Pathological mechanisms of white matter hyperintensities

白质高信号的病理机制

基本信息

批准号：
10297644
负责人：
Swati Rane
金额：
$ 72.26万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10297644
关键词：
Affect Albumins Alzheimer&apos s Disease Alzheimer&apos s disease risk Anatomy Appearance Arteries Atrophic Autopsy Axon Benchmarking Biological Markers Blood - brain barrier anatomy Blood Vessels Brain Caliber Cell Adhesion Molecules Cerebrovascular Circulation Cerebrovascular Disorders Clinical Cognition Cognitive Cognitive deficits Corpus striatum structure Demyelinations Diffusion Diffusion Magnetic Resonance Imaging Disease E-Selectin Elderly Endothelium Ensure Extravasation Fiber Functional Magnetic Resonance Imaging Functional disorder Future Gold Growth Image Impaired cognition Impairment Individual Inflammation Inflammatory Interruption Ipsilateral Knowledge Liquid substance Location Magnetic Resonance Imaging Measurement Measures Mediating Mediation Mediator of activation protein Methods Myelin Myelin Basic Proteins Nerve Degeneration Nerve Fibers Neurobehavioral Manifestations Neurons Oligodendroglia Participant Pathologic Pathologic Processes Pathology Perfusion Prevention Process Research Resources Risk Factors Sampling Severities Smooth Muscle Actin Staining Method Specificity Spin Labels Spinal Puncture Stains Structure System Techniques Testing Time Tissue Sample Tissues Universities Validation Vascular Cell Adhesion Molecule-1 Washington Water White Matter Hyperintensity Work base biomarker validation blood-brain barrier disruption blood-brain barrier function blood-brain barrier permeabilization brain tissue cerebral atrophy cerebrovascular cerebrovascular pathology cognitive function cognitive testing cohort density executive function feeding gray matter hypoperfusion imaging biomarker immunohistochemical markers in vivo in vivo imaging innovation intercellular cell adhesion molecule mild cognitive impairment neuropathology novel precision medicine prevent processing speed quantitative imaging recruit relating to nervous system success tau Proteins vascular injury white matter white matter damage

项目摘要

SUMMARY This project applies advanced in vivo imaging to determine the pathological mechanisms of white matter hyperintensities (WMHs) and their contribution to cognitive decline in older adults at risk of Alzheimer's disease (AD). WMHs are bright patches on T2- MRI but do not inform the pathology underlying their appearance. Our work is innovative because it utilizes, for the first time, non-invasive methods to quantify axon and myelin rarefaction, fluid retention, WMHs-associated cortical atrophy, and blood-brain barrier dysfunction as in vivo drivers of WMHs formation. We will also test typical pathological markers of WMHs, i.e., hypoperfusion and compromised vascular reactivity. All imaging measurements will be validated against well-established CSF markers. Our scientific premise is that different locations of WMHs (deep vs. periventricular) correspond to distinct mechanisms (vascular vs. neurodegenerative) and cognitive profiles. Thus, our work will allow the use of pathological drivers of WMHs to develop targeted strategies to stop their growth and ameliorate associated cognitive decline in the future. In Aim 1, we will test the hypothesis that vascular pathology predominates in deep WMHs by measuring cortical cerebral blood flow, vascular reactivity, and blood-brain barrier dysfunction. We will use specialized arterial spin labeling and a hypercapnic functional MRI approach for these measurements. We will validate measurements with CSF markers of vascular injury (e-selectin), inflammation (adhesion molecules, VCAM/ICAM), and blood-brain barrier permeability (albumin extravasation). In Aim 2, we will test the hypothesis that neurodegenerative pathology predominates in periventricular WMHs by measuring axon rarefaction, demyelination, and fluid retention using advanced diffusion imaging and myelin water fraction imaging. Validation markers will be CSF levels of tau and myelin basic protein. In independent ex vivo samples of donor brain tissue, we will quantify vascular pathology using smooth muscle actin and albumin immunohistochemical stains in the two WMHs. We will also quantify axon and myelin density in the WMHs and normal-appearing white matter and perform neuron counting in gray matter using an array of stains. Postmortem MRI will be used to identify WMHs on donor brains. The quantitative neuropathology will serve as an independent validation of our hypotheses regarding WMHs location and mechanisms. In Aim 3, we will test the hypothesis that deep WMHs interrupt discrete short-range association fibers and striatal fibers, causing specific cognitive deficits, especially those related to processing speed. Periventricular WMHs, on the other hand, interrupt long-range association tracts causing global cognitive impairment. We will use mediation analysis to explain whether the two types of WMHs influence the relationship between the different imaging markers and distinct cognitive symptoms. The proposal takes advantage of the Cores and affiliates of the University of Washington's Alzheimer's Disease Research Center for recruitment, lumbar punctures, CSF analyses, postmortem MRI matched to ex vivo tissue sections, and systematic anatomic sampling of those sections, ensuring the success of the PI's first independent R01.

概括该项目应用先进的体内成像技术来确定白质的病理机制高信号（WMH）及其对有阿尔茨海默病风险的老年人认知能力下降的影响（广告）。 WMH 是 T2-MRI 上的明亮斑块，但不能告知其外观背后的病理学信息。我们的这项工作具有创新性，因为它首次利用非侵入性方法来量化轴突和髓磷脂体内稀薄、液体潴留、WMHs相关皮质萎缩和血脑屏障功能障碍 WMH 形成的驱动因素。我们还将测试 WMH 的典型病理标志物，即灌注不足和血管反应性受损。所有成像测量都将根据成熟的 CSF 进行验证标记。我们的科学前提是 WMH 的不同位置（深部与脑室周围）对应于不同的机制（血管与神经退行性）和认知特征。因此，我们的工作将允许使用 WMH 的病理驱动因素，以制定有针对性的策略来阻止其生长并改善相关的未来的认知能力下降。在目标 1 中，我们将检验血管病理学在深部占主导地位的假设。通过测量皮质脑血流量、血管反应性和血脑屏障功能障碍来测量 WMH。我们将使用专门的动脉自旋标记和高碳酸功能 MRI 方法进行这些测量。我们将验证血管损伤（e-选择素）、炎症（粘附分子、 VCAM/ICAM）和血脑屏障通透性（白蛋白外渗）。在目标 2 中，我们将检验假设通过测量轴突稀疏，神经退行性病理学在脑室周围 WMH 中占主导地位，使用先进的扩散成像和髓磷脂水分数成像进行脱髓鞘和液体潴留。验证标记物是脑脊液中 tau 蛋白和髓磷脂碱性蛋白的水平。在供体脑组织的独立离体样本中，我们将使用平滑肌肌动蛋白和白蛋白免疫组织化学染色来量化血管病理学两个 WMH。我们还将量化 WMH 中的轴突和髓磷脂密度以及正常出现的白质和使用一系列染色剂对灰质中的神经元进行计数。尸检 MRI 将用于识别 WMH 在捐赠者的大脑上。定量神经病理学将作为我们假设的独立验证关于 WMH 的位置和机制。在目标 3 中，我们将测试深度 WMH 中断的假设离散的短程关联纤维和纹状体纤维，导致特定的认知缺陷，尤其是那些与处理速度有关。另一方面，脑室周围 WMH 会中断远程关联束造成整体认知障碍。我们将使用中介分析来解释两种类型的 WMH 是否影响不同成像标记与不同认知症状之间的关系。提案利用华盛顿大学阿尔茨海默病研究中心和附属机构的优势招募中心、腰椎穿刺、脑脊液分析、与离体组织切片匹配的死后 MRI、并对这些部分进行系统的解剖采样，确保 PI 的第一个独立 R01 的成功。