BBB Permeability Imaging in CADASIL

项目概要/摘要 该中美生物医学研究合作项目的目的是了解中美生物医学研究合作项目的作用 血脑屏障（BBB）在脑小血管疾病（SVD）发病机制中的作用并验证BBB 渗透性成像作为 SVD 的早期标志。 SVD 是中风、白质 (WM) 疾病的主要原因 和痴呆症，但大脑损伤和认知能力下降的机制在很大程度上仍然难以捉摸。这个 该提案将检验以下假设：血脑屏障崩溃会引发人类疾病的发作和进展 基因定义的 SVD（NOTCH3 突变携带者，患有常染色体显性脑动脉病 伴有皮质下梗死和白质脑病或 CADASIL）。该提案将使用一组独特的 中国 CADASIL 患者已在首都医科大学宣武医院排队接受研究 在北京。采用 3 特斯拉和 7 特斯拉的尖端 BBB 渗透性成像技术，使用动态对比度 增强 (DCE) MRI 和扩散加权动脉自旋标记 (DW ASL) 以及其他创新技术 作为 MarkVCID 联盟 (www.markvcid.org) 的一部分，我们将系统地研究 SVD 的生物标志物 CADASIL 进展期间的临床、神经心理学和影像学变化。在3个目标中，我们首先 评估 BBB 对钆基造影剂的渗透性之间的重复性和相关性 中国 CADASIL 患者队列中分别存在 (GBCA) 和水。通过纵向研究，我们将 然后使用 DCE MRI 和 DW ASL 在中国人群中确定 BBB 破裂的起始作用 CADASIL 患者检验 NOTCH3 突变携带者 BBB 通透性增加的假设 引发疾病的发作和进展，例如脑血流量 (CBF) 减少、WM 的发展 病变和游离水含量、缺血性梗塞和微出血以及认知能力下降。我们将进一步 为 CADASIL 患者开发和评估多参数 MRI 方案，包括 BBB 通透性 7T超高场成像。利用中国 CADASIL 患者的独特队列，并应用 3T 和 7T 的尖端成像方法，这个美中生物医学合作项目将定义 BBB 功能障碍在脑 SVD 中的启动作用，并将 BBB 确立为新的关键靶点 CADASIL 和扩展的 SVD 的治疗干预。该项目还将产生尖端的 BBB 3 和 7T 的渗透性成像协议作为 SVD 的早期成像标记。

Project Summary/Abstract The purpose of this US-China Biomedical Research Collaboration project is to understand the role of the blood-brain barrier (BBB) in the pathogenesis of cerebral small vessel disease (SVD) and to validate BBB permeability imaging as an early marker of SVD. SVD is a major cause of stroke, white matter (WM) disease and dementia, but the mechanisms underlying brain damage and cognitive decline remain largely elusive. This proposal will test the hypothesis that BBB breakdown initiates disease onset and progression in humans with genetically defined SVD (NOTCH3 mutation carriers suffering from cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy or CADASIL). The proposal will use a unique cohort of Chinese CADASIL patients already lined up for study inclusion at Xuanwu Hospital, Capital Medical University in Beijing. With cutting-edge BBB permeability imaging techniques at 3 and 7 Tesla, using dynamic contrast enhanced (DCE) MRI and diffusion-weighted arterial spin labeling (DW ASL), as well as other innovative biomarkers of SVD as part of the MarkVCID consortium (www.markvcid.org), we will systematically investigate the clinical, neuropsychological, and imaging changes during CADASIL progression. In 3 aims, we will first evaluate the repeatability and correlation between BBB permeability to Gadolinium-based contrast agent (GBCA) and water respectively in the cohort of Chinese CADASIL patients. Using a longitudinal study, we will then determine the initiating role of BBB breakdown using DCE MRI and DW ASL in the cohort of Chinese CADASIL patients to test the hypothesis that increased BBB permeability in NOTCH3 mutation carriers initiates disease onset and progression, such as cerebral blood flow (CBF) reductions, development of WM lesions and free water content, ischemic infracts and mircrohemorhages, and cognitive decline. We will further develop and evaluate a multiparametric MRI protocol for CADASIL patients including BBB permeability imaging at ultrahigh field of 7T. Leveraging a unique cohort of Chinese CADASIL patients, and applying cutting-edge imaging approaches at 3 and 7T, this US-China Biomedical Collaboration project will define the initiating role of BBB dysfunction in cerebral SVD, and will establish the BBB as a new key target for therapeutic interventions in CADASIL and by extension SVD. This project will also result in cutting-edge BBB permeability imaging protocols at 3 and 7T as early imaging markers of SVD.