Cerebral amyloid angiopathy fluid biomarkers evaluation (CAFE)

脑淀粉样血管病液体生物标志物评估（CAFE）

• 批准号: 10204132
• 负责人: William E. Van Nostrand
• 金额: $ 63.46万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10204132
• 关键词: Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid; Amyloid beta-Protein; Autopsy; Biochemical; Biological; Biological Assay; Biological Markers; Biopsy; Blood; Blood specimen; Boston; Brain; Cell Culture Techniques; Cerebral Amyloid Angiopathy; Cerebral hemisphere hemorrhage; Cerebral small vessel disease; Clinical Trials; Comparative Study; Complement; Data; Dementia; Detection; Development; Diagnosis; Disease; Disease Progression; Early Diagnosis; Elderly; Goals; Heat shock proteins; Hemorrhage; Histologic; Human; Hypertension; Image; Laboratories; Lesion; Link; Liquid substance; Lobar; Location; Magnetic Resonance Imaging; Measures; Methods; Microvascular Dysfunction; Modality; Modeling; Molecular Chaperones; Neurologic; Pathology; Patients; Peptide Hydrolases; Peptides; Phase; Plasma; Plasminogen; Process; Proteins; Proteomics; Rattus; Reagent; Risk; Rodent Model; Sampling; Senile Plaques; Serum; Severities; Severity of illness; Siderosis; Specificity; Stroke; Tissues; Transgenic Organisms; Urokinase; Validation; Work; abeta accumulation; accurate diagnosis; amyloid pathology; base; biomarker development; biomarker evaluation; brain tissue; candidate marker; cerebrovascular; cohort; comorbidity; early detection biomarkers; experimental study; immunotherapy trials; insight; nervous system disorder; neuroimaging; novel; potential biomarker; protein biomarkers; protein misfolding; treatment trial; vascular cognitive impairment and dementia

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.

淀粉样蛋白B蛋白（AB）的脑血管积累，这种疾病称为脑淀粉样蛋白 血管病（CAA）是古老的一种常见小血管疾病，是血管认知的重要驱动力 障碍和痴呆（VCID）以及阿尔茨海默氏病（AD）患者的突出合并症。尽管 对CAA对VCID的贡献的认识日益认识到这种情况的早期和准确的诊断 仍然难以捉摸，很大程度上依赖于神经影像的方式，这些方式仅在 疾病。 CAA的当前“波士顿MRI标准”基于存在多个Lobar Microbleeds 大脑。但是，神经影像学方法受到限制，因为神经病理学的发现表明 大量的CAA在疾病的早期阶段普遍存在，而没有微粒，特别是在患者中 与广告。这是在存在微粒之前需要生物标志物的疾病早期阶段 通过神经影像检测。 IS项目的目的是通过开发和验证来填补这一空白 CAA的强大生物流体标记。 我们实验室的最新工作已经确定了看起来针对CAA的新型候选生物标志物 并且可以机械地与疾病过程有关，并且可以在生物液中进行测量。这些 候选者是源自生化和免疫化学方法的组合，并使用潜力和免疫化学方法 特定的人类脑血管细胞培养和CAA的啮齿动物模型，它们的存在一直是 在人CAA组织中确认。该提议的总体假设是这些新颖的候选人 生物标志物是CAA独特的，并且特定于CAA，并将在早期且准确的CAA-诊断中有助于 相关的小血管疾病。该项目有两个具体的目标。首先，我们将研究 CAA生物标志物在CAA的转基因大鼠模型中，从预符号相（微粒之前）到 有症状的阶段（突出的微孔）。该模型为 研究CSF和血清生物标志物与疾病进展的纵向表达 严重性，尤其是在前驱国家，这是人类无法使用的机会。此外，我们的CAA老鼠 模型将用于使用完整的蛋白质组学方法来识别其他候选生物标志物。 最后，将使用实质斑块淀粉样蛋白病理学的大鼠模型或 高血压/中风，另一种常见的脑小血管疾病，以进一步建立CAA的特异性 生物标志物。其次，我们将进一步表征，开发和验证候选蛋白生物标志物的测定法 为了诊断CAA，包括：AB40 Pepper的完整和衍生物，这是脑的主要组成部分 血管淀粉样蛋白积累，热休克蛋白B2（HSPB2）和尿激酶型纤溶酶原激活剂 （UPA）。我们计划的优先事项是共享我们的数据，提供开发的测定法，关键试剂，患者样本以及 大鼠模型和其他群体和财团，以推动小血管疾病生物标志物的发展。