Enhanced Detection of Cerebral Microinfarcts in Dementia Using MRI

项目摘要。 血管性认知障碍（VCI）是一种渐进性损害记忆和认知功能的隐匿性疾病， 功能随着年龄的增长。随着美国老年人口的不断增长，VCI将成为一个重大的医疗保健负担 在未来几十年内。脑微梗死是一种小的脑病变（直径0.1至3 mm）， 小的脑血管阻塞据估计，在痴呆症患者的大脑中，这种现象的普遍性是正常人的两倍。 最近的进展已经证明了7T磁共振检测微梗死的可行性 这一结果支持了它们作为VCI的成像生物标志物的潜力。然而，电流的一个关键障碍 进展是无法将这些异常信号与特定年龄，大小和细胞的微梗死联系起来， 病理我们的长期目标是阐明基于微梗死的组织病理学， MRI方法中的对比度，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死进行纵向成像， 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。通过结合相同动物的TPLSM和MRI，我们将能够将特定的 在细胞水平上的病理事件与相应的DWI信号，因为它们随着时间的推移而演变。我们将使用一个 我们开发的一种新的小鼠微梗死模型，它提供了对病变的精确控制， 大小位置和发病时间这项建议符合我们的长远目标，目的是 确定神经胶质细胞的反应性如何影响DWI信号对比度。我们的核心假设是， 小胶质细胞浸润和星形胶质细胞增殖引起的显著组织密度变化， 微梗死是DWI信号改变的主要来源。这个假设是基于我们的过去 组织学研究表明，啮齿类动物的微梗塞，像人类的微梗塞一样， GFAP阳性星形胶质细胞和CD68阳性巨噬细胞在亚急性期数天至数周。我们将 用两个目标来检验假设。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， 在两个转基因小鼠系中使用TPLSM观察微梗塞生长期间的反应性， 这些细胞中的荧光蛋白。在目标2中，我们将研究微梗死特异性DWI与 信号和通过TPLSM测量的来自相同动物的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 微梗死检测，与传统DWI相比。我们的方法是创新的，因为它使用了 在微梗死期间，通过结合两种完全体内策略将细胞病理学与MRI信号联系起来， 强大的成像模式：TPLSM和7T MRI。这项研究意义重大，因为结果 可以立即影响DWI看到的小异常信号的解释，因此可以改善 在老年人出现认知障碍之前检测VCI。

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.