Effect of White Matter Disease on Gait and Balance in Cerebral Amyloid Angiopathy

描述(申请人提供)：脑淀粉样血管病(CAA)导致脑血管内淀粉样蛋白沉积，导致血管脆性和脑出血(ICH)。脑白质疾病在CAA中的高患病率可能继发于血管功能障碍和血管功能不全。在NIH资助的一项正在进行的前瞻性队列研究的背景下，该项目旨在测试CAA中白质疾病的程度和位置都是神经和功能损害的独立贡献者的假设。申请者是麻省总医院神经科初级教员和哈佛医学院神经病学助理教授。申请者的职业目标是获得脑白质血管疾病的临床和放射学调查方面的专业知识。他计划在赠款期间利用广泛的多学科机构网络获得针对这一提议的必要的教学培训。他不仅将利用导师K24资助的以患者为导向的研究培训计划(5K24NS056207-02)，还将有一个针对其特定研究兴趣的个性化培训计划。通过与该奖项相关的严格研究和教育培训，申请者寻求成为脑部小血管疾病领域的独立临床医生和研究员。申请者的主要导师Steven Greenberg博士目前是哈佛医学院的神经学教授和MGH神经病学临床试验单位的联席主任。他是国际公认的脑出血和CAA领域的领导者，在该领域发表了许多著名的出版物。格林伯格博士制定了一项非常强大的研究计划，涉及许多多学科的子专业。马提诺斯生物成像中心副主任A·格雷戈里·索伦森博士将是申请者这项提案的共同导师。作为核磁共振研究领域的领导者之一，索伦森博士致力于在与放射成像相关的研究设计和数据分析方面为申请者提供帮助。申请人隶属于MGH卒中服务和MGH记忆障碍单元(MDU)。MGH卒中服务中心是国家认可的急慢性脑血管疾病患者转诊中心，拥有最先进的神经成像设施。这项服务将提供对所有脑血管疾病的暴露，包括每年约120例脑内出血，这是申请者研究的重点。记忆障碍中心成立于1982年，是马萨诸塞州阿尔茨海默病研究中心(ADRC)不可或缺的一部分，该中心正在进行一项由美国国立卫生研究院资助的临床研究，招募患有包括血管性痴呆和CAA在内的所有类型记忆障碍的患者。它是由约翰·格罗登博士建立的，目前由两位著名的调查人员布拉德利·海曼博士领导。将检验三个具体假设：(1)CAA中白质疾病的程度(以WMH体积和平均DTI测量)与步态和平衡障碍、认知障碍和残疾有关，(2)白质疾病的解剖位置(以感兴趣区(ROI)和基于体素的分析测量)与这些结果测量相关，(3)CAA中白质疾病的进展(通过WMH体积增加和纵向随访中的平均DTI测量)导致这些神经缺陷的可测量增加。步态和平衡受损的程度将使用既定的定性和定量措施进行评估。T2加权MRI序列上的白质病变程度将使用有效的体积测量方法进行评估。白质疾病的位置将使用基于体素的高分辨率MRI序列分析来评估。16个月和36个月的重复磁共振成像将进行类似的评估，以评估白质疾病进展的程度及其对测量结果的影响。由于晚期CAA的病理过程代表了一个相对同质的微血管过程，因此它是脑血管功能障碍的理想模型。这项拟议研究得出的数据不仅对CAA相关脑出血患者有重大意义，而且对临床上“沉默”的CAA老年人群也有重要意义。与其他常见的小血管疾病如动脉硬化不同，CAA在病程早期仍难以诊断。这项研究的结果可能有助于识别那些在脑出血或认知障碍之前患有“无症状”CAA的患者，因此对旨在预防这种疾病破坏性影响的未来试验至关重要。 公共卫生相关性：由于晚期CAA的病理过程代表了一个相对同质的微血管过程，因此它是脑血管功能障碍的理想模型。这项拟议研究得出的数据不仅对CAA相关脑出血患者有重大意义，而且对临床上“沉默”的CAA老年人群也有重要意义。与其他常见的小血管疾病如动脉硬化不同，CAA在病程早期仍难以诊断。这项研究的结果可能有助于识别那些在脑出血或认知障碍之前患有“无症状”CAA的患者，因此对旨在预防这种疾病破坏性影响的未来试验至关重要。

DESCRIPTION (provided by applicant): Cerebral amyloid angiopathy (CAA) leads to cerebrovascular deposition of ss-amyloid resulting in vessel fragility and intracerebral hemorrhage (ICH). The high prevalence of white matter disease in CAA is possibly secondary to vessel dysfunction and vascular insufficiency. In the context of an ongoing NIH-funded prospective cohort study, this project aims to test the hypotheses that both the degree and location of white matter disease in CAA is an independent contributor to neurologic and functional impairment. The applicant is a junior faculty member in the Department of Neurology at Massachusetts General Hospital and Assistant Professor of Neurology at Harvard Medical School. It is the applicant's career goal to obtain expertise in the clinical and radiologic investigation of vascular diseases of white matter. He plans to obtain the necessary didactic training specific to this proposal during the grant period using an extensive multidisciplinary institutional network. He will not only take advantage of the Mentor's K24-funded training program in patient-oriented research (5K24NS056207-02), but will have an individualized training program tailored to his specific research interests. Through the rigorous research and educational training associated with this award the applicant seeks to become an independent clinician-investigator in the field of cerebral small vessel disease. The applicant's primary mentor, Dr. Steven Greenberg, is currently Professor of Neurology at Harvard Medical School and Co-Director of the MGH Neurology Clinical Trials Unit. He is an internationally recognized leader in intracerebral hemorrhage and CAA with numerous prominent publications in the field. Dr. Greenberg has developed a very strong research program involving numerous multidisciplinary subspecialties. Dr. A. Gregory Sorensen, the Associate Director of the Martinos Center for Bioimaging will be applicant's co-mentor for this proposal. As one of the leaders in field of MRI research, Dr. Sorensen is strongly committed to aiding the applicant in the elements of study design and data analysis pertaining to radiological imaging. The applicant is attached to both the MGH Stroke Service and the MGH Memory Disorders Unit (MDU). The MGH Stroke Service is a nationally recognized referral center for patients with acute or chronic cerebrovascular diseases with state-of-the-art neuroimaging facilities. The service will provide an exposure to the entire spectrum of cerebrovascular disease, including the approximately 120 cases per year of intracerebral hemorrhage, the focus of the applicant's study. The Memory Disorders Unit was first established in 1982 and is an integral part of the Massachusetts Alzheimer's Disease Research Center (ADRC) which has an ongoing NIH-funded clinical research study enrolling patients affected with all types of memory disorders, including vascular dementia and CAA. It was established by Dr. John Growdon and currently led by Dr. Bradley Hyman, two highly-renowned investigators. Three specific hypotheses will be tested: (1) extent of white matter disease (as measured by WMH volume and mean DTI measures) in CAA is associated with gait and balance dysfunction, cognitive impairment and disability, (2) the anatomic location of white matter disease (measured in regions of interest (ROIs) and voxel- based analysis) correlates with these outcome measures and (3) the progression of white matter disease (measured by increase in WMH volume and mean DTI measures in longitudinal follow-up) in CAA results in a measurable increase in these neurological deficits. Degree of gait and balance impairment will be assessed using established qualitative and quantitative measures. The extent of white matter disease on T2-weighted MRI sequences will be evaluated using validated volumetric methods. The location of white matter disease will be assessed using voxel-based analysis of high-resolution MRI sequences. Repeat MRIs at 16 and 36 months will be similarly evaluated to assess degree white matter disease progression and its impact on the measured outcomes. As the pathology of advanced CAA represents a relatively homogenous microvascular process, it serves an ideal model of cerebral vessel dysfunction. The data resulting from the proposed study would have significant implications for not only those patients with CAA-related intracerebral hemorrhage, but the broader elderly population with clinically "silent" CAA. Unlike other common small vessel diseases such as arteriolosclerosis, CAA remains difficult to diagnose early in its course. The results from this study could potentially help identify those patients with "asymptomatic" CAA prior to ICH or cognitive impairment, thus being of paramount importance for future trials aimed at preventing the devastating effects of this disease. PUBLIC HEALTH RELEVANCE: As the pathology of advanced CAA represents a relatively homogenous microvascular process, it serves an ideal model of cerebral vessel dysfunction. The data resulting from the proposed study would have significant implications for not only those patients with CAA-related intracerebral hemorrhage, but the broader elderly population with clinically "silent" CAA. Unlike other common small vessel diseases such as arteriolosclerosis, CAA remains difficult to diagnose early in its course. The results from this study could potentially help identify those patients with "asymptomatic" CAA prior to ICH or cognitive impairment, thus being of paramount importance for future trials aimed at preventing the devastating effects of this disease.