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.

摘要/摘要 血管认知障碍痴呆（VCID）是一种异质疾病，是重要原因 痴呆症。该建议是对RFA的响应，以识别生物标志物将患者分为亚组 用于治疗试验。尽管对单独的多种生物标志物知之甚少，但我们的差距很大 了解在协作研究中使用的最佳研究，这是该提案的目的。皮质下 缺血性血管疾病（SIVD）是进行性小血管疾病（SVD）形式，最适合 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。白色的 物质损坏是SIVD的标志，MRI是显示渐进变化的最佳方法。 CSF的生化研究显示了白蛋白，基质金属蛋白酶（MMP）的炎症生物标志物 和细胞因子。在正在进行的SIVD临床研究中，我们的小组已经确定了MRI的微观结构研究 CSF中MMP的生化研究是两个最有前途的生物标志物。这个两相， 里程碑驱动的建议是确定最佳的微观结构和生化生物标志物，以识别 SIVD亚组并用作进展的替代标记。在第一个U2阶段，最佳方法 测量CSF MMP将确定患者分类和最佳MRI生物标志物显示 将确定进展。正常的白质（NAWM），这是一个正常天赋的区域 信号通常具有异常的扩散信号，表明组织有风险（前驱）。假设是CSF MRI生物标志物可用于分类CSF的SIVD患者，主要是分类 和分类的MRI和作为预测疾病进展的替代标记的MRI 用于患者治疗决策。有三个具体的目的：1）证明 可以根据生物标志物预测，Flair图像定义的白质高强度（WMHS）可以预测 根据多壳高价值扩散MRI（DMRI）计算； 2）确定功能性大脑连接， 结构性大脑连通性和灰质萎缩生物标志物可以预测认知能力下降（执行和 在两到三年的VCID受试者中的记忆函数）； 3）比较MMP 用zymography制成的测量，采用两种新方法，包括基于ELISA的方法和一个 基于免疫接种和荧光肽裂解的活性测定，以优化生化 研究。该建议将填补有关用于协作研究的最佳生物标志物的知识空白。 主要目的与完善患者选择的生物标志物相关，这将在U2中进行 通过将现有新墨西哥州大学（UNM）队列的规模从100名患者增加到200例，阶段 并进行CSF研究进行患者分类和DMRI研究，以定义替代物 在U3阶段进行临床试验中用于结果测量的标记。长期目标是拥有 计划在第五年计划未来的治疗试验时，生​​物标志物就位了。