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: 10435462
• 负责人: William E. Van Nostrand
• 金额: $ 62.5万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10435462
• 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.

脑血管中淀粉样蛋白b蛋白（Ab）的积聚，称为脑淀粉样蛋白 血管病（CAA）是老年人常见的小血管疾病，是血管认知障碍的重要驱动因素 痴呆症（VCID）和阿尔茨海默病（AD）患者的显著合并症。尽管 随着对CAA对VCID的贡献的日益认识，对这种疾病的早期和准确诊断， 仍然难以捉摸，主要依赖于神经影像学方式，这些方式仅在晚期有效。 疾病目前CAA的“波士顿MRI标准”是基于 大脑然而，神经影像学方法是有限的，因为神经病理学结果表明， 在没有微出血的疾病早期，尤其是在患者中， 与AD因此，需要在微出血出现之前的疾病早期阶段的生物标志物 通过神经成像检测到。IS项目的目的就是通过开发和验证来填补这一空白 用于CAA的强大生物流体标记物。 我们实验室最近的工作已经确定了对CAA具有特异性的新型候选生物标志物 并且在机制上可以与疾病过程相关联，并且可以在生物流体中测量。这些 候选物是从生物化学和免疫化学方法的组合中获得的， 特定的人脑血管细胞培养物和CAA的啮齿动物模型，它们的存在已经被 在人体CAA组织中得到证实。该提案的总体假设是，这些新的候选人 生物标志物对于CAA是独特的和特异的，并且将有助于CAA的早期和准确的诊断。 相关的小血管疾病。该项目有两个具体目标。首先，我们将研究 CAA转基因大鼠模型中从症状前期（微出血前）至 症状期（显著微出血）。这一模型为解决这一问题提供了强大而独特的前景， 研究与疾病进展相关的CSF和血清生物标志物的纵向表达 严重性，特别是在前驱状态下，这是人类无法获得的机会。此外，我们的CAA大鼠 模型将用于使用互补蛋白质组学方法鉴定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质生物标志物的检测方法 用于CAA诊断的抗体包括：脑组织主要成分Ab 40肽的完整肽和衍生物， 血管淀粉样蛋白积聚、热休克蛋白B2（HSPB 2）和尿激酶型纤溶酶原激活剂 （uPA）。我们计划的一个优先事项是分享我们的数据，提供开发的检测方法、关键试剂、患者样本和 将大鼠模型提供给其他群体和财团，以推进小血管疾病生物标志物的开发。

项目成果

Cerebrospinal fluid shotgun proteomics identifies distinct proteomic patterns in cerebral amyloid angiopathy rodent models and human patients.

• DOI: 10.1186/s40478-023-01698-4
• 发表时间: 2024-01-08
• 期刊: Acta neuropathologica communications
• 影响因子: 7.1

Robust neuroinflammation and perivascular pathology in rTg-DI rats, a novel model of microvascular cerebral amyloid angiopathy.

rTg-DI 大鼠中强烈的神经炎症和血管周围病理学，这是一种新型的微血管脑淀粉样血管病模型。

• DOI: 10.1186/s12974-020-01755-y
• 发表时间: 2020
• 期刊: Journal of neuroinflammation
• 影响因子: 9.3
• 作者: Zhu,Xiaoyue;Hatfield,Joshua;Sullivan,JosephK;Xu,Feng;VanNostrand,WilliamE
• 通讯作者: VanNostrand,WilliamE

Plasma amyloid beta 42 is a biomarker for patients with hereditary, but not sporadic, cerebral amyloid angiopathy.

• DOI: 10.1186/s13195-023-01245-2
• 发表时间: 2023-06-03
• 期刊: Alzheimer's research & therapy

Prevalence of cerebral amyloid angiopathy: A systematic review and meta-analysis.

• DOI: 10.1002/alz.12366
• 发表时间: 2022-01
• 期刊: ALZHEIMERS & DEMENTIA
• 影响因子: 14
• 作者: Jakel, Lieke;De Kort, Anna M.;Klijn, Catharina J. M.;Schreuder, Floris H. B. M.;Verbeek, Marcel M.
• 通讯作者: Verbeek, Marcel M.

Elevated expression of urokinase plasminogen activator in rodent models and patients with cerebral amyloid angiopathy.

啮齿动物模型和脑淀粉样血管病患者中尿激酶纤溶酶原激活剂的表达升高。

• DOI: 10.1111/nan.12804
• 发表时间: 2022
• 期刊: Neuropathology and applied neurobiology
• 影响因子: 5
• 作者: Vervuurt,Marc;Zhu,Xiaoyue;Schrader,Joseph;deKort,AnnaM;Marques,TaináM;Kersten,Iris;PetersvanTon,AnnemiekeM;Abdo,WilsonF;Schreuder,FlorisHBM;Rasing,Ingeborg;Terwindt,GiselaM;Wermer,MariekeJH;Greenberg,StevenM;Klijn,
• 通讯作者: Klijn,