Neuroinflammmation in alcohol dependence

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

Neuroinflammmation in alcohol dependence

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

Characterisation of the contribution of the GABA-benzodiazepine α1 receptor subtype to [11C]Ro15-4513 PET images

This positron emission tomography (PET) study aimed to further define selectivity of [11C]Ro15-4513 binding to the GABARα5 relative to the GABARα1 benzodiazepine receptor subtype. The impact of zolpidem, a GABARα1-selective agonist, on [11C]Ro15-4513, which shows selectivity for GABARα5, and the nonselective benzodiazepine ligand [11C]flumazenil binding was assessed in humans. Compartmental modelling of the kinetics of [11C]Ro15-4513 time-activity curves was used to describe distribution volume (VT) differences in regions populated by different GABA receptor subtypes. Those with low α5 were best fitted by one-tissue compartment models; and those with high α5 required a more complex model. The heterogeneity between brain regions suggested spectral analysis as a more appropriate method to quantify binding as it does not a priori specify compartments. Spectral analysis revealed that zolpidem caused a significant VT decrease (∼10%) in [11C]flumazenil, but no decrease in [11C]Ro15-4513 binding. Further analysis of [11C]Ro15-4513 kinetics revealed additional frequency components present in regions containing both α1 and α5 subtypes compared with those containing only α1. Zolpidem reduced one component (mean±s.d.: 71%±41%), presumed to reflect α1-subtype binding, but not another (13%±22%), presumed to reflect α5. The proposed method for [11C]Ro15-4513 analysis may allow more accurate selective binding assays and estimation of drug occupancy for other nonselective ligands

Trends in deaths following drug use in England before, during, and after the COVID-19 lockdowns

AimThis research aimed to describe how the characteristics of deaths following drug use changed during the COVID-19 pandemic in England, and how this can inform future strategy to support the health and social care of people who use drugs in future emergency scenarios.MethodAll deaths reported to the National Programme on Substance Abuse Deaths which occurred between January 2018 and December 2021 inclusive were extracted for analysis. Exponential smoothing models were constructed to determine any differences between forecasted vs. actual trends.Key resultsFollowing the first lockdown period in England there were significant increases in the proportion of people who died at home beyond the 95% confidence bounds of the exponential smoothing model and concurrent decreases in the proportion of people who died in hospital. Whilst the overall proportion of deaths attributable to opioids did not significantly deviate from the forecasted trend, there were significant increases in methadone-related deaths and decreases in heroin/morphine-related death beyond the 95% confidence bounds. The proportion of deaths concluded as suicide increased, as did those implicating antidepressant use. There were no changes in the proportion of deaths following use of other drug classes, alcohol use in combination with psychoactive drugs, or on decedent demographics (gender, age, and drug user status). A small number of deaths due to drug use had COVID-19 infection itself listed as a cause of death (n = 23).ConclusionFor people who use drugs, the impact of the restrictions due to the COVID-19 pandemic was greater than that of infection from the virus itself. The health and social care strategy for these people needs to be pre-emptively adapted to mitigate against the specific risk factors for fatal drug overdose associated with future emergency scenarios

A PET-CT study on neuroinflammation in Huntington’s disease patients participating in a randomized trial with laquinimod

Microglia activation, an indicator of central nervous system inflammation, is believed to contribute to the pathology of Huntington's disease. Laquinimod is capable of regulating microglia. By targeting the translocator protein, 11C-PBR28 PET-CT imaging can be used to assess the state of regional gliosis in vivo and explore the effects of laquinimod treatment. This study relates to the LEGATO-HD, multi-centre, double-blinded, Phase 2 clinical trial with laquinimod (US National Registration: NCT02215616). Fifteen patients of the UK LEGATO-HD cohort (mean age: 45.2 ± 7.4 years; disease duration: 5.6 ± 3.0 years) were treated with laquinimod (0.5 mg, N = 4; 1.0 mg, N = 6) or placebo (N = 5) daily. All participants had one 11C-PBR28 PET-CT and one brain MRI scan before laquinimod (or placebo) and at the end of treatment (12 months apart). PET imaging data were quantified to produce 11C-PBR28 distribution volume ratios. These ratios were calculated for the caudate and putamen using the reference Logan plot with the corpus callosum as the reference region. Partial volume effect corrections (Müller-Gartner algorithm) were applied. Differences were sought in Unified Huntington's Disease Rating Scale scores and regional distribution volume ratios between baseline and follow-up and between the two treatment groups (laquinimod versus placebo). No significant change in 11C-PBR28 distribution volume ratios was found post treatment in the caudate and putamen for both those treated with laquinimod (N = 10) and those treated with placebo (N = 5). Over time, the patients treated with laquinimod did not show a significant clinical improvement. Data from the 11C-PBR28 PET-CT study indicate that laquinimod may not have affected regional translocator protein expression and clinical performance over the studied period

Treatment and Intervention for Opiate Dependence in the United Kingdom:Lessons from Triumph and Failure

The history of opiate treatment in the United Kingdom (UK) since the early 1980s is a rich source of learning about the benefits and pitfalls of drug treatment policy. We present five possible lessons to be learnt about how factors outside the clinic, including government, charities and researchers can influence treatment and outcomes. First, do not let a crisis go to waste. The philosophical shift from abstinence to harm reduction in the 1980s, in response to an HIV outbreak in injecting users, facilitated expansion in addiction services and made a harm reduction approach more acceptable. Second, studies of drug-related deaths can lead to advances in care. By elucidating the pattern of mortality, and designing interventions to address the causes, researchers have improved patient safety in certain contexts, though significant investment in Scotland has not arrested rising mortality. Third, collection of longitudinal data and its use to inform clinical guidelines, as pursued from the mid-1990s, can form an enduring evidence base and shape policy, sometimes in unintended ways. Fourth, beware of the presentation of harm reduction and recovery as in conflict. At the least, this reduces patient choice, and at worst, it has caused some services to be redesigned in a manner that jeopardises patient safety. Fifth, the relationship between the third and state sectors must be carefully nurtured. In the UK, early collaboration has been replaced by competition, driven by changes in funding, to the detriment of service provision

GABAA receptor subtype involvement in addictive behaviour

GABAA receptors form the major class of inhibitory neurotransmitter receptors in the mammalian brain. This review sets out to summarise the evidence that variations in genes encoding GABAA receptor isoforms are associated with aspects of addictive behaviour in humans, while animal models of addictive behaviour also implicate certain subtypes of GABAA receptor. In addition to outlining the evidence for the involvement of specific subtypes in addiction, we summarise the particular contributions of these isoforms in control over the functioning of brain circuits, especially the mesolimbic system, and make a first attempt to bring together evidence from several fields to understanding potential involvement of GABAA Receptor Subtypes in addictive behaviour. While the weight of the published literature is on alcohol dependency, the underlying principles outlined are relevant across a number of different aspects of addictive behaviour