional study of BBB function. We show that liver- or muscle-specific knockout of Hfe2 induces BBB breakdown, leading to accumulation of toxic-blood-derived fibrinogen in the brain, lower cortical neuron numbers, and behavioral deficits. In healthy animals, soluble Hfe2 competes with its homologue RGMa for binding to Neogenin, thereby blocking RGMa-induced downregulation of PDGF-B and Claudin-5 in endothelial cells and the ensuing BBB disruption. Hfe2 administration in an animal model of multiple sclerosis prevented paralysis and immune cell infiltration by inhibiting RGMa-mediated BBB alteration. This study has implications for the pathogenesis and potential treatment of diseases associated with BBB dysfunction such as multiple sclerosis.

scholarly journals Contribution of Tissue Inflammation and Blood-Brain Barrier Disruption to Brain Softening in a Mouse Model of Multiple Sclerosis

2021 ◽  
Vol 15 ◽  
Author(s):  
Rafaela Vieira Silva ◽  
Anna S. Morr ◽  
Susanne Mueller ◽  
Stefan Paul Koch ◽  
Philipp Boehm-Sturm ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Blood Brain Barrier ◽  
Immune Cell ◽  
Brain Barrier ◽  
Brain Atlas ◽  
Similar Degree ◽  
Iron Oxide Particles ◽  
Whole Brain ◽  
Blood Brain ◽  
Inflammatory Processes

Neuroinflammatory processes occurring during multiple sclerosis cause disseminated softening of brain tissue, as quantified by in vivo magnetic resonance elastography (MRE). However, inflammation-mediated tissue alterations underlying the mechanical integrity of the brain remain unclear. We previously showed that blood-brain barrier (BBB) disruption visualized by MRI using gadolinium-based contrast agent (GBCA) does not correlate with tissue softening in active experimental autoimmune encephalomyelitis (EAE). However, it is unknown how confined BBB changes and other inflammatory processes may determine local elasticity changes. Therefore, we aim to elucidate which inflammatory hallmarks are determinant for local viscoelastic changes observed in EAE brains. Hence, novel multifrequency MRE was applied in combination with GBCA-based MRI or very small superparamagnetic iron oxide particles (VSOPs) in female SJL mice with induced adoptive transfer EAE (n = 21). VSOPs were doped with europium (Eu-VSOPs) to facilitate the post-mortem analysis. Accumulation of Eu-VSOPs, which was previously demonstrated to be sensitive to immune cell infiltration and ECM remodeling, was also found to be independent of GBCA enhancement. Following registration to a reference brain atlas, viscoelastic properties of the whole brain and areas visualized by either Gd or VSOP were quantified. MRE revealed marked disseminated softening across the whole brain in mice with established EAE (baseline: 3.1 ± 0.1 m/s vs. EAE: 2.9 ± 0.2 m/s, p &lt; 0.0001). A similar degree of softening was observed in sites of GBCA enhancement i.e., mainly within cerebral cortex and brain stem (baseline: 3.3 ± 0.4 m/s vs. EAE: 3.0 ± 0.5 m/s, p = 0.018). However, locations in which only Eu-VSOP accumulated, mainly in fiber tracts (baseline: 3.0 ± 0.4 m/s vs. EAE: 2.6 ± 0.5 m/s, p = 0.023), softening was more pronounced when compared to non-hypointense areas (percent change of stiffness for Eu-VSOP accumulation: −16.81 ± 16.49% vs. for non-hypointense regions: −5.85 ± 3.81%, p = 0.048). Our findings suggest that multifrequency MRE is sensitive to differentiate between local inflammatory processes with a strong immune cell infiltrate that lead to VSOP accumulation, from disseminated inflammation and BBB leakage visualized by GBCA. These pathological events visualized by Eu-VSOP MRI and MRE may include gliosis, macrophage infiltration, alterations of endothelial matrix components, and/or extracellular matrix remodeling. MRE may therefore represent a promising imaging tool for non-invasive clinical assessment of different pathological aspects of neuroinflammation.

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