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: 9768242
• 负责人: Gary Allen Rosenberg
• 金额: $ 110.13万
• 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 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9768242
• 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; disorder subtype; gray matter; independent component analysis; indexing; magnetic resonance imaging biomarker; neuroinflammation; novel; optimal treatments; 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.

总结/摘要 血管性认知障碍性痴呆（VCID）是一种异质性疾病， 老年痴呆症该提案是对RFA的回应，旨在识别生物标志物，将患者分为亚组 用于治疗试验。虽然我们对多种生物标志物的了解很多，但在我们的研究中存在重大差距。 了解在合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）的形式， 治疗试验MRI模式和CSF生化研究提供了最有希望的生物标志物。白色 SIVD以物质损害为特征，MRI是显示SIVD进行性改变的最佳方法。 脑脊液的生化研究显示白蛋白、基质金属蛋白酶（MMPs） 和细胞因子。在一项正在进行的SIVD临床研究中，我们的小组已经确定了MRI的微观结构研究， 和CSF中MMPs的生物化学研究作为两种最有前途的生物标志物。这两个阶段， 里程碑驱动的建议是确定最佳的微观结构和生物化学生物标志物， SIVD亚组，并用作进展的替代标志物。在第一个U2阶段，最佳方法 将确定用于测量CSF MMPs的患者分类和最佳MRI生物标志物，以显示 进展将被确定。外观正常的白色物质（NAWM），是FLAIR正常的区域 信号，通常有异常扩散信号，表明组织处于危险（前驱）。假设脑脊液 MRI生物标志物可用于SIVD患者的CSF初步分类 和MRI用于分类和作为预测疾病进展的替代标记， 用于患者治疗决策。有三个具体目标：（1）证明增长 基于生物标记物，可以预测由FLAIR图像定义的白色高信号（WMH 从多壳、高b值扩散MRI（dMRI）计算; 2）为了识别功能性脑连接， 预测认知能力下降的结构性脑连接和灰质萎缩生物标志物（执行和 记忆功能）;以及，3）比较MMP 用酶谱法进行的测量有两种新的方法，包括基于ELISA的方法和 基于免疫捕获和荧光肽切割的活性测定，以优化生物化学 问题研究该提案将填补关于用于合作研究的最佳生物标志物的知识空白。 主要目标是完善用于患者选择的生物标志物集，这将在U2中完成 通过将现有的新墨西哥州大学（UNM）队列的规模从100名患者增加到200名患者， 并进行CSF研究以进行患者分类，纵向进行dMRI研究以确定替代 用于U3期临床试验结果测量的标志物。长期目标是让 生物标志物到位的时候，未来的治疗试验计划在第五年。