Early Detection of Cerebral Amyloid Angiopathy

描述（由申请方提供）：脑血管中β-淀粉样蛋白（Ass）沉积（脑淀粉样蛋白血管病或CAA）是出血性卒中的主要原因，是血管性认知障碍的促成因素，也是尝试开发抗淀粉样蛋白免疫疗法的复杂因素。目前检测CAA的方法主要集中在识别CAA相关的脑血管疾病，通常是在发生严重出血性中风后。越来越多的证据（包括普通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也非常常见。目前的提案旨在通过验证和应用新型体内检测方法来对没有出血性中风的个体进行晚期CAA的早期诊断。初步数据支持三种候选检测方法：1）淀粉样蛋白配体匹兹堡化合物B（Pi B）在枕区占优势的模式中的保留增加，2）β-淀粉样蛋白Ass 40和Ass 42肽的脑脊液浓度降低，和3）脑血管对视觉刺激的反应性钝化。我们将在两组确诊为晚期CAA的患者中验证这三种方法：在马萨诸塞州总医院招募的多发性脑叶微出血的散发性患者（特定目标1）和在莱顿大学医学中心招募的遗传学诊断为荷兰型遗传性CAA的家族性患者（特定目标2）。基于在这两个患者组中确定的诊断临界点，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）确定的具有严格肺叶微出血的无症状人群受试者。三个研究组中的每个研究组将由来自同一研究中心的20例病例受试者和20例相似年龄的对照受试者组成。接受者操作者特征技术将用于建立区分CAA病例与非CAA对照的最佳方法，将两个CAA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的存在仍然未知。三个研究人群代表了最大和最全面表征的散发性CAA患者（马萨诸塞州综合医院）、遗传性CAA患者（莱顿大学医学中心）和通过针对微出血检测优化的MRI方法扫描的基于人群的受试者（鹿特丹扫描研究）。该提案还建立在主要研究者在开发一系列用于表征CAA的新工具方面取得的相当大的成功的基础上。成功完成拟议的研究将对出血性中风，血管性认知障碍和Ass免疫治疗领域产生潜在的重大影响，通过提供有关个人未来出血风险的新信息，定义CAA对年龄相关认知下降的真正贡献，并可能产生抗淀粉样蛋白免疫治疗的新安全标志物。

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.