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Title: Exploring the relationship between circulating inflammatory markers and the brain
Author: Krishnadas, Rajeev
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2014
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Over the last decade, there has been a burgeoning interest in clinical research that link psychiatric illnesses - particularly major depressive disorder - to inflammatory processes. Most of the evidence that link inflammation to major depressive disorder in humans come from three observations - a) findings from at least 3 meta-analytic studies suggest that major depressive disorder is associated with elevated circulating inflammatory biomarkers; b) inflammatory illnesses - both central (brain) and peripheral (e.g. arthritis) - are associated with greater rates of major depressive disorder than the general population and c) patients treated with cytokines - both experimentally as well as therapeutically (for cancer or hepatitis) are at greater risk of developing a major depressive illness. As a corollary, anecdotal and experimental evidence suggest that anti-inflammatory medications may have some antidepressant effects. In fact, a number of preclinical studies have provided clues towards potential mechanistic pathways through which inflammatory processes may directly have an effect on the brain, causing changes that may contribute to the aetiopathogenesis of major depressive disorder. The aim of the project was to explore the relationship between circulating (peripheral blood) inflammatory markers and brain structure in humans using state of the art magnetic resonance imaging (MRI) and single photon emission tomography (SPECT). I explored this relationship in two datasets. Firstly, in a series of cross sectional observational analyses on the PSOBID study sample (, I examined the association between circulating inflammatory markers and cortical thickness (MRI - surface based morphometry) in a group of neurologically healthy adult males. I found that circulating inflammatory markers explained significant variance in cortical thickness. Greater inflammatory marker levels were associated with cortical thinning across the cortical mantle. Using mediation analysis, I found that greater circulating inflammatory markers mediated the association between neighbourhood-level deprivation (a high risk condition for major mental illnesses) and cortical thinning. I then used complex network analysis using graph theory to show that greater inflammation mediated the association between neighbourhood-level deprivation and poorer network structural properties of cortical thickness covariance networks. I also showed that greater inflammatory markers mediated the association between neighbourhood deprivation and smaller volumes pertaining to the limbic stress network. Next, in an experimental study, I examined the association between circulating inflammatory markers and serotonin transporters in the midbrain of patients with psoriasis/psoriatic arthritis using SPECT. I found that greater inflammatory marker levels were associated with greater serotonin transporter levels in the midbrain. I also showed that administration of an anti-inflammatory medication (anti-TNF-α agent) was associated with a reduction in the serotonin transporter levels. These findings provide some evidence to suggest that circulating inflammatory markers account for significant differences in cortical thickness and subcortical volumes in the human brain. I have shown that circulating inflammatory markers may mediate the association between high risk conditions - like neighbourhood deprivation and inflammatory medical conditions - and brain changes that may underlie the pathophysiology of major depressive disorder. Future work will focus on cementing the precise role of inflammation in depressive illness, through sophisticated animal models and clinical neuroscience. This may result in potential biomarkers that may facilitate diagnosis, help predict prognosis and aid the development of beneficial treatments for what remains a significantly disabling psychiatric illness.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QH345 Biochemistry