Pathological mechanisms of white matter hyperintensities

白质高信号的病理机制

• 批准号: 10631136
• 负责人: Swati Rane
• 金额: $ 69.63万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 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/10631136
• 关键词: Actins; Affect; Albumins; Alzheimer' s Disease; Alzheimer' s disease risk; Anatomy; Appearance; Arteries; Atrophic; Autopsy; Axon; Benchmarking; Biological Markers; Blood - brain barrier anatomy; Blood Vessels; Blood brain barrier dysfunction; Brain; Cell Adhesion Molecules; Cerebral cortex; Cerebrovascular Circulation; Cerebrovascular Disorders; Clinical; Cognition; Cognitive; Cognitive deficits; Corpus striatum structure; Dementia; Demyelinations; Diameter; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; E-Selectin; Elderly; Endothelium; Ensure; Extravasation; Fiber; Functional Magnetic Resonance Imaging; Future; Growth; Image; Impaired cognition; Impairment; Individual; Inflammation; Inflammatory; Interruption; Ipsilateral; Knowledge; Liquid substance; Location; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Mediation; Mediator; 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; Specificity; Spinal Puncture; Stains; Structure; System; Techniques; Testing; Time; Tissue Sample; Tissues; Universities; Validation; Vascular Cell Adhesion Molecule-1; Ventricular; Washington; Water; White Matter Hyperintensity; Work; arterial spin labeling; 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; glial activation; gray matter; hypoperfusion; imaging biomarker; immunohistochemical markers; in vivo; in vivo imaging; innovation; intercellular cell adhesion molecule; magnetic resonance imaging biomarker; mild cognitive impairment; neural; neuropathology; novel; precision medicine; prevent; processing speed; quantitative imaging; recruit; success; tau Proteins; vascular injury; white matter; white matter damage

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 该项目采用先进的体内成像来确定白质的病理机制 高透明性（WMHS）及其对老年人患有阿尔茨海默氏病风险的认知能力下降的贡献 （广告）。 WMHS是T2-MRI上的明亮斑块，但并不告知其外观的病理。我们的 工作具有创新性，因为它首次利用了量化轴突和髓磷脂的非侵入性方法 稀疏，液体保留，WMHS相关皮质萎缩和血脑屏障功能障碍如体内 WMHS组的驱动因素。我们还将测试WMHS的典型病理标志物，即灌注灌注和 受损的血管反应性。所有成像测量结果都将针对良好的CSF进行验证 标记。我们的科学前提是，WMH的不同位置（深度与脑室）对应于 不同的机制（血管与神经退行性）和认知谱。因此，我们的工作将允许使用 WMHS的病理驱动因素制定有针对性的策略以停止其增长并改善相关 未来的认知能力下降。在AIM 1中，我们将检验以下假设，即血管病理在深处占主导地位 通过测量皮质脑血流，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超含量功能MRI方法进行这些测量。我们 将用血管损伤（E-选择素），炎症（粘附分子，，粘附分子， VCAM/ICAM）和血脑屏障渗透性（白蛋白渗出）。在AIM 2中，我们将检验假设 神经退行性病理学主要通过测量轴突稀疏性，占主导地位。 使用高级扩散成像和髓磷脂水分成像的脱髓鞘和液体保留。验证 标记将是tau和髓磷脂碱性蛋白的CSF水平。在独立的供体脑组织的离体样品中， 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 两个WMHS。我们还将在WMH和正常的白质中量化轴突和髓磷脂密度， 使用一系列污渍在灰质中进行神经元计数。验尸MRI将用于识别WMHS 关于捐赠者的大脑。定量神经病理学将作为我们假设的独立验证 关于WMHS的位置和机制。在AIM 3中，我们将测试深WMH中断的假设 离散的短距离关联纤维和纹状体纤维，导致特定的认知缺陷，尤其是那些缺陷 与处理速度有关。另一方面，脑室周围的WMH中断了远距离关联区 引起全球认知障碍。我们将使用调解分析来解释这两种类型的WMH 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氏病研究的核心和分支机构 招募中心，腰椎穿刺，CSF分析，验化后MRI与体内组织截面相匹配， 这些部分的系统解剖学采样，确保了PI的第一个独立R01的成功。