Enhanced Detection of Cerebral Microinfarcts in Dementia Using MRI

项目总结。 血管性认知障碍(VCI)是一种渐进性损害记忆和认知的潜伏性疾病 随着年龄的增长而发挥作用。随着美国老年人口的增长，VCI将成为重大的医疗负担 在未来几十年内。脑微梗塞是指出现的小脑部病变(直径0.1至3毫米)。 由小脑血管阻塞引起。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磁共振检测微小脑梗塞的可行性 成像(MRI)，支持它们作为VCI的成像生物标记物的潜力。然而，当前的一个关键障碍是 进展是不能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。 病理学。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 对比度在磁共振成像方法中，如弥散加权成像(DWI)，以优化其检测非 侵犯性的。我们的方法是使用活体双光子激光纵向成像小鼠的微梗塞- 扫描显微镜(TPLSM)，一种可以重复探测完整大脑中的细胞结构的方法 千分尺精度。通过结合TPLSM和相同动物的MRI，我们将能够将特定的 随着时间的推移，细胞水平的病理事件与各自的DWI信号一起变化。我们将使用 我们开发的新的小鼠微梗塞模型，它提供了对病变的精细控制 发作的大小、位置和时间。这项建议的目的是追求我们的长期目标，即 确定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显著变化 微梗塞是DWI信号改变的主要来源。这一假说是根据我们的过去提出的 组织学研究表明，啮齿动物的微梗塞，就像人类的微梗塞一样，密集地挤满了 亚急性期星形胶质细胞和CD68阳性巨噬细胞表达GFAP和CD68。我们会 用两个目标来检验这一假设。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进程。 TPLSM在两个特异性表达的转基因小鼠系微梗塞生长过程中的反应性 这些细胞中的荧光蛋白。在目标2中，我们将检验微梗塞特异性弥散加权成像之间的相关性。 信号和TPLSM从同一动物测量的神经胶质细胞反应性的时空变化。最后， 我们将测试一种新的DWI技术，扩散峰度成像(DKI)是否可以提高对 与常规的弥散加权成像相比，微梗塞的检测。我们的方法是创新的，因为它使用了 将微梗塞期间的细胞病理与MRI信号相结合的完全在体策略 强大的成像方式：TPLSM和7T MRI。这项拟议的研究意义重大，因为 可以立即影响对DWI所看到的微小异常信号的解释，因此可能会改善 老年人认知功能障碍发病前的VCI检测

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.