Neuroinflammmation in alcohol dependence

Abstract

Alcohol dependence damages the brain through a multiplicity of factors including thiamine deficiency, liver disease, head injuries, and repeated episodes of alcohol withdrawal. Alcohol withdrawal is a potential opportunity for reducing damage as it is an intensive time of contact between doctors and patients. Pre-clinical models of alcohol dependence have demonstrated activation of microglia, resident tissue macrophages, and expression of cytokines and other inflammatory mediators both in the brain and peripheral blood during alcohol withdrawal. These changes were associated with neuronal death, and learning deficits. Similar processes may occur in man as increased microglial numbers, increased chemokine expression and raised circulating pro-inflammatory cytokines have been reported in alcohol dependence. The aim of the thesis was to characterise the peripheral cytokine profile during alcohol detoxification, to investigate whether there are relationships between peripheral cytokines and clinical features of alcohol withdrawal, to investigate neuroinflammation in alcohol dependence by using [11C]PBR28 Positron Emission Tomography to assess microglial activation in recently abstinent alcohol dependent patients in vivo and to investigate how these processes relate to elevated cortisol and elevated cerebral glutamate reported in alcohol withdrawal respectively. The longitudinal study undertaken in 51 alcohol dependent patients during detoxification demonstrated that both pro- and anti-inflammatory cytokines, and chemokines, decreased significantly during detoxification while T cell cytokines increase. IL-6 was positively associated with withdrawal severity and depressive symptoms during withdrawal. The chemokine CCL-2 was positively associated with performance on cognitive tasks. Serum cortisol was in the high normal range and decreased during detoxification. The salivary Cortisol Awakening Response (CAR) was also in the normal range at all time points. Both serum cortisol and the CAR were positively correlated with IL-6 concentrations suggesting hyperfunction of the HPA axis during alcohol detoxification may relate in part to inflammatory stimulation. The PET study comparing alcohol dependent men in early abstinence and healthy controls was undertaken using the ligand, [11C]PBR28 that binds to the Translocator Protein 18 kDa (TSPO) richly expressed in microglia. Alcohol dependent patients had lower TSPO binding in the hippocampi than healthy controls. TSPO binding in the hippocampus was also positively correlated with performance on tests of verbal memory. This suggests that hippocampal microglial loss or dysfunction may be related to memory problems in alcohol dependence. Given that benzodiazepines are used to treat alcohol withdrawal, an in vitro binding study was conducted to investigate whether benzodiazepines would significantly block [11C]PBR28 binding and found that benzodiazepines do not block a significant proportion of TSPO at all but the highest clinical doses. The relationship between brain glutamate, as measured with Magnetic Resonance Spectroscopy, and microglial activation was investigated. Alcohol dependent patients had significantly lower glutamate + glutamine (Glx) concentrations in the occipital cortex with no difference in glutamate concentrations in the anterior cingulate cortex (ACC). In summary, there are changes in both peripheral and brain inflammatory processes in early abstinence from alcohol dependence that are related to clinical symptoms. Peripheral pro-inflammatory cytokines are raised early in detoxification relative to late detoxification and are related to withdrawal and affective symptoms. Surprisingly, evidence of decreased microglial function in the hippocampus was found and this related to poorer cognitive function, suggesting a positive role for immune cells in the brain in alcohol dependence. Inflammatory processes were related to HPA axis function during detoxification but not to changes in brain glutamate concentrations. In conclusion, characterisation of inflammation through multiple approaches in this series of studies demonstrates the likely importance of such processes and provides novel approaches for treatment to reduce brain damage due to alcoholism.Open Acces