Alcohol-associated liver disease and behavioral and medical cofactors: unmet needs and opportunities.

Chronic liver disease is a leading cause of death in the US and is often preventable. Rising burden, cost, and fatality due to liver disease are driven by intensified alcohol use in the US population and the contributions of comorbid conditions. This mini-review focuses on the topic of liver health in the context of chronic, behavioral cofactors of disease, using research-based examples from the Brown University Center for Addiction and Disease Risk Exacerbation (CADRE). Our aim is to illustrate the current challenges and opportunities in clinical research addressing liver health in the context of behavioral and medical comorbidity and to highlight next steps in this crucial area of public health research and clinical care.

Immune biomarkers in non-treatment-seeking heavy drinkers who used a probiotic supplement for 30 days: An open-label pilot study.

Alcohol use disorder (AUD) is associated with significant psychological and economic burdens, as well as physical comorbidities that can lead to death. Previous research has found that probiotics may reduce inflammatory biomarkers in persons with AUD and comorbid conditions such as cirrhosis of the liver. This relationship has not been explored in heavy drinkers without comorbid conditions. In a proof-of-concept study, individuals who were heavy drinkers without known comorbidities received a 30-day course of a daily probiotic supplement in an open-label pilot trial. Eligible participants (N = 16) met NIAAA guidelines for heavy alcohol use and did not report any preexisting medical problems. Blood samples were taken at four timepoints: prior to the probiotic course, at the midpoint, at the end, and after a washout period of at least one month. Immunoassays were conducted on plasma samples to quantify the following inflammatory biomarkers: IL-6, IL-8, IL-10, LBP, MCP-1, sCD14, sCD163, and TNF-α. Linear mixed models were used to test within-subjects changes in biomarker concentrations over the study period, with alcohol use included as a time-varying covariate. Biomarker concentrations did not change significantly. A higher number of heavy drinking days was statistically associated with higher concentrations of IL-6 (F(1,8) = 6.66, p = 0.0326) and IL-8 (F(1,17) = 6.38, p = 0.0218). Greater days since last drink was associated with a lower concentration of MCP-1 (F(1,17) = 5.77, p = 0.028). In summary, biomarker trajectories were associated with alcohol consumption variables, but not probiotic use, in this open-label pilot study. Randomized controlled trials are needed to evaluate fully the potential benefits of probiotics in heavy drinkers without known comorbidities and under conditions of non-abstinence.

Exposure to the Death of Others during the COVID-19 Pandemic: Growing Mistrust in Medical Institutions as a Result of Personal Loss.

BACKGROUND AND AIMS: The prominence of death during the COVID-19 pandemic was heightened by the potential of personally knowing someone who lost their life to the virus. The terror management theory (TMT) suggests that the salient presence of death has a pronounced effect on behavior and may result in the ossification of beliefs and actions aligned with one's worldview (i.e., the mortality salience hypothesis). In this study, we evaluated how death exposure early in the COVID-19 pandemic could enact the process of firming up held beliefs and attitudes related to health and safety. Specifically, we tested the hypothesis that exposure to a personal loss during the pandemic would strengthen participants' baseline attitudes and behaviors regarding COVID-19 safety guidelines. METHOD: Data were analyzed from a prospective, regional survey administered at two time points during the pandemic, June-July 2020 and May 2021, in five United States northeastern states. Baseline and follow-up surveys were administered approximately 12 months apart, with adherence to public guidance and death exposure measured at both timepoints and other safety measures at follow-up only. FINDINGS: Our results indicated that there were significant main effects of death exposure on guideline adherence and support for COVID-related public policy. Contrary to the mortality salience hypothesis, death exposures after baseline were related to higher medical mistrust at follow-up for those high in adherence at baseline, rather than those with low adherence. CONCLUSION: Our results offer some conflicting evidence to the mortality salience hypothesis. Rather than entrench people in their worldviews, death in the context of the COVID-19 pandemic appeared to sway people away from their initial stances. This finding has important implications for TMT literature and for the COVID-19 pandemic response.

Access to medication for opioid use disorder supported by telemedicine and healthcare coverage: A web-based survey during the COVID-19 pandemic.

Background and Aims: Medications for opioid use disorder (MOUD) are highly effective in improving treatment outcomes and reducing overdose. Concerns about interrupted access to critical MOUD services led to expansion of telemedicine services during the COVID-19 pandemic in the US. The current study tested the hypothesis that telemedicine usage and healthcare coverage would be significantly associated with access to MOUD in the early phase of the COVID-19 pandemic. Design: A cross-sectional online survey was administered to a non-probability sample from June 18-July 19, 2020 using the Amazon Mechanical Turk platform. Setting: Northeastern United States during the early phase of the COVID-19 pandemic. At the time of the survey, federal regulators had waived the longstanding requirement for in-office visits for MOUD prescription receipt and provided guidance on increasing third-party payer reimbursement rates for telehealth visits in order to mitigate barriers to care associated with COVID-19 safety guidelines. Participants: Individuals 18 years or older residing in Connecticut, Massachusetts, New Jersey, New York, or Rhode Island were eligible to complete the survey. The analytic sample was participants who reported using opioids not as prescribed by a physician in the past seven days. Measurements: Demographics, telemedicine usage, and healthcare coverage were assessed as explanatory variables. The primary outcome was whether participants reported ability to access MOUD in the past four weeks. Findings: In this sample of individuals who used illicit opioids in the past week (N = 191), one in two individuals who utilized telehealth or had healthcare coverage were able to access MOUD, whereas only one in five of their respective counterparts who did not have telehealth access or healthcare coverage were able to access these medications. Conclusions: Telemedicine and healthcare coverage were associated with greater MOUD access early in the COVID-19 pandemic, when barriers to care were high. Such findings speak to the importance of not only extending but also formalizing temporary policy changes instituted during the pandemic to allow MOUD prescribing via telemedicine.

Alcohol consumption and oral microbiome composition in a sample of healthy young adults.

The oral microbiomes of 24 healthy adults (50% female; mean age = 24.3) were examined using 16 s ribosomal RNA sequencing and compared between light and heavy drinkers. Beta diversity was related at the trend level to drinking group, and light drinkers had significantly higher abundances of key oral taxa such as Lactobacillales. These preliminary results may offer insight into early effects of heavy drinking on the composition of the oral microbiome.

COVID-19-Related Stressors and Clinical Mental Health Symptoms in a Northeast US Sample.

Research has linked specific COVID-19-related stressors to the mental health burden, yet most previous studies have examined only a limited number of stressors and have paid little attention to their clinical significance. This study tested the hypothesis that individuals who reported greater COVID-19-related stressors would be more likely to have elevated levels of anxiety, posttraumatic stress symptoms, and serious psychological distress. METHODS: An online survey was administered to a convenience sample from 18 June to 19 July 2020, in US states that were most affected by COVID-19 infections and deaths at the time. Individuals who were 18 or older and residents of five Northeast US states were eligible to participate (N = 1079). In preregistered analyses, we used logistic regression models to test the associations of COVID-19 stressors with symptoms on the Generalized Anxiety Disorder-7 (GAD-7), Impact of Event Scale-Revised, and K6, adjusting for sociodemographic covariates. RESULTS: COVID-19-related stressors (i.e., essential worker status, worry about COVID-19 infection, knowing someone hospitalized by COVID-19, having children under 14 at home, loneliness, barriers to environmental rewards, food insecurity, loss of employment) were associated with meeting thresholds (i.e., positive screening) for anxiety, posttraumatic stress, and/or serious psychological distress. Loneliness and barriers to environmental rewards were associated with all mental health outcomes. LIMITATIONS: We used a non-probability sample and cannot assume temporal precedence of stressors with regard to development of mental health symptoms. CONCLUSIONS: These findings link specific stressors to the mental health burden of the COVID-19 pandemic.

Medical Mistrust, Perceived Discrimination, and Race: a Longitudinal Analysis of Predictors of COVID-19 Vaccine Hesitancy in US Adults.

The current manuscript has two aims. First, we examined whether race and ethnicity, perceived discrimination, medical mistrust, and other demographic factors were predictors of COVID-19 vaccine hesitancy and vaccine behavior. Second, we sought to assess whether medical mistrust and perceived discrimination mediate the relationship between race and ethnicity and vaccine behavior. Specifically, we hypothesized that individuals of color had increased COVID-19 vaccine hesitancy as compared to White individuals and perceived discrimination and medical mistrust mediated this relationship. Results revealed that when accounting for sociodemographic characteristics and COVID-19-related variables those with greater medical mistrust were more likely to have vaccine hesitancy. Additionally, after accounting for medical mistrust, Black non-Hispanic/Black Hispanic/White Hispanic individuals had lower odds of having the COVID-19 vaccine compared to White non-Hispanic individuals. Furthermore, combined perceived discrimination and medical mistrust indirectly mediated the relationship between race and ethnicity and having the COVID-19 vaccine. The findings of this study indicate the need for public health efforts to address sentiments of medical mistrust and experiences of perceived discrimination when combating COVID-19 vaccine hesitancy, especially within communities of color.

Adherence to COVID-19 Guidelines among Current, Former, and Never Smokers.

Objectives: In this paper, we explore the adherence patterns to US Centers for Disease Control and Prevention (CDC) COVID-19 mitigation guidelines among current, former, and never smokers. Methods: We used an online cross-sectional survey of adults 18 years or older in 5 northeastern states of the US (N=1084). Results: Unadjusted analyses revealed that current smokers reported lower adherence to the CDC guidelines than former smokers (27.5 vs 29.4, p<.05). After accounting for sociodemographic covariates, this finding was no longer statistically significant. However, compared to former smokers, never smokers reported wearing their mask less often (OR=0.65; 95% CI=0.45-0.94) and current smokers were less likely to report always practicing illness-related hygiene skills (OR=0.60; 95% CI=0.39-0.93).Conclusions: Never smokers had poorer adherence to CDC guidelines than former smokers, namely wearing their masks, and current smokers were less likely to always follow the hygiene recommendations. Results should inform future public health efforts in targeting current smokers with lower adherence to CDC guidelines and learning from the ability of former smokers to demonstrate high adherence.

Associations between alcohol and cannabis use before and during the COVID-19 pandemic: Results of a community survey.

The COVID-19 pandemic has impacted individuals around the world, creating unprecedented challenges. Due to lockdowns and social distancing measures, many people have turned to contactless modes of obtaining alcohol and other substances (e.g., home delivery). This study investigated associations between alcohol and cannabis use before and during the initial months of the COVID-19 pandemic and factors associated with use. An online, cross-sectional survey with a non-probability sample (N = 1126) was conducted in Northeast states during June-July 2020. Outcomes examined prevalence of alcohol and cannabis use for the overall sample and predictors of use in individuals who used substances. In the overall sample, we found that alcohol and cannabis use decreased from before to during the pandemic. For individuals who drank alcohol, higher pre-pandemic drinking, mid-range household income, and obtaining alcohol through home delivery were associated with higher alcohol drinking during the pandemic. For individuals who used cannabis, higher pre-pandemic cannabis use and obtaining cannabis through home delivery were associated with higher cannabis use during the pandemic. Overall, from before to during the pandemic, we found a decrease in the proportion of individuals who used substances and no changes in quantity for individuals who continued to use substances. Home delivery was associated with greater use of alcohol and marijuana, supporting a need for further research on risk factors for heavier substance use.

Associations of alcohol use, HIV infection, and age with brain white matter microstructure.

Heavy drinking and HIV infection are independently associated with damage to the brain's white matter. The purpose of the current study was to investigate whether current alcohol consumption, HIV infection, and associated characteristics were associated with indices of white matter microstructural integrity in people living with HIV (PLWH) and seronegative individuals. PLWH and controls were categorized as non-drinkers, moderate drinkers, or heavy drinkers. White matter fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) were assessed using diffusion tensor imaging (DTI). Voxelwise analyses using tract-based spatial statistics were followed by confirmatory region-of-interest (ROI) analyses. Data from 108 participants (62 PLWH, 46 controls) were suitable for analysis. Average age (± standard deviation) was 45.2 ± 11.1 years, and the sample was 42% female. The majority of PLWH were on antiretroviral therapy (94%) and were virally suppressed (69%). PLWH and controls did not differ on substance use. Heavier alcohol intake was significantly associated with lower FA and higher RD in widespread areas. Heavy drinking was significantly associated with higher AD in a small region. The main effect of HIV was not significant, but a significant HIV-age interaction was observed. Follow-up ROI analyses confirmed the main effect of drinking group and HIV-age interaction. In conclusion, results are consistent with a dose-dependent association of alcohol use with lower white matter microstructural coherence. Concordance between FA and RD findings suggests dysmyelination as a mechanism. Findings underscore the need to address unhealthy alcohol use in HIV-positive and seronegative individuals, the consequences of which may be exacerbated by aging.

Association of Substance Use With Behavioral Adherence to Centers for Disease Control and Prevention Guidelines for COVID-19 Mitigation: Cross-sectional Web-Based Survey.

BACKGROUND: Substance use is a risk factor for COVID-19 infection and adverse outcomes. However, reasons for elevated risk for COVID-19 in substance users are not well understood. OBJECTIVE: The aim of this study was to evaluate whether alcohol or other drug use is associated with adherence to Centers for Disease Control and Prevention (CDC) guidelines for COVID-19 mitigation. Preregistered analyses tested the hypothesis that greater use of alcohol and other drugs would be associated with lower CDC guideline adherence. A secondary objective was to determine whether substance use was associated with the likelihood of COVID-19 testing or outcome. METHODS: A cross-sectional web-based survey was administered to a convenience sample recruited through Amazon's Mechanical Turk platform from June 18 to July 19, 2020. Individuals aged 18 years or older and residing in Connecticut, Massachusetts, New Jersey, New York, or Rhode Island were eligible to participate. The exposure of interest was past 7-day use of alcohol, cigarettes, electronic cigarettes, cannabis, stimulants, and nonmedical opioids. The primary outcome was CDC guideline adherence measured using a scale developed from behaviors advised to reduce the spread of COVID-19. Secondary outcomes were likelihood of COVID-19 testing and a positive COVID-19 test result. All analyses accounted for the sociodemographic characteristics. RESULTS: The sample consisted of 1084 individuals (mean age 40.9 [SD 13.4] years): 529 (48.8%) men, 543 (50.1%) women, 12 (1.1%) other gender identity, 742 (68.5%) White individuals, 267 (24.6%) Black individuals, and 276 (25.5%) Hispanic individuals. Daily opioid users reported lower CDC guideline adherence than nondaily users (B=-0.24, 95% CI -0.44 to -0.05) and nonusers (B=-0.57, 95% CI -0.76 to -0.38). Daily alcohol drinkers reported lower adherence than nondaily drinkers (B=-0.16, 95% CI -0.30 to -0.02). Nondaily alcohol drinkers reported higher adherence than nondrinkers (B=0.10, 95% CI 0.02-0.17). Daily opioid use was related to greater odds of COVID-19 testing, and daily stimulant use was related to greater odds of a positive COVID-19 test. CONCLUSIONS: In a regionally-specific, racially, and ethnically diverse convenience sample, adults who engaged in daily alcohol or opioid use reported lower CDC guideline adherence for COVID-19 mitigation. Any opioid use was associated with greater odds of COVID-19 testing, and daily stimulant use was associated with greater odds of COVID-19 infection. Cigarettes, electronic cigarettes, cannabis, or stimulant use were not statistically associated with CDC guideline adherence, after accounting for sociodemographic covariates and other substance use variables. Findings support further investigation into whether COVID-19 testing and vaccination should be expanded among individuals with substance-related risk factors.

The neurobiology of wellness: 1H-MRS correlates of agency, flexibility and neuroaffective reserves in healthy young adults.

Proton magnetic resonance spectroscopy (1H-MRS) is a noninvasive imaging technique that measures the concentration of metabolites in defined areas of the human brain in vivo. The underlying structure of natural metabolism-emotion relationships is unknown. Further, there is a wide range of between-person differences in metabolite concentration in healthy individuals, but the significance of this variation for understanding emotion in healthy humans is unclear. Here we investigated the relationship of two emotional constructs, agency and flexibility, with the metabolites glutamate and glutamine (Glx), N-acetylaspartate (tNAA), choline (Cho), creatine (tCr), and myo-inositol (Ins) in the right dorsal anterior cingulate cortex (dACC) in medically and psychiatrically healthy volunteers (N = 20, 9 female; mean age = 22.8 years, SD = 3.40). The dACC was selected because this region is an integrative hub involved in multiple brain networks of emotion, cognition and behavior. Emotional traits were assessed using the Multidimensional Personality Questionnaire Brief Form (MPQ-BF), an empirically derived self-report instrument with an orthogonal factor structure. Phenotypes evaluated were positive and negative agency (MPQ-BF Social Potency, Aggression), emotional and behavioral flexibility (MPQ-BF Absorption, Control-reversed), and positive and negative affect (MPQ-BF Social Closeness; Stress Reaction, Alienation). The resting concentration of tNAA in the dACC was robustly positively correlated with Absorption (r = +0.56, unadjusted p = .005), moderately positively correlated with Social Potency (r = +0.42, unadjusted p = .03), and robustly negatively correlated with Aggression (r = -0.59, unadjusted p = .003). Absorption and Aggression accounted for substantial variance in tNAA (R2 = 0.31, 0.35; combined R2 = 0.50), and survived correction for multiple comparisons (Holm-Bonferroni adjusted p = .032, 0.021, respectively). dACC Glx and Cho had modest relationships with behavioral flexibility and social affiliation that did not survive this multiple correction, providing effect sizes for future work. Principal Component Analysis (PCA) revealed a three-factor orthogonal solution indicating specific relationships between: 1) Glx and behavioral engagement; 2) Cho and affiliative bonding; and 3) tNAA and a novel dimension that we term neuroaffective reserves. Our results inform the neurobiology of agency and flexibility and lay the groundwork for understanding mechanisms of natural emotion using 1H-MRS.

Immune Response to an Acute Moderate Dose of Alcohol in Healthy Young Adults.

Prior research on alcohol and the immune system has tended to focus on binge doses or chronic heavy drinking. The aim of this single-session preliminary study was to characterize immune response to moderate alcohol (0.60 g alcohol per kilogram body weight) in healthy, nonchronic drinkers. The sample (N = 11) averaged 26.6 years of age and was balanced in gender. Plasma samples were collected at baseline and 1, 2 and 3 hours postconsumption. Markers of microbial translocation [lipopolysaccharide (LPS)] and innate immune response [LPS-binding protein (LBP), soluble cluster of differentiation 14 (sCD14), and selected cytokines] were measured using immunoassays. Participants completed self-report questionnaires on subjective alcohol response and craving. Linear mixed models were used to assess changes in biomarkers and self-report measures. Breath alcohol concentration peaked at 0.069 ± 0.008% 1 hour postconsumption. LPS showed a significant linear decrease. LBP and sCD14 showed significant, nonlinear (U-shaped) trajectories wherein levels decreased at 1 hour then rebounded by 3 hours. Of nine cytokines tested, only MCP-1 and IL-8 were detectable in ≥50% of samples. IL-8 did not change significantly. MCP-1 showed a significant linear decrease and also accounted for significant variance in alcohol craving, with higher levels associated with stronger craving. Results offer novel evidence on acute immune response to moderate alcohol. Changes in LBP and sCD14, relative to LPS, may reflect their role in LPS clearance. Results also support further investigation into the role of MCP-1 in alcohol craving. Limitations include small sample size and lack of a placebo condition.

Cerebral Metabolites on the Descending Limb of Acute Alcohol: A Preliminary 1H MRS Study.

AIMS: Chronic alcohol use is associated with cerebral metabolite abnormalities, yet alcohol's acute effects on neurometabolism are not well understood. This preliminary study investigated cerebral metabolite changes in vivo on the descending limb of blood alcohol in healthy moderate drinkers. METHODS: In a pre/post design, participants (N = 13) completed magnetic resonance imaging (MRI) scans prior to and approximately 5 hours after consuming a moderate dose of alcohol (0.60 grams alcohol per kilogram of body weight). Magnetic resonance spectroscopy (1H MRS) was used to quantify cerebral metabolites related to glutamatergic transmission (Glx) and neuroimmune activity (Cho, GSH, myo-inositol) in the thalamus and frontal white matter. RESULTS: Breath alcohol concentration (BrAC) peaked at 0.070±0.008% (mean ± standard deviation) and averaged 0.025±0.011% directly prior to the descending limb scan. In the thalamus, Glx/Cr and Cho/Cr were significantly elevated on the descending limb scan relative to baseline. BrAC area under the curve, an index of alcohol exposure during the session, was significantly, positively associated with levels of Glx/Cr, Cho/Cr and GSH/Cr in the thalamus. GSH/Cr on the descending limb was inversely correlated with subjective alcohol sedation. CONCLUSIONS: This study offers preliminary evidence of alcohol-related increases in Glx/Cr, Cho/Cr and GSH/Cr on the descending limb of blood alcohol concentration. Findings add novel information to previous research on neurometabolic changes at peak blood alcohol in healthy individuals and during withdrawal in individuals with alcohol use disorder.

HIV Infection, HCV Coinfection, and Alcohol Use: Associations with Microbial Translocation and Immune Activation.

BACKGROUND: Human immunodeficiency virus (HIV) infection and heavy drinking independently promote microbial translocation and inflammation. However, it is not known how alcohol use may affect these processes in people living with HIV (PLWH). This study tested the hypothesis that alcohol exacerbates innate immune dysfunction in PLWH. METHODS: Participants were 75 PLWH and 34 uninfected controls. Groups were recruited to have similar proportions of nondrinkers, moderate drinkers, and heavy drinkers. Substance use data and plasma samples were collected at up to 3 visits over a 5-year study period. Recent alcohol use was assessed with the Timeline Followback Interview. Biomarkers of microbial translocation (lipopolysaccharide, LPS) and immune activation (lipopolysaccharide binding protein, LBP; soluble CD14, sCD14; soluble CD163, sCD163) were quantified using enzyme-linked immunosorbent assays. Analyses tested 2 hypotheses: (i) that biomarker levels would be significantly higher in PLWH than controls with comparable alcohol use and (ii) that current alcohol use would exacerbate biomarker elevations in PLWH. The second analysis included the interaction of alcohol use with hepatitis C virus (HCV) coinfection. RESULTS: Groups were matched on alcohol use, smoking, and other drug use. All biomarkers were significantly higher in PLWH relative to controls (LBP: p = 0.005; LPS: p = 0.014; sCD14: p < 0.001; sCD163: p < 0.001). In PLWH, alcohol use showed a significant, positive association with sCD163, but not with other biomarkers. However, the interaction of alcohol use with HCV coinfection was significant for all biomarkers (LBP: p = 0.002; LPS: p = 0.026; sCD14: p = 0.0004; sCD163: p = 0.001). In pairwise tests with sequential Bonferroni correction, HIV/HCV coinfected individuals who drank heavily had significantly higher sCD163 compared to coinfected nondrinkers and to HIV monoinfected nondrinkers, moderate drinkers, and heavy drinkers (ps < 0.005). Coinfected moderate drinkers had significantly higher sCD163 than each monoinfected group (ps < 0.003). In addition, sCD14 was significantly higher in coinfected moderate drinkers than coinfected nondrinkers (p = 0.027). CONCLUSIONS: As predicted, PLWH had higher levels of LBP, LPS, sCD14, and sCD163 than uninfected individuals with similar alcohol use. In PLWH, alcohol by itself was significantly associated only with higher sCD163. However, heavy or moderate alcohol use was associated with elevations in macrophage activation (sCD163) and monocyte activation (sCD14) in HIV/HCV coinfected individuals.

Psychostimulant drug effects on glutamate, Glx, and creatine in the anterior cingulate cortex and subjective response in healthy humans.

Prescription psychostimulants produce rapid changes in mood, energy, and attention. These drugs are widely used and abused. However, their effects in human neocortex on glutamate and glutamine (pooled as Glx), and key neurometabolites such as N-acetylaspartate (tNAA), creatine (tCr), choline (Cho), and myo-inositol (Ins) are poorly understood. Changes in these compounds could inform the mechanism of action of psychostimulant drugs and their abuse potential in humans. We investigated the acute impact of two FDA-approved psychostimulant drugs on neurometabolites using magnetic resonance spectroscopy (1H MRS). Single clinically relevant doses of d-amphetamine (AMP, 20 mg oral), methamphetamine (MA, 20 mg oral; Desoxyn®), or placebo were administered to healthy participants (n = 26) on three separate test days in a placebo-controlled, double-blinded, within-subjects crossover design. Each participant experienced all three conditions and thus served as his/her own control. 1H MRS was conducted in the dorsal anterior cingulate cortex (dACC), an integrative neocortical hub, during the peak period of drug responses (140-150 m post ingestion). D-amphetamine increased the level of Glu (p = .0001), Glx (p = .003), and tCr (p = .0067) in the dACC. Methamphetamine increased Glu in females, producing a significant crossover interaction pattern with gender (p = .02). Drug effects on Glu, tCr, and Glx were positively correlated with subjective drug responses, predicting both the duration of AMP liking (Glu: r = +.49, p = .02; tCr: r = +.41, p = .047) and the magnitude of peak drug high to MA (Glu: r = +.52, p = .016; Glx: r = +.42, p = .049). Neither drug affected the levels of tNAA, Cho, or Ins after correction for multiple comparisons. We conclude that d-amphetamine increased the concentration of glutamate, Glx, and tCr in the dACC in male and female volunteers 21/2 hours after drug consumption. There was evidence that methamphetamine differentially affects dACC Glu levels in women and men. These findings provide the first experimental evidence that specific psychostimulants increase the level of glutamatergic compounds in the human brain, and that glutamatergic changes predict the extent and magnitude of subjective responses to psychostimulants.

Convergent and discriminant validity of the ImPACT with traditional neuropsychological measures.

Neuropsychological assessment of cognitive sequelae secondary to sports concussion is limited by lengthy administration times and lack of readily available neuropsychologists. Brief computerized test batteries are now under development to address this, but the validity of these measures is not yet established. The validity of one such computerized test battery, the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT), was administered to 93 healthy NCAA Division I athletes, aged 18-24, along with a battery of traditional, well-described neuropsychological tests. Convergent and discriminant validity between the ImPACT and traditional measures was investigated using multitrait-multimethod matrix (MTMM) analysis. As an example, the ImPACT Visual Motor Speed composite demonstrated reasonably good convergent validity secondary to moderate correlations with traditional measures of processing speed, but it demonstrated relatively poor discriminant validity as it significantly correlated with the Reaction Time composite score. MTMM results were variable across ImPACT composites and data for each are presented. The ImPACT composite's validity was further investigated using exploratory factor analysis (EFA). Six principal components were termed processing speed, visual memory, verbal memory, attention & working memory, and verbal fluency, based upon traditional test loadings, and a sixth loaded only on the ImPACT Reaction Time composite. EFA indicated content validity of moderate strength for the Visual Motor Speed and Visual Memory composites, but revealed problems with specificity for the other composites. Based upon the present findings, validity problems render the interpretability of the ImPACT composites somewhat questionable, and more research is necessary prior to using the ImPACT for assessment of clinical populations.

Markers of Microbial Translocation and Immune Activation Predict Cognitive Processing Speed in Heavy-Drinking Men Living with HIV.

HIV infection and alcohol use disorder are associated with deficits in neurocognitive function. Emerging evidence points to pro-inflammatory perturbations of the gut-brain axis as potentially contributing to neurocognitive impairment in the context of HIV and chronic heavy alcohol use. This study examined whether plasma markers of microbial translocation (LPS) from the gastrointestinal tract and related immune activation (sCD14, EndoCAb) were associated with neurocognition in 21 men living with HIV who were virally suppressed on antiretroviral therapy. All participants met federal criteria for heavy drinking and were enrolled in a randomized controlled trial (RCT) of a brief alcohol intervention. This secondary analysis utilized blood samples and cognitive scores (learning, memory, executive function, verbal fluency, and processing speed) obtained at baseline and three-month follow-up of the RCT. In generalized estimating equation models, LPS, sCD14, and EndoCAb individually were significant predictors of processing speed. In a model with all biomarkers, higher LPS and sCD14 both remained significant predictors of lower processing speed. These preliminary findings suggest that inflammation stemming from HIV and/or alcohol could have negative effects on the gut-brain axis, manifested as diminished processing speed. Associations of microbial translocation and immune activation with processing speed in heavy-drinking PLWH warrant further investigation in larger-scale studies.

Immune activation and neuroinflammation in alcohol use and HIV infection: evidence for shared mechanisms.

BACKGROUND: Emerging research points to innate immune mechanisms in the neuropathological and behavioral consequences of heavy alcohol use. Alcohol use is common among people living with HIV infection (PLWH), a chronic condition that carries its own set of long-term effects on brain and behavior. Notably, neurobiological and cognitive profiles associated with heavy alcohol use and HIV infection share several prominent features. This observation raises questions about interacting biological mechanisms as well as compounded impairment when HIV infection and heavy drinking co-occur. OBJECTIVE AND METHOD: This narrative overview discusses peer-reviewed research on specific immune mechanisms of alcohol that exhibit apparent potential to compound the neurobiological and psychiatric sequelae of HIV infection. These include microbial translocation, systemic immune activation, blood-brain barrier compromise, microglial activation, and neuroinflammation. RESULTS: Clinical and preclinical evidence supports overlapping mechanistic actions of HIV and alcohol use on peripheral and neural immune systems. In preclinical studies, innate immune signaling mediates many of the detrimental neurocognitive and behavioral effects of alcohol use. Neuropsychopharmacological research suggests potential for a feed-forward cycle in which heavy drinking induces innate immune signaling, which in turn stimulates subsequent alcohol use behavior. CONCLUSION: Alcohol-induced immune activation and neuroinflammation are a serious health concern for PLWH. Future research to investigate specific immune effects of alcohol in the context of HIV infection has potential to identify novel targets for therapeutic intervention.