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。迫切需要对阿尔茨海默病的表型进行早期成像，并对提出的治疗方法进行可测量的结果。K01奖将允许候选人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者，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疾病生物标志物的多学科视角。这将在经验丰富的导师的指导下成为可能，他们具有独特的专业知识，都位于杜克大学西校区。体内显微术中心（CIVM）主任艾伦·约翰逊博士是临床前动物成像方面的专家。CIVM的成像设备可以在小动物模型中提供脑结构和功能方面的综合视图。卡罗尔·科尔顿博士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小鼠提供了一种模型，在这种模型中，AD的大多数病理都可以复制，治疗方法也可以进行测试。威廉·韦塞尔博士是杜克大学神经内分泌和行为研究所主任，他是独立评估疾病进展的行为分析方面的专家。培训过程将包括：1)ad样病理背景下的神经解剖学、病理学和行为；2)成像方案设计和MR序列编程；3)先进的图像处理、统计和多模态集成；4)负责任的研究行为。我们将专注于将高分辨率成像与认知测量相结合，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。具体目标将解决：1)磁共振组织学和弥散张量成像在AD样表型制图中的价值；2)血管方面的体内多变量成像生物标志物；3)影像学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恢复。该奖项将有助于建立阿尔茨海默病小鼠模型的成像和认知变化时间表，并为疾病进展提供解剖学、血管和认知标志物，并作为假定治疗的可测量结果。拟议的培训将使候选人具备一套独特的技能，成为神经退行性疾病（如阿尔茨海默病）模型表征和评估拟议疗法的多学科方法的思想领袖。

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.