Investigating the role of chronic inflammation and stress on the neurobiological features of major depressive disorder
Item statusRestricted Access
Embargo end date28/09/2023
Green, Claire Caroline Lorraine
Chronic inflammation and stress are both implicated in the aetiology of Major Depressive Disorder (MDD); however, the relationships between inflammation, stress hormones, brain structure and depression remain unclear, partly due to complexities around the use of acute/phasic biomarkers. The current thesis presents neurobiological associations with two stable longer-term biomarkers of inflammation and stress and their associations with depression status and symptoms in a large subgroup of Generation Scotland with imaging data (N~1000). The first two research chapters focus on a DNA methylation (DNAm) marker of C-reactive protein (CRP). The first of these studies presents associations between markers of inflammation, structural neuroimaging phenotypes (T1 and DTI MRI) and depression symptoms. Serum CRP was significantly associated with somatic symptoms of depression and reduced entorhinal cortex thickness, whereas DNAm CRP was robustly associated with imaging markers of widespread decreased structural white matter integrity and had larger effect sizes overall than the serum measure of CRP. Inflammation has also been linked to advanced ageing termed ‘inflammaging’, including cognitive decline and brain atrophy. Furthermore, MDD has also been associated with advanced ageing trajectories, however, the potential involvement of inflammation in this association remains unclear. In the second study I therefore investigated associations between DNAm CRP, depression (MDD) and markers of brain ageing (brain age and white matter hyperintensity scores) in the Generation Scotland imaging subgroup. DNAm CRP was found to be significantly associated with increased brain age controlling for sex, age, study site, smoking status and body mass index. These findings were also replicated in an independent sample: the Lothian Birth Cohort 1936 (LBC1936), with a similar effect size. Depression was associated with increased white matter hyperintensities (WMH) in the frontal and parietal lobes, however, there were no interaction effects between inflammation and MDD on any WMH measure. This study indicates that while inflammation and MDD both have associations with brain ageing phenotypes, the inflammation- related brain ageing associations weren’t specific to MDD in this relatively well community-based sample. Glucocorticoids are also known to modulate inflammatory activity and may play a key role in the association between inflammation and MDD symptomatology. The final research chapter therefore utilised a temporally stable measure of glucocorticoids from hair which does not show the highly phasic diurnal variation of blood/saliva measures of glucocorticoids. I investigated hair glucocorticoid associations (cortisol/cortisone and their total) with depression, childhood adversity and structural neuroimaging-derived phenotypes (T1 and DTI MRI). Hair cortisone was significantly associated with MDD status/symptoms, childhood adversity (emotional abuse and physical neglect), reduced global cortical volumes and regionally was associated with decreased nucleus accumbens volume. Hair cortisol was more strongly associated with structural neuroimaging features including decreased global volumes and decreased frontal, temporal and cingulate volumes. These findings provide important foundations for future mechanistic studies to formally explore causal relationships between early-life adversity, chronic rather than acute measures of glucocorticoids, and neurobiological associations relevant to the aetiology of MDD. In summary, this thesis has found links between inflammation and somatic symptoms of depression and changes in brain structure including white matter connectivity. Longer-term measures of stress were also robustly associated with depression, early-life adversity and changes in grey matter volumes, indicating that both stress and inflammation have important associations with MDD and the brain which requires further research in terms of mechanisms and causality.