Quantitative Measurement of Cerebrovascular Permeability in Early Dementia

描述（由申请人提供）：本申请提出了一项培训计划，以将PI先前的研究工作整合到衰老和阿尔茨海默病（AD）的研究中。安德森博士以前的大部分研究都涉及与生物医学相关的方法学，但都是在对临床需求和复杂性只有基本了解的情况下完成的。拟议的项目将提供广泛的经验指导经验，重点是老龄化和AD的临床方面，以及在血管生理学和高场磁共振成像（MRI）的额外知识。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，使她能够从事生物医学研究。 阿尔茨海默病是老年人中最常见的痴呆症。虽然传统上认为是一种神经元缠结和淀粉样斑块的疾病，但AD患者的脑血管结构和功能发生了深刻的改变，并可能直接导致氧化应激、神经元损伤和死亡。许多不符合AD常见病理学标准的老年痴呆患者可能在微血管基础上患有痴呆，这一点不容易理解。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疾病至关重要。动态对比增强MRI（DCE-MRI）提供了活体人脑中血管完整性的定量测量。该项目的长期目标是以高精度和准确度量化人类大脑沿着健康衰老-AD连续体的微血管特性。具体目标是：（1）定义早期AD和健康老年脑的微血管特性;（2）定义早期AD中的“微血管渗透性”网络;和（3）检查健康老年和轻度AD脑中的白色物质损伤的毛细血管完整性。为了最大限度地提高时空分辨率，将在7 T下进行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的精密度和准确度以及由此得出的图谱的实质性改善。这些图谱为将先进的MR技术转化为早期AD的新成像生物标志物的识别提供了关键。 公共卫生相关性：拟议的项目将产生精确，准确的血管渗透性的体内措施，并将在高分辨率映射的微血管特性的早期阿尔茨海默氏病（AD）和认知未受损的老年人的大脑。这些知识可以提高我们对从健康大脑老化到痴呆症的转变的理解，并提出早期AD的新的成像生物标志物。

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.