Vascular Pathology in Early and Asymptomatic Cerebral Amyloid Angiopathy

早期和无症状脑淀粉样血管病的血管病理学

• 批准号: 10208000
• 负责人: Anand Viswanathan
• 金额: $ 80.32万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10208000
• 关键词: Affect; Alzheimer' s disease pathology; Ambulatory Blood Pressure Monitoring; Amyloid; Amyloid beta-Protein; Arteries; Biological; Biological Markers; Blood Pressure; Blood Vessels; Brain hemorrhage; Cerebral Amyloid Angiopathy; Cerebral hemisphere hemorrhage; Cerebral small vessel disease; Cerebrum; Clinical; Collaborations; Communities; Data; Dementia; Deposition; Development; Disease; Disease Progression; Elderly; Event; Exhibits; Funding; Hemorrhage; Impaired cognition; Individual; Intervention; Lesion; Link; Lobar; Magnetic Resonance Imaging; Measures; Methods; Microvascular Dysfunction; Neurofibrillary Tangles; Outcome; Pathologic; Pathology; Patients; Population; Positron-Emission Tomography; Prospective cohort; Recording of previous events; Recurrence; Risk; Risk Factors; Role; Scanning; Senile Plaques; Siderosis; Specificity; Stroke; Testing; Vascular Diseases; abeta deposition; age related; amyloid imaging; amyloid pathology; base; blood pressure variability; cognitive development; cost; epidemiology study; modifiable risk; non-demented; pre-clinical; prevent; secondary analysis; tau Proteins; tau aggregation; vascular cognitive impairment and dementia

PROJECT SUMMARY/ABSTRACT Cerebral amyloid angiopathy (CAA) is an age-related cerebral small vessel disease that is common in elderly. CAA causes two principle, potentially devastating, outcomes in this population: lobar intracerebral hemorrhage (ICH) and vascular cognitive impairment and dementia (VCID). CAA is characterized by progressive deposition of β-amyloid (Aβ) in the walls of cortical and leptomeningeal arteries leading to vascular dysfunction. Vascular dysfunction underlies the lesions of small vessel disease typically seen in CAA such as lobar microbleeds (MB) and cortical superficial siderosis (cSS). In addition to exhibiting vascular dysfunction, a significant proportion of CAA patients harbor the amyloid plaques and tau-based neurofibrillary tangles typical of Alzheimer’s pathology which may also influence disease course. Although CAA is often identified in patients after they develop lobar ICH or dementia, neuropathological and epidemiologic studies suggest that early, yet pathologically advanced pre-clinical forms of CAA are common. Data generated from this project during the initial funding period have shown that these previously understudied patients can now be reliably identified with high specificity using MRI-based biomarkers. The critical next step is to identify modifiable risk factors that may influence early disease course in CAA. In contrast to other forms of stroke, modifiable risk factors to prevent CAA-related outcomes have not been identified. Preliminary evidence suggests that in CAA patients with lobar ICH, elevated mean blood pressure (BP) predicts increased risk of ICH recurrence. Emerging evidence has linked increased BP variability to elevated risk of cerebral small vessel disease, stroke and dementia above and beyond the role of mean BP levels. It is, however, unknown whether BP variability may also contribute to subclinical disease course in CAA patients. In early CAA patients who do not develop incident ICH, nearly a third develop dementia over 2 years. Is dementia caused by progressive vascular dysfunction or tau or amyloid pathology in the disease? Our preliminary data suggests that BP variability influences tau accumulation. The underlying biologic mechanisms are poorly understood. Using a prospective cohort of patients with CAA without previous history of ICH, we will answer the following three key questions: 1) Does abnormal BP, characterized by elevated BP level and variability, increase the risk of bleeding events in patients with early CAA? 2) Does BP affect progression of CAA-related vascular or tau or amyloid pathology? 3) In patients with early CAA does BP influence development of cognitive impairment and dementia?

项目总结/摘要 脑淀粉样血管病（CAA）是一种与年龄相关的脑小血管疾病， 老人CAA导致两个主要的，潜在的破坏性的结果，在这一人群中： 出血（ICH）和血管性认知障碍和痴呆（VCID）。CAA的特点是 β-淀粉样蛋白（Aβ）在皮质和软脑膜动脉壁中进行性沉积，导致血管 功能障碍血管功能障碍是CAA中常见的小血管病变的基础， 脑叶微出血（MB）和皮质浅表铁质沉着症（cSS）。除了表现出血管功能障碍外， 很大比例的CAA患者具有典型的淀粉样斑块和基于tau蛋白的神经元缠结， 阿尔茨海默病的病理学，这也可能影响疾病的进程。 虽然CAA通常在患者发生脑叶ICH或痴呆后被发现，但神经病理学 流行病学研究表明，早期，但病理先进的临床前形式的CAA是 共同该项目在最初供资期间产生的数据表明，这些项目以前 现在可以使用基于MRI的生物标志物以高特异性可靠地鉴定未充分研究的患者。的 关键的下一步是确定可能影响CAA早期病程的可改变的危险因素。 与其他形式的中风相比，预防CAA相关结局的可改变的风险因素尚未得到证实。 鉴定初步证据表明，在CAA患者脑叶ICH，平均血压升高， (BP)预测ICH复发风险增加。新出现的证据表明，血压变异性增加与 脑小血管疾病、中风和痴呆的风险升高，超过平均血压的作用 程度.然而，尚不清楚血压变异性是否也可能导致CAA的亚临床病程 患者在没有发生ICH的早期CAA患者中，近三分之一的患者在2年内发展为痴呆。 痴呆症是由进行性血管功能障碍或tau蛋白或淀粉样蛋白病变引起的吗？我们 初步数据表明BP的变化影响tau蛋白的积累。潜在的生物学机制 我们对此知之甚少。使用无ICH既往史的CAA患者的前瞻性队列，我们将 回答以下三个关键问题：1）血压异常，其特征是血压水平升高， 变异性，增加早期CAA患者出血事件的风险？2)BP是否影响 CAA相关的血管或tau或淀粉样病变？3)在早期CAA患者中， 认知障碍和痴呆症的发展