Quantitative MR Microscopy of Phenotypic Biomarkers in Alzheimer's Disease

描述（由申请人提供）：阿尔茨海默病（AD）的病因尚不清楚，治疗方法尚不可用，但到2050年，仅在美国，其衰弱效应将影响约1000万人。AD表型的早期成像和所提出的治疗的可测量的结果是迫切需要的。这个K 01奖项将允许候选人Alexandra Badea博士在杜克大学医学中心接受培训，发展成为一名独立的研究人员，在小动物模型中评估神经退行性疾病的定量方法。目标是通过培训实现对疾病生物标志物的多学科观点。这将是可能的指导下，从经验丰富的导师与独特的专业知识，都位于杜克大学西校区。体内显微镜中心（CIVM）主任G Allan约翰逊博士是临床前动物成像方面的专家。CIVM的成像设备可以提供小动物模型大脑结构和功能方面的综合视图。Carol Colton博士的实验室研究了先天免疫反应在大脑中的作用及其在神经变性中的作用。她的CVN小鼠提供了一个模型，其中AD大多数病理被复制，并且可以测试疗法。杜克大学神经内分泌和行为研究所所长威廉·韦塞尔博士是独立评估疾病进展的行为分析专家。培训过程将涵盖：1）AD样病理学背景下的神经解剖学、病理学和行为学; 2）成像方案设计和MR序列编程; 3）高级图像处理、统计学和多模态集成; 4）负责任的研究行为。我们将专注于整合高分辨率成像与认知测量，为AD模型提供多变量生物标志物。候选人希望推进以下方法：1）形态测量学的图像分析，重点是扩散张量和血管数据; 2）多种解剖，生理和认知标记的整合。具体目的将涉及：1）磁共振组织学和扩散张量成像在绘制AD样表型中的价值; 2）涉及血管方面的体内多变量成像生物标志物; 3）成像标志物与认知和嗅觉缺陷的关系，以及鼻内治疗后这些表型反应的挽救。该奖项将有助于建立AD小鼠模型的成像和认知变化的时间轴，并为疾病进展提供解剖学，血管和认知标志物，并作为推定疗法的可测量结果。拟议的培训将使候选人具备一套独特的技能，成为多学科方法的思想领袖，用于表征神经退行性疾病（如AD）的模型，并评估拟议的疗法。

DESCRIPTION (provided by applicant): The etiology of Alzheimer's disease (AD) is not yet known, therapies are not yet available, yet its debilitating effects will impact ~ 10 million in th US alone by 2050. Early imaging of AD phenotypes and measurable outcomes of proposed therapies are urgently needed. This K01 award will allow the candidate, Alexandra Badea, PhD, to train at Duke University Medical Center to develop into an independent investigator in quantitative methods for assessing neurodegenerative diseases in small animal models. The goal is to achieve through training a multidisciplinary perspective on disease biomarkers. This will be possible under guidance from experienced mentors with distinct expertise, all located on the Duke University West Campus. Dr. G Allan Johnson, director of the Center for In Vivo Microscopy (CIVM) is an expert in preclinical animal imaging. The imaging equipment at CIVM can offer an integrated view on aspects of brain structure and function in small animal models. Dr. Carol Colton laboratory examines the role of the innate immune response in the brain and its role in neurodegeneration. Her CVN mouse offers a model in which AD most pathologies are replicated and therapies can be tested. Dr. William Wetsel, director of the Neuroendocrine and Behavioral Facility at Duke is an expert on behavioral assays that will independently evaluate disease progression. The training process will cover: 1) neuroanatomy, pathology, and behavior in the context of AD-like pathology; 2) imaging protocol de- sign and MR sequence programming; 3) advanced image processing, statistics, and multimodal integration; 4) responsible conduct of research. We will focus on integrating high-resolution imaging with cognitive measures, to provide multivariate biomarkers for AD models. The candidate expects to advance methods for: 1) image analysis for morphometry, with a focus on diffusion tensor and vascular data; 2) integration of multiple anatomical, physiological and cognitive markers. The Specific Aims will address: 1) the value of magnetic resonance histology and diffusion tensor imaging in charting AD like phenotypes; 2) in vivo multivariate imaging biomarkers addressing the vascular aspect; 3) the relationship of imaging markers with cognitive and olfactory deficits, and the rescue of these phenotypes response following intranasal therapy. This award will help establish a timeline of imaging and cognitive changes in mouse models of AD, and provide anatomical, vascular and cognitive markers for disease progression, and as measurable outcomes of putative therapies. The proposed training will equip the candidate with unique a set of skills to become a thought leader in multidisciplinary approaches for characterizing models of neurodegenerative diseases, such as AD, and evaluating proposed therapies.