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Contribution of Tissue Inflammation and Blood-Brain Barrier Disruption to Brain Softening in a Mouse Model of Multiple Sclerosis.
Frontiers in Neuroscience ( IF 4.3 ) Pub Date : 2021-08-23 , DOI: 10.3389/fnins.2021.701308
Rafaela Vieira Silva 1, 2 , Anna S Morr 3 , Susanne Mueller 4, 5 , Stefan Paul Koch 4, 5 , Philipp Boehm-Sturm 4, 5 , Yasmina Rodriguez-Sillke 6 , Désirée Kunkel 6 , Heiko Tzschätzsch 3 , Anja A Kühl 7 , Jörg Schnorr 3 , Matthias Taupitz 3 , Ingolf Sack 3 , Carmen Infante-Duarte 1, 2, 8
Affiliation  

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 < 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.

中文翻译:

组织炎症和血脑屏障破坏对多发性硬化症小鼠模型脑软化的贡献。

多发性硬化期间发生的神经炎症过程会导致脑组织弥散性软化,如体内磁共振弹性成像 (MRE) 所量化的那样。然而,大脑机械完整性背后的炎症介导的组织改变仍不清楚。我们之前表明,使用钆造影剂 (GBCA) 通过 MRI 观察到的血脑屏障 (BBB) 破坏与活动性实验性自身免疫性脑脊髓炎 (EAE) 中的组织软化无关。然而,目前尚不清楚局限的 BBB 变化和其他炎症过程如何决定局部弹性变化。因此,我们的目标是阐明哪些炎症标志是在 EAE 大脑中观察到的局部粘弹性变化的决定因素。因此,新型多频 MRE 与基于 GBCA 的 MRI 或非常小的超顺磁性氧化铁颗粒 (VSOP) 结合应用于具有诱导过继转移 EAE 的雌性 SJL 小鼠(n = 21)。VSOPs 掺杂铕 (Eu-VSOPs) 以促进尸检分析。之前被证明对免疫细胞浸润和 ECM 重塑敏感的 Eu-VSOPs 的积累也被发现与 GBCA 增强无关。在注册到参考脑图谱后,量化了整个大脑和由 Gd 或 VSOP 可视化的区域的粘弹性。MRE 显示,EAE 小鼠整个大脑出现明显的弥散性软化(基线:3.1 ± 0.1 m/s 与 EAE:2.9 ± 0.2 m/s,p < 0.0001)。在 GBCA 增强部位观察到类似程度的软化,即,主要在大脑皮层和脑干内(基线:3.3 ± 0.4 m/s 与 EAE:3.0 ± 0.5 m/s,p = 0.018)。然而,仅 Eu-VSOP 积累的位置,主要是在纤维束中(基线:3.0 ± 0.4 m/s 与 EAE:2.6 ± 0.5 m/s,p = 0.023),与非低信号相比,软化更为明显区域(Eu-VSOP 积累的刚度变化百分比:-16.81 ± 16.49% 与非低信号区域:-5.85 ± 3.81%,p = 0.048)。我们的研究结果表明,多频 MRE 对区分局部炎症过程很敏感,免疫细胞浸润导致 VSOP 积聚,GBCA 显示的播散性炎症和 BBB 渗漏。Eu-VSOP MRI 和 MRE 显示的这些病理事件可能包括神经胶质增生、巨噬细胞浸润、内皮基质成分的改变、和/或细胞外基质重塑。因此,MRE 可能代表一种有前途的成像工具,用于对神经炎症的不同病理方面进行非侵入性临床评估。
更新日期:2021-08-23
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