Early Detection of Cerebral Amyloid Angiopathy

脑淀粉样血管病的早期检测

• 批准号: 8495434
• 负责人: Steven M Greenberg
• 金额: $ 44.77万
• 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: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8495434
• 关键词: Academic Medical Centers; Adverse effects; Affect; Age; Age-associated memory impairment; Alzheimer' s Disease; Amino Acids; Amyloid; Appearance; Asses; Autopsy; Biopsy; Blood Circulation; Blood Vessels; Brain; Brain Injuries; Brain hemorrhage; Cerebral Amyloid Angiopathy; Cerebral hemisphere hemorrhage; Cerebrospinal Fluid; Cerebrum; Characteristics; Data; Degenerative Disorder; Deposition; Detection; Diagnosis; Diagnostic; Disease; Dutch Type Hereditary Cerebral Amyloid Angiopathy; Early Diagnosis; Elderly; Family; Functional Magnetic Resonance Imaging; Future; General Hospitals; Genetic; Goals; Hemorrhage; Hereditary Cerebral Amyloid Angiopathy; High Prevalence; Immunotherapy; Individual; Life; Ligands; Lobar; Location; MRI Scans; Massachusetts; Measures; Memory; Memory Loss; Methods; Patients; Pattern; Peptides; Photic Stimulation; Physiological; Pittsburgh Compound-B; Population; Population Study; Positron-Emission Tomography; Principal Investigator; Process; Receiver Operator Characteristics; Recruitment Activity; Risk; Safety; Scanning; Series; Site; Sporadic Cerebral Amyloid Angiopathy; Stroke; Stroke prevention; Symptoms; Techniques; Vascular Cognitive Impairment; Work; age related; aged; amyloid peptide; base; cerebrovascular; disease diagnosis; improved; in vivo; neuroimaging; novel; population based; public health relevance; success; tool; vaccine development

DESCRIPTION (provided by applicant): Deposition of ss-amyloid (Ass) in the cerebral vessels (cerebral amyloid angiopathy or CAA) is a major cause of hemorrhagic stroke, a contributor to vascular cognitive impairment, and a complicating factor in attempts to develop anti-amyloid immunotherapies. Current methods for detecting CAA during life are focused on identifying CAA-associated hemorrhages, typically after major hemorrhagic stroke has occurred. Growing evidence (including the high prevalence of lobar microbleeds in the general elderly population) suggests that advanced CAA is extremely common even in the absence of hemorrhagic stroke. The current proposal seeks to establish the early diagnosis of advanced CAA by validating and applying novel in vivo detection methods for individuals without hemorrhagic stroke. Preliminary data support three candidate detection methods: 1) increased retention of the amyloid ligand Pittsburgh Compound B (PiB) in an occipital-predominant pattern, 2) reduction of cerebrospinal fluid concentrations of the ss-amyloid Ass40 and Ass42 peptides, and 3) blunting of cerebrovascular reactivity to visual stimulation. We will validate these three approaches in two groups of patients with well established diagnoses of advanced CAA: sporadic patients with multiple lobar cerebral microbleeds recruited at Massachusetts General Hospital (Specific Aim 1) and familial patients genetically diagnosed with Dutch-type hereditary CAA recruited at Leiden University Medical Center (Specific Aim 2). Based on the diagnostic cut-points established in these two patients groups, we will then proceed to apply the detection methods to asymptomatic population-based subjects with strictly lobar microbleeds identified by the Rotterdam Scan Study (Specific Aim 3). Each of the three study groups will consist of 20 case subjects and 20 similar aged control subjects from the same site. Receiver operator characteristic techniques will be used to establish optimum methods for distinguishing CAA cases from non-CAA controls, applying results from the two patient groups with established CAA to the population-based Rotterdam Scan subjects where the presence of advanced CAA remains unknown. The three study populations represent the largest and most thoroughly characterized groups of sporadic CAA patients (Massachusetts General Hospital), hereditary CAA patients (Leiden University Medical Center) and population-based subjects scanned by MRI methods optimized for microbleed detection (Rotterdam Scan Study). This proposal also builds on the Principal Investigator's considerable success in developing a range of novel tools for characterizing CAA during life. Successful completion of the proposed studies will have potentially major impact on the fields of hemorrhagic stroke, vascular cognitive impairment, and Ass immunotherapy, by providing new information on an individual's risk of future hemorrhage, defining the true contribution of CAA to age-related cognitive decline, and possibly yielding new safety markers for anti-amyloid immunotherapy.

描述（由申请人提供）：β-淀粉样蛋白（Ass）在脑血管中的沉积（脑淀粉样血管病或 CAA）是出血性中风的主要原因，是血管性认知障碍的一个因素，也是开发抗淀粉样蛋白药物的复杂化因素。 -淀粉样蛋白免疫疗法。目前在生命期间检测 CAA 的方法主要集中于识别与 CAA 相关的出血，通常是在严重出血性中风发生后。越来越多的证据（包括一般老年人群中脑叶微出血的高患病率）表明，即使没有出血性中风，晚期 CAA 也极为常见。目前的提案旨在通过对没有出血性中风的个体验证和应用新型体内检测方法来建立晚期 CAA 的早期诊断。初步数据支持三种候选检测方法：1) 枕骨为主模式中淀粉样蛋白配体匹兹堡化合物 B (PiB) 的保留增加，2) 脑脊液中 ss-淀粉样蛋白 Ass40 和 Ass42 肽的浓度降低，3) 钝化脑血管对视觉刺激的反应。我们将在两组已明确诊断为晚期 CAA 的患者中验证这三种方法：在马萨诸塞州总医院招募的患有多发性脑叶微出血的散发患者（具体目标 1）和在莱顿招募的基因诊断为荷兰型遗传性 CAA 的家族患者大学医学中心（具体目标 2）。根据在这两个患者组中建立的诊断切点，我们将继续将检测方法应用于鹿特丹扫描研究（具体目标 3）确定的严格肺叶微出血的无症状人群受试者。三个研究组均由来自同一地点的 20 名病例受试者和 20 名类似的老年对照受试者组成。接收器操作员特征技术将用于建立区分 CAA 病例与非 CAA 对照的最佳方法，将已建立 CAA 的两个患者组的结果应用于基于人群的鹿特丹扫描受试者，其中晚期 CAA 的存在仍未知。这三个研究人群代表了最大且特征最彻底的群体，即散发性 CAA 患者（麻省总医院）、遗传性 CAA 患者（莱顿大学医学中心）以及通过针对微出血检测优化的 MRI 方法进行扫描的人群受试者（鹿特丹扫描研究）。该提案还建立在首席研究员在开发一系列用于表征生活中 CAA 的新颖工具方面取得的巨大成功的基础上。成功完成拟议研究将提供有关个体未来出血风险的新信息，确定 CAA 对与年龄相关的认知衰退的真正贡献，从而对出血性中风、血管性认知障碍和 Ass 免疫治疗领域产生潜在的重大影响，并可能产生抗淀粉样蛋白免疫疗法的新安全标记。