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

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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.