Deciphering the Cerebral Microinfarct and its Role in Vascular Cognitive Impairment

解读脑微梗塞及其在血管认知障碍中的作用

• 批准号: 9919013
• 负责人: Andy Y Shih
• 金额: $ 68.56万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-05 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9919013
• 关键词: Acute; Address; Affect; Aging; Area; Autopsy; Axon; Behavior; Behavioral; Behavioral Paradigm; Biological; Biological Process; Brain; Brain Pathology; Calcium; Caliber; Cerebral hemisphere; Chronic; Chronic Phase; Clinical; Clinical Research; Cognitive deficits; Collection; Complement; Data; Data Set; Dementia; Demyelinations; Dendrites; Diffusion Magnetic Resonance Imaging; Disease; Dissection; Equilibrium; Fiber; Fluorescence; Functional disorder; Histologic; Histology; Histopathology; Human; Image; Imaging Techniques; Impaired cognition; Impairment; Individual; Infarction; Injury; Lasers; Lead; Lesion; Life; Light; Location; MRI Scans; Magnetic Resonance Imaging; Measures; Mediator of activation protein; Methods; Microscopic; Modeling; Molecular; Mus; Neuronal Dysfunction; Neurons; Obstruction; Optics; Outcome; Pathogenesis; Pathologic; Pathology; Perception; Performance; Physiological; Pre-Clinical Model; Process; Radiology Specialty; Reporting; Research; Resolution; Rodent; Role; Sensory; Shapes; Signal Transduction; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Ursidae Family; Vascular Cognitive Impairment; Vibrissae; Work; arteriole; base; brain dysfunction; brain tissue; cerebral microinfarct; cognitive function; cognitive task; cognitive testing; density; excitatory neuron; experimental group; functional disability; gray matter; hemodynamics; in vivo; in vivo calcium imaging; in vivo two-photon imaging; ischemic injury; ischemic lesion; magnetic resonance imaging biomarker; morris water maze; mouse model; novel; novel therapeutics; object recognition; pre-clinical; programs; receptor; relating to nervous system; sensory cortex; sensory system; spatiotemporal; time use; tractography; two photon microscopy; two-photon; vascular cognitive impairment and dementia; vascular factor; white matter; white matter damage; white matter injury

Project Summary. Numerous clinical studies have shown that cerebral microinfarcts are likely contributors to vascular cognitive impairment and dementia (VCID). However, the mechanism by which these small, but prevalent lesions lead to brain-wide neural dysfunction remains unknown. Our central hypothesis is that microinfarct injury leads to neural impairments that extend well beyond the restricted lesion cores seen during histological and radiological examination. These remote effects, when accumulated, are a mechanism by which microinfarcts cause large- scale disruption of brain function and cognitive decline. The rationale of the proposed research is to use a mouse model where the timing and location of microinfarcts can be controlled in order to better understand how they cause brain dysfunction. We plan to examine: i) the spatial extent and chronicity of functional impairments induced by individual microinfarcts, ii) the cumulative effects of multiple microinfarcts, and iii) the cellular/molecular changes that underlie their remote effects. Our model uses state-of-the-art methods for controlled optical occlusion of targeted cortical penetrating arterioles, individually and in multiples, to precisely and non-invasively form small regions of ischemic injury that mimic human microinfarcts. The associated injury processes can then be studied in vivo over time using parallel high-resolution two-photon fluorescence calcium imaging and 7T MRI to reveal detailed aspects of brain pathophysiology that are potentially invisible to MRI or histopathology. We further use behavioral paradigms that are sensitive to microinfarcts to uncover their effects on sensory perception and cognitive function. Aim 1 of the project tests the hypothesis that cortical microinfarcts induce sustained neuronal deficits beyond their lesion core following their strategic induction within the mouse vibrissa sensory system. It further examines whether aberrant change in excitatory-inhibitory balance contributes to these deficits. Aim 2 of the project tests the hypothesis that the accumulation of multiple microinfarcts, spatially distributed throughout the cortices of both cerebral hemispheres, is sufficient to cause subcortical white matter degeneration (assessed in vivo with diffusion MRI tractography and ex vivo with histology) and impairment in cognitive tasks. This work will complement clinical research on VCID in several ways. First, it will provide detailed mechanistic information on how, and to what extent, microinfarcts impair remote brain tissues. Second, it will clarify what aspects of microinfarct injury are visible or invisible to MRI, the primary means to detect these lesions during life. Third, it will provide unique in vivo MRI-ex vivo histopathology comparisons to reveal the underlying biological processes that cause MRI signal change during gray and white matter injury. Fourth, it will establish a first-of-its-kind in vivo experimental platform to study mechanisms of microinfarct-induced pathology and to gauge the utility of new therapeutic agents.

项目摘要。 大量的临床研究表明，脑微梗死可能是血管认知功能障碍的贡献者， 痴呆症（VCID）。然而，这些小而普遍的病变导致 全脑神经功能障碍仍然未知。我们的中心假设是微梗死损伤导致 在组织学和放射学检查中观察到的神经损伤远远超出了限制性病变核心 考试这些远程影响，当积累起来时，是一种机制，通过这种机制，微梗塞引起大的- 大脑功能的大规模破坏和认知能力的下降。拟议研究的基本原理是使用 为了更好地了解微梗死的时间和位置， 它们是如何导致大脑功能障碍的我们计划研究：i）功能的空间范围和长期性 由单个微梗塞引起的损伤，ii）多个微梗塞的累积效应，和iii）微梗塞的累积效应。 细胞/分子的变化，这些变化是其远程效应的基础。 我们的模型使用了最先进的方法来控制目标皮层穿透的光学闭塞 小动脉，单独和多个，精确和非侵入性地形成小区域的缺血性损伤 模拟人类的微梗塞然后，可以在体内研究相关的损伤过程，随着时间的推移， 并行高分辨率双光子荧光钙成像和7 T MRI，以揭示 MRI或组织病理学可能看不到的脑病理生理学。我们进一步使用行为 对微梗塞敏感的范例，以揭示其对感觉知觉和认知的影响， 功能该项目的目的1检验皮质微梗死诱导持续神经元缺损的假设 在小鼠触须感觉系统内的策略性诱导后，它们的损伤核心之外。它进一步 检查是否异常变化兴奋抑制平衡有助于这些赤字。目标2 该项目测试的假设是，多个微梗死的积累，空间分布在整个 两个大脑半球的皮质，足以引起皮质下白色物质变性（在 体内扩散MRI纤维束成像和离体组织学）和认知任务的损害。 这项工作将在几个方面补充VCID的临床研究。首先，它将提供详细的机制 关于微梗塞如何以及在何种程度上损害远端脑组织的信息。第二，它将阐明 微梗死损伤的各个方面对MRI是可见或不可见的，MRI是在脑梗死过程中检测这些病变的主要手段。 生活第三，它将提供独特的体内MRI-离体组织病理学比较，以揭示潜在的 在灰质和白色物质损伤期间引起MRI信号变化的生物过程。第四，建立 这是第一个研究微梗死诱导病理机制的体内实验平台， 评估新治疗药物的效用