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）：SS-淀粉样蛋白（ASS）在大脑血管中的沉积（脑淀粉样蛋白血管病或CAA）是出血性中风的主要原因，这是血管认知损害的原因，是导致抗氨基氨基免疫治疗的尝试的复杂因素。当前检测CAA生命中CAA的方法集中在鉴定与CAA相关的出血，通常是在发生重大出血性中风之后。越来越多的证据（包括一般老年人口中的洛巴尔微血管的高患病率）表明，即使没有出血性中风，晚期CAA也非常普遍。当前的提案旨在通过验证和应用新颖的体内检测方法来确定晚期CAA的早期诊断。初步数据支持三种候选检测方法：1）以枕偏见的模式增加了淀粉样配体匹兹堡化合物B（PIB），2）SS-淀粉样酶Ass40和Ass42肽的脑脊液浓度的降低，以及3）脑刺激性刺激性刺激性。我们将验证两组患有晚期CAA诊断的患者的这三种方法：在马萨诸塞州综合医院招募的多个Lobar脑大脑微粒患者（特定的AIM 1）和在遗传诊断患有荷兰型遗传性CAA的家族性诊断的患者（特定的AIM AIM 1），在Leiden University Medical Medical Center中招募了CAA（特定的AIM AIM 2）。基于这两个患者组中确定的诊断切点，然后我们将继续将检测方法应用于鹿特丹扫描研究确定的严格LOBAR微粒的无症状基于人群的受试者（特定目标3）。这三个研究组中的每个组将包括20个病例受试者和来自同一站点的20个相似的对照受试者。接收器操作员的特征技术将用于建立最佳方法，以区分CAA病例和非CAA对照，将两个具有既定CAA的患者群体的结果应用于基于人群的鹿特丹扫描受试者，而高级CAA的存在仍然未知。这三个研究人群是零星CAA患者（马萨诸塞州综合医院），遗传性CAA患者（Leiden University Medical Center）和通过MRI方法扫描的微型检测（鹿特丹扫描研究）扫描的基于人群的受试者。该建议还基于主要研究者在开发一系列新颖的工具来表征CAA中的一系列新型工具的基础上。成功完成拟议的研究将对出血性中风，血管认知障碍和ASS免疫疗法领域产生重大影响，通过提供有关个人未来出血风险的新信息，从而定义了CAA对年龄相关认知能力下降的真正贡献，并可能导致对抗肿瘤的新安全标记抗肿瘤的抗药性疗法。