Early Detection of Cerebral Amyloid Angiopathy

描述（由申请人提供）：ss-淀粉样蛋白（Ass）在脑血管中的沉积（脑淀粉样蛋白血管病或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免疫疗法的一个复杂因素。目前在生活中检测CAA的方法主要集中在识别CAA相关的出血，通常在发生出血性中风后。越来越多的证据（包括老年人群中脑叶微出血的高患病率）表明，即使在没有出血性中风的情况下，晚期CAA也是非常常见的。目前的提案旨在通过验证和应用新的体内检测方法来建立晚期CAA的早期诊断，用于无出血性中风的个体。初步数据支持三种候选检测方法：1)增加淀粉样蛋白配体匹兹堡化合物B （PiB）以枕部为主模式的保留，2)减少ss-淀粉样蛋白Ass40和Ass42肽的脑脊液浓度，以及3)减弱脑血管对视觉刺激的反应性。我们将在两组确诊为晚期CAA的患者中验证这三种方法：马萨诸塞州总医院招募的散发性多叶性脑微出血患者（特异性目标1）和莱顿大学医学中心招募的遗传性诊断为荷兰型遗传性CAA的家族性患者（特异性目标2）。基于在这两组患者中建立的诊断切点，我们将继续将检测方法应用于鹿特丹扫描研究（Specific Aim 3）确定的严格的大叶微出血的无症状人群受试者。每个研究组将由来自同一地点的20名病例受试者和20名年龄相仿的对照受试者组成。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，将已确定CAA的两组患者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。这三个研究人群代表了散发性CAA患者（马萨诸塞州总医院）、遗传性CAA患者（莱顿大学医学中心）和基于人群的受试者（鹿特丹扫描研究），这些受试者通过优化的微出血检测MRI方法进行扫描。该建议还建立在首席研究员在开发一系列用于表征生命中的CAA的新工具方面取得的巨大成功的基础上。通过提供关于个体未来出血风险的新信息，确定CAA对年龄相关认知能力下降的真正贡献，以及可能产生抗淀粉样蛋白免疫治疗的新安全标记，拟议研究的成功完成将对出血性卒中、血管性认知障碍和Ass免疫治疗领域产生潜在的重大影响。

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. PUBLIC HEALTH RELEVANCE: We propose a study of new detection methods for cerebral amyloid angiopathy (or CAA), an age-related degenerative condition of the blood vessels of the brain. Severe CAA is an important cause of bleeding strokes in the elderly, a likely contributor to memory loss related to impaired circulation, and a possible barrier to ongoing attempts to develop a vaccine for Alzheimer disease. The current proposal seeks to implement newly developed methods for detecting CAA before it causes a bleeding stroke, potentially leading both to improved treatments for stroke prevention and better understanding of how this common degenerative process affects memory.