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.

项目概要： 脑白质高信号 (WMH) 是脑血管小血管疾病的一种表型 (cSVD)，估计占 cSVD 疾病负担的 40%，与 WMH 表型密切相关。 与神经血管单位的损伤有关，被认为会导致认知障碍、缺陷 了解 WMH 如何受到血管危险因素和进展的影响。 时间是了解影响认知的血管贡献的国家研究重点的一部分 关于 WMH 在年轻群体中的进展情况存在知识差距。 （40-50 岁）这项研究解决了有关早期进展的两个重要问题：(i) 如何进展。 室周 WMH (PVWMH) 和皮层下深部 WMH (DWMH) 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）的渗透性和 这项研究增加了对微血管变化与病变扩展的理解。 WMH 进展的病理生理学，支持早期预防和缓解的发展。 GeneSTAR 是一项针对早产儿患者无症状的较年轻（40-50 岁）兄弟姐妹的血管研究 冠状动脉疾病富含 WMH。 GeneSTAR 人群具有丰富的血管表型。 特征，无症状 WMH 的患病率很高，并且在第一次 MRI 时相对较年轻。 将通过回忆来利用这些功能以及我们研究 PVWMH、DWMH 和 BBB 渗透性的经验 这些参与者并重复 3T MRI 体积测量，并添加两个独立的 BBB 测量 这项研究将包括相对年轻的非裔美国人和欧洲裔美国人 (n=500)。 GeneSTAR 基线时的平均年龄为 50.8±10.4 岁，现在将在 61.9±10.5 岁时重新成像。 我们会将 WMH 量的任何变化与：(i) 血管危险因素（高血压、糖尿病、血脂、 (ii) 血管功能的变化（颈动脉壁硬度、脉压和肱动脉 直径），以及（iii）认知功能的变化（即时记忆、工作记忆、信息检索、 多领域认知技能和运动功能）我们还将在几年内召回 130 名提议的参与者。 4 和 5 研究 WMH 进展与 BBB 通透性和平均值增加之间的关系 使用连续成像的传输时间 (MTT) 在第 3 年或第 4 年进行的第二次 MRI 的目的是测量间隔。 第 1 年测量的所有 MRI 表型的变化并将 WMH 体积进展与 BBB 通透性联系起来 以及第一年到第四年或第五年测量的平均通过时间。我们将研究 BBB 的变化 通透性和灌注是：(i) 与 WMH 体积变化有关，(ii) 受血管危险因素影响，以及 (iii) 与认知变化有关。