Cerebral amyloid angiopathy fluid biomarkers evaluation (CAFE)

脑血管中淀粉样b蛋白(Ab)的积聚，这种情况称为大脑淀粉样蛋白 血管病变(CAA)是一种常见的老年人小血管疾病，是血管认知的重要驱动因素 损害和痴呆(VCID)和阿尔茨海默病(AD)患者的显著共病。尽管 随着对CAA对VCID的贡献的认识日益加深，对这种情况的早期和准确诊断已经 仍然难以捉摸，很大程度上依赖于仅在晚期有效的神经成像手段 疾病。目前对CAA的“波士顿磁共振诊断标准”是基于存在多个肺叶微出血。 大脑。然而，神经成像方法是有限的，因为神经病理结果表明 大量的CAA在疾病的早期阶段普遍存在，没有微出血的存在，特别是在患者中 使用AD。因此，在出现微出血之前，需要用于疾病早期阶段的生物标记物。 通过神经成像检测到。IS项目的目的是通过开发和验证来填补这一空白 用于CAA的强健生物体液标志物。 我们实验室最近的工作已经确定了新的候选生物标记物，这些标记物似乎是CAA特有的 从机制上讲，可以与疾病过程联系在一起，并可以在生物体液中进行测量。这些 候选人是从生化和免疫化学方法的组合中获得的，使用有效的和 用于CAA的特定的人脑血管细胞培养和啮齿动物模型，它们的存在已经 在人类CAA组织中得到证实。这项提议的总体假设是，这些新奇的候选人 生物标志物对CAA具有独特的特异性，有助于CAA的早期准确诊断。 相关的小血管疾病。这个项目有两个具体目标。首先，我们将研究一下 CAA转基因大鼠模型中的CAA生物标志物从症状前(微出血前)到 症状期(明显的微出血)。这一模式提供了强大而独特的前景 脑脊液和血清生物标志物的纵向表达与疾病进展的关系 严重程度，特别是在前驱状态下，这是人类没有的机会。此外，我们的CAA比率 模型将用于使用互补蛋白质组方法来识别其他候选生物标记物。 最后，将使用实质斑块淀粉样变性大鼠模型进行比较研究。 高血压/卒中，另一种常见的脑部小血管疾病，以进一步确定CAA的特异性 生物标志物。其次，我们将进一步确定、开发和验证候选蛋白质生物标记物的分析方法。 用于CAA的诊断，包括：脑组织的主要成分Ab40的完整和衍生物 血管淀粉样蛋白积聚、热休克蛋白B2和尿激酶型纤溶酶原激活物 (Upa)。我们计划的一个优先事项是共享我们的数据，提供开发的分析、关键试剂、患者样本和 将大鼠模型推广到其他组织和财团，以促进小血管疾病生物标志物的开发。

Cerebrovascular accumulation of the amyloid b-protein (Ab), a condition known as cerebral amyloid angiopathy (CAA), is a common small vessel disease in the elderly, an important driver of vascular cognitive impairment and dementia (VCID) and a prominent comorbidity of patients with Alzheimer’s disease (AD). Despite the growing recognition of the contribution of CAA to VCID, early and accurate diagnosis of this condition has remained elusive and largely relies on neuroimaging modalities that are only effective in late stages of the disease. The current “Boston MRI criteria” for CAA are based on the presence of multiple lobar microbleeds in the brain. However, the neuroimaging approaches are limited in that neuropathological findings demonstrate that abundant CAA is prevalent at early stages of disease without the presence of microbleeds, particularly in patients with AD. Thus, there is a need for biomarkers for early stages of disease prior to the presence of microbleeds detected by neuroimaging. The purpose of the is project is to fill in this void by developing and validating robust biological fluid markers for CAA. Recent work from our laboratories has identified novel candidate biomarkers that appear specific for CAA and mechanistically can be linked to the disease process and can be measured in biological fluids. These candidates were derived from a combination of biochemical and immunochemical approaches using potent and specific human cerebral vascular cell cultures and rodent models for CAA, and their presence has been confirmed in human CAA tissues. The overall hypothesis of this proposal is that these novel candidate biomarkers are unique and specific for CAA and will facilitate in an early and accurate diagnosis of CAA- related small vessel disease. There are two specific aims of this project. First, we will study the trajectory of CAA biomarkers in a transgenic rat model for CAA from the presymptomatic phase (prior to microbleeds) to the symptomatic phase (prominent microbleeds). This model provides the powerful and unique prospect to investigate the longitudinal expression of CSF and serum biomarkers in relation to the progression of disease severity, particularly in prodromal states, an opportunity that is not available in humans. Further, our CAA rat model will be used to identify additional candidate biomarkers using complementary proteomic approaches. Lastly, comparative studies will be performed using rat models of parenchymal plaque amyloid pathology or hypertension/stroke, another common cerebral small vessel disease, to further establish the specificity of CAA biomarkers. Second, we will further characterize, develop and validate assays for candidate protein biomarkers for the diagnosis of CAA including: intact and derivatives of Ab40 peptide, the chief component of cerebral vascular amyloid accumulation, heat shock protein B2 (HSPB2), and urokinase-type plasminogen activator (uPA). A priority of our plan is to share our data, provide developed assays, key reagents, patient samples and rat models to other groups and consortiums to advance small vessel disease biomarker development.