Enhanced Detection of Cerebral Microinfarcts in Dementia Using MRI

描述（由申请人提供）：血管性认知障碍（VCI）是一种随着年龄增长逐渐破坏记忆和认知功能的隐匿性疾病。随着美国老年人口的不断增长，VCI将在未来几十年内成为一个重大的医疗负担。脑微梗塞是由脑小血管阻塞引起的脑小病变（直径0.1至3 mm）。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磁共振成像（MRI）检测微梗死的可行性，支持其作为VCI成像生物标志物的潜力。然而，目前进展的一个关键障碍是无法将这些异常信号与特定年龄、大小和细胞病理学的微梗死联系起来。我们的长期目标是阐明基于微梗死的组织病理学，这些病理学在MRI方法（如扩散加权成像（DWI））中产生信号对比，以优化其非侵入性检测。我们的方法是使用体内双光子激光扫描显微镜（TPLSM）对小鼠的微梗塞进行纵向成像，这种方法可以以微米精度重复探测完整大脑中的细胞结构。通过结合相同动物的TPLSM和MRI，我们将能够在细胞水平上将特定的病理事件与各自的DWI信号联系起来 随着时间的推移而演变。我们将使用一种新的小鼠微梗死模型，我们已经开发，它提供了精致的控制病变的大小，位置和发病时间。本提案的目的是为了实现我们的长期目标，即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，在微梗死过程中小胶质细胞浸润和星形胶质细胞增殖引起的戏剧性组织密度变化是DWI信号变化的主要来源。这一假设是基于我们过去的组织学工作制定的，其揭示了啮齿动物微梗死，如人类微梗死，在亚急性期的几天到几周内密集地挤满了GFAP阳性星形胶质细胞和CD68阳性巨噬细胞。我们将用两个目标来检验这个假设。在目标1中，我们计划在两个转基因小鼠品系，特异性表达荧光蛋白的细胞中，使用TPLSM来表征微梗死生长过程中小胶质细胞和星形胶质细胞反应性的时间过程。在目标2中，我们将研究微梗死特异性DWI信号与TPLSM测量的相同动物胶质反应性时空变化之间的相关性。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的灵敏度，与传统DWI相比。我们的方法是创新的，因为它使用了一个完全在体内的策略，通过结合两种强大的成像模式：TPLSM和7T MRI，在微梗死期间将细胞病理学与MRI信号联系起来。这项拟议的研究意义重大，因为其结果可以立即影响DWI看到的微小异常信号的解释，因此可能会改善老年人在认知障碍发生之前对VCI的检测。

DESCRIPTION (provided by applicant): 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 t 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 dramati 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.