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原的途径， 纤维蛋白的形成和降解可能是导致 神经炎症的启动和神经变性的促进，在各种 神经系统疾病，包括创伤性脑损伤、阿尔茨海默病和多发性硬化。 硬化症（MS），一种CNS和CNS的神经炎性和神经变性病症， 第二个最常见的原因神经功能障碍（创伤后）在年轻的成年人， 西方国家纤维蛋白原是一种340 kDa的糖蛋白，通常被认为是一种良好的蛋白质。 血脑屏障（BBB）破坏的替代标志物， 限制于血管内隔室和在健康CNS中缺乏表达。 凝血级联反应激活后，纤维蛋白原转化为不溶性纤维蛋白 通过凝血酶。以前的研究表明，纤维蛋白沉积是一个突出的， MS的病理特征，并存在于整个疾病过程中。 离体进行性MS脑的神经病理学检查提供了 有证据表明，疾病中的纤维蛋白沉积不仅限于白色物质 (WM)，但它也可以广泛和频繁地在MS皮层，在那里它与 神经元缺失在MS中，皮质脱髓鞘和神经变性是主要的 疾病病理学的组成部分，特别是在进行性阶段，和关键底物 不可逆转的神经系统残疾 在这里，我们建议将联合收割机7特斯拉超高分辨率磁共振 磁共振成像（MRI），其显示相对于低场MRI对皮质 病变病理学，使用64 Cu-FBP 8的分子正电子发射断层扫描，a 马萨诸塞州总医院开发的一种新型分子成像探针， 选择性地结合到纤维蛋白，以成像和定量体内纤维蛋白的病理沉积， 进行性MS患者的大脑，特别关注皮质及其 与局部病变和组织缺损相关。安全数据表明，64 Cu-FBP 8 显示出对纤维蛋白的纳摩尔亲和力，对纤维蛋白的选择性高于血浆蛋白， 代谢稳定，并迅速经肾脏排泄。 沉积在MS将是至关重要的，更好地了解病理事件，导致 MS中的神经炎症和皮质损伤，以及开发新的生物标志物 用于监测导致MS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.