Quantitative Measurement of Cerebrovascular Permeability in Early Dementia

早期痴呆脑血管通透性的定量测量

• 批准号: 8306203
• 负责人: VALERIE C ANDERSON
• 金额: $ 14.1万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8306203
• 关键词: Active Biological Transport; Aging; Alleles; Alzheimer' s Disease; Amyloid; Anatomy; Apolipoprotein E; Area; Biological Markers; Biomedical Research; Blood - brain barrier anatomy; Blood Vessels; Blood Volume; Blood capillaries; Bolus Infusion; Brain; Cessation of life; Clinical; Cognitive; Data; Dementia; Development; Diffusion; Disease; Drug Kinetics; Elderly; Exposure to; Extravasation; Functional disorder; Funding; Goals; Health; Hippocampus (Brain); Human; Image; Impaired cognition; Injection of therapeutic agent; Investigation; K-Series Research Career Programs; Knowledge; Lead; Lesion; Life; Magnetic Resonance Imaging; Maps; Measurement; Measures; Medial; Medical; Membrane; Memory; Mentors; Methodology; Microvascular Permeability; Molecular Weight; Neurofibrillary Tangles; Neuronal Injury; Oxidative Stress; Pathogenesis; Pathology; Patients; Performance; Permeability; Physiological; Physiology; Play; Positioning Attribute; Prevalence; Property; Protons; Quality of life; Reagent; Relaxation; Research; Resolution; Risk; Risk Factors; Role; Senile Plaques; Staging; Structure; Surface; Techniques; Temporal Lobe; Therapeutic Intervention; Time; Tissues; Training; Training Programs; Translations; Variant; Vascular Permeabilities; Water; Water Movements; Work; aged; aging brain; base; bioimaging; capillary; career; cerebrovascular; clinically significant; computerized data processing; density; experience; gray matter; healthy aging; hemodynamics; improved; in vivo; meetings; pharmacokinetic model; public health relevance; spatiotemporal; tau Proteins; water channel; white matter; white matter change

DESCRIPTION (provided by applicant): This application proposes a training program to integrate the PI's previous research efforts into investigations of aging and Alzheimer's disease (AD). Much of Dr. Anderson's previous research has involved methodologies related to biomedicine, but has been done with only a basic understanding of the clinical needs and complexities. The proposed project would provide a broad experiential mentoring experience focused on clinical aspects of aging and AD, as well as added knowledge in vascular physiology and high field magnetic resonance imaging (MRI). The overall goal is to expand the PI's experience and training in biomedicine and bioimaging to position her for a career in biomedical research. Alzheimer's disease is the most common form of dementia in the elderly. Although traditionally considered a disease of neurofibrillary tangles and amyloid plaques, cerebrovascular structure and function is profoundly altered in AD and may contribute directly to oxidative stress, neuronal injury and death. Many older demented patients not meeting common pathological criteria for AD may have dementia on a microvascular basis that is not readily appreciated. Since vascular dysfunction often precedes cognitive impairment, understanding the role of vascular abnormalities in AD pathogenesis is critical to the rational treatment of the disease. Dynamic contrast-enhanced MRI (DCE-MRI) provides quantitative measures of vessel integrity in the living human brain. The long-term goal of this project is to quantify with high precision and accuracy the microvascular properties of the human brain along the healthy aging-AD continuum. The specific aims are to: (1) define the microvascular properties of the early AD and healthy aged brain; (2) define a 'microvascular permeability' network in early AD; and (3) examine the capillary integrity of white matter lesions in the healthy aged and mild AD brain. To maximize the spatiotemporal resolution, DCE-MRI studies will be performed at 7T. We anticipate that use of this ultra-high field will lead to substantial improvement in the precision and accuracy of pharmacokinetic parameters and the maps derived from them. These maps provide the key to translation of advanced MR techniques to the identification of new imaging biomarkers of incipient AD. PUBLIC HEALTH RELEVANCE: The proposed project will yield precise, accurate in vivo measures of vascular permeability and will map at high resolution the microvascular properties of the early Alzheimer's disease (AD) and cognitively unimpaired elderly brain. This knowledge could improve our understanding of the transition from healthy brain aging to dementia and suggest new imaging biomarkers of incipient AD.

描述（由申请人提供）：本申请提出了一项培训计划，旨在将 PI 之前的研究工作整合到衰老和阿尔茨海默病 (AD) 的研究中。安德森博士之前的大部分研究都涉及与生物医学相关的方法，但只是在对临床需求和复杂性有基本了解的情况下完成的。拟议的项目将提供广泛的体验式指导经验，重点关注衰老和 AD 的临床方面，以及血管生理学和高场磁共振成像 (MRI) 方面的补充知识。总体目标是扩大 PI 在生物医学和生物成像方面的经验和培训，为她在生物医学研究领域的职业生涯奠定基础。 阿尔茨海默病是老年人最常见的痴呆症。尽管传统上认为 AD 是一种神经原纤维缠结和淀粉样斑块疾病，但 AD 患者的脑血管结构和功能发生了深刻的改变，可能直接导致氧化应激、神经元损伤和死亡。许多不符合 AD 常见病理标准的老年痴呆患者可能患有微血管基础上的痴呆，但这种痴呆并不容易被认识到。由于血管功能障碍通常先于认知障碍发生，因此了解血管异常在 AD 发病机制中的作用对于合理治疗该疾病至关重要。动态对比增强 MRI (DCE-MRI) 可定量测量活人大脑中的血管完整性。该项目的长期目标是高精度地量化人脑在健康衰老-AD 连续过程中的微血管特性。具体目标是：（1）定义早期AD和健康老年大脑的微血管特性； (2) 定义早期 AD 的“微血管通透性”网络； (3)检查健康老年人和轻度AD大脑中白质病变的毛细血管完整性。为了最大限度地提高时空分辨率，DCE-MRI 研究将以 7T 进行。我们预计，这种超高场的使用将大大提高药代动力学参数及其衍生图谱的精确度和准确度。这些图谱为将先进的 MR 技术转化为识别早期 AD 的新成像生物标志物提供了关键。 公共健康相关性：拟议的项目将产生精确、准确的血管通透性体内测量结果，并将以高分辨率绘制早期阿尔茨海默病 (AD) 和认知未受损的老年人大脑的微血管特性。这些知识可以提高我们对从健康大脑老化到痴呆的转变的理解，并提出早期 AD 的新成像生物标志物。