brain barrier disruption
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2022 ◽  
Author(s):  
Christopher C Hemond ◽  
Jonggyu Baek ◽  
Carolina Ionete ◽  
Daniel S Reich

Background and Objective: Paramagnetic rims have been observed as a feature of some MS lesions on susceptibility-sensitive MRI and indicate ongoing inflammation, principally consisting of compartmentalized activated microglia/macrophages. We investigated clinical, MRI, and intrathecal (cerebrospinal fluid, CSF) associations of paramagnetic rim lesions (PRL) using 3T MRI in MS. Methods: This is a retrospective, cross-sectional analysis of patients at a single neuroimmunology clinic. All patients had standardized 3T MRI using a multiecho T2*-weighted sequence with susceptibility postprocessing (SWAN protocol, GE) as part of the inclusion criteria. SWAN-derived filtered phase maps and corresponding T2-FLAIR images were manually reviewed by one expert rater blinded to clinical data, and PRL were determined based on qualitative assessment of hypointense paramagnetic edges on corresponding T2-hyperintense lesions. Descriptive statistics, t-tests, ANOVA, and linear regression determined demographic, clinical, MRI, and intrathecal profile associations with the presence of one or more PRL. Results: One hundred and forty-seven (147) MS patients were included in this analysis (2 clinically isolated syndrome, 118 relapsing-remitting, 14 secondary progressive, 13 primary progressive). Baseline mean age was 48.8 years, disease duration 12.8 years, and median EDSS 2, with 79% women. Seventy-five percent of patients were receiving a disease-modifying therapy, and 79 patients (54%) had available cerebrospinal fluid (CSF) analysis. Sixty-three patients (43%) had at least 1 PRL. PRL status (presence or absence) did not vary by sex or EDSS but was associated with younger age (51 vs 46 years; p=0.01) and shorter disease duration (14.5 vs 10.5 years; p=0.01). PRL status was also associated with worse disease (MS severity score: 2.8 vs 3.7; p=0.05) and blood-brain barrier disruption as determined by higher protein and pathologically elevated albumin quotient, as well as the presence of CSF oligoclonal bands (all p≤0.05); there was no association with immunoglobulin index or synthesis rate. PRL status was additionally associated with higher burden of T2-hyperintense cerebral lesion volume (T2LV), higher age-adjusted cerebral brain volume loss (especially of gray matter), and poorer performance on multiple clinical measures, including the 9-hole peg test and symbol digit modalities test (but not timed 25-foot walk speed). Clinical and intrathecal profiles remained associated with PRL after adjustment for age and in many cases T2LV as well. Sensitivity analyses limited to subgroups of patients without disease activity at the time of CSF sampling remained supportive of results. Patients with PRL were being treated with higher-efficacy disease-modifying therapies at the time of the data query. Conclusions: PRL, an emerging noninvasive biomarker of chronic cerebral neuroinflammation in MS, are confirmed to be associated with greater disease severity and newly shown to be associated with intrathecal inflammation and blood-brain-barrier disruption.


2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Xiuping Li ◽  
Xiaolin Gao ◽  
Wenyan Zhang ◽  
Mingming Liu ◽  
Zhaoli Han ◽  
...  

AbstractAged microglia display augmented inflammatory activity after neural injury. Although aging is a risk factor for poor outcome after brain insults, the precise impact of aging-related alterations in microglia on neural injury remains poorly understood. Microglia can be eliminated via pharmacological inhibition of the colony–stimulating factor 1 receptor (CSF1R). Upon withdrawal of CSF1R inhibitors, microglia rapidly repopulate the entire brain, leading to replacement of the microglial compartment. In this study, we investigated the impact of microglial replacement in the aged brain on neural injury using a mouse model of intracerebral hemorrhage (ICH) induced by collagenase injection. We found that replacement of microglia in the aged brain reduced neurological deficits and brain edema after ICH. Microglial replacement-induced attenuation of ICH injury was accompanied with alleviated blood-brain barrier disruption and leukocyte infiltration. Notably, newly repopulated microglia had reduced expression of IL-1β, TNF-α and CD86, and upregulation of CD206 in response to ICH. Our findings suggest that replacement of microglia in the aged brain restricts neuroinflammation and brain injury following ICH.


Author(s):  
Sahab Arinrad ◽  
Justus B. H. Wilke ◽  
Anna Seelbach ◽  
José Doeren ◽  
Martin Hindermann ◽  
...  

AbstractEncephalitis has an estimated prevalence of ≤0.01%. Even with extensive diagnostic work-up, an infectious etiology is identified or suspected in <50% of cases, suggesting a role for etiologically unclear, noninfectious processes. Mild encephalitis runs frequently unnoticed, despite slight neuroinflammation detectable postmortem in many neuropsychiatric illnesses. A widely unexplored field in humans, though clearly documented in rodents, is genetic brain inflammation, particularly that associated with myelin abnormalities, inducing primary white matter encephalitis. We hypothesized that “autoimmune encephalitides” may result from any brain inflammation concurring with the presence of brain antigen-directed autoantibodies, e.g., against N-methyl-D-aspartate-receptor NR1 (NMDAR1-AB), which are not causal of, but may considerably shape the encephalitis phenotype. We therefore immunized young female Cnp−/− mice lacking the structural myelin protein 2′-3′-cyclic nucleotide 3′-phosphodiesterase (Cnp) with a “cocktail” of NMDAR1 peptides. Cnp−/− mice exhibit early low-grade inflammation of white matter tracts and blood–brain barrier disruption. Our novel mental-time-travel test disclosed that Cnp−/− mice are compromised in what–where–when orientation, but this episodic memory readout was not further deteriorated by NMDAR1-AB. In contrast, comparing wild-type and Cnp−/− mice without/with NMDAR1-AB regarding hippocampal learning/memory and motor balance/coordination revealed distinct stair patterns of behavioral pathology. To elucidate a potential contribution of oligodendroglial NMDAR downregulation to NMDAR1-AB effects, we generated conditional NR1 knockout mice. These mice displayed normal Morris water maze and mental-time-travel, but beam balance performance was similar to immunized Cnp−/−. Immunohistochemistry confirmed neuroinflammation/neurodegeneration in Cnp−/− mice, yet without add-on effect of NMDAR1-AB. To conclude, genetic brain inflammation may explain an encephalitic component underlying autoimmune conditions.


2021 ◽  
Author(s):  
Angelika Hoffmann ◽  
Jessica Jin ◽  
Mame Aida ◽  
Chi Ho Wai ◽  
Sanjib Mohanty ◽  
...  

Brain swelling occurs in cerebral malaria (CM) and may either reverse or result in fatal outcome. It is currently unknown how brain swelling in CM reverses, as investigations have been hampered by inadequate animal models. In this study, we show that reversible brain swelling in experimental murine cerebral malaria (ECM) can be induced reliably after single vaccination with radiation-attenuated sporozoites as revealed by in vivo high-field (9.4T) magnetic resonance imaging. Our results provide evidence that parenchymal fluid increase and consecutive brain swelling results from transcellular blood-brain barrier disruption (BBBD), as revealed by electron microscopy. This mechanism enables reversal of brain swelling but does not prevent persistent focal brain damage, evidenced by microhemorrhages, in areas of most severe BBBD. In a cohort of 27 pediatric and adult CM patients (n=4 fatal, n=23 non-fatal) two out of four fatal CM patients (50%) and 8 out of 23 non-fatal CM patients (35%) showed microhemorrhages on MRI at clinical field strength of 1.5T, emphasizing the translational potential of the experimental model.


2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Takeshi Okada ◽  
Hidenori Suzuki ◽  
Zachary D. Travis ◽  
Orhan Altay ◽  
Jiping Tang ◽  
...  

Blood-brain barrier (BBB) disruption is a common and critical pathology following subarachnoid hemorrhage (SAH). We investigated the BBB disruption property of secreted protein acidic and rich in cysteine (SPARC) after SAH. A total of 197 rats underwent endovascular perforation to induce SAH or sham operation. Small interfering ribonucleic acid (siRNA) for SPARC or scrambled siRNA was administered intracerebroventricularly to rats 48 h before SAH. Anti-SPARC monoclonal antibody (mAb) 236 for functional blocking or normal mouse immunoglobulin G (IgG) was administered intracerebroventricularly 1 h after SAH. Selective integrin αVβ3 inhibitor cyclo(-RGDfK) or phosphate-buffered saline was administered intranasally 1 h before SAH, along with recombinant SPARC treatment. Neurobehavior, SAH severity, brain edema, immunohistochemical staining, and Western blot were evaluated. The expression of SPARC and integrin αVβ3 was upregulated after SAH in the endothelial cells. SPARC siRNA and anti-SPARC mAb 236 prevented neuroimpairments and brain edema through protection of BBB as measured by IgG extravasation 24 and 72 h after SAH. Recombinant SPARC aggravated neuroimpairments and cyclo(-RGDfK) suppressed the harmful neurological effects via inhibition of activated c-Jun N-terminal kinase, p38, and matrix metalloproteinase-9 followed by retention of endothelial junction proteins. SPARC may induce post-SAH BBB disruption via integrin αVβ3 signaling pathway.


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