Vascular Contributors to Blood Brain Barrier Permeability and Regional White Matter Hyperintensity Progression in Young Asymptomatic People

血管对年轻无症状人群血脑屏障通透性和局部白质高信号进展的影响

• 批准号: 10501246
• 负责人: Paul Alan Nyquist
• 金额: $ 240.7万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10501246
• 关键词: Address; Adult; Affect; African American; Age; American; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain scan; Caliber; Carotid Arteries; Cerebrovascular Disorders; Cerebrum; Chronic; Clinical; Cognition; Coronary Arteriosclerosis; Dementia; Development; Diabetes Mellitus; Enrollment; European; Follow-Up Studies; Functional disorder; Goals; High Prevalence; Hypertension; Image; Impaired cognition; Individual; Information Retrieval; Injury; Knowledge; Lead; Lesion; Magnetic Resonance Imaging; Measures; Methods; Microvascular Dysfunction; Motor; Outcome; Participant; Pathogenesis; Patients; Perfusion; Persons; Phenotype; Population; Prevalence; Prevention; Property; Pulse Pressure; Reporting; Research Priority; Risk Factors; Role; Scanning; Short-Term Memory; Siblings; Smoking; Stroke; Symptoms; Thromboplastin; Time; Visit; White Matter Hyperintensity; age group; blood lipid; blood-brain barrier disruption; blood-brain barrier permeabilization; burden of illness; cerebrovascular; cognitive change; cognitive function; cognitive performance; cognitive skill; disorder risk; experience; follow-up; hypoperfusion; motor control; neurovascular unit; patient subsets; premature; risk variant; serial imaging; spatial relationship; time use; vascular cognitive impairment and dementia; vascular contributions; vascular risk factor; white matter

Project Summary: White matter hyperintensities (WMHs) of the brain are a phenotype of cerebrovascular small vessel disease (cSVD) and estimated to represent 40% of the cSVD disease burden . The WMH phenotype is closely associated with damage to the neurovascular unit and is thought to contribute to cognitive impairment, deficits in motor control, and stroke. Understanding how WMHs are affected by vascular risk factors and progress over time is a part of a national research priority of understanding vascular contributions that influence cognitive decline and dementia (VCID). There is a knowledge gap about how WMHs progress in younger age groups (age 40-50). This study addresses two issues of significance regarding early progression: (i) how periventricular WMHs (PVWMHs) and subcortically located deep WMHs (DWMHs) progress independently and influence different clinical outcomes and (ii) how increasing blood–brain barrier (BBB) permeability and microvascular changes are associated with lesion expansion. This study adds to the understanding of the pathophysiology of WMH progression, supporting the development of earlier prevention and mitigation. GeneSTAR is a vascular study of asymptomatic younger (age 40-50) siblings of patients with premature coronary artery disease enriched for WMH. The GeneSTAR population is deeply phenotyped for vascular properties, has a high prevalence of asymptomatic WMHs, and is relatively young at the time of first MRI. We will leverage these features and our experience studying PVWMH, DWMH, and BBB permeability by recalling these participants and repeating the 3T MRI volumetrics with adding two independent measures of BBB permeability. This study will include relatively young African American and European American adults (n=500) with a mean age of 50.8±10.4 at baseline in GeneSTAR and will now reimage them at age 61.9±10.5 years. We will relate any changes in WMH volume to: (i) vascular risk factors (hypertension, diabetes, blood lipids, smoking), (ii) changes in vascular function (carotid artery wall stiffness, pulse pressure, and brachial arterial diameter), and (iii) changes in cognitive function (immediate memory, working memory, information retrieval, multi-domain cognitive skills, and motor function). We also will recall 130 of our proposed participants in years 4 and 5 to study the relationship between WMH progression and increases in BBB permeability and mean transit time (MTT) using serial imaging. This second MRI at year 3 or 4 has the goal of measuring the interval change in all MRI phenotypes measured at year 1 and relate WMH volume progression to BBB permeability and mean transit time measured in year 1 to that at years 4 or 5. We will study how changes in BBB permeability and perfusion are: (i) related to WMH volume changes, (ii) affected by vascular risk factors, and (iii) associated with cognitive changes.

项目摘要： 大脑的白质超强度（WMH）是脑血管小血管疾病的表型 （CSVD），估计占CSVD疾病的40％。 WMH表型紧密 与神经血管单元的损害相关，被认为会导致认知障碍，缺乏症 在运动控制和中风中。了解WMH如何受到血管危险因素的影响并逐渐发展 时间是了解影响认知的血管贡献的国家研究优先事项的一部分 衰落和痴呆（VCID）。关于WMHS如何在年轻年龄段中进步有一个知识差距 （40-50岁）。这项研究解决了有关早期进展的两个重要问题：（i） 周期性WMHS（PVWMHS）和下层深WMHS（DWMHS）独立进展 并影响不同的临床结果，以及（ii）如何增加血脑屏障（BBB）渗透性和 微血管变化与病变扩张有关。这项研究增加了对 WMH进展的病理生理学，支持早期预防和缓解的发展。 Genestar是对早产患者渐近年轻（40-50岁）兄弟姐妹的血管研究 富含WMH的冠状动脉疾病。基因人群被深深表现为血管 属性，渐近WMHS的患病率很高，并且在第一次MRI时相对较小。我们 将通过召回PVWMH，DWMH和BBB渗透性来利用这些功能以及我们研究PVWMH，DWMH和BBB的经验 这些参与者并通过添加两个独立的BBB测量来重复3T MRI体积 渗透性。这项研究将包括相对年轻的非洲裔美国和欧美成年人（n = 500） Genestar的基线时平均年龄为50.8±10.4，现在将在61.9±10.5岁时重新形容它们。 我们将将WMH体积的任何变化与：（i）血管危险因素（高血压，糖尿病，血脂，， 吸烟），（ii）血管功能的变化（颈动脉壁刚度，脉压和肱动脉 直径）和（iii）认知功能的变化（立即记忆，工作记忆，信息检索， 多域认知技能和运动功能）。我们还将回忆起我们多年来提出的130名参与者 4和5研究WMH进展与BBB渗透率增加与平均值之间的关系 使用串行成像的运输时间（MTT）。 3年级或4年的第二个MRI的目标是测量间隔 在第1年测量的所有MRI表型的变化，并将WMH体积的进展与BBB渗透率相关联 以及在第4年或第5年中测得的平均运输时间。我们将研究BBB的变化如何 渗透性和灌注是：（i）与WMH体积变化有关，（ii）受血管危险因素的影响，以及 （iii）与认知变化有关。