Quantitative Measurement of Cerebrovascular Permeability in Early Dementia

描述(由申请者提供)：本申请提出了一项培训计划，将PI以前的研究工作整合到老龄化和阿尔茨海默病(AD)的调查中。安德森博士之前的许多研究都涉及与生物医学相关的方法，但在完成时只对临床需求和复杂性有一个基本的了解。拟议的项目将提供广泛的经验指导经验，侧重于老龄化和阿尔茨海默病的临床方面，以及增加血管生理学和高场磁共振成像(MRI)的知识。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做好准备。阿尔茨海默病是老年人中最常见的痴呆症形式。虽然传统上被认为是一种神经原纤维缠结和淀粉样斑块的疾病，但AD的脑血管结构和功能发生了深刻的变化，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在微血管的基础上患有痴呆，这一点并不容易被认识到。由于血管功能障碍往往先于认知功能障碍，了解血管异常在AD发病机制中的作用对于合理治疗该病至关重要。动态增强磁共振成像(DCE-MRI)提供了活体人脑血管完整性的定量测量。该项目的长期目标是沿着健康的衰老-AD连续体，以高精度和精确度量化人脑的微血管特性。其具体目的是：(1)定义早期AD和健康老年脑的微血管特性；(2)定义早期AD的微血管通透性网络；(3)检查健康老年组和轻度AD脑内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，将在7T进行DCE-MRI研究。我们预计，这种超高场的使用将导致药代动力学参数和由此得出的地图的精确度和准确度的大幅提高。这些图谱为将先进的磁共振技术转化为识别早期AD的新的成像生物标志物提供了关键。 与公共健康相关：拟议的项目将产生精确、准确的血管渗透性活体测量，并将以高分辨率绘制早期阿尔茨海默病(AD)和认知正常的老年人大脑的微血管属性图。这些知识可以提高我们对从健康的大脑老化到痴呆症的转变的理解，并提出新的早期AD的成像生物标记物。

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.