Enhanced Detection of Cerebral Microinfarcts in Dementia Using MRI

描述(申请人提供)：血管性认知障碍(VCI)是一种随着年龄的增长逐渐破坏记忆和认知功能的潜伏性疾病。随着美国老年人口的不断增长，VCI将在未来几十年内成为重大的医疗负担。脑微梗塞是由小脑血管阻塞引起的小脑部病变(直径0.1至3 mm)。据估计，它们在痴呆症大脑中的流行程度是前者的两倍。最近的进展证明了7T磁共振成像(MRI)检测微梗塞的可行性，支持其作为VCI的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、大小和细胞病理的微梗塞联系起来。我们的长期目标是阐明在弥散加权成像(DWI)等MRI方法中产生信号对比的基于微梗塞的组织病理学，以便优化其非侵入性检测。我们的方法是使用活体双光子激光扫描显微镜(TPLSM)对小鼠的微梗塞进行纵向成像，这是一种可以以微米级的精度重复探测完整大脑中的细胞结构的方法。通过结合相同动物的TPLSM和MRI，我们将能够将细胞水平上的特定病理事件与各自的DWI信号联系起来 因为它们随着时间的推移而进化。我们将使用我们开发的一种新的小鼠微梗塞模型，它可以精确地控制病变的大小、位置和发病时间。这项建议的目标是确定胶质细胞的反应性如何影响DWI信号对比度，这是我们追求的长期目标。我们的中心假设是，在微梗塞过程中，小胶质细胞的渗透和星形胶质细胞的增殖引起的德拉马蒂组织密度改变是弥散加权成像信号改变的主要来源。这一假说是基于我们过去的组织学工作提出的，该工作揭示了啮齿动物微梗塞与人类微梗塞一样，在亚急性期几天到几周内密集分布着GFAP阳性的星形胶质细胞和CD68阳性的巨噬细胞。我们将通过两个目标来检验这一假设。在目标1中，我们计划使用TPLSM在两个在这些细胞中特异表达荧光蛋白的转基因小鼠系中表征小胶质细胞和星形胶质细胞在微梗塞生长过程中的反应过程。在目标2中，我们将检验微梗塞特异性DWI信号与TPLSM从相同动物中测量的神经胶质细胞反应性的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)是否可以提高微梗塞检测的灵敏度，与传统的DWI相比。我们的方法是创新的，因为它使用了一种完全在体的策略，通过结合两种强大的成像方式：TPLSM和7T MRI，将微梗塞期间的细胞病理与MRI信号联系起来。这项拟议的研究具有重要意义，因为该结果可以立即影响对DWI所看到的微小异常信号的解释，因此可能会在认知障碍发生之前改善对老年人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.