Compartmentalized meningeal inflammation is thought to represent one of the key players in the pathogenesis of cortical demyelination in multiple sclerosis. Positron emission tomography targeting the 18 kDa mitochondrial Translocator Protein (TSPO) is a molecular-specific approach to quantify immune cell-mediated density in the cortico-meningeal tissue compartment in vivo. The aim of this study was to characterize cortical and meningeal TSPO expression in a heterogeneous cohort of multiple sclerosis cases using in vivo simultaneous MR-PET with 11C-PBR28, a second-generation TSPO radioligand, and ex vivo immunohistochemistry. Forty-nine multiple sclerosis patients (21 with secondary progressive and 28 with relapsing-remitting multiple sclerosis) with mixed or high affinity binding for 11C-PBR28 underwent 90-min 11C-PBR28 simultaneous MR-PET. Tracer binding was measured using 60-90 min normalized standardized uptake value ratio values sampled at mid-cortical depth and ∼3 mm above the pial surface. Data in multiple sclerosis patients were compared to 21 age-matched healthy controls. To characterize the nature of 11C-PBR28 PET uptake, the meningeal and cortical lesion cellular expression of TSPO was further described in post-mortem brain tissue from 20 cases with secondary progressive multiple sclerosis and five age-matched healthy donors. Relative to healthy controls, patients with multiple sclerosis exhibited abnormally increased TSPO signal in the cortex and meningeal tissue, diffusively in progressive disease and more localized in relapsing-remitting multiple sclerosis. In multiple sclerosis, increased meningeal TSPO levels were associated with increased Expanded Disability Status Scale scores (p = 0.007, by linear regression). Immunohistochemistry, validated using in-situ sequencing analysis, revealed increased TSPO expression in the meninges and adjacent subpial cortical lesions of post-mortem secondary progressive multiple sclerosis cases relative to control tissue. In these cases, increased TSPO expression was related to meningeal inflammation. Translocator Protein immunostaining was detected on meningeal major histocompatibility complex (MHC)-class II + macrophages and cortical activated MHC-class II + transmembrane protein (TMEM)119+ microglia. In vivo arterial blood data and neuropathology showed that endothelial binding did not significantly account for increased TSPO cortico-meningeal expression in multiple sclerosis. Our findings support the use of TSPO-PET in multiple sclerosis for imaging in vivo inflammation in the cortico-meningeal brain tissue compartment and provide in vivo evidence implicating meningeal inflammation in the pathogenesis of the disease.

中文翻译：

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多发性硬化症中皮质脑膜易位蛋白表达的特征

室室化脑膜炎症被认为是多发性硬化症皮质脱髓鞘发病机制的关键因素之一。针对 18 kDa 线粒体易位蛋白 (TSPO) 的正电子发射断层扫描是一种分子特异性方法，用于量化体内皮质脑膜组织区室中免疫细胞介导的密度。本研究的目的是使用体内同步 MR-PET 与 11C-PBR28（第二代 TSPO 放射性配体）和离体免疫组织化学来表征多发性硬化症病例的异质队列中的皮质和脑膜 TSPO 表达。 49 名 11C-PBR28 混合或高亲和力结合的多发性硬化症患者（21 名继发进展型和 28 名复发缓解型多发性硬化症）接受了 90 分钟的 11C-PBR28 同步 MR-PET。使用在中皮质深度和软脑膜表面上方约 3 毫米处采样的 60-90 分钟归一化标准化摄取值比率值来测量示踪剂结合。多发性硬化症患者的数据与 21 名年龄匹配的健康对照者进行了比较。为了表征 11C-PBR28 PET 摄取的性质，在 20 例继发性进行性多发性硬化症患者和 5 名年龄匹配的健康供体的死后脑组织中进一步描述了 TSPO 的脑膜和皮质病变细胞表达。与健康对照相比，多发性硬化症患者的皮质和脑膜组织中的 TSPO 信号异常增加，在进展性疾病中呈扩散性，在复发缓解型多发性硬化症中更为局域化。在多发性硬化症中，脑膜 TSPO 水平升高与扩展残疾状态量表评分升高相关（通过线性回归，p = 0.007）。使用原位测序分析验证的免疫组织化学显示，与对照组织相比，死后继发性进行性多发性硬化症病例的脑膜和邻近软膜下皮质病变中 TSPO 表达增加。在这些病例中，TSPO 表达增加与脑膜炎症有关。在脑膜主要组织相容性复合物 (MHC)-II 类 + 巨噬细胞和皮质激活的 MHC-II 类 + 跨膜蛋白 (TMEM)119+ 小胶质细胞上检测到易位蛋白免疫染色。体内动脉血数据和神经病理学表明，内皮结合并不能显着解释多发性硬化症中 TSPO 皮质脑膜表达的增加。我们的研究结果支持在多发性硬化症中使用 TSPO-PET 对皮质脑膜脑组织区室中的体内炎症进行成像，并提供暗示脑膜炎症在该疾病发病机制中的体内证据。