Quantitative MR Microscopy of Phenotypic Biomarkers in Alzheimer's Disease

描述(申请人提供)：阿尔茨海默病(AD)的病因尚不清楚，治疗方法尚未推出，但其衰弱效应到2050年将仅在美国就影响到约1000万人。迫切需要对AD表型和拟议治疗的可测量结果进行早期成像。这一K01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，发展成为在小动物模型中评估神经退行性疾病的定量方法的独立研究员。其目标是通过培训实现对疾病生物标记物的多学科视角。在位于杜克大学西校区的具有不同专业知识的经验丰富的导师的指导下，这将是可能的。活体显微镜中心(CIVM)主任G·艾伦·约翰逊博士是临床前动物成像方面的专家。CIVM的成像设备可以提供小动物模型大脑结构和功能方面的综合视图。卡罗尔·科尔顿博士的实验室研究了大脑中先天免疫反应的作用及其在神经退行性变中的作用。她的CVN小鼠提供了一种AD模型，在该模型中，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设施的主任，是行为分析方面的专家，他将独立评估疾病的进展。培训过程将涵盖：1)AD类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)高级图像处理、统计和多模式集成；4)负责任的研究工作。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。候选人希望提出以下方法：1)形态测量的图像分析，重点是扩散张量和血管数据；2)多个解剖、生理和认知标记的集成。具体目标将涉及：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)体内针对血管方面的多变量成像生物标记物；3)成像标记物与认知和嗅觉障碍的关系，以及鼻腔治疗后这些表型反应的挽救。该奖项将有助于在AD小鼠模型中建立成像和认知变化的时间表，并为疾病进展提供解剖学、血管和认知标记物，以及作为推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，成为多学科方法的思维领导者，以表征神经退行性疾病的模型，如AD，并评估拟议的治疗方法。

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.