Enhanced Detection of Cerebral Microinfarcts in Dementia Using MRI

使用 MRI 增强痴呆症脑微梗死的检测

• 批准号: 8619678
• 负责人: Andy Y Shih
• 金额: $ 18.69万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8619678
• 关键词: Acute; Age; Aging; Animal Model; Animals; Astrocytes; Basic Science; Beds; Biological Markers; Biological Models; Brain; Brain imaging; Caliber; Cell Aggregation; Cells; Cellular Structures; Cerebral cortex; Cerebrum; Chronic; Data; Decision Making; Dementia; Detection; Diagnosis; Diffusion weighted imaging; Disease; Early Diagnosis; Elderly; Etiology; Event; Exhibits; Functional disorder; Future; Glial Fibrillary Acidic Protein; Goals; Growth; Healthcare; Human; Image; Imaging Device; Imaging Techniques; Impaired cognition; Individual; Infiltration; Inflammatory; Injury; Ischemia; Knowledge; Laser Scanning Microscopy; Lesion; Life; Link; Location; Magnetic Resonance Imaging; Measures; Memory; Methods; Modality; Mus; Neuroglia; Non-Invasive Cancer Detection; Obstruction; Outcome; Pathology; Population; Proteins; Public Health; Research; Resolution; Risk; Rodent; Signal Transduction; Source; Staging; Structure; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Validation; Vascular Cognitive Impairment; Work; aged; base; cellular pathology; cognitive function; density; gray matter; imaging modality; improved; in vivo; innovation; macrophage; mouse model; neuroimaging; novel; public health relevance; research clinical testing; spatiotemporal; therapy development; tool; translational approach; two-photon

Project summary. Vascular cognitive impairment (VCI) is an insidious disease that progressively destroys memory and cognitive function with age. With a growing elderly population in the US, VCI will become a significant healthcare burden within the coming decades. Cerebral microinfarcts are small brain lesions (0.1 to 3 mm in diameter) that arise from obstruction of small cerebral vessels. They are estimated to be twice as prevalent in the demented brain. Recent advances have demonstrated the feasibility of detecting microinfarcts with 7T magnetic resonance imaging (MRI), supporting their potential as imaging biomarkers of VCI. However, a critical barrier for current progress is an inability to link these anomalous signals with microinfarcts of a specific age, size, and cellular pathology. Our long-term goal is to elucidate microinfarct-based tissue pathologies that generate signal contrast in MRI methods such as diffusion-weighted imaging (DWI), in order to optimize their detection non- invasively. Our approach is to longitudinally image microinfarcts in mice using in vivo two-photon laser- scanning microscopy (TPLSM), a method that can repeatedly probe cellular structure in the intact brain with micrometer precision. By combining TPLSM and MRI of the same animals, we will be able to link specific pathological events at the cellular level with respective DWI signals as they evolve over time. We will use a novel mouse model of microinfarction that we have developed, which provides exquisite control over lesion size, location, and timing of onset. The objective of this proposal, which is in pursuit of our long-term goal, is to determine how the reactivity of glial cells can influence DWI signal contrast. Our central hypothesis is that dramatic tissue density change caused by microglial infiltration and astroglial proliferation during microinfarction is a principle source of DWI signal change. This hypothesis is formulated based on our past histological work, which revealed that rodent microinfarcts, like human microinfarcts, are densely packed with GFAP-positive astrocytes and CD68-positive macrophages in the sub-acute period of days to weeks. We will test the hypothesis with two Aims. In Aim 1, we plan to characterize the time-course of microglial and astroglial reactivity during microinfarct growth using TPLSM in two transgenic mouse lines that specifically express fluorescent proteins in those cells. In Aim 2, we will examine the correlation between microinfarct-specific DWI signal and the spatiotemporal change in glial reactivity measured by TPLSM from the same animals. Finally, we will test whether a new DWI technique, diffusional kurtosis imaging (DKI) can improve the sensitivity of microinfarct detection, compared to conventional DWI. Our approach is innovative because it uses a completely in vivo strategy to link cellular pathology with MRI signals during microinfarction by combining two powerful imaging modalities: TPLSM and 7T MRI. The proposed research is significant because the results can immediately impact the interpretation of small anomalous signals seen by DWI, and may therefore improve detection of VCI in aged individuals before the onset of cognitive impairment.

项目总结。 血管性认知障碍（VCI）是一种隐匿的疾病，会逐渐破坏记忆和认知能力 功能随年龄增长。随着美国老年人口的不断增加，VCI 将成为重大的医疗负担 未来几十年内。脑微梗死是指发生的小脑损伤（直径 0.1 至 3 毫米） 由于小脑血管阻塞。据估计，它们在痴呆大脑中的患病率是正常人的两倍。 最近的进展证明了利用 7T 磁共振检测微梗塞的可行性 成像 (MRI)，支持其作为 VCI 成像生物标志物的潜力。然而，当前的一个关键障碍 进展是无法将这些异常信号与特定年龄、大小和细胞的微梗塞联系起来 病理。我们的长期目标是阐明产生信号的基于微梗塞的组织病理学 对比 MRI 方法，例如扩散加权成像 (DWI)，以优化其检测非 侵入性地。我们的方法是使用体内双光子激光对小鼠的微梗塞进行纵向成像 扫描显微镜（TPLSM），一种可以重复探测完整大脑中细胞结构的方法 微米精度。通过结合同一动物的 TPLSM 和 MRI，我们将能够将特定的 细胞水平上的病理事件以及随时间演变的相应 DWI 信号。我们将使用一个 我们开发的新型小鼠微梗塞模型，可对病变提供精确的控制 大小、位置和发作时间。该提案的目的是为了实现我们的长期目标 确定神经胶质细胞的反应性如何影响 DWI 信号对比度。我们的中心假设是 小胶质细胞浸润和星形胶质细胞增殖引起的组织密度急剧变化 微梗塞是 DWI 信号变化的主要来源。这个假设是根据我们过去的经验提出的 组织学工作表明，啮齿动物的微梗塞，就像人类的微梗塞一样，密集地充满了 数天至数周的亚急性期 GFAP 阳性星形胶质细胞和 CD68 阳性巨噬细胞。我们将 用两个目标检验假设。在目标 1 中，我们计划描述小胶质细胞和星形胶质细胞的时间过程。 使用 TPLSM 在两个特异性表达的转基因小鼠系中观察微梗死生长期间的反应性 这些细胞中的荧光蛋白。在目标 2 中，我们将检查微梗塞特异性 DWI 之间的相关性 通过 TPLSM 测量同一动物的信号和神经胶质反应性的时空变化。最后， 我们将测试一种新的 DWI 技术——扩散峰度成像 (DKI) 是否可以提高 与传统 DWI 相比，微梗塞检测。我们的方法是创新的，因为它使用了 通过结合两种方法，在微梗死期间将细胞病理学与 MRI 信号联系起来的完全体内策略 强大的成像方式：TPLSM 和 7T MRI。拟议的研究意义重大，因为结果 可以立即影响 DWI 所见小异常信号的解释，因此可能会改善 在老年人出现认知障碍之前检测 VCI。