Clinical, Radiographic, and Genetic Associations in Cerebral Amyloid Angiopathy

描述(申请人提供)：目前还没有已知的治疗脑淀粉样血管病(CAA)的方法，这是出血性中风的重要原因，也是越来越多人认识到的导致血管认知障碍和神经功能障碍的因素。我们建议将我们对CAA相关脑出血患者的前瞻性纵向研究作为CAA影响神经功能机制的多学科研究的核心，并为中风和血管认知障碍领域的早期研究人员提供临床研究培训计划。在该原则的Investigator在确定CAA的诊断、临床病程和病理生理学方面取得开创性成功的基础上，建议的研究集中在1)CAA相关出血和白质损害之间的相互关系，2)这些损害对认知、抑郁症状、功能技能和步态的影响，以及3)它们与遗传和生化危险因素的关系。这些研究的成功完成将代表着朝着为未来旨在预防CAA相关出血和认知功能障碍的试验开发诊断标记、结果标记和候选治疗迈出的关键一步。这些研究将作为与马蒂诺斯生物医学成像中心(联席主任A.Gregory Sorensen博士)、医学和人口遗传学项目(David Altschuler博士，主任)和生物统计中心(Rebecca Betensky博士)研究人员(来自丰富的哈佛医学院研究环境)长期合作的一部分进行。合作伙伴的多学科团队还将在神经学研究的关键方面作为强化以患者为中心的研究培训计划的基础，包括以患者为中心的研究原则、脑出血受试者的神经学和认知评估、计算机辅助放射图像分析、人类基因分析和生物统计学。首席调查员在指导早期临床调查人员方面有着出色的记录，见习生在出版、研究资金和向独立职业生涯过渡方面的成功证明了这一点。Prof Investigator在定义基于生物学的方法来解决引人注目的研究问题和获得NIH资助的R01支持方面一直取得成功，这使得拟议的研究极有可能作为尖端临床研究和培训新一代中风研究人员的工具而成功。

DESCRIPTION (provided by applicant): There is no known treatment for cerebral amyloid angiopathy (CAA), an important cause of hemorrhagic stroke and increasingly recognized contributor to vascular cognitive impairment and neurological dysfunction. We propose to use our prospective longitudinal study of patients with CAA-related intracerebral hemorrhage as the centerpiece of both a multidisciplinary investigation of the mechanisms by which CAA affects neurological function and a clinical research training program for early investigators in the fields of stroke and vascular cognitive impairment. Building on the Principle's Investigator's groundbreaking success in defining the diagnosis, clinical course, and pathophysiology of CAA, the proposed studies focus on 1) the interrelationship between CAA-related hemorrhages and white matter lesions, 2) the effects of these lesions on cognition, depressive symptoms, functional skills, and gait, and 3) their association with genetic and biochemical risk factors. Successful completion of these studies will represent a key step towards developing diagnostic markers, outcome markers, and candidate treatments for future trials aimed at prevention of CAA-related hemorrhage and cognitive dysfunction. The studies will be performed as part of long-standing collaborations with investigators (drawn from the rich Harvard Medical School research environment) at the Martinos Center for Biomedical Imaging (Dr. A. Gregory Sorensen, Co-Director), Program in Medical and Population Genetics (Dr. David Altschuler, Director), and Biostatistics Center (Dr. Rebecca Betensky). The multidisciplinary team of collaborators will also serve as the basis for an intensive patient-oriented research training program in key aspects of neurological research, including principles of patient-oriented research, neurological and cognitive assessment of intracerebral hemorrhage subjects, computer-assisted radiographic image analysis, human genetic analysis, and biostatistics. The Principle Investigator has an outstanding record of mentoring early clinical investigators, demonstrated by trainees' success in publication, research funding, and transition to independent careers. The Principle Investigator's consistent success in defining biologically based approaches to compelling research questions and obtaining NIH-funded R01 support make it extremely likely that the proposed studies will succeed both as cutting-edge clinical investigation and tools for training a new generation of stroke investigators.