Immunometabolic dysregulation associates with brain atrophy in depression and predates illness onset

Brisbane Convention & Exhibition Centre 

Depression often presents with co-occurring physical health conditions, including heart disease, diabetes, and obesity. While dysregulation of the immunometabolic system is posited to underpin several of these physical comorbidities, the prevalence and course of immunometabolic dysregulation in depression is poorly understood and its impact on structural brain changes linked to the disorder is unknown. Using brain imaging and high throughput metabolomics data from the UK Biobank, we comprehensively evaluate cross-sectional and longitudinal immunometabolic profiles in depression, including systemic inflammatory markers and metabolites related to lipid, glucose and amino acid metabolism. Crucially, we find that immunometabolic dysfunction predates illness onset (7 years on average), manifesting a relatively persistent pattern over time of elevated inflammation, upregulated very-low-density lipoprotein and lipids, and downregulated high-density lipoprotein. We also map network-level systemic changes in metabolites in depression, implicating the core role of glycolysis. We show that peripheral immunometabolic dysfunction, particularly elevated inflammation, is associated with brain gray matter atrophy. We conclude that altered lipids and inflammatory markers predate the onset of depression, remain altered throughout the illness course, and explain the severity of brain atrophy. By comprehensively profiling immunometabolic dysfunction in depression and related brain changes, our work highlights the importance of treating chronic low-grade inflammation and altered lipid and glucose metabolism in the disorder.