MRI and CSF Biomarkers of White Matter Injury in VCID

VCID 患者脑白质损伤的 MRI 和 CSF 生物标志物

• 批准号: 9356351
• 负责人: Gary Allen Rosenberg
• 金额: $ 106.41万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9356351
• 关键词: Albumins; Alzheimer' s Disease; Anisotropy; Atrophic; Biochemical; Biological Assay; Biological Markers; Brain; Brain region; Classification; Clinical Research; Clinical Trials; Cognition; Data; Dementia; Diffuse; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Early identification; Enzyme-Linked Immunosorbent Assay; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Growth; Health; Image; Impaired cognition; Individual; Inflammatory; Joints; Knowledge; Longitudinal Studies; Magnetic Resonance Imaging; Measurement; Measures; Memory; Methods; Microvascular Dysfunction; Modality; Neurites; New Mexico; Outcome Measure; Patient Selection; Patients; Peptides; Pharmaceutical Preparations; Phase; Prevalence; Process; Radial; Reproducibility; Rest; Risk; Signal Transduction; Structure; Subgroup; Surrogate Markers; Testing; Time; Tissues; Universities; Vascular Cognitive Impairment; White Matter Hyperintensity; base; cohort; cost; cytokine; density; gray matter; independent component analysis; indexing; magnetic resonance imaging biomarker; neuroinflammation; novel; patient biomarkers; predictive marker; progression marker; response; subcortical ischemic vascular disease; treatment trial; white matter; white matter damage; white matter injury

Summary/Abstract Vascular cognitive impairment dementia (VCID) is a heterogeneous disease that is an important cause of dementia. This proposal is in response to a RFA to identify biomarkers to separate patients into subgroups for treatment trials. Although much is known about multiple biomarkers individually, there is a major gap in our understanding of the optimal ones to use in collaborative studies, which is the aim of this proposal. Subcortical ischemic vascular disease (SIVD) is the progressive small vessel disease (SVD) form that is optimal for treatment trials. MRI modalities and CSF biochemical studies provide the most promising biomarkers. White matter damage is the hallmark of SIVD, and MRI is the optimal method to show the progressive changes. Biochemical studies of CSF show the inflammatory biomarkers of albumin, matrix metaloproteinases (MMPs) and cytokines. In an on-going clinical study of SIVD, our group has identified microstructural studies with MRI and biochemical studies of MMPs in the CSF as the two most promising biomarkers. This two-phase, milestone-driven proposal is to identify the optimal microstructural and biochemical biomarkers to both identify the SIVD subgroup and to use as surrogate markers of progression. In the first U2 phase, the optimal method to measure CSF MMPs will be determined for patient classification and the optimal MRI biomarkers to show progression will be determined. Normal-appearing white matter (NAWM), which is a region with normal FLAIR signal, often has abnormal diffusion signals, indicating tissue at risk (prodromal). The hypothesis is that CSF and MRI biomarkers can be used for classification of SIVD patients with CSF for primarily classification and MRI for both classification and as a surrogate marker for predicting disease progression that can be used for patient treatment decisions. There are three specific aims: 1) to demonstrate that the growth of white matter hyperintensities (WMHs) as defined by FLAIR images can be predicted based on biomarkers calculated from multi-shell, high b-value diffusion MRI (dMRI); 2) to identify functional brain connectivity, structural brain connectivity and gray matter atrophy biomarkers that predict cognitive decline (executive and memory function) in VCID subjects over a period of two to three years; and, 3) to compare MMP measurements made with zymography with two novel methods, including an ELISA-based method and an activity assay based on immunocapture and fluorescent peptide cleavage in order to optimize the biochemical studies. This proposal will fill a gap in knowledge as to the optimal biomarkers to use for collaborative studies. The major aims are related to refining the set of biomarkers for patient selection, which will be done in the U2 phase by increasing the size of the existing University of New Mexico (UNM) cohort from 100 to 200 patients, and to perform the CSF studies for patient classification and the dMRI studies longitudinally to define surrogate markers to use for outcome measures in clinical trials in the U3 phase. The long-term goal is to have the biomarkers in place by the time the future treatment trials are planned in the fifth year.

摘要/摘要 血管性认知功能障碍痴呆(VCID)是一种异质性疾病，是一种重要的病因 痴呆症。这项提议是为了响应射频消融，以确定生物标记物以将患者分成亚组。 用于治疗试验。虽然对多个生物标记物单独的了解很多，但在我们的 了解在协作研究中使用的最佳方法，这是本提案的目的。皮质下 缺血性血管疾病(SIVD)是进行性小血管疾病(SVD)的一种形式，对 治疗试验。磁共振成像和脑脊液生化研究提供了最有前景的生物标志物。白色 物质损害是SIVD的标志，MRI是显示进行性改变的最佳方法。 脑脊液生化研究显示炎症生物标志物白蛋白、基质金属蛋白酶(MMPs) 和细胞因子。在一项正在进行的SIVD的临床研究中，我们的团队已经确定了MRI的微结构研究 脑脊液中MMPs的生化研究是两个最有前景的生物标志物。这两个阶段， 里程碑驱动的建议是确定最佳的微结构和生化生物标记物，以同时识别 SIVD亚群，并用作进展的替代标志物。在第一个U2阶段，最优方法 为了测量脑脊液中的MMPs，将根据患者的分类和显示的最佳MRI生物标志物来确定 进展情况将会确定。正常外观白质(NAWM)，这是一个具有正常视觉的区域 信号，通常有异常的扩散信号，表明组织处于危险状态(前驱症状)。假设是脑脊液 MRI生物标志物可用于脑脊液SIVD患者的初步分型 和MRI进行分类，并作为预测疾病进展的替代标志，可以 用于患者的治疗决策。有三个具体目标：1)证明 FLAIR图像所定义的白质高强度(WMH)可以根据生物标志物进行预测 从多层、高b值扩散磁共振成像(DMRI)计算；2)为了识别脑功能连接， 预测认知衰退的结构性脑连接和灰质萎缩生物标志物(执行和 VCID受试者在两到三年期间的记忆功能)；以及，3)比较 用两种新的方法用酶谱进行测量，包括一种基于ELISA的方法和一种 基于免疫捕获和荧光肽裂解的活性测定优化生化方法 学习。这一提议将填补关于用于合作研究的最佳生物标记物的知识空白。 主要目标是精炼一组用于患者选择的生物标志物，这将在U2完成 阶段通过将新墨西哥大学(UNM)现有队列的规模从100人增加到200人， 并执行用于患者分类的脑脊液研究和纵向的dMRI研究以确定替代者 在U3阶段临床试验中用于结果测量的标记物。我们的长期目标是拥有 到第五年计划未来的治疗试验时，生物标志物就到位了。