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，目前的非侵入性方法来检测和 在体内表征神经炎症是有限的。正电子发射断层扫描（PET）- 基于18 kDa转运蛋白（TSPO）的靶向，TSPO在大肠杆菌中过表达。 激活的神经胶质细胞，但在健康的大脑中以非常低的水平存在， 目前的金标准成像在人脑中的体内神经胶质激活。宠物 然而，成像与辐射暴露有关，这限制了其在儿童中的使用 和生育妇女，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 在各种病理损伤的“激活”之后。先进的磁 磁共振（MR）弥散加权成像（DWI）是一种敏感的方法， 相关的细胞内和细胞外微结构变化的侵入性测量 神经胶质细胞激活。我们开发了一种新型的DWI多室显微结构 模型（MCM）的成像小胶质细胞和星形胶质细胞激活，我们在一个验证， 实验性大鼠灰质（GM）炎症模型。 在这里，我们建议将这个模型转化为大脑皮层神经胶质细胞激活的研究， 健康对照和MS患者，并验证死后MS的体内发现 脑组织MS是中枢神经系统的慢性炎症性和神经退行性疾病， 神经系统，代表非创伤性神经系统疾病的主要原因 美国年轻人的残疾。有确凿的证据表明，广泛的小胶质细胞 激活是MS中皮质病理的主要病理特征。 我们的总体假设是，MCM衍生指数对皮质 与神经胶质活化相关的显微结构变化，证据为强相关性 用11 C-PBR 28（第二代TSPO放射性配体）在PET上测定TSPO水平， 通过神经病理学验证。一种非侵入性的方法， 并描述GM中神经炎症的贡献将有一个 巨大的影响，在澄清疾病机制的MS，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.