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 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.

scholarly journals Genetic disruption of the Blood Brain Barrier leads to protective barrier formation at the Glia Limitans

2020 ◽  
Author(s):  
Pierre-Louis Hollier ◽  
Sarah Guimbal ◽  
Pierre Mora ◽  
Aïssata Diop ◽  
Lauriane Cornuault ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Tight Junction ◽  
Blood Brain Barrier ◽  
Treatment Strategies ◽  
Brain Barrier ◽  
Double Barrier ◽  
Cns Inflammation ◽  
Glia Limitans ◽  
Inflammatory Conditions ◽  
Blood Brain

AbstractRecent work demonstrated that Central Nervous System (CNS) inflammation induces endothelial Blood Brain Barrier (BBB) opening as well as the formation of a tight junction barrier between reactive astrocytes at the Glia Limitans. We hypothesized that these two barriers may be reciprocally regulated by each other state and further, that the CNS parenchyma may acquire protection from the reactive astrocytic Glia Limitans not only in neuro-inflammation but also when BBB integrity is compromised under resting condition, without pathology. Previous studies identified Sonic hedgehog (Shh) astrocytic secretion as implicated in stabilizing the BBB during neuropathology and we recently demonstrated that desert hedgehog (Dhh) is expressed at the BBB in adults.Here we unraveled the role of the morphogen Dhh in maintaining BBB tightness and, using endothelial Dhh knockdown as a model of permeable BBB, we demonstrated that a double barrier system comprising both the BBB and Glia Limitans, is implemented in the CNS and regulated by a crosstalk going from endothelial cell to astrocytes.First, we showed that, under neuro-inflammatory conditions, Dhh expression is severely down regulated at the BBB and that Dhh is necessary for endothelial intercellular junction integrity as Dhh knockdown leads to CNS vascular leakage. We then demonstrated that, in Dhh endothelial knockout (DhhECKO) mice which display an open BBB, astrocytes are reactive and express the tight junction Claudin 4 (Cldn4) and showed that astrocytes can respond to signals secreted by the permeable endothelial BBB by becoming reactive and expressing Cldn4. To examine the consequences of the above results on disease severity, we finally induced multiple sclerosis in DhhECKO mice versus control littermates and showed that the pathology is less severe in the knockout animals due to Glia Limitans tightening, in response to BBB leakage, which drives inflammatory infiltrate entrapment into the perivascular space. Altogether these results suggest that genetic disruption of the BBB generates endothelial signals capable of driving the implementation of a secondary barrier at the Glia Limitans to protect the parenchyma. The concept of a reciprocally regulated CNS double barrier system has implications for treatment strategies in both the acute and chronic phases of multiple sclerosis pathophysiology.

scholarly journals Blood–brain barrier genetic disruption leads to protective barrier formation at the Glia Limitans

PLoS Biology ◽  
2020 ◽  
Vol 18 (11) ◽  
pp. e3000946
Author(s):  
Pierre Mora ◽  
Pierre-Louis Hollier ◽  
Sarah Guimbal ◽  
Alice Abelanet ◽  
Aïssata Diop ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Blood Brain Barrier ◽  
Resting State ◽  
Brain Barrier ◽  
Protective Effects ◽  
Cns Inflammation ◽  
Glia Limitans ◽  
Protective Barrier ◽  
Blood Brain ◽  
Bbb Opening

Inflammation of the central nervous system (CNS) induces endothelial blood–brain barrier (BBB) opening as well as the formation of a tight junction barrier between reactive astrocytes at the Glia Limitans. We hypothesized that the CNS parenchyma may acquire protection from the reactive astrocytic Glia Limitans not only during neuroinflammation but also when BBB integrity is compromised in the resting state. Previous studies found that astrocyte-derived Sonic hedgehog (SHH) stabilizes the BBB during CNS inflammatory disease, while endothelial-derived desert hedgehog (DHH) is expressed at the BBB under resting conditions. Here, we investigated the effects of endothelial Dhh on the integrity of the BBB and Glia Limitans. We first characterized DHH expression within endothelial cells at the BBB, then demonstrated that DHH is down-regulated during experimental autoimmune encephalomyelitis (EAE). Using a mouse model in which endothelial Dhh is inducibly deleted, we found that endothelial Dhh both opens the BBB via the modulation of forkhead box O1 (FoxO1) transcriptional activity and induces a tight junctional barrier at the Glia Limitans. We confirmed the relevance of this glial barrier system in human multiple sclerosis active lesions. These results provide evidence for the novel concept of “chronic neuroinflammatory tolerance” in which BBB opening in the resting state is sufficient to stimulate a protective barrier at the Glia Limitans that limits the severity of subsequent neuroinflammatory disease. In summary, genetic disruption of the BBB generates endothelial signals that drive the formation under resting conditions of a secondary barrier at the Glia Limitans with protective effects against subsequent CNS inflammation. The concept of a reciprocally regulated CNS double barrier system has implications for treatment strategies in both the acute and chronic phases of multiple sclerosis pathophysiology.

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.

scholarly journals Inhibitory Effect of Matrine on Blood-Brain Barrier Disruption for the Treatment of Experimental Autoimmune Encephalomyelitis

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Su Zhang ◽  
Quan-Cheng Kan ◽  
Yuming Xu ◽  
Guang-Xian Zhang ◽  
Lin Zhu
Keyword(s):  
Basement Membrane ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Blood Brain Barrier ◽  
Adaptor Protein ◽  
Brain Barrier ◽  
Autoimmune Encephalomyelitis ◽  
Novel Therapy ◽  
Cns Inflammation ◽  
Blood Brain ◽  
Experimental Autoimmune

Dysfunction of the blood-brain barrier (BBB) is a primary characteristic of experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS). Matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae Flave, has been recently found to suppress clinical EAE and CNS inflammation. However, whether this effect of MAT is through protecting the integrity and function of the BBB is not known. In the present study, we show that MAT treatment had a therapeutic effect comparable to dexamethasone (DEX) in EAE rats, with reduced Evans Blue extravasation, increased expression of collagen IV, the major component of the basement membrane, and the structure of tight junction (TJ) adaptor protein Zonula occludens-1 (ZO-1). Furthermore, MAT treatment attenuated expression of matrix metalloproteinase-9 and -2 (MMP-9/-2), while it increased the expression of tissue inhibitors of metalloproteinase-1 and -2 (TIMP-1/-2). Our findings demonstrate that MAT reduces BBB leakage by strengthening basement membrane, inhibiting activities of MMP-2 and -9, and upregulating their inhibitors. Taken together, our results identify a novel mechanism underlying the effect of MAT, a natural compound that could be a novel therapy for MS.

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