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

白质疾病对脑淀粉样血管病步态和平衡的影响

• 批准号: 8070429
• 负责人: Anand Viswanathan
• 金额: $ 16.46万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8070429
• 关键词: Accounting; Acute; Affect; Alzheimer' s Disease; Amyloid; Anatomy; Arterioloscleroses; Award; Blood Vessels; Cerebral Amyloid Angiopathy; Cerebral hemisphere hemorrhage; Cerebrovascular Disorders; Cerebrum; Chronic; Clinical; Clinical Research; Clinical Trials Unit; Clinical/Radiologic; Cohort Studies; Commit; Data; Data Analyses; Deposition; Detection; Diagnosis; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Early Diagnosis; Elderly; Enrollment; Equilibrium; Evaluation; Exposure to; Faculty; Functional disorder; Funding; Future; Gait; General Hospitals; Goals; Grant; High Prevalence; Image; Impaired cognition; Impairment; Indium; Investigation; Lesion; Location; MRI Scans; Magnetic Resonance Imaging; Maps; Massachusetts; Measurable; Measures; Memory Disorders; Mental Depression; Mentors; Methods; Modeling; Neurologic; Neurologic Dysfunctions; Neurologic Manifestations; Neurological outcome; Neurology; Outcome Measure; Pathology; Patients; Performance; Population; Process; Publications; Research; Research Design; Research Personnel; Resolution; Role; Secondary to; Services; Stroke; Testing; Time; Tissues; Training; Training Programs; United States National Institutes of Health; Urinary Incontinence; Vascular Dementia; Vascular Diseases; Weight; White Matter Disease; base; bioimaging; career; cerebrovascular; clinical effect; cognitive function; cohort; disability; equilibration disorder; follow-up; functional disability; imaging modality; interest; medical schools; member; multidisciplinary; neuroimaging; patient oriented; patient oriented research; prevent; primary outcome; professor; programs; prospective; public health relevance; research study; white matter; white matter change

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.

描述（由申请人提供）：脑淀粉样血管病（CAA）导致脑血管沉积β-淀粉样蛋白，导致血管脆性和脑出血（ICH）。 CAA 中白质疾病的高患病率可能继发于血管功能障碍和血管供血不足。在 NIH 资助的一项正在进行的前瞻性队列研究的背景下，该项目旨在检验以下假设：CAA 中白质疾病的程度和位置是神经和功能损伤的独立因素。申请人是马萨诸塞州总医院神经内科的初级教员、哈佛医学院神经内科助理教授。申请人的职业目标是获得白质血管疾病的临床和放射学研究方面的专业知识。他计划在资助期间利用广泛的多学科机构网络获得针对该提案的必要教学培训。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)，还将获得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，申请人力求成为脑小血管疾病领域的独立临床医生研究员。申请人的主要导师史蒂文·格林伯格博士现任哈佛医学院神经病学教授兼麻省总医院神经病学临床试验部联席主任。他是脑出血和 CAA 领域国际公认的领导者，在该领域发表了大量著名论文。格林伯格博士制定了一项非常强大的研究计划，涉及众多多学科子专业。马蒂诺斯生物成像中心副主任 A. Gregory Sorensen 博士将担任申请人本提案的共同导师。作为 MRI 研究领域的领导者之一，Sorensen 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人提供帮助。申请人隶属于 MGH 中风服务中心和 MGH 记忆障碍科 (MDU)。 MGH 中风服务中心是全国公认的急性或慢性脑血管疾病患者转诊中心，拥有最先进的神经影像设施。该服务将提供对所有脑血管疾病的了解，包括每年约 120 例脑出血病例，这是申请人研究的重点。记忆障碍科首次成立于 1982 年，是马萨诸塞州阿尔茨海默病研究中心 (ADRC) 的组成部分，该中心正在进行一项由 NIH 资助的临床研究，招募患有所有类型记忆障碍的患者，包括血管性痴呆和 CAA。它由约翰·格罗登（John Growdon）博士创立，目前由两位高度知名的研究人员布拉德利·海曼（Bradley Hyman）博士领导。将测试三个具体假设：(1) CAA 中白质疾病的程度（通过 WMH 体积和平均 DTI 测量来测量）与步态和平衡功能障碍、认​​知障碍和残疾相关，(2) 白质疾病的解剖位置（在感兴趣区域 (ROI) 和基于体素的分析中测量）与这些结果测量相关，以及 (3) 白质疾病的进展（通过测量来测量） CAA 中 WMH 体积和纵向随访中平均 DTI 测量值的增加导致这些神经功能缺陷显着增加。将使用既定的定性和定量措施来评估步态和平衡障碍的程度。将使用经过验证的体积方法评估 T2 加权 MRI 序列上的白质疾病程度。将使用基于体素的高分辨率 MRI 序列分析来评估白质疾病的位置。将在 16 个月和 36 个月时重复进行 MRI 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 的病理学代表了相对均质的微血管过程，因此它是脑血管功能障碍的理想模型。拟议研究得出的数据不仅对患有 CAA 相关脑出血的患者具有重大意义，而且对更广泛的患有临床“沉默”CAA 的老年人群也具有重要意义。与动脉硬化等其他常见小血管疾病不同，CAA 在病程早期仍难以诊断。这项研究的结果可能有助于在 ICH 或认知障碍之前识别那些患有“无症状”CAA 的患者，因此对于未来旨在预防这种疾病的破坏性影响的试验至关重要。 公众健康相关性：由于晚期 CAA 的病理学代表了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。拟议研究得出的数据不仅对患有 CAA 相关脑出血的患者具有重大意义，而且对更广泛的患有临床“沉默”CAA 的老年人群也具有重要意义。与动脉硬化等其他常见小血管疾病不同，CAA 在病程早期仍难以诊断。这项研究的结果可能有助于在 ICH 或认知障碍之前识别那些患有“无症状”CAA 的患者，因此对于未来旨在预防这种疾病的破坏性影响的试验至关重要。