Longitudinal Immune Dysregulation in Low-Weight Eating Disorders and Association with Weight Fluctuations

项目摘要 这项小额拨款计划的目标是调查青少年炎症标志物的纵向变化。 和患有低体重饮食紊乱的年轻人(LW-EDS)与(1)体重变化和(2)奖励的关系 神经回路被激活。低体重饮食紊乱(LW-EDS)；包括神经性厌食症及相关 非典型变种是最致残和致命的精神疾病之一，在青春期很常见 (~15%)，并经常演变为慢性病。新出现的临床前工作支持参与 对饥饿和体重变化的反应中的炎症标志物，提示炎症特征 可能代表一个州特有的生物标记物，区分疾病的急性阶段。我们之前的流行病学 研究提供了与健康体重对照组(HC)相比，LW-EDS患者免疫失调的证据。更多 最近，使用一种新的蛋白质组血浆图谱方法，我们的横截面试点数据表明 20个蛋白炎症标志物的水平区分LW-EDs和HC，提示炎症在 LW-EDS可能是状态依赖的。来自临床前研究的其他数据提供了炎症性的证据 标志物主要作用于与食欲和奖赏有关的区域，如伏隔核(NAcc)和 海马体，表明异常炎症蛋白可能通过哪些途径影响食物摄入量和 推动LW-EDS的重量变化。然而，在对炎症的纵向过程的理解上存在差距。 LW-EDs的蛋白质组学特征以及炎症特征与食物奖赏回路的关系 在LW-EDS中发挥作用。我们的中心假设是LW-EDS中的异常炎症(1)代表一种状态 由体重减轻驱动的生物标记物，以及(2)与食物奖励网络的失调有关(海马体， DLPFC、NAcc、dACC)。在患有LW-EDS并增加体重的个体中，我们预测食物奖励的中断 神经回路和炎症蛋白谱将稳定(抗炎蛋白表达水平 增加，促炎水平降低)。利用最近完成的R01(MH103402)，其中 炎症蛋白图谱已经在BL进行了表征，这个二次数据分析将检查 101例女性青少年/青壮年(11.1-22.5岁)9-14岁LW-EDS(n=61)和HC(n=40)的概况 使用一种新的蛋白质组学血浆图谱方法进行一个月(9M)的随访(9M)以表征STORED中的图谱 血清学样本。这将允许(1)调查9米处的剖面，以及(2)纵向分析(BL至 9m)。将结合体重从BL到9米的变化、临床特征来研究侧写 (包括饥饿和饱腹感评级)和fMRI食物提示反应性数据。年龄匹配的健康对照将是 用作阴性对照组，以确定炎症特征的变化是否特定于LW- ED组，而不是随时间的随机波动。这项提案将确定州特有的生物标记物和 低体重进食障碍(LW-EDs)的治疗目标，这是众所周知的具有挑战性的障碍的治疗。

Project Summary The goal of this small grant proposal is to investigate longitudinal changes in inflammatory markers in adolescents and young adults with low-weight eating disorders (LW-EDs) in relation to (1) weight change and (2) reward neural circuitry activation. Low-weight eating disorders (LW-EDs); including anorexia nervosa and related atypical variants, are among the most disabling and fatal psychiatric illnesses, are common in adolescence (~15%), and often evolve into a chronic condition. Emerging preclinical work supports the involvement of inflammatory markers in response to starvation and changes in body weight, suggesting inflammatory profiles may represent a state-specific biomarker demarcating the acute stage of illness. The Our prior epidemiological work provides evidence of immune dysregulation in LW-EDs compared to healthy-weight controls (HC). More recently, using a novel proteomic plasma profiling approach, our cross-sectional pilot data demonstrate that levels of 20 protein inflammation markers distinguish between LW-EDs and HC, suggesting that inflammation in LW-EDs might be state-dependent. Additional data from pre-clinical studies provides evidence that inflammatory markers act centrally on regions involved in appetite and reward such as the nucleus accumbens (NAcc) and hippocampus, indicating pathways through which aberrant inflammatory proteins might impact food intake and drive weight change in LW-EDs. However, there is a gap in understanding the longitudinal course of inflammation proteomic profiles in, LW-EDs and relationships between inflammatory profiles and food reward circuitry functioning in LW-EDs. Our central hypothesis is that aberrant inflammation in LW-EDs (1) represents a state biomarker driven by weight loss, and (2) is associated with dysregulation in food reward networks (hippocampus, DLPFC, NAcc, dACC). Among individuals with LW-EDs who gain weight, we predict that disruption in food reward neural circuitry and inflammation protein profiles will stabilize (anti-inflammatory protein expression levels increase, and pro-inflammatory levels decrease). Leveraging a recently completed R01 (MH103402) in which inflammation protein profiles have already been characterized at BL, this secondary data analysis will examine profiles of 101 female adolescents/young adults (11.1-22.5 years) with LW-EDs (n=61) and HC (n=40) at 9- month follow-up (9M) using a novel proteomics plasma profiling approach to characterize profiles in stored serological samples. This will allow for (1) investigation of profiles at 9M, and (2) longitudinal analyses (BL to 9M). Profiles will be investigated in combination with weight change from BL to 9M, clinical characteristics (including hunger and satiety ratings), and fMRI food cues reactivity data. Age-matched healthy controls will be used as a negative control group to determine whether changes in inflammatory profiles are specific to the LW- ED group, rather than random fluctuations over time. This proposal will identify state-specific biomarkers and therapeutic targets in low-weight eating disorders (LW-EDs), which are notoriously challenging disorders to treat.