Cortical Complexity Changes in Normal Aging and Alzheimer's Disease

描述(由申请者提供)：这个修订后的比森患者导向研究职业发展奖(K23)项目将提供指导、教学课程和个性化指导，以将理查德·D·金医学博士、博士培养成老年学研究的领先者。这将建立在他在计算神经科学方面的研究生工作，以及他在神经学住院医师和研究员培训中产生的老化大脑紊乱方面的专业知识。金博士的培训目标包括1)积累神经成像分析软件开发的技术和计算方面的专业知识，2)在老年人群中熟练使用认知神经科学方法，3)学习如何管理老年患者中常见的复杂流行病因素，4)通过将新的成像分析工具转化为临床实践来提高熟练程度。通过本申请中概述的培训计划和研究计划，金博士将获得成为独立医生兼科学家所需的广泛专业知识和知识基础，专注于老年受试者的认知障碍。建议的研究是开发一种新的结构成像分析技术，该技术基于一种称为分维(F3D)的定量度量。这种方法有几个新颖的方面。首先，F3D非常适合于检测人类大脑皮层萎缩时发生的形状变化。其次，F3D是一种形状的量化测量，它提供了比目前的定性主观评估标准(即“轻度”或“中度”萎缩)更可靠的评估。第三，F3D集成了一系列空间尺度上的信息。金博士已经编写了软件，使用从高对比度磁共振(MR)图像中提取的大脑皮层3D模型来计算F3D。了解随着健康衰老而发生的大小和形状变化的范围和分布是至关重要的，因为这些变化中的许多与认知功能障碍无关。在认知老化、计算机科学和统计学专家导师的指导下，金博士将使用两个数据库中健康受试者的磁共振图像，创建一份关于健康大脑老化的标准化统计成像图谱。然后，按年龄加权的标准图谱将被用来通过使用轻度认知障碍和轻度阿尔茨海默病受试者的磁共振图像来统计量化神经退行性疾病对皮质F3D值的影响。最后，为了了解这种成像方法如何在临床实践中使用，重要的是超越使用高度精选的临床人群的研究。金博士将使用来自寻求临床评估的认知主诉患者的预期成像数据进行皮质F3D分析。这些数据将使关于皮质F3D在临床实践中的作用的前瞻性试验成为可能。

DESCRIPTION (provided by applicant): This revised Beeson Patient-Oriented Research Career Development Award (K23) project will provide the mentorship, didactic coursework and individualized instruction to develop Richard D. King, MD, PhD, into a leader in geriatric research. This will build upon his graduate work in computational neuroscience, and his expertise in the disorders of the aging brain derived from his residency and fellowship training in neurology. Dr. King's training goals include 1) building expertise in technical and computational aspects of neuroimaging analysis software development, 2) gaining proficiency with methods of cognitive neuroscience in the geriatric population, 3) learning how to manage complex epidemiologic factors common in elderly patients, and 4) developing proficiency with translating novel imaging analysis tools into clinical practice. Through the training program and research plan outlined in this application, Dr. King will acquire the broad expertise and knowledge base needed to become and independent physician-scientist with a focus on cognitive disorder of elderly subjects. The proposed research is to develop a new structural imaging analysis technique based upon a quantitative metric known as fractal dimension (f3D). There are several novel aspects to this approach. First, f3D is perfectly suited to detect shape changes that occur with atrophy of the human cerebral cortex. Secondly, f3D is a quantitative measure of shape which provides a more robust evaluation than the current standard of qualitative subjective assessments (i.e. "mild" or "moderate" atrophy). Thirdly, f3D integrates information over a range of spatial scales. Dr. King has written software to compute f3D using 3D models of the cortex extracted from high-contrast magnetic resonance (MR) images. It is essential to understand the extent and distribution of size and shape changes occurring with healthy aging because many of these changes are not associated with cognitive dysfunction. With the guidance of mentors expert in cognitive aging, computer science and statistics, Dr. King will create a normative statistical imaging atlas of healthy brain aging using MR images of healthy subjects from two databases. The age-weighted normative atlas will then be used to statistically quantify the effects of neurodegenerative disease on cortical f3D values using MR images of subjects with mild cognitive impairment and mild Alzheimer's disease. Finally, to understand how this imaging approach may be used in clinical practice, it is important to move beyond studies that use highly-selected clinical populations. Dr. King will perform the cortical f3D analysis using prospective imaging data from patients with cognitive complaints seeking clinical evaluation. The data will enable a prospective trial on the role of cortical f3D in clinical practice.