Table of Contents
Fiscal Year (FY) 2018
The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is currently closing out FY 2018. In FY 2018, the National Institutes of Health (NIH) received a total of $37.2 billion, $2.9 billion above the FY 2017 enacted level. This funding includes specific increases for research on opioids, Alzheimer’s disease, antimicrobial resistance, and influenza. The bill provides a general increase to all NIH Institutes and Centers (ICs) and continues to support the Gabriella Miller Kids First Act pediatric research initiative.
The FY 2018 appropriation for NIAAA provides $509.6 million. This represents a $27.2 million or a 5.6 percent increase over the FY 2017 budget level. The NIAAA appropriation includes $5.8 million set aside for the Brain Research through Advancing Innovative Neurotechnologies Initiative. NIAAA estimates it will support a total of 759 research project grants (RPGs) in FY 2018.
The FY2019 budget is still under discussion in the House and Senate.
NIAAA Budget Mechanism - Total (Dollars in Thousands)
| Subtotal, RPGs
|Research Project Grants
|Res. Centers in Minority Instit.
| Subtotal, Centers
|Cooperative Clinical Research
|Biomedical Research Support
|Minority Biomed. Research Support
| Subtotal, Other Research
|Total Research Grants
|Research & Develop. Contracts
|Res. Management & Support
|Total, NIAAA Budget Authority
NIAAA RELOCATES ITS EXTRAMURAL OFFICES
NIAAA’s extramural offices moved from Fishers Lane in Rockville, Maryland, to 6700B Rockledge Drive in Bethesda, Maryland, on July 6, 2018. The intramural laboratories and offices remain at Fishers Lane.
COLLABORATIVE RESEARCH ON ADDICTION AT NIH (CRAN) UPDATE
Adolescent Brain Cognitive Development (ABCD) Study
The ABCD Study (https://abcdstudy.org/) continues to move along very well as it nears the end of subject recruitment. As of September 10, 2018, the study had enrolled 11,323 subjects. The final enrollment date has been moved up to October 15, 2018, with the goal of bringing enrollment to 11,900 subjects. To date, there has been a 99.6 percent retention rate. Key statistics reported by the Data Analysis and Informatics Center include that the study so far has a 94 percent image completeness rate, and 82 percent of the cases have 11.5 or more motion-free minutes of resting state fMRI data. The population makeup of the sample to date is 97 percent of the goal and currently is 51 percent White, 13 percent Black, 23 percent Hispanic, 2 percent Asian and 11 percent Other, which includes Native Americans, Pacific Islanders and multi-race participants. Recruitment has also been extended to increase the number of subjects in key demographic groups, such as Blacks and low-socioeconomic-status Whites and Asians.
The second-year protocol has been approved and sites have begun scheduling participant visits. This protocol has been expanded to include fitness tracker data on a sample of the children at some sites, as well as a nutrition questionnaire, blood pressure measures, and blood draws at all sites. The National Heart Lung and Blood Institute and the Office of Behavioral and Social Science Research, NIH, are providing additional funding for these measures, and staff there have been working with study investigators on developing these new portions of the protocol.
MODERATE ALCOHOL CARDIOVASCULAR TRIAL (MACH)
A working group of the NIH Advisory Committee to the Director (ACD), completed its review of the MACH study and reported on its findings to the full ACD on June 15, 2018. The review brought to light significant concerns about the study, including significant process irregularities in the development of the funding opportunities and design issues. Under these circumstances, NIAAA could not justify continuing the study. NIAAA is working with the NIH Office of the Director and the grantee institution, Beth Israel Deaconess Medical Center, to conduct an orderly closeout of the study.
NIAAA’s Director, George F. Koob, Ph.D., made several important presentations between April 1, 2018, and July 31, 2018:
- “New Thinking on Addiction: NIAAA Update” at the National Press Foundation Fellowship for Journalists meeting in San Diego, California, on April 11, 2018;
- “NIAAA Update: Accomplishments and Challenges” at the American Society of Addiction Medicine annual meeting, San Diego, California, on April 13, 2018;
- “Neurobiology of Addiction: The Gain in the Brain is in the Pain” at the annual meeting of Presidents’ Circle of the National Academies of Sciences, Engineering, and Medicine, Washington, D.C., on April 18, 2018;
- “Neurobiology of Addiction: The Gain in the Brain is in the Pain” at Rutgers University, Piscataway, New Jersey, on June 29, 2018;
- “Mechanisms of Opioid Addiction” at the 2018 American Society for Clinical Oncology Annual Meeting, Chicago, Illinois, on June 2, 2018;
- “What Science Can Tell Us About the Prevention, Diagnosis and Treatment of Alcohol Use Disorders” at the Addictions Conference at the University of Utah Health Sciences, Salt Lake City, Utah, on June 7, 2018 [This talk was filmed and can be viewed online at https://www.niaaa.nih.gov/publications/presentations-and-videocasts];
- Deaths of Despair: Alcohol Misuse, Pain and Negative Reinforcement” at a joint symposium of the annual meeting of the College on Problems of Drug Dependence and the International Narcotic Research Conference, in San Diego, California, on June 14, 2018;
- “NIAAA: Emerging Issues in Recovery” at the Research Society on Alcoholism Mutual Help Workshop, San Diego, California, on June 16, 2018;
- “NIAAA Update” at the annual meeting of the Research Society on Alcoholism, San Diego, California, on June 17, 2018;
- “Drug Addiction: The Gain in the Brain is in the Pain” a special seminar at the Institut de Neurosciences de la Timone, Marseille, France, on July 2, 2018;
- “How Science Informs the Diagnosis, Prevention and Treatment of Alcohol Use Disorders” at the Institut National de la Santé et de la Recherche Médicale (Inserm) meeting, Marseille, France, on July 3, 2018; and
- “Drug Addiction: The Gain in the Brain is in the Pain” at the Institut de Neurosciences Cognitives et Intégratives d'Aquitaine, Bordeaux, France, on July 5, 2018.
Rachel Anderson, Ph.D
., joined the Science Policy Branch as a Science and Technology Policy Fellow of the American Association for the Advancement of Science. Dr. Anderson earned her Ph.D. in Behavioral Neuroscience at Binghamton University, Binghamton, New York, where she studied developmental differences in alcohol sensitivity in the laboratory of Dr. Linda Spear. She then studied interactions of stress and alcohol dependence as a postdoctoral fellow in Dr. Howard Becker’s laboratory at the Medical University of South Carolina. Dr. Anderson completed the first year of her fellowship at the National Institute of Justice within the Department of Justice. During this time, she provided programmatic support for multiple criminal justice research initiatives while learning about alcohol and drug policy.
Emily Buzgierski joined the Administrative Services Branch (ASB) in August 2018, as an Administrative Officer supporting the extramural offices and divisions within NIAAA. Prior to joining NIAAA, she worked for nearly six years at the Center for Scientific Review (CSR), NIH, supporting the Executive Officer and Senior Advisor to the Deputy Director. While at CSR, Emily quickly moved up to serve as a Management Analyst for the Division of AIDS, Behavioral, and Population Sciences, where she became well-versed in the many facets of administration and peer review at NIH.
I-Jen Castle, Ph.D.
, joined the Division of Epidemiology and Prevention Research (DEPR) in July 2018 as a Health Scientist Administrator. Dr. Castle previously served as an Epidemiologist in the Center for Drug Evaluation and Research at the Food and Drug Administration. From 2010 through 2016, she was a project manager and senior research analyst at CSR, Incorporated. At CSR, she managed the NIAAA-funded Alcohol Epidemiologic Data System, which supports research on numerous scientific areas and produces surveillance reports on topics including U.S. per capita alcohol consumption and alcohol morbidity and mortality. Dr. Castle has authored numerous peer-reviewed articles and government reports on such epidemiologic topics as alcohol involvement in motor vehicle crash fatalities, alcohol use and alcohol use disorder (AUD) in the United States, and alcohol consumption in the elderly. In DEPR, she will manage a research portfolio focused on the epidemiology of health comorbidities, drinking across the lifespan, and other topics.
Kate Masterton joined the Communications and Public Liaison Branch in August 2018 as Web Coordinator. Kate came to NIAAA from the National Library of Medicine (NLM), where she supported the MedlinePlus consumer health website through a variety of activities including digital analytics, search engine optimization, usability testing, and content strategy. Prior to joining NLM, Kate received a master’s in Library and Information Science from Drexel University, Philadelphia, Pennsylvania.
Minoo McFarland, MSN, CFNP, joined the Laboratory of Neuroimaging as a nurse practitioner in January 2017. She earned her Master of Science in Nursing in 2001 from George Mason University in collaboration with the George Washington University School of Medicine. Prior to joining NIAAA, she worked at an internal medicine office as a nurse practitioner caring for patients with diseases of allergy and asthma.
Dr. Jeesun Jung, joined the NIAAA Section on Clinical Genomics and Experimental Therapeutics as a staff scientist on May 18, 2018, after seven years as a staff scientist with the NIAAA Epidemiology and Biometry Branch.
Dr. Lauren Dobbs accepted a tenure-track assistant professor position at the University of Texas, Austin following several years at NIAAA as a post-doctoral intramural research training award fellow in the NIAAA Laboratory on the Neurobiology of Compulsive Behaviors. While at NIAAA, she also had a fellowship from the Center on Compulsive Behaviors at NIH.
Roger Pickering retired from the NIAAA Epidemiology and Biometry Branch on July 20, 2018, after approximately 35 years of federal service.
Dr. Kornel Schuebel of the NIAAA Laboratory of Neurogenetics has been appointed Director of the Genomic Core Facility at Johns Hopkins University School of Medicine in Baltimore, Maryland.
HONORS AND AWARDS
The following staff received the 2018 NIH Director’s Award:
- Drs. Mark Egli and Qi-Ying Liu for their work on the HHS-VA Collaboratory – For extraordinary multiagency collaboration and leadership in facilitating research on the treatment of chronic pain with nonpharmacologic approaches within the HHS-VA-DoD [U.S. Department of Health and Human Services-U.S. Department of Veterans Affairs-U.S. Department of Defense] Collaboratory project.
- Amy Matush for her work on the Optimize NIH Subcommittee Team - For exceptional contributions in data gathering and process mapping for Optimize NIH Phase I Implementation of Ethics, Freedom of Information Act, and Committee Management.
- Vicki Buckley for her work on the NIH IC POC Team - For outstanding work to communicate and engage stakeholders in the Optimize NIH Phase I implementation of Ethics, Freedom of Information Act, and Committee Management.
- Laurie Torchinsky for her work on the NIH Risk Culture Day Team - For outstanding achievement in conceptualizing, creating, planning, coordinating, hosting and facilitating NIH's first Risk Culture Day.
- Marci Better, Cara Anjos Breeden, Fred Donodeo, Dr. Lori Ducharme, Maureen Gardner, Dr. Robert Huebner, Paulina Puig, Gregory Roa, and Donald Wilcox for their work on the NIAAA Alcohol Treatment Navigator Development Team - In recognition of the development and dissemination of the NIAAA Alcohol Treatment Navigator, helping to point the way to evidence-based care for alcohol use disorder.
Dr. George F. Koob was awarded the Jellinek Memorial Award for 2018 for his outstanding contributions to understanding the behavioral course of addiction.
Dr. Young-Eun Cho in the Laboratory of Membrane Biochemistry and Biophysics (mentor: Dr. B. J. Song) has been honored with a 2018 Research Society on Alcoholism Junior Scientist Investigator Award.
Dr. Armando Salinas, a postdoctoral fellow in the Laboratory for Integrative Neuroscience (mentor: Dr. David Lovinger), received a K99 transitional career development grant from NIAAA.
NEW REQUESTS FOR APPLICATIONS (RFAs) AND PROGRAM ANNOUNCEMENTS (PAs)
Funding Opportunity Announcements (FOA) Issued by NIAAA
Alcohol and Other Drug Interactions: Unintentional Injuries and Overdoses: Epidemiology and Prevention (PA-18-863 R01 - Clinical Trial Optional) (PA-18-861 R03 - Clinical Trial Optional) (PA-18-862 R21 - Clinical Trial Optional) These FOAs solicit applications that explore whether and how alcohol and other illicit drugs or illicitly used prescription drugs interact to contribute to unintentional injuries and poisonings and how to prevent and/or reduce simultaneous use of alcohol or drugs, singly or in combination.
Wearable Alcohol Biosensors (STTR PA-18-785 R41/R42- Clinical Trial Optional) (SBIR PA-18-786 R43/R44 - Clinical Trial Optional) These FOAs solicit applications from eligible small business organizations that will design and produce a non-invasive, discreet, wearable device to monitor blood alcohol levels in real time. Methods that quantify alcohol in blood or interstitial fluid as opposed to detection of alcohol that has exuded through the skin are of highest priority.
NIH-Wide FOAs with NIAAA’s Participation
Administrative Supplements to Promote Diversity in Research and Development (Small Businesses-SBIR/STTR PA-18-837 – Clinical Trial Not Allowed) and in Health-Related Research (PA-18-906 – Clinical Trial Not Allowed)
Administrative Supplements for Research on Dietary Supplements (PA-18-817 – Clinical Trial Not Allowed)
BRAIN Initiative: Development of Novel Tools to Probe Cell-Specific and Circuit-Specific Processes in Human and Non-Human Primate Brain (RFA-MH-19-135 UG3/UH3 - Clinical Trial Optional)
BRAIN Initiative: Development Optimization, and Validation of Novel Tools and Technologies for Neuroscience Research (SBIR PA-18-871 R43/R44 - Clinical Trial Not Allowed) (STTR PA-18-870 R41/R42 - Clinical Trial Not Allowed)
BRAIN Initiative: Integration and Analysis of BRAIN Initiative Data (RFA-MH-19-147 R01 - Clinical Trial Not Allowed)
BRAIN Initiative: Data Archives for the BRAIN Initiative (RFA-MH-19-145 R24 - Clinical Trial Optional)
BRAIN Initiative: Standards to Define Experiments Related to the BRAIN Initiative (RFA-MH-19-146 R01 - Clinical Trial Not Allowed)
BRAIN Initiative: Advanced Postdoctoral Career Transition Award to Promote Diversity (PAR-18-813 K99/R00 – Independent Clinical Trial Required) (PAR-18-814 K99/R00 – Independent Clinical Trial Not Allowed)
BRAIN Initiative: Development and Validation of Novel Tools to Probe Cell-Specific and Circuit-Specific Processes in the Brain (RFA-MH-19-136 R01 - Clinical Trial Not Allowed)
Diet and Physical Activity Assessment Methodology (PA-18-856 R01 - Clinical Trial Not Allowed) (PAR-18-857 R21 - Clinical Trial Not Allowed)
Pilot and Feasibility Studies in Preparation for Drug and Alcohol Abuse Prevention Trials (PA-18-775 R34 - Clinical Trial Optional)
Pilot Health Services and Economic Research on the Treatment of Drug, Alcohol, and Tobacco Use Disorders (PA-18-774 R34 - Clinical Trial Optional)
NOTABLE NIAAA STAFF ACTIVITIES
The Epidemiology and Biometry Branch’s Database of Genotypes and Phenotypes (dbGaP) team (Drs. Haitao Zhang (team lead), June Ruan, Boji Huang and Bradley Kerridge) prepared and uploaded the initial submission of the NESARC III genetic data for the NIH dbGaP system. Currently, the data is being verified by the curators of dbGaP. This first submission contains the most critical phenotypic information including sociodemographic data and alcohol use disorder and other substance use disorder (e.g., nicotine, cannabis and opioid use disorders) variables.
Dr. Pal Pacher has been elected to be President of the International Cannabinoid Research Society.
Dr. Pal Pacher was an invited speaker at the Frontiers in CardioVascular Biology meeting of the European Society of Cardiology in Vienna, Austria, where he chaired the session “New Strategies for Cardioprotection to Prevent Heart Failure” on April 20, 2018.
Dr. Lorenzo Leggio joined the Editorial Board of Addiction Biology in May 2018.
Dr. Daniel Falk presented a talk titled, “Reduction in World Health Organization (WHO) Drinking Risk Level as a Primary Endpoint for Alcohol Treatment Trials” at the annual meeting of the American Society of Clinical Psychopharmacology, Miami, Florida, on May 29, 2018.
Dr. Lorenzo Leggio gave a plenary talk on behalf of Dr. Koob titled “NIAAA Update” at the Federal Agencies Plenary Session, American Society of Clinical Psychopharmacology, in Miami, Florida, on May 31, 2018.
Dr. Robert Freeman organized a workshop titled "NIAAA Workshop to Assess the State of Research on Alcohol Use and Related Problems among Sexual and Gender Minority Populations,” held at NIH in, Bethesda, Maryland, on June 5, 2018.
Dr. Judith Arroyo presented on the NativeAIR pilot at the annual meetings of the Intervention Research to Improve Native American Health investigators, hosted by Dr. Dan Calac at the Indian Health Center in Southern California on June 15, 2018, and the Association of American Indian Physicians in Phoenix, Arizona, on July 28, 2018.
Dr. Aaron White served as scientific review editor and Drs. Jennifer Hobin and Troy Zarcone served as co-editors-in-chief of the “Binge Drinking: Predictors, Patterns, and Consequences” issue of NIAAA’s journal, Alcohol Research: Current Reviews, which was released in August 2018.
NIAAA Staff Activities at the 2018 Research Society on Alcoholism (RSA) Annual Meeting, June 16–20, 2018, San Diego, California
“Integrating Alcohol Use Disorder Care in the Management of Alcoholic Hepatitis” (Dr. Svetlana Radaeva, co-organizer, Dr. M. Katherine (Kathy) Jung, introductory presenter, Dr. Lorenzo Leggio, speaker and moderator)
“Fetal Alcohol Spectrum Disorder (FASD) Study Group” (Dr. Bill Dunty, presenter)
“10th Annual Charles Lieber Satellite: Alcohol, Cannabis Brain-Liver-Gut Link” (Dr. Kathy Jung, discussant)
“Mechanisms of Behavior Change (MOBC)” satellite, (Dr. Brett Hagman, speaker)
“Integrative Neurosciences Initiative on Alcoholism – Neuroimmune and Stress Satellite Meeting” (Dr. Antonio Noronha, speaker)
“New Findings on Alcohol and Injury from Emergency Room Studies” (Dr. Ralph Hingson, discussant)
“Understanding and Preventing Impaired Driving and Riding with an Impaired Driving” (Dr. Ralph Hingson, discussant)
“Advances in Clarifying Alcohol’s Role in HIV Acquisition in Sub-Sahara Africa (Dr. Robert Freeman, organizer and chair)
“Medication Development Efforts for AUD Via Novel Gut-Brain Neuroendocrine Pathways” (Dr. Lorenzo Leggio, speaker and co-chair)
“MicroRNA Differential Expression Resulting in or From Alcohol Use Disorders” (Dr. Abbas Parsian, organizer and chair)
“Timing Matters: Macrophage and Hepatocyte Death and Their Consequences and the Progression of Alcohol-Induced Liver Injury” (Dr. Joe Wang, organizer and chair, Dr. Kathy Jung, co-organizer, Dr. Li Lin, co-chair)
“Young Scientists Forum on Alcohol-Induced Cellular and Tissue Damage” (Dr. Gary Murray, organizer and co-chair)
“Alcohol and Health: Essential Knowledge for Health Professions” (Dr. Peggy Murray and Joan Romaine, organizers and discussion leaders)
“Extracellular Vesicles and Non-coding RNA in Alcohol-induced Organ Damage: Mechanisms and Therapeutic Targeting” (Dr. Peter Gao, co-chair)
“Current Advances in Alcohol-Induced Immune Dysfunction” (Dr. Li Lin, discussant)
“Identifying Prenatal Alcohol-Affected Individuals Early in Life: The Use of Novel Screening Tools and Methodologies in Human Populations” (Dr. Bill Dunty, co-organizer, introductory presenter)
“Addressing Alcohol Related Health Disparities on Multiple Levels” (Dr. Judith Arroyo, discussant)
“Leveraging National Epidemiological Data to Advance an Empirical Understanding of Substance Misuse in LGBT Sub-Populations” (Dr. Judith Arroyo, discussant)
“The Adolescent Brain and Cognitive Development (ABCD) Study: Emerging Findings on Substance Use, Risk and Protective Factors, and Neuroimaging” (Dr. Peggy Murray, chair)
“What Is Evidence-Based Alcohol Treatment and Where Do You Find It?” (Dr. Lori Ducharme, organizer and discussion leader)
“Towards a More Comprehensive Understanding of Relapse and Recovery: Current Trends and Future Directions” (Dr. Brett Hagman organizer and speaker)
“Integration of Genetic and Genomics to Identify Novel Mechanisms underlying Alcohol Use Disorders” (Dr. Hemin Chin, discussant and moderator)
“Non-Coding RNA in Alcoholism: Mechanisms, Biomarkers and Therapeutic Targets” (Drs. Antonio Noronha, co-organizer and speaker, and Subhash Pandey, co-organizer)
“Comorbidities promoting excessive alcohol drinking” (Dr. Soundar Regunathan, discussant)
“Astrocytes and Alcohol – Beyond Inflammation” (Dr. Soundar Regunathan)
Other RSA Activities
Dr. Daniel Falk and Dr. Patricia Powell, along with Dr. Gregory Farber of NIMH and several NIMH contractors, held a special training session on an NIH Guide to Grants and Contracts Notice (June 4, 2018; https://grants.nih.gov/grants/guide/notice-files/NOT-AA-18-010.html
) developed by Dr. Falk, announcing NIAAA’s new policy to create a comprehensive data repository for all NIAAA studies involving human subjects.
The Division of Medications Development team (Ds. Daniel Falk, Dr. Raye Litten, Dr., Joanne Fertig, and Megan Ryan) presented a poster titled, “Gabapentin Enacarbil Extended-Release for Alcohol Use Disorder: A Randomized, Double-Blind, Placebo-Controlled, Multisite Trial Assessing Efficacy and Safety.”
NIAAA and the National Institute on Drug Abuse (NIDA) will again sponsor the Frontiers in Addiction Research Mini-Convention as a satellite event to the Society for Neuroscience annual meeting in San Diego, California. The mini-convention will be on November 2, 2018. Scientific sessions will cover data science approaches, effects of early life adversity on substance use disorder-related circuitry, and novel opioid receptor signaling in pain and addiction, along with the Jacob Waletzky Memorial Award lecture and the Early Career Investigator Showcase. Dr. John Matochik is the program contact.
NIAAA RESEARCH HIGHLIGHTS
Significance: Kupffer cells are resident macrophages in the liver, best known for their pivotal role in alcohol-induced liver injury. The current report suggests, in contrast, that at the initial stages of alcohol exposure, some of these cells have a host-protective role. After alcohol feeding in mice, Kupffer cells undergo early apoptosis (programmed cell death) and, in doing so, protect the host by promoting the differentiation of infiltrating macrophages to an anti-inflammatory phenotype. The study first demonstrated that alcohol-induced death of these cells is dependent on a multifunctional transcription factor, FOXO3. The protective role of Kupffer cell death was then confirmed by genetic knockout of FOXO3, thus blocking Kupffer cell death. This manipulation led to a pro-inflammatory condition and a greater level of injury. Taken together, these results indicate the role of Kupffer cells in alcohol-induced liver injury is binary: at the early/acute stage, they have a host-protective role that allows the host to adapt; with persistent cumulative alcohol exposure, Kupffer cells mediate the injury.
Alcohol consumption is generally well tolerated by the liver but in some individuals, it results in persistent inflammation and liver disease. The mechanisms that regulate alcohol-induced liver inflammation are poorly understood. The transcription factor FOXO3 has previously been shown to be involved in suppressing alcohol-induced liver injury. In this study we demonstrate that in response to alcohol, approximately 10% of mouse hepatic macrophages undergo FOXO3-dependent apoptosis. By 3 days of alcohol exposure total hepatic macrophage numbers declined by 30% but these were restored to normal after 10 days of continued exposure. Whole body or myeloid specific Foxo3-/- mice failed to show this apoptotic response. After 10 days of alcohol exposure, Foxo3-/- mice had an increased basal inflammatory phenotype and an increase in the proportion of pro-inflammatory CD11b+, Ly6C+ infiltrating macrophages (IMs) infiltrating. This led to marked sensitivity to LPS with a 5-fold ALT elevation and liver injury after LPS challenge in Foxo3-/- but not WT mice. Restoring the early macrophage apoptosis burst with a pulse of intravenous GdCl3 at day 2 had no effect on the day 10 phenotype of WT mice but it corrected the hyper-inflammatory phenotype in Foxo3-/- mice. In conclusion, FOXO3-dependent hepatic macrophage apoptosis in response to ethanol serves to promote differentiation of infiltrating macrophages thus limiting the magnitude of the inflammatory response to ethanol. (Li Z, Zhao J, Zhang S, and Weinman SA. Cell Death Discov. 2018 Feb 13;4:16. doi: 10.1038/s41420-017-0020-7)
Significance: The gut-liver axis plays an important role in the pathogenesis of chronic liver disease. Alcohol consumption causes loss of barrier integrity and leads to gut dysbiosis. These gut disruptions contribute significantly to alcohol-associated liver diseases. Intestinal epithelial hypoxia inducible factor 1a (HIF-1a) regulates multiple gut barrier protecting factors in response to alcohol exposure. Short-term alcohol consumption leads to elevated HIF-1a, which seems to be a protective response. This response is decreased after extended alcohol exposure. Because the relative role of intestinal HIF-1a in alcoholic liver disease has not been evaluated, the authors conducted studies in mice in which the HIF-1a gene had been deleted specifically in intestinal epithelial cells. The knock-out animals were more sensitive to alcohol consumption, showing greater epithelial barrier damage in the gut, as well as more severe alcoholic liver disease compared to wild type mice exposed to the same alcohol feeding. Upregulation of HIF-1a in the intestine may be a potential therapeutic or preventive approach.
Background & Aims: Alcoholic liver disease (ALD) is characterized by gut dysbiosis and increased gut permeability. Hypoxia inducible factor 1α (HIF-1α) has been implicated in transcriptional regulation of intestinal barrier integrity and inflammation. We aimed to test the hypothesis that HIF-1α plays a critical role in gut microbiota homeostasis and the maintenance of intestinal barrier integrity in a mouse model of ALD. Methods: Wild-type (WT) and intestinal epithelial-specific Hif1a knockout mice (IEhif1α−/−) were pair-fed modified Lieber-DeCarli liquid diet containing 5% (w/v) alcohol or isocaloric maltose dextrin for 24 days. Serum levels of alanine aminotransferase and endotoxin were determined. Fecal microbiota were assessed. Liver steatosis and injury, and intestinal barrier integrity were evaluated. Results: Alcohol feeding increased serum levels of alanine aminotransferase and lipopolysaccharide, hepatic triglyceride concentration, and liver injury in the WT mice. These deleterious effects were exaggerated in IEhif1α−/− mice. Alcohol exposure resulted in greater reduction of the expression of intestinal epithelial tight junction proteins, claudin-1 and occludin, in IEhif1α−/− mice. In addition, cathelicidin-related antimicrobial peptide and intestinal trefoil factor were further decreased by alcohol in IEhif1α−/− mice. Metagenomic analysis showed increased gut dysbiosis and significantly decreased Firmicutes/Bacteroidetes ratio in IEhif1α−/− mice compared to the WT mice exposed to alcohol. An increased abundance of Akkermansia and a decreased level of Lactobacillus in IEhif1α−/− mice were also observed. Non-absorbable antibiotic treatment reversed the liver steatosis in both WT and IEhif1α−/− mice. Conclusion: Intestinal HIF-1α is essential for the adaptative response to alcohol-induced changes in intestinal microbiota and barrier function associated with elevated endotoxemia and hepatic steatosis and injury. (Shao T, Zhao C, Li F, Gu Z, Liu L, Zhang L, Wang Y, He L, Liu Y, Liu Q, Chen Y, Donde H, Wang R, Jala VR, Barve S, Chen S, Zhang X, Chen Y, McClain CJ, and Feng W. J Hepatol. Epub 2018 May 15. doi: 10.1016/j.jhep.2018.05.021)
Significance: A body of literature supports the observation that alcohol consumption alters the quantity and composition of the intestinal microbiome. The identification of microbiota in the circulation of healthy individuals raises the question of the effects of alcohol consumption on the blood-borne microbiome. In this study, the qualitative and quantitative changes of the circulating microbiome were analyzed in individuals with 1) heavy alcohol consumption but no evidence of liver disease, 2) moderate alcoholic hepatitis (AH), and 3) severe AH compared to 4) non-drinking controls. Decreases in relative abundance of the phylum Bacteroidetes between all alcohol-consuming groups vs. non-drinking controls confirmed alcohol effects. Other data revealed a distinction in the microbial families enriched in people with moderate AH from those enriched in people with severe AH. In addition, analysis of phyla and families using inferred and functional metagenomics demonstrated that the anthranilate degradation pathway was enriched in patients with severe AH. These initial observations will lead to further research into the roles of changes in the circulating microbiome in AH.
Intestinal dysbiosis is implicated in alcoholic hepatitis (AH). However, changes in the circulating microbiome, its association with the presence and severity of AH, and its functional relevance in AH is unknown. Qualitative and quantitative assessment of changes in the circulating microbiome were performed by sequencing bacterial DNA in subjects with moderate AH (MAH) (n = 18) or severe AH (SAH) (n = 19). These data were compared with heavy drinking controls (HDCs) without obvious liver disease (n = 19) and non-alcohol-consuming controls (NACs, n = 20). The data were related to endotoxin levels and markers of monocyte activation. Linear discriminant analysis effect size (LEfSe) analysis, inferred metagenomics, and predictive functional analysis using PICRUSt were performed. There was a significant increase in 16S copies/ng DNA both in MAH (P < 0.01) and SAH (P < 0.001) subjects. Compared with NACs, the relative abundance of phylum Bacteroidetes was significantly decreased in HDCs, MAH, and SAH (P < 0.001). In contrast, all alcohol-consuming groups had enrichment with Fusobacteria; this was greatest for HDCs and decreased progressively in MAH and SAH. Subjects with SAH had significantly higher endotoxemia (P = 0.01). Compared with alcohol-consuming groups, predictive functional metagenomics indicated an enrichment of bacteria with genes related to methanogenesis and denitrification. Furthermore, both HDCs and SAH showed activation of a type III secretion system that has been linked to gram-negative bacterial virulence. Metagenomics in SAH versus NACs predicted increased isoprenoid synthesis via mevalonate and anthranilate degradation, known modulators of gram-positive bacterial growth and biofilm production, respectively. CONCLUSION: Heavy alcohol consumption appears to be the primary driver of changes in the circulating microbiome associated with a shift in its inferred metabolic functions. (Puri P, Liangpunsakul S, Christensen JE, Shah VH, Kamath PS, Gores GJ, Walker S, Comerford M, Katz B, Borst A, Yu Q, Kumar DP, Mirshahi F, Radaeva S, Chalasani NP, Crabb DW, and Sanyal AJ; TREAT Consortium. Hepatology. 2018 Apr;67(4):1284-1302. doi: 10.1002/hep.29623)
Significance: Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme that detoxifies acetaldehyde in the liver. This study demonstrated that, after alcohol consumption, mice or humans with ALDH2 deficiency have elevated levels of acetaldehyde and glucocorticoids, which inhibit T-cell metabolism and cause immunosuppression. Given that elevated levels of cortisol and acetaldehyde may contribute to the pathogenesis of alcohol-associated diseases, physicians should pay attention to potential immunosuppression among patients with alcohol use disorder and the inactive ALDH2 gene.
Objective: Aldehyde dehydrogenase 2 (ALDH2), a key enzyme to detoxify acetaldehyde in the liver, exists in both active and inactive forms in humans. Individuals with inactive ALDH2 accumulate acetaldehyde after alcohol consumption. However, how acetaldehyde affects T-cell hepatitis remains unknown. Design: Wild-type and Aldh2-/- mice were subjected to chronic ethanol feeding and concanavalin A (ConA)-induced T-cell hepatitis. Effects of acetaldehyde on T-cell glucose metabolism were investigated in vitro. Human subjects were recruited for acute alcohol drinking and plasma cortisol and corticosterone measurement. Results: Ethanol feeding exacerbated ConA-induced hepatitis in wild-type mice but surprisingly attenuated it in Aldh2-/- mice despite higher acetaldehyde levels in Aldh2-/- mice. Elevation of serum cytokines and their downstream signals in the liver post ConA injection was attenuated in ethanol-fed Aldh2-/- mice compared to wild-type mice. In vitro exposure to acetaldehyde inhibited ConA-induced production of several cytokines without affecting their mRNAs in mouse splenocytes. Acetaldehyde also attenuated IFN-g production in phytohemagglutinin-stimulated human peripheral lymphocytes. Mechanistically, acetaldehyde interfered with glucose metabolism in T cells by inhibiting aerobic glycolysis-related signal pathways. Finally, compared to wild-type mice, ethanol-fed Aldh2-/- mice had higher levels of serum corticosterone, a well-known factor that inhibits aerobic glycolysis. Blockade of corticosterone partially restored ConA-mediated hepatitis in ethanol-fed Aldh2-/- mice. Acute alcohol drinking elevated plasma cortisol and corticosterone levels in human subjects with higher levels in those with inactive ALDH2 than those with active ALDH2. Conclusions: ALDH2 deficiency is associated with elevated acetaldehyde and glucocorticoids post alcohol consumption, thereby inhibiting T-cell activation and hepatitis. (Gao Y, Zhou Z, Ren T, Kim S-J, He Y, Seo W, Guillot A, Ding Y, Wu R, Shao S, Wang X, Zhang H, Wang W, Feng D, Xu M, Han E, Zhong W, Zhou Z, Pacher P, Niu J, and Gao B. Gut. Epub 2018 Aug 18. doi: 10.1136/gutjnl-2018-316221)
Significance: Alcohol consumption a significant contributing factor to broken bones, and the presence of alcohol prior to fracture is associated with increased risk of incomplete healing. Bone morphogenic protein (BMP) signaling plays an important role in the formation of cartilage and bone and fracture healing. Recombinant BMP2 (rBMP2) therapy is currently being used clinically as an adjunct to surgical intervention for types of fracture injuries with higher risks of delayed healing or nonunion. This study examined the effects of episodic alcohol exposure on fracture callus–associated BMP2 signaling during critical periods of fracture callus formation in a rat model of open tibia fracture injury. Results indicated that alcohol exposure perturbed callus-associated BMP2 signaling. These data suggest that altered BMP2 signaling could underlie alcohol consumption-associated defects in fracture repair and that exogenous rBMP2 therapy may have limited efficacy in patients who misuse alcohol and have orthopedic injuries that are generally amenable to BMP2 treatment. This work contributes to the molecular understanding of alcohol’s effects on fracture healing and will guide future research and clinical treatment of bone fracture patients who misuse alcohol.
Abstract: OBJECTIVES: To explore how alcohol affects the BMP-2 signaling pathway, which is known to play a critical role in bone and cartilage formation during fracture healing. METHODS: A rat model was used to demonstrate the detrimental effects of alcohol exposure on tibia fracture healing. Specific components of the BMP-2 pathway were analyzed in fracture callus on days 3, 7, 14, and 21 after fracture via western immunoassays and enzyme-linked immunosorbent assay. RESULTS: Alcohol exposure before tibia fracture demonstrated attenuation of downstream BMP-2 signaling. The BMP-2 antagonist, Chordin, may be the central component of the BMP-2-related changes demonstrated in this study. Although alcohol affected BMP-related proteins at all time points, it seems that day 14 after fracture is a critical time point for alcohol-related modulation of callus formation in our model. CONCLUSIONS: This study may provide the scientific basis for further studies addressing whether the application of exogenous BMP-2 in patients with a history of alcohol abuse who sustain long bone fractures may or may not be of benefit. (Bratton A, Eisenberg J, Vuchkovska A, Roper P, and Callaci JJ. J Orthop Trauma. 2018 Jun;32(6):288-295. doi: 10.1097/BOT.0000000000001160)
Significance: Neuroimmune activation is a key feature of pathology associated with alcohol use disorder (AUD). HMGB1 and IL-1β are proteins that amplify inflammatory responses, and this study observed increased expression of HMGB1, IL-1β, and HMGB1/IL-1β complexes in the brains of humans with AUD and brains of mice treated with acute binge alcohol. These results suggest a novel mechanism for alcohol-induced central immune activation and the neuropathology of AUD.
Neuroimmune activation is a key feature of the pathologies of numerous psychiatric disorders including alcoholism, depression, and anxiety. Both HMGB1 and IL-1β have been implicated in brain disorders. Previous studies find HMGB1 and IL-1β form heterocomplexes in vitro with enhanced immune responses, lead to our hypothesis that HMGB1 and IL-1β heterocomplexes formed in vivo to contribute to the pathology of alcoholism. HMGB1/IL-1β heterocomplexes were prepared in vitro and found to potentiate IL-1β receptor proinflammatory gene induction compared to IL-1β alone in hippocampal brain slice culture. These HMGB1/IL-1β complexes were found to be increased in post-mortem human alcoholic hippocampus by co-immunoprecipiation. In mice, acute binge ethanol induced both HMGB1 and IL-1β in the brain and plasma. HMGB1 and IL-1β complexes were found only in mouse brain, with confocal microscopy revealing an ethanol-induced HMGB1 and IL-1β cytoplasmic co-localization. Surprisingly, IL-1β was found primarily in neurons. Studies in hippocampal brain slice culture found ethanol increased HMGB1/IL-1β complexes in the media. These studies suggest a novel neuroimmune mechanism in the pathology of alcoholism. Immunogenic HMGB1/IL-1β complexes represent a novel target for immune modulatory therapy in alcohol use disorders, and should be investigated in other psychiatric diseases that involve a neuroimmune component. (Coleman LG Jr, Zou J, Qin L, and Crews FT. Brain Behav Immun. 2018 Aug;72:61-77. doi: 10.1016/j.bbi.2017.10.027)
Significance: Evidence suggests that overexpression or aberrant activity of cyclin-dependent kinase 5 (CDK5) leads to neuronal dysfunction, but the role of CDK5 in alcohol-induced neuronal anomalies is poorly understood. Using a rodent model of fetal alcohol spectrum disorders (FASD), this study observed that postnatal ethanol exposure generates p25, a CDK5-activating peptide, and causes epigenetic suppression of Rac1 expression in a cannabinoid receptor type 1 (CB1R)-dependent manner. Suppression of Rac1 occurs through histone methylation via recruitment of G9a on the Rac1 promoter and persists into adulthood. Pharmacological inhibition of CDK5 before postnatal ethanol administration reversed persistent alcohol-induced biochemical and behavioral changes in adult animals. These results provide evidence that the CB1R-Caspase3-P25-CDK5 signaling cascade in the hippocampus and neocortex plays a key role in neurodegeneration and persistent cognitive impairment in a model of FASD.
Fetal alcohol spectrum disorders (FASD) represent a wide array of defects that arise from ethanol exposure during development. However, the underlying molecular mechanisms are limited. In the current report, we aimed to further evaluate the cannabinoid receptor type 1 (CB1R)-mediated mechanisms in a postnatal ethanol-exposed animal model. We report that the exposure of postnatal day 7 (P7) mice to ethanol generates p25, a CDK5-activating peptide, in a time- and CB1R-dependent manner in the hippocampus and neocortex brain regions. Pharmacological inhibition of CDK5 activity before ethanol exposure prevented accumulation of cleaved caspase-3 (CC3) and hyperphosphorylated tau (PHF1) (a marker for neurodegeneration) in neonatal mice and reversed cAMP response element-binding protein (CREB) activation and activity-regulated cytoskeleton-associated protein (Arc) expression. We also found that postnatal ethanol exposure caused a loss of RhoGTPase-related, Rac1, gene expression in a CB1R and CDK5 activity-dependent manner, which persisted to adulthood. Our epigenetic analysis of the Rac1 gene promoter suggested that persistent suppression of Rac1 expression is mediated by enhanced histone H3 lysine 9 dimethylation (H3K9me2), a repressive chromatin state, via G9a recruitment. The inhibition of CDK5/p25 activity before postnatal ethanol exposure rescued CREB activation, Arc, chromatin remodeling and Rac1 expression, spatial memory and long-term potentiation (LTP) abnormalities in adult mice. Together, these findings propose that the postnatal ethanol-induced CB1R-mediated activation of CDK5 suppresses Arc and Rac1 expression in the mouse brain and is responsible for persistent synaptic plasticity and learning and memory defects in adult mice. This CB1R-mediated activation of CDK5 signaling during active synaptic development may slow down the maturation of synaptic circuits and may cause neurobehavioral defects, as found in this FASD animal model. (Joshi V, Subbanna S, Shivakumar M and Basavarajappa BS. Neuropsychopharmacology. Epub 2018 Aug 22. doi: 10.1038/s41386-018-0181-y)
Significance: Dysregulation of the maternal immune system can result in deviations in fetal cytokine balance, altering the course of typical brain development. This study from the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD) examined whether alterations in the maternal immune milieu, as measured in maternal blood collected during the second and third trimesters, could be linked to alcohol-associated child neurodevelopmental delay. The study identified distinct clusters of activated and inhibited cytokines that are altered in a manner consistent with alcohol-related neurodevelopmental delay. The study extends a previous CIFASD publication (Sowell et al., 2018) which examined the relationship among maternal alcohol consumption, maternal immune profile, and mental and psychomotor development. Importantly, these findings may contribute to the development of biomarkers for early identification of children prenatally exposed to alcohol.
Cytokines and chemokines are potent modulators of brain development and as such, dysregulation of the maternal immune system can result in deviations in the fetal cytokine balance, altering the course of typical brain development, and putting the individual on a "pathway to pathology". In the current study, we used a multi-variate approach to evaluate networks of interacting cytokines and investigated whether alterations in the maternal immune milieu could be linked to alcohol-related and alcohol-independent child neurodevelopmental delay. This was achieved through the measurement of 40 cytokines/chemokines from maternal blood samples collected during the second and third trimesters of pregnancy. Importantly, during the second trimester we identified network enrichment in levels of cytokines including IFN-ɣ, IL-10, TNF-β, TNF-α, and CRP associated with offspring neurodevelopmental delay. However, as elevations in levels of these cytokines have previously been reported in a wide range of neurodevelopmental disorders including autism spectrum disorder and schizophrenia, we suggest that this cytokine profile is likely not disorder specific, but rather may be an indicator of neurodevelopmental delay in general. By contrast, distinct clusters of activated/inhibited cytokines were identified based on maternal alcohol consumption and child neurodevelopmental outcome. Specifically, cytokines including IL-15, IL-10, MDC, and members of the VEGF sub-family were highest in alcohol-consuming mothers of children with neurodevelopmental delay and were identified in both network analyses and examination of individual cytokines, whereas a differential and unique cytokine profile was identified in the case of alcohol-independent child neurodevelopmental delay. We propose that the current findings could provide a critical step towards the development of early biomarkers and possibly interventions for alcohol-related neurodevelopmental delay. Importantly, the current approach could be informative for understanding mechanisms linking maternal immune system dysfunction and adverse child outcomes in a range of other neurodevelopmental disorders. (Bodnar TS, Raineki C, Wertelecki W, Yevtushok L, Plotka L, Zymak-Zakutnya N, Honerkamp-Smith G, Wells A, Rolland M, Woodward TS, Coles CD, Kable JA, Chambers CD, and Weinberg J; Collaborative Initiative on Fetal Alcohol Spectrum Disorders [CIFASD]. Brain Behav Immun. Epub 2018 May 5. doi: 10.1016/j.bbi.2018.05.004)
Significance: Studies have shown that choline supplementation in rats can lessen the deleterious effects of prenatal alcohol exposure (PAE) on neurobehavioral development. This study assessed the eﬃcacy of high-dose choline supplementation (2 grams) initiated early in pregnancy in mitigating eﬀects of heavy PAE on eyeblink conditioning and other infant developmental outcomes known to be aﬀected by alcohol exposure. The findings suggest that prenatal choline supplementation may have the potential to protect against a range of alcohol-related cognitive deficits that do not become evident until later in childhood.
BACKGROUND: We recently demonstrated the acceptability and feasibility of a randomized, double-blind choline supplementation intervention for heavy drinking women during pregnancy. In this study, we report our results relating to the efficacy of this intervention in mitigating adverse effects of prenatal alcohol exposure (PAE) on infant growth and cognitive function. METHODS: Sixty-nine Cape Coloured (mixed ancestry) heavy drinkers in Cape Town, South Africa, recruited in mid-pregnancy, were randomly assigned to receive a daily oral dose of either 2 g of choline or placebo from time of enrollment until delivery. Each dose consisted of an individually wrapped packet of powder that, when mixed with water, produced a sweet tasting grape-flavored drink. The primary outcome, eyeblink conditioning (EBC), was assessed at 6.5 months. Somatic growth was measured at birth, 6.5, and 12 months, recognition memory and processing speed on the Fagan Test of Infant Intelligence, at 6.5 and 12 months. RESULTS: Infants born to choline-treated mothers were more likely to meet criterion for conditioning on EBC than the placebo group. Moreover, within the choline arm, degree of maternal adherence to the supplementation protocol strongly predicted EBC performance. Both groups were small at birth, but choline-treated infants showed considerable catch-up growth in weight and head circumference at 6.5 and 12 months. At 12 months, the infants in the choline treatment arm had higher novelty preference scores, indicating better visual recognition memory. CONCLUSIONS: This exploratory study is the first to provide evidence that a high dose of choline administered early in pregnancy can mitigate adverse effects of heavy PAE on EBC, postnatal growth, and cognition in human infants. These findings are consistent with studies of alcohol-exposed animals that have demonstrated beneficial effects of choline supplementation on classical conditioning, learning, and memory. (Jacobson SW, Carter RC, Molteno CD, Stanton ME, Herbert JS, Lindinger NM, Lewis CE, Dodge NC, Hoyme HE, Zeisel SH, Meintjes EM, Duggan CP, and Jacobson JL. Alcohol Clin Exp Res. 2018 July;42(7):1327-1341. doi: 10.1111/acer.13769)
Significance: It is well known that many college students drink alcohol even though they are under the minimum legal drinking age, with a significant percentage of those students drinking at binge levels. This study found that over a two-year period between freshman and junior years, college students with higher drinking levels had accelerated gray matter volume decline in the hippocampal and parahippocampal regions of the brain, which are critically involved in memory processes. These volumetric reductions were associated with poorer performance on memory tasks and more self-reported memory blackouts after a drinking bout. The results of this study suggest that academic performance may be compromised by heavy alcohol use and provide persuasive evidence about the hazards of drinking during the college years.
BACKGROUND: The hazardous effects of alcohol consumption on both the hippocampus and memory have been well established. However, the longitudinal effects of ethanol on the developing brain and related consequences on memory are not well explored. Given the above, we investigated the longitudinal effects of college drinking on hippocampal volume in emerging college adults. METHODS: Data were derived from the longitudinal Brain and Alcohol Research with College Students study. A subset of 146 freshmen (mean age at baseline = 18.5 years) underwent brain magnetic resonance imaging scans at baseline and 24 months later. Four drinking-related measures derived from monthly surveys were reduced to a single alcohol use index using principal component analysis. Gray matter volumetric change (GMV-c) data were derived using a longitudinal pipeline. Voxelwise hippocampal/para-hippocampal GMV-c associations with the drinking index were derived using a multiple regression framework within SPM12. Supplementary associations were assessed between GMV-c and memory scores computed from the California Verbal Learning Test-II (assessed at the end of the study), and between GMV-c and total alcohol-induced memory blackouts. RESULTS: Larger alcohol use index was associated with an accelerated GMV decline in the hippocampus/para-hippocampus. Also, larger hippocampal volume decline was associated with poorer memory performance and more memory blackouts. CONCLUSIONS: Our study extends prior cross-sectional literature by showing that a heavier drinking burden while in college is associated with greater hippocampal GMV decline that is in turn associated with poorer memory scores, all of which could ultimately have a significant impact on student success. (Meda SA, Hawkins KA, Dager AD, Tennen H, Khadka S, Austad CS, Wood RM, Raskin S, Fallahi CR, and Pearlson GD. Biol Psychiatry Cogn Neurosci and Neuroimaging. 2018 Jul;3(7):610-617. doi: 10.1016/j.bpsc.2018.02.006)
Significance: Longitudinal magnetic resonance imaging (MRI) studies have shown that regional brain volume losses in alcohol-dependent individuals are partially reversible during abstinence from alcohol. This study, conducted in alcohol-dependent individuals, demonstrated significant volume changes in multiple brain regions known to be affected by alcohol misuse during short- and long-term abstinence. Over the period of abstinence, recovery of brain regional volumes approached the level of unaffected controls. The pattern of recovery in the dorsolateral and orbitofrontal cortices and the insula, regions involved in the brain’s executive control and salience networks, showed that over 50 percent of the volume increases occurred within the first month of abstinence, indicating the importance of refraining from alcohol during this early critical period. While the volume of the hippocampus did recover during abstinence, it did not reach the unaffected control level. This finding suggests lingering hippocampal deficits that could impact the ability to remain abstinent. Knowing how the brain changes during early and later stages of abstinence is important for designing more effective strategies to prevent relapse.
BACKGROUND: Widespread brain atrophy in alcohol-dependent individuals (ALC) has been consistently documented in pathological and magnetic resonance imaging (MRI) studies. Longitudinal MRI studies have shown that the regional brain volume losses in ALC are partially reversible during abstinence from alcohol. The goal of this study was to determine volume reductions in cortical and subcortical regions functionally important to substance use behavior and their changes during short-term (1 week to 1 month) and long-term abstinence (1 to 7 months) from alcohol. The regions of interest (ROIs) were as follows: anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC), insula, amygdala, and hippocampus. METHODS: A total of 85 unique ALC were assessed at 1 week (n = 65), 1 month (n = 82), and 7 months (n = 36) of abstinence. In addition, 17 light/nondrinking healthy controls (CON) were assessed at baseline and follow-up over a 10-month interval. Regional brain volumes were derived from FreeSurfer. Cross-sectional statistical analyses using 1-way analysis of variance or Fisher's exact test were applied to identify group differences. Longitudinal statistical analyses using linear mixed models were applied to identify regional volume increases and nonlinear volume recovery trajectories. RESULTS: We demonstrated significant regional volume reductions in ACC, DLPFC, and hippocampus. Older age was associated with smaller DLPFC and OFC, and higher average monthly drinking over 1 year prior to study was associated with smaller OFC. We also demonstrated significant volume increases of all ROIs except amygdala in ALC and significant nonlinear volume recovery trajectories of DLPFC, OFC, and insula. CONCLUSIONS: Results showed significant volume reductions in key regions of the executive control, salience, and emotion networks in ALC at entry into treatment and significant volume increases during short-term and long-term abstinence that were nonlinear over the entire abstinence period for the DLPFC, OFC, and insula. This gray matter plasticity during alcohol abstinence may have important neurobiological and neurocognitive implications in ALC, and it may contribute to an individual's ability to maintain abstinence from alcohol at different phases. (Zou X, Durazzo TC, and Meyerhoff DJ. Alcohol Clin Exp Res. 2018 June;42(6):1062-1072. doi: 10.1111/acer.13757)
Significance: Rodent studies have demonstrated that ghrelin receptor blockade reduces alcohol consumption, but compounds that block ghrelin receptors have not yet been clinically evaluated in people who drink alcohol heavily. In this study, a ghrelin receptor blocker (PF-5190457) was administered to a population of people with alcohol use disorder (AUD) who drink heavily. Together with data from rats, results from this Phase 1b study demonstrate the safety and tolerability of the co-administration of PF-5190457 and alcohol. Furthermore, preliminary data indicated that PF-5190457 reduced both food and alcohol cue-induced craving in a bar-laboratory setting, supporting the need for further research on the role of the ghrelin receptor as a promising target to treat AUD.
Rodent studies indicate that ghrelin receptor blockade reduces alcohol consumption. However, no ghrelin receptor blockers have been administered to heavy alcohol drinking individuals. Therefore, we evaluated the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD) and behavioral effects of a novel ghrelin receptor inverse agonist, PF-5190457, when co-administered with alcohol. We tested the effects of PF-5190457 combined with alcohol on locomotor activity, loss-of-righting reflex (a measure of alcohol sedative actions), and on blood PF-5190457 concentrations in rats. Then, we performed a single-blind, placebo-controlled, within-subject human study with PF-5190457 (placebo/0 mg b.i.d., 50 mg b.i.d., 100 mg b.i.d.). Twelve heavy drinkers during three identical visits completed an alcohol administration session, subjective assessments, and an alcohol cue-reactivity procedure, and gave blood samples for PK/PD testing. In rats, PF-5190457 did not interact with the effects of alcohol on locomotor activity or loss-of-righting reflex. Alcohol did not affect blood PF-5190457 concentrations. In humans, all adverse events were mild or moderate and did not require discontinuation or dose reductions. Drug dose did not alter alcohol concentration or elimination, alcohol-induced stimulation or sedation, or mood during alcohol administration. Potential PD markers of PF-5190457 were acyl-to-total ghrelin ratio and insulin-like growth factor-1. PF-5190457 (100 mg b.i.d.) reduced alcohol craving during the cue-reactivity procedure. This study provides the first translational evidence of safety and tolerability of the ghrelin receptor inverse agonist PF-5190457 when co-administered with alcohol. PK/PD/behavioral findings support continued research of PF-5190457 as a potential pharmacological agent to treat alcohol use disorder. (Lee MR, Tapocik JD, Ghareeb M, Schwandt ML, Dias AA, Le AN, Cobbina E, Farinelli LA, Bouhlal S, Farokhnia M, Heilig M, Akhlaghi F, and Leggio L. Mol Psychiatry. Epub 2018 May 4. doi: 10.1038/s41380-018-0064-y)
Significance: This study validated the NIAAA two-item screening guide for identifying adolescents at risk for alcohol use disorder (AUD) in primary care clinics serving racially and ethnically diverse patients in two cities. The optimal cutpoints for identifying patients with AUD (number of reported days of drinking in the past year) varied by age and grade in school, in line with the NIAAA screener. For older adolescents, a lower drinking threshold is recommended to permit clinicians to intervene earlier.
The National Institute on Alcohol Abuse and Alcoholism (NIAAA) screening guide (SG) uses a 2-question screening process to identify adolescents at risk for alcohol use. The aim of this study was to identify the optimal screening rule in terms of identifying adolescents with alcohol use disorder (AUD) using the NIAAA questions by examining whether the cutpoint should vary by gender, race/ethnicity, grade, and/or age. Youth aged 12 through 18 years (N = 1,573; 27% Black, 51% Hispanic) were screened using the NIAAA SG, and then completed a survey. We used receiver operating characteristic curve analyses to identify the optimal cutpoint for the NIAAA screener question on self-use with AUD as the outcome. We compared the resulting screening rule with the NIAAA SG rule. We found that the optimal cutpoint depended on age and grade of adolescents. The resulting screening rule was the same as the NIAAA SG, and thus independently validated the NIAAA SG, with the exception of screening for adolescents 18 years of age, for which a lower cutpoint was indicated. The performance of both screening rules was highly similar when applied to the study sample, with a sensitivity of 0.89 for the optimal screening rule and a sensitivity of 0.87 for the NIAAA SG. In settings in which the cost of a false positive is relatively low (depending on available resources and cost of the intervention), lower cutpoints for older adolescents should be considered, as this may increase sensitivity of identifying these individuals at risk for AUD. (Parast L, Meredith LS, Stein BD, Shadel WG, and D’Amico EJ. Psychol Addict Behav. 2018 Aug;32(5):508-516. doi: 10.1037/adb0000377)
NIAAA COMMUNICATIONS ACTIVITIES
Press and Publications Activities:
Recent News Media Interviews: NIAAA Director Dr. George F. Koob and other NIAAA experts continue to speak with a variety of national and international news outlets on timely topics related to NIAAA’s research and its impact on treatment and prevention of alcohol misuse and alcohol use disorders. In addition to the examples below, notable interviews since May include those with The Washington Post, TheFix.com, VICE.com, The Columbus Dispatch, Huffington Post, and Cosmopolitan magazine.
On July 18, 2018, WebMD ran a comprehensive article about alcohol and women, in which interviews with NIAAA’s Drs. Aaron White and Deidra Roach were featured prominently. The article will help raise awareness of the slippery slope of alcohol misuse for women.
Milwaukee Journal Sentinel
On June 28, 2018, NIAAA Director George F. Koob was quoted in an article about the biology of alcohol tolerance and the brain changes that occur with chronic alcohol misuse.
On June 14, 2018, Drs. Ralph Hingson and Aaron White spoke with the BBC about why only some people experience alcohol-induced blackouts. Dr. White discussed the physiology of blackouts and Dr. Hingson discussed his recent Alcoholism: Clinical and Experimental Research paper, “Alcohol-Induced Blackouts as Predictors of Other Drinking Related Harms Among Emerging Young Adults.”
On July 2, 2018, NIAAA Director Dr. George F. Koob was interviewed on the WBZ Women’s Watch radio program. He addressed AUD among women and the rise of extreme binge drinking among the public as a whole.
- Lack of sleep may be linked to risk factor for Alzheimer’s disease (April 13, 2018)
- Researchers identify key brain circuits involved in reward-seeking and avoidance behavior (August 22, 2018)
Please see the News and Events section of the NIAAA website for these and other news releases.
Publication and Multimedia Statistics: In the month of July, NIAAA filled orders for 17,354 copies of print publications. As of July, there were 30,290 Granicus listserv subscribers to Alcohol Research: Current Reviews; 22,378 to the NIAAA Spectrum; 284 to News Alerts; and 21,914 to receive general information.
Social Media Highlights:
NIAAA Expands Digital Footprint to Instagram: NIAAA is now on Instagram. To help diversify NIAAA’s social media presence and reach a younger audience, NIAAA launched an Instagram account (@niaaanews) on July 1, 2018. This account will feature seasonally focused social media graphics, as well as promotion for new NIAAA research, public education messages, and resources.
Continued Growth on Twitter: As of August, NIAAA has more than 21,000 followers on Twitter and continues to be active in alcohol-related Twitter chats. In late June, NIAAA joined a Salud America chat on drinking in the Latino community, part of their popular #SaludTues series. NIAAA joined the National Institute on Minority Health and Health Disparities in July for a chat on mental health issues and addiction among minority groups. In early August, NIAAA and NIDA held a back-to-school chat about important tips for students.
Navigator Promotion: In July, NIAAA initiated an enhanced digital marketing effort for the Treatment Navigator. Targeted efforts on Twitter to increase awareness of the Alcohol Treatment Navigator resulted in a 480 percent increase in visits to the Navigator website.
Partnerships, Outreach and Public Liaison Activities:
High School Graduation
The NIAAA fact sheet titled “Parents—Talk with Your High School Grads About Celebrating Safely” was disseminated to the media through PR Newswire on May 17 and 22, 2018. The fact sheet was posted by Internet news outlets such as Yahoo!, Spoke, MarketWatch, and The Boston Herald, as well as business journals, industry publications, and by numerous major television network (FOX, NBC, CBS, ABC) local affiliates nationwide.
Summer Safety Promotion
The NIAAA fact sheet titled “Risky Drinking Can Put a Chill on Your Summer Fun” was disseminated to the media through PR Newswire on June 12 and 25, 2018, as part of NIAAA’s seasonal efforts to educate the public about risky drinking habits. The fact sheet was posted by Internet news outlets such as Yahoo!, Spoke, MarketWatch, Daily Herald, and the Pittsburgh Post-Gazette, as well as business journals, industry publications, and numerous major television network (FOX, NBC, CBS, ABC) local affiliates nationwide
Back to College
The NIAAA fact sheet titled “Fall Semester–A Time for Parents to Discuss the Risks of College Drinking” was disseminated to the media through Cision/PR Newswire’s US1 distribution with AP photo release on August 1 and 9, 2018. The fact sheet was posted by Internet news outlets such as MarketWatch, The Boston Herald, and Spoke, as well as business journals, industry publications, and major television network (FOX, NBC, CBS, ABC) local affiliates nationwide. It also appeared on Cision’s Times Square billboard 13 times on August 1, 2018, and a Cision email blast was distributed on August 1 to local and national TV, radio, print, consumer, health/wellness, and education reporters, and parenting blogs.
Select Partnership Updates
- Community Anti-Drug Coalitions of America (CADCA): In July, Dr. Ralph Hingson presented a session titled “New Research Since the Surgeon General’s Call to Action to Prevent and Reduce Underage Drinking” at the CADCA Mid-Year Training Institute in Orlando, Florida.
- American Academy of Addiction Psychiatry (AAAP): The AAAP posted an article in their summer newsletter about “Alcohol-Related Emergency Department Visits on the Rise.”
- New York State Office of Alcoholism and Substance Abuse Services (OASAS): Dr. Lori Ducharme presented a webinar to OASAS senior staff in July.
- Optum: A link to the NIAAA Treatment Navigator was posted on Optum’s Live and Work Well website, which provides behavioral health resources to Optum subscribers. Optum is a company that provides behavioral health and substance abuse services as part of UnitedHealth Group.
- National Organization on Fetal Alcohol Syndrome (NOFAS): NOFAS, with input from NIAAA, hosted an event with the Indian Health Council to gather feedback from several North San Diego County tribal communities on the significance of AUD and FASD.