Longitudinal imaging of microglial activation in different clinical variants of Alzheimer's disease

项目摘要/摘要。虽然神经炎症被认为是阿尔茨海默病(AD)的一个因素， 炎症、tau病理和神经变性残留物之间的时空关系 不清楚。我们的长期目标是了解如何利用小胶质细胞的反应来预测和监测AD 进展，并有可能被操纵用于治疗目的。我们的目标是确定小胶质细胞 用PET成像测量的激活与tau病理和tau病理在空间和时间上相关 阿尔茨海默病的神经退行性变。我们的中心假设是小胶质细胞生物标记物TSPO与tau相关 病理和神经退行性变，并先于tau和神经退行性变的扩散 纵向的。我们还假设新出现的脑脊液生物标记物YKL-40和sTREM2与TSPO相关 密度，强化了TSPO增加是病理性炎症信号的论点。我们的理论基础 这表明炎症机制是如何在时间上与tau病理和 神经退行性变将确定免疫调节疗法最有益的时间点。 在先前关于AD的TSPO研究中，不一致的部分原因可能是发病年龄、模式的异质性 纳入患者的认知障碍和神经退行性变的地形图。为了克服这些困惑， 我们将招募具有特定临床变种的AD患者-遗忘性AD、后部皮质萎缩(PCA)和 对数遗传性变异型原发性进行性失语(LvPPA)。通过这种招聘方式，我们将获得相对 疾病预计有焦点震中并以可预测的神经解剖学方式传播的统一队列 分发。我们将获得TSPO和tau PET，神经退行性变的MRI标记物，以及 在一项为期两年的纵向研究中，PCa、lvPPA和遗忘性AD患者以及对照组的炎症反应。这个 具体目标是1)确定不同AD亚型的小胶质细胞激活的局部模式，2) 确定不同阿尔茨海默病患者神经炎症和tau病理的时空关系 亚型，以及3)决定了神经炎症和基于MRI的时间和空间关系 阿尔茨海默病不同亚型的神经变性标志物。对于第一个目标，我们将使用状态- 最先进的放射性配基11C-ER176，与早期的示踪剂相比具有实质性的优势，并已通过 我们实验室在AD患者中。在第二个目标中，我们将使用改进的放射性配体18F-MK-6240来测量 陶氏病理学。在第三个目标中，我们将使用新的降维和多元统计方法 将TSPO与tau病理和基于MRI的神经退行性变生物标记物联系起来，这是一项无偏见的、数据驱动的、 和严谨的态度。我们的创新方法在临床上同时使用了PET和CSF两种炎症测量方法 同质队列，和新的统计程序，将TSPO与tau病理和神经变性联系起来。 这项拟议的研究具有重要意义，因为它将为使用TSPO PET预测和监测AD进展提供信息 和对新疗法的反应，并为未来的炎症靶点提供一个强大的成像生物标志物。

Project Summary/Abstract. While neuroinflammation is a proposed contributor to Alzheimer's disease (AD), the spatial and temporal relationship among inflammation, tau pathology and neurodegeneration remains unclear. Our long-term goal is to understand how microglial responses can be used to predict and monitor AD progression and potentially be manipulated for therapeutic purposes. Our objective is to determine how microglial activation, measured with PET imaging, is spatially and temporally related to tau pathology and neurodegeneration in AD. Our central hypothesis is that the microglial biomarker TSPO correlates with tau pathology and neurodegeneration cross-sectionally, and precedes the spread of tau and neurodegeneration longitudinally. We also postulate that the emerging CSF biomarkers YKL-40 and sTREM2 correlate with TSPO density, strengthening the argument that increased TSPO is a signal of pathological inflammation. Our rationale is that demonstrating how inflammatory mechanisms temporally correlate with tau pathology and neurodegeneration will identify time-points where immune-modulating therapeutics would be most beneficial. Inconsistencies in prior TSPO studies in AD are likely due in part to heterogeneity of age-of-onset, pattern of cognitive impairment, and topography of neurodegeneration in included patients. To overcome these confounds, we will enroll patients with specific clinical variants of AD – amnestic AD, posterior cortical atrophy (PCA), and logopenic variant primary progressive aphasia (lvPPA). With this recruitment approach, we will acquire relatively uniform cohorts where disease is expected to have focal epicenters and spread in a predictable neuroanatomic distribution. We will acquire TSPO and tau PET, MRI markers of neurodegeneration, and CSF markers of inflammation in PCA, lvPPA, and amnestic AD patients, and in controls in a two-year longitudinal study. The specific aims are 1) Determine the topographical pattern of microglial activation in different AD subtypes, 2) Determine the spatial and temporal relationships between neuroinflammation and tau pathology in different AD subtypes, and 3) Determine the spatial and temporal relationship between neuroinflammation and MRI-based markers of neurodegeneration in different AD subtypes. For the first aim, we will measure TSPO using the state- of-the-art radioligand 11C-ER176, which has substantial advantages over earlier tracers and has been tested by our laboratory in AD patients. In the second aim, we will use the improved radioligand 18F-MK-6240 to measure tau pathology. In the third aim, we will use novel dimensionality reduction and multivariate statistical procedures to relate TSPO to tau pathology and MRI-based biomarkers of neurodegeneration in an unbiased, data-driven, and rigorous manner. Our innovative approach uses both PET and CSF measures of inflammation, clinically homogeneous cohorts, and novel statistical procedures to relate TSPO to tau pathology and neurodegeneration. The proposed research is significant, as it will inform use of TSPO PET to predict and monitor AD progression and response to novel therapeutics, and provide a robust imaging biomarker for future inflammatory targets.