Imaging antibody effects in SLE patients

项目摘要/摘要--项目2 据报道，系统性红斑狼疮患者的认知障碍患病率为30%-80%，行为障碍 变化从17%到75%不等，对生活质量和个人有显著影响 生产力。该计划的一个假设是，自身抗体与 DsDNA和NMDA受体，DNRAb，有助于认知和行为障碍 SLE患者。项目2的目标是继续开发FDG-PET作为生物标记物 对于NPSLE患者的认知和行为障碍，并利用其他新的成像技术 以加深对DNRAb作用于脑的相关病理机制的了解。 静息脑葡萄糖代谢的FDG-PET横断面研究显示异常 系统性红斑狼疮患者海马区的高代谢。海马区高代谢和 血清DNRAb滴度升高对记忆有更高的预测价值 这两个变量中的任何一个都不是单独的损伤。这是始终如一且健壮的 既反映功能受损状态又反映拟议致病因素的影像表现 NPSLE的发病机制。项目2中提出的纵向研究将进行验证和扩展 这些联想。系统性红斑狼疮队列中的受试者将被选择服用一系列血清 DNRAb滴度在正常滴度到高滴度的范围内均匀分布。建议数 纵向研究将告诉我们随着时间的推移认知和行为变化的相关性 使用FDG-PET成像(目标1)。此外，我们还将探索人类的NMDAR生物学 具有新的PET配体[11C]-CNS5161的受试者用于定位和定量NMDAR 激活(目标2)，并探讨血脑屏障(BBB)完整性在认知和 行为障碍(目标3)。这些研究补充了项目1中提议的研究 这将为探索小鼠海马区高代谢的分子细胞基础奠定基础。 容易获得组织的模型。在进行这些纵向研究时，我们亦会 确定对疾病进展具有敏感性的最佳生物标志物，可用作 临床试验的指标。

PROJECT SUMMARY/ABSTRACT - PROJECT 2 Reported prevalence of cognitive impairment in SLE ranges from 30-80% and behavioral alterations range from 17-75% with significant effects on quality of life and individual productivity. A hypothesis of this Program Grant is that autoantibodies cross-reactive with dsDNA and NMDA receptors, DNRAbs, contribute to cognitive and behavioral impairment in SLE patients. The goals of Project 2 are to continue development of FDG-PET as a biomarker for cognitive and behavioral impairment in NPSLE and to utilize other novel imaging techniques to enhance our understanding of pathologic mechanisms related to DNRAb effects on the brain. Cross-sectional FDG-PET studies of resting brain glucose metabolism demonstrate abnormal hypermetabolism in the hippocampus of SLE subjects. Hippocampus hypermetabolism and elevated serum titers of DNRAb combined have a higher predictive value for memory impairment than either variable alone. This is the first example of a consistent and robust imaging finding that reflects both impaired functional status and a proposed pathogenic mechanism in NPSLE. The longitudinal study proposed in Project 2 will validate and extend these associations. Subjects in the SLE cohort will be selected to have a range of serum DNRAb titers that is equally distributed across a spectrum of normal to high titers. The proposed longitudinal study will inform us about correlates of cognitive and behavioral change over time using FDG-PET imaging (Aim 1). Additionally, we will explore NMDAR biology in human subjects with a novel PET ligand, [11C]-CNS5161, used to localize and quantify NMDAR activation (Aim 2) and explore the role of blood brain barrier (BBB) integrity in cognitive and behavioral impairment (Aim 3). These studies complement the studies proposed in Project 1 that will explore the molecular and cellular basis for the hippocampal hypermetabolism in mouse models where tissue is readily available. In conducting these longitudinal studies, we will also determine the best biomarker with sensitivity for disease progression that can be used as a metric for a clinical trial.