In Vivo Imaging of Cortical Glial Activation Using Advanced Diffusion Magnetic Resonance Imaging

项目摘要 通过神经胶质细胞(小胶质细胞和星形胶质细胞)激活的神经炎症被认为是 在几种精神疾病和神经退行性疾病的发病机制中起关键作用 不同病因的疾病，包括抑郁症、精神分裂症、阿尔茨海默病 多发性硬化症(MS)。尽管如此，目前非侵入性方法检测和 体内神经炎症的特征是有限的。正电子发射断层扫描(PET)- 基于靶向的18 kDa转运蛋白(TSPO)，该蛋白在 激活的胶质细胞，但在健康的大脑中存在于非常低的水平，是 目前的金标准成像在活体胶质细胞激活的人脑。宠物 然而，成像与辐射暴露有关，这限制了它在儿童中的使用 和生育妇女，而且随着时间的推移。 小胶质细胞和星形胶质细胞是能够改变形态和功能的动态细胞 从各种病理性的侮辱中“激活”出来。先进磁力 磁共振(MR)弥散加权成像(DWI)是一种敏感的方法 相关细胞内外微结构变化的侵入性测量 神经胶质细胞被激活。我们开发了一种新型的弥散射多室微结构 用于成像小胶质细胞和星形胶质细胞激活的模型(MCM)，我们在 实验性大鼠灰质炎症模型。 在这里，我们建议将该模型转化为对大脑皮质胶质细胞激活的研究。 健康对照和多发性硬化症患者，并验证在死后多发性硬化症的活体结果 脑组织。MS是一种慢性炎症性和中枢神经退行性疾病。 神经系统是非创伤性神经系统的主要原因 美国年轻人的残疾状况。有确凿证据表明广泛的小胶质细胞 激活是MS皮质病理的主要病理特征。 我们的总体假设是MCM派生的指数对皮质敏感 与神经胶质细胞激活相关的微结构变化与强相关性 第二代TSPO放射性配体11C-PBR28在PET上的TSPO水平，以及 经神经病理学验证。允许调查的非侵入性方法 而表征神经炎症在GM中的作用将有一个 在阐明多发性硬化症的疾病机制方面以及在广泛的 一系列神经和精神疾病。

Project Summary Neuroinflammation by means of glial (microglia and astrocytes) activation is thought to play a key role in the pathogenesis of several psychiatric and neurodegenerative disorders of different etiology including depression, schizophrenia, Alzheimer’s disease and multiple sclerosis (MS). Still, current noninvasive methods to detect and characterize neuroinflammation in vivo are limited. Positron emission tomography (PET)- based targeting of the 18kDa translocator protein (TSPO), which is overexpressed in activated glial cells but otherwise present at very low levels in the healthy brain, is the current gold-standard for imaging in vivo glial activation in the human brain. PET imaging, however, is associated with radiation exposure, which limits its use in children and child-bearing women, and over time. Microglia and astrocytes are dynamic cells able to change morphology and function following “activation” from a variety of pathological insults. Advanced magnetic resonance (MR) diffusion weighted imaging (DWI) is a sensitive approach for non- invasive measurement of intra- and extra-cellular microstructural changes associated with glial activation. We have developed a novel DWI multi-compartment microstructural model (MCM) for imaging microglia and astrocyte activation, which we validated in an experimental rat model of grey matter (GM) inflammation. Here, we propose to translate this model to the study of cortical glial activation in healthy controls and patients with MS, and to validate in vivo findings in post-mortem MS brain tissue. MS is a chronic inflammatory and neurodegenerative disorder of the central nervous system that represents the leading cause of non-traumatic neurological disability in young adults in the US. There is solid evidence that extensive microglia activation is a main pathological feature of cortical pathology in MS. Our overall hypothesis is that MCM-derived indices are sensitive to cortical microstructural changes related to glial activation as evidenced by a strong correlation with TSPO levels on PET with 11C-PBR28, a second generation TSPO radioligand, and by neuropathological verification. A non-invasive methodology that allows investigating and characterizing the contribution of neuroinflammation in the GM will have a tremendous impact in clarifying disease mechanisms in MS, as well as in a wide- spectrum of neurological and psychiatric conditions.