Abstract
Inflammatory processes are implicated in the aetiology of Major Depressive Disorder (MDD); however, the relationship between peripheral inflammation, brain structure and depression remains unclear, partly due to complexities around the use of acute/phasic inflammatory biomarkers.Here, we report the first large-scale study of both serological and methylomic signatures of CRP (considered to represent acute and chronic measures of inflammation respectively) and their associations with depression status/symptoms, and structural neuroimaging phenotypes (T1 and diffusion MRI) in a large community-based sample (Generation Scotland; NMDD cases = 271, Ncontrols = 609).Serum CRP was associated with overall MDD severity, and specifically with current somatic symptoms- general interest (β = 0.145, PFDR = 6 × 10−4) and energy levels (β = 0.101, PFDR = 0.027), along with reduced entorhinal cortex thickness (β = −0.095, PFDR = 0.037). DNAm CRP was significantly associated with reduced global grey matter/cortical volume and widespread reductions in integrity of 16/24 white matter tracts (with greatest regional effects in the external and internal capsules, βFA= −0.12 to −0.14). In general, the methylation-based measures showed stronger associations with imaging metrics than serum-based CRP measures (βaverage = −0.15 versus βaverage = 0.01 respectively).These findings provide evidence for central effects of peripheral inflammation from both serological and epigenetic markers of inflammation, including in brain regions previously implicated in depression. This suggests that these imaging measures may be involved in the relationship between peripheral inflammation and somatic/depressive symptoms. Notably, greater effects on brain morphology were seen for methylation-based rather than serum-based measures of inflammation, indicating the importance of such measures for future studies.
Highlights
Major depressive disorder (MDD) is the most common mental health condition in the general population (Whiteford et al, 2013)
We show that serological C-reactive protein (CRP) exhibited significant as sociations with overall current Major Depressive Disorder (MDD) symptoms, in particular somatic symptoms, as measured by Quick Inventory of Depressive Symptomatology (QIDS) scores
In terms of brain morphology, serum CRP was associated with decreased thickness of the entorhinal cortex, whereas DNAm CRP was more robustly associated with wide spread imaging features including decreased global cortical volume, grey matter and decreased white matter integrity, with the greatest loss of integrity in the external capsule and the anterior limb of the internal capsule (ALIC)
Summary
Major depressive disorder (MDD) is the most common mental health condition in the general population (Whiteford et al, 2013). CRP plays a key role in human inflammation and can provide a proxy esti mate for inflammatory activity (Lowe, 2005). It is widely used in clinical practice as a marker of acute inflammation and is a candidate biomarker for investigating inflammatory processes in MDD (Osimo et al, 2019). Meta-analyses have shown that serum CRP levels are reliably elevated in MDD (Valkanova et al, 2013) and have been found to predict future development of depression as well as resistance to standard antide pressant therapies (Au et al, 2015; Chamberlain et al, 2019; Straw bridge et al, 2015)
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