Non invasive in vivo imaging of pathological fibrin deposition in the human brain

摘要： 越来越多的证据表明，纤维蛋白原和控制 纤维蛋白的形成和降解可能是导致 在多种疾病中引发神经炎症和促进神经变性 神经疾病，包括创伤性脑损伤、阿尔茨海默病和多发性 硬化症(MS)，一种中枢神经系统的神经炎性和神经退行性疾病 年年轻人神经功能障碍(仅次于创伤)的第二大常见原因 西方国家。纤维蛋白原是一种340 kDa的糖蛋白，通常被认为是一种 血脑屏障(BBB)破坏的替代标志，因为它的丰富， 仅限于血管内间隔，在健康中枢神经系统中缺乏表达。 一旦凝血级联被激活，纤维蛋白原就会转化为不溶性纤维蛋白。 通过凝血酶。以前的研究表明，纤维蛋白沉积是一种显著的 多发性硬化症的病理特征，并存在于整个病程。 对体外进展性多发性硬化症大脑的神经病理学检查提供了 有证据表明，这种疾病中的纤维蛋白沉积不仅限于脑白质 (Wm)，但它在MS皮质也可以广泛和频繁，在那里它与 神经元丢失。在MS中，主要表现为皮质脱髓鞘和神经变性。 疾病病理学的组成部分，特别是进展期，以及关键底物 不可逆转的神经性残疾。 在这里，我们建议结合7-特斯拉超高分辨率磁共振 成像(MRI)，显示相对于低场MRI对皮质的敏感度增加 病变病理，用64Cu-FBP8分子正电子发射断层扫描 马萨诸塞州总医院研发的新型分子成像探针 选择性地与纤维蛋白结合，成像和定量纤维蛋白在体内的病理沉积 进行性多发性硬化症患者的大脑，特别关注皮质及其 与局部损伤和组织丢失有关。安全数据表明，64Cu-FBP8 显示对纤维蛋白的纳摩尔亲和力，对纤维蛋白的高选择性超过血浆蛋白，是 代谢稳定，肾脏排泄迅速。体内追踪纤维蛋白的能力 多发性硬化症的沉积对于更好地理解导致 多发性硬化症的神经炎症和皮质损伤，以及开发新的生物标记物 用于监测导致多发性硬化症神经炎症的早期事件。

Abstract: A growing body of evidence indicates that fibrinogen and the pathways that control the formation and degradation of fibrin could represent early triggers that contribute to the initiation of neuroinflammation and the promotion of neurodegeneration in a variety of neurological disorders including traumatic brain injury, Alzheimer disease, and multiple sclerosis (MS), a neuroinflammatory and neurodegenerative disorder of the CNS and the second most common cause of neurological disability (after trauma) in young adults in Western countries. Fibrinogen is a 340 kDa glycoprotein generally considered a good surrogate marker of blood brain barrier (BBB) disruption because of its abundance, restriction to the intravascular compartment and lack of expression in the healthy CNS. Upon activation of the coagulation cascade, fibrinogen is converted into insoluble fibrin by thrombin. Previous studies have demonstrated that fibrin deposition is a prominent pathological feature of MS and is present throughout the course of the disease. Neuropathological examinations of ex vivo progressive MS brains have provided evidence that fibrin deposition in the disease is not only confined to the white matter (WM), but it can be also extensive and frequent in the MS cortex, where it correlates with neuronal loss. In MS, cortical demyelination and neurodegeneration represent main components of disease pathology, particularly in progressive stages, and key substrates of irreversible neurological disability. Here, we propose to combine 7-Tesla ultra-high resolution magnetic resonance imaging (MRI), which shows increased sensitivity relative to lower field MRI to cortical lesion pathology, with molecular positron emission tomography using 64Cu-FBP8, a novel molecular imaging probe developed at Massachusetts General Hospital, which selectively binds to fibrin, to image and quantify in vivo pathological deposition of fibrin in the brain of people with progressive MS, with a specific focus on the cortex and its association to local lesions and tissue loss. Safety data demonstrate that 64Cu-FBP8 shows nanomolar affinity for fibrin, high selectivity for fibrin over plasma proteins, is metabolically stable, and is rapidly renally excreted.The ability to track in vivo fibrin deposition in MS will be crucial for better understanding the pathological events that lead to neuroinflammation and cortical damage in MS, and for developing novel biomarkers for monitoring early events that lead to neuroinflammation in MS.