BBB Permeability Imaging in CADASIL

CADASIL 中的 BBB 渗透性成像

• 批准号: 10548228
• 负责人: Danny JJ WANG
• 金额: $ 24.75万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10548228
• 关键词: Acceleration; Affect; Age; Arterial Disorder; Arteries; Biological Markers; Biomedical Research; Blood - brain barrier anatomy; Blood Tests; Blood Vessels; Blood brain barrier dysfunction; Blood capillaries; Brain; Brain Injuries; CADASIL; California; Capital; Central Nervous System; Central Nervous System Infections; Cerebral small vessel disease; Cerebrovascular Circulation; Cerebrum; China; Chinese; Clinical; Cognition; Cognitive; Collaborations; Contrast Media; Dementia; Development; Disease; Disease Progression; Elderly; Evaluation; Failure; Family member; Gadolinium; Genetic; Goals; Guidelines; Hemorrhage; Hospitals; Human; Image; Imaging Techniques; Impaired cognition; Infarction; Ischemia; Joints; Lacunar Infarctions; Lesion; Longitudinal Studies; Magnetic Resonance Imaging; Measurement; Measures; Medical; Microvascular Dysfunction; Mutation; NOTCH3 gene; Nerve Degeneration; Neuropsychology; Noise; Nutrient; Onset of illness; Oxygen; Pathogenesis; Pathology; Patients; Pericytes; Play; Prevention; Protocols documentation; Public Health; Publications; Resources; Role; Signal Transduction; Smooth Muscle Myocytes; Stroke; Subcortical Infarctions; Subcortical Leukoencephalopathy; Technology; Testing; Therapeutic Intervention; Universities; Vascular Diseases; Vascular Smooth Muscle; Visit; Water; White Matter Disease; White Matter Hyperintensity; aging population; arterial spin labeling; arteriole; autosome; blood-brain barrier permeabilization; burden of illness; cell type; cerebrovascular; cohort; contrast enhanced; detection sensitivity; diffusion weighted; imaging approach; imaging biomarker; innovation; mutation carrier; neuroimaging; targeted treatment; vascular cognitive impairment and dementia; white matter

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.

项目总结/摘要 这个中美生物医学研究合作项目的目的是了解 血脑屏障（BBB）在脑小血管病（SVD）发病机制中的作用， 渗透性成像作为SVD的早期标志。SVD是脑卒中、白色物质（WM）疾病的主要原因 和痴呆症，但脑损伤和认知能力下降的潜在机制在很大程度上仍然难以捉摸。这 一项提案将检验BBB破坏引发人类疾病发作和进展的假设， 遗传定义的SVD（患有常染色体显性遗传性脑动脉病的NOTCH 3突变携带者 伴有皮质下梗死和白质脑病或CADASIL）。该提案将使用一个独特的队列， 中国CADASIL患者已经在首都医科大学宣武医院排队参加研究 在北京采用尖端的BBB渗透性成像技术，在3和7特斯拉下，使用动态对比度 增强（DCE）MRI和弥散加权动脉自旋标记（DW ASL），以及其他创新的 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。在三个目标中，我们将首先 评价BBB通透性与钆基造影剂之间的可重复性和相关性 （GBCA）和水分别在中国CADASIL患者队列中。通过纵向研究，我们将 然后在中国队列中使用DCE MRI和DW ASL确定BBB崩溃的起始作用 CADASIL患者，以检验NOTCH 3突变携带者中BBB通透性增加的假设 启动疾病发作和进展，如脑血流量（CBF）减少，WM的发展 病变和游离水含量、缺血性梗死和微出血以及认知能力下降。我们将进一步 制定并评价CADASIL患者的多参数MRI方案，包括BBB渗透性 在7 T的双视野下成像。利用独特的中国CADASIL患者队列， 在3和7 T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中的起始作用，并将建立BBB作为新的关键靶点， CADASIL和扩展SVD的治疗干预。该项目还将导致尖端的BBB 在3和7 T下的渗透性成像方案作为SVD的早期成像标志物。