DEPARTMENT OF HEALTH AND HUMAN SERVICES
NATIONAL INSTITUTES OF HEALTH
NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
152nd Meeting of the
NATIONAL ADVISORY COUNCIL ON ALCOHOL ABUSE AND ALCOHOLISM
September 12, 2019
The National Advisory Council on Alcohol Abuse and Alcoholism (NIAAA) convened for its 152nd meeting at 9:00 a.m. on Thursday, September 12, 2019, at NIAAA headquarters in Rockville, Maryland. The Council met in closed session from 9:00 a.m. to 9:42 a.m. to review grant applications and cooperative agreements. Dr. Abraham Bautista, Director, Office of Extramural Activities, presided over the Council’s review session, which, in accordance with the provisions of Sections 552b(C)(6), Title 5, U.S.C., and 10(d) of Public Law 92-463, excluded the public for the review, discussion, and evaluation of individual applications for Federal grant-in-aid funds. The closed session recessed at 9:42 a.m.
Council Members Present:
Carmen Albizu-Garcia, M.D.
Louis E. Baxter, M.D.
Jill B. Becker, Ph.D.
Daniel J. Calac, M.D.
Alex M. Dopico, M.D., Ph.D.
Tatiana M. Foroud, Ph.D.
Robert J. Hitzemann, Ph.D. (by telephone)
Constance M. Horgan, Sc.D.
Joe L. Martinez, Jr., Ph.D. (by telephone)
Scott J. Russo, Ph.D.
Arun J. Sanyal, M.D.
Vijay H. Shah, M.D.
Frank A. Sloan, Ph.D.
Susan M. Smith, Ph.D.
Edith Vioni Sullivan, Ph.D.
Constance M. Weisner, Dr.P.H.
NIAAA Director and Chair: George F. Koob, Ph.D.
NIAAA Deputy Director: Patricia Powell, Ph.D.
Executive Secretary: Abraham P. Bautista, Ph.D.
Senior Staff: Vicki Buckley, M.B.A.; David Goldman, M.D.; Michael Hilton, Ph.D.; M. Katherine Jung, Ph.D; George Kunos, M.D., Ph.D.; Raye Litten, Ph.D., Antonio Noronha, Ph.D.; Megan Ryan, M.B.A.; and Bridget Williams-Simmons, Ph.D.
Other Attendees at the Open Session:
Approximately 40 observers attended the open session, including representatives from constituency groups, liaison organizations, NIAAA staff, and members of the general public.
Call to Order and Introductions
NIAAA Director George Koob, Ph.D., called the open session of the Council meeting to order at 9:44 a.m. on Thursday, September 12, 2019. Council members and senior NIAAA staff introduced themselves.
Announcement of Retiring Members
Dr. Koob announced the retirement of Council members Carmen Albizu-Garcia, M.D.; Howard Becker, Ph.D.; Tatiana Foroud, Ph.D.; Joe Martinez, Jr., Ph.D.; Arun Sanyal, M.D.; Frank Sloan, Ph.D.; and Constance Weisner, Dr.P.H., and expressed his appreciation for their service.
Dr. Koob highlighted key recent NIAAA activities, referring to the written Director’s Report, which was distributed to Council members.
Staff Transitions: Dr. Koob announced the deaths of R. Thomas (Tom) Gentry, Ph.D., a retired program officer for the Division of Metabolism and Health Effects, who advanced efforts to develop a wearable alcohol biosensor, and Robert E. Taylor, M.D., Ph.D., Dean of the College of Medicine, Chair of the Department of Pharmacology, and Director of the NIAAA-funded Collaborative Alcohol Research Center at Howard University, who served as an NIAAA Council member from 2002-2006 and more recently as an ad hoc member of the Council’s Working Group on Diversity and Health Disparities in the Biomedical Workforce. Dr. Koob welcomed new NIAAA staff members Gabriela Coello and Cassie Williams, Administrative Officers in the Administrative Services, and Yong He, Ph.D., Research Fellow in the Visiting Program in the Laboratory of Liver Diseases (LLD). He also noted the following new roles resulting from internal staff transitions: Tatiana Balachova, Ph.D., Senior Scientific Administrator, Division of Epidemiology and Prevention Research; Svetlana Radaeva, Ph.D., Deputy Director, Division of Metabolism and Health Effects (DMHE); Mehdi Farokhnia, M.D., Research Fellow, Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology (CPN); Laura Kwako, Ph.D., Program Officer, Division of Treatment and Recovery Research; and Rachel Anderson, Ph.D., Health Science Policy Analyst, Science Policy Branch. Finally, Dr. Koob bid farewell to these departing staff members: Erin Bryant, Science Writer and Social Media Strategist in the Communications and Public Liaison Branch; Yolanda Carter, Administrative Laboratory Manager with Laboratory of Integrative Neuroscience; Abhishek Desai, Ph.D., Fellow in the Laboratory of Molecular Signaling; Lori Ducharme, Ph.D., Program Director in the Division of Treatment and Recovery Research; Lynn Morin, Chair of the Centers and Training Working Group and Diversity Supplement Program Coordinator for the NIAAA Office of Extramural Activities; and Kamilah Smith, Administrative Assistant with the Division of Neuroscience and Behavior. He also noted the retirements of Monte Philips, Biologist in the Section on Clinical Genomics and Experimental Therapeutics, and Richard Rippe, Ph.D., Scientific Review Officer, Extramural Project Review Branch, Office of Extramural Activities.
Budget: NIAAA’s Fiscal Year (FY) 2019 budget was $525.6 million, which funded 782 Research Projects Grants (RPG), 192 competing awards, 194 other research grants, 21 research centers, and 295 training positions. NIAAA awarded $34 million in research and development contracts. The FY 2020 budget is under development.
Funding Opportunity Announcements (FOAs): The following FOAs have been issued since the last Council meeting: Mechanisms of Tolerance (R21/R33 Clinical Trial Required); Specialized Alcohol Research Centers (P50 Clinical Trial Optional); and Comprehensive Alcohol Research Centers (P60 Clinical Trial Optional). NIAAA is participating in these NIH-wide FOAs: Secondary Analyses of Existing Datasets of Tobacco Use and Health (R21 Clinical Trial Not Allowed); Maximizing the Scientific Value of Existing Biospecimen Collections: Scientific Opportunities for Exploratory Research (R21 Clinical Trial Not Allowed); Methods to Improve Reproducibility of Human iPSC Derivation, Growth and Differentiation (SBIR) (R44 Clinical Trial Not Allowed); and Dissemination and Implementation Research in Health (R01 Clinical Trial Optional; R21 Clinical Trial Optional; R03 Clinical Trial Not Allowed). In addition, NIAAA is participating in the following new Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative FOAs: Non-Invasive Neuromodulation - New Tools and Techniques for Spatiotemporal Precision (R01 Clinical Trial Optional); Proof of Concept Development of Early Stage Next Generation Human Brain Imaging (R01 Clinical Trial Not Allowed); Development of Next Generation Human Brain Imaging Tools and Technologies (U01 Clinical Trial not allowed); Marmoset Coordination Center (U24 Clinical Trials Not Allowed); Marmoset Colonies for Neuroscience Research (U24 Clinical Trials Not Allowed); and Research to Develop and Validate Advanced Human Cell-Based Assays To Model Brain Structure and Function (R01 Clinical Trial Not Allowed).
Updates to the NIAAA Treatment Navigator: The NIAAA Alcohol Treatment Navigator now includes a portal for healthcare professionals to help clinicians build or expand their referral lists to include providers offering evidence-based alcohol use disorder (AUD) treatments that meet the varied needs of their patients. It also provides tips for sharing the tool directly with patients who wish to search on their own. The Navigator has also been updated to include expanded content on types of treatment to promote better awareness of the full range of options, as well as a new filter to its program search tool to make it easier for clinicians and the public to locate telehealth services for AUD.
Upcoming Events: Upcoming events include an Alcoholic and Nonalcoholic Steatohepatitis: Pathogenesis and Mechanisms of Liver Injury Workshop on September 16-17, 2019, in Bethesda, MD, jointly sponsored by NIAAA and the National Institute on Diabetes and Digestive and Kidney Diseases (NIDDK). NIAAA and the National Institute on Drug Abuse (NIDA), along with the National Institute on Minority Health and Health Disparities (NIMHD), will again sponsor the National Hispanic Science Network annual meeting on October 9-11, 2019, in New Orleans, LA. In addition to scientific sessions on basic and clinical addiction research, the program includes two invited symposia on alcohol-related research. Finally, the Cancer Moonshot Collaborative Meeting will be held November 18-20, 2019, in Rockville, MD.
Research Highlights: Dr. Koob presented highlights of recent NIAAA-supported research:
“ALDH2 Deficiency Promotes Alcohol-Associated Liver Cancer by Activating Oncogenic Pathways via Oxidized DNA Enriched Extracellular Vesicles” was published in the Journal of Hepatology (2019 Jul 4. pii: S0168-827830390-3) by W Seo, Y Gao, Y He, J Sun, H Xu, D Feng, S Hee Park, YE Cho, A Guillot, T Ren, R Wu, J Wang, SJ Kim, S Hwang, S Liangpunsakul, Y Yang, J Niu, and B Gao. Aldehyde Dehydrogenase 2 (ALDH2) is a key enzyme that detoxifies the alcohol metabolite acetaldehyde in the liver. This study demonstrated that ALDH2-deficient mice or humans with chronic liver disease and alcohol consumption are more susceptible to liver cancer, due to increased production of oxidized mitochondrial DNA-enriched extracellular vesicles that activate multiple oncogenic pathways. Inhibition of oxidized mitochondrial DNA-enriched extracellular vesicle production could be a novel therapeutic strategy for ameliorating alcohol-associated liver cancer in ALDH2-deficient individuals.
“Targeting Peripheral CB1 Receptors Reduces Ethanol Intake via a Gut-Brain Axis” was published in Cell Metabolism (2019 Jun 4; 29(6):1320-1333.e8) by G Godlewski, R Cinar, NJ Coffey, J Liu, T Jourdan, B Mukhopadhyay, L Chedester, Z Liu, D Osei-Hyiaman, MR Iyer, JK Park, RG Smith, H Iwakura, and G Kunos. Endocannabinoids and ghrelin are both implicated in promoting alcohol intake, but interactions between the two systems have not been characterized. This study demonstrated that cannabinoid-1 receptor (CB1R) signaling in ghrelin-producing stomach cells modulates the formation of biologically active ghrelin, which then activates a gut-brain signaling pathway that leads to increased alcohol consumption. Peripherally-restricted pharmacological inhibition of CB1R, which avoids the psychiatric side effects of blocking CB1R in the central nervous system, reduced ethanol drinking in mice. Thus, peripheral CB1 receptor blockade may have therapeutic potential in the treatment of AUD.
“Maternal Circulating miRNAs that Predict Infant FASD Outcomes Influence Placental Maturation” was published in Life Science Alliance ( 2019 Mar 4; 2. pii: e201800252) by AM Tseng, AH Mahnke, AB Wells, NA Salem, AM Allan, VH Roberts, N Newman, NA Walter, CD Kroenke, KA Grant, LK Akison, KM Moritz, CD Chambers, and RC Miranda, Collaborative Initiative on Fetal Alcohol Spectrum Disorders (FASD). Previous research identified 11 miRNAs in the plasma of pregnant women that predict infant FASD outcomes following prenatal alcohol exposure. In the current report, the same team demonstrated that these miRNAs restrict placental maturation by inhibiting trophoblast epithelial-mesenchymal transition (EMT), a key process for development of the placenta. In vitro cell data also supported the potential of targeting these miRNAs for therapeutic intervention. Collectively, these findings suggest that prenatal alcohol results in fetal growth restriction in part by impairing placental function via specific miRNAs.
“Activation of Glycine Receptors in the Lateral Habenula Rescues Anxiety- and Depression-like Behaviors Associated with Alcohol Withdrawal and Reduces Alcohol Intake in Rats” was published in Neuropharmacology (2019 Oct; 157:107688) by W Li, W Zuo, W Wu, QK Zuo, R Fu, L Wu, H Zhang, M Ndukwe, and JH Ye. The negative emotional state associated with alcohol withdrawal is a driving force for alcohol relapse; however, the underlying neurobiological mechanisms are not fully understood. In this study, activation of glycine receptors in the lateral habenula alleviated alcohol withdrawal-induced anxiety- and depression-like behaviors and reduced alcohol consumption in rats. This study demonstrates a role for glycine signaling in the lateral habenula in negative affective states associated with alcohol withdrawal, offering a potential therapeutic target for AUD.
“Stroop-related Cerebellar and Temporal Activation is Correlated with Negative Affect and Alcohol Use Disorder Severity” was published in Brain Imaging and Behavior (2019 May 22. doi: 10.1007/s11682-019-00126-3) by CE Wilcox, J Clifford, J Ling, AR Mayer, R Bigelow, MP Bogenschutz, and JS Tonigan. This study used functional brain imaging to study the relationships between cognitive control, the severity of AUD, and measures of negative affect such as anxiety, depression, and affective lability. There was greater activation in the cerebellum and temporal cortex during a cognitive interference task that was correlated with a greater degree of AUD severity and increased negative affect. Activation in the cerebellum was still associated with negative affect after controlling for the effects of drinking history and AUD severity. These results suggest that the cerebellum may play a more prominent role in negative affect and AUD than previously realized and provides a potential target for intervention.
“Sex Differences in Trait Anxiety’s Association with Alcohol Problems in Emerging Adults: The Influence of Symptoms of Depression and Borderline Personality” was published in the Journal of Substance Use (2019. 24:3, 323-328) by EA Atkinson and PR Finn. Lifetime alcohol drinking is often associated with anxiety, depression, and other mental health conditions such as borderline personality disorder (BPD). However, the extent to which sex differences contribute to these conditions in relation to drinking problems is not well understood. This study assessed trait anxiety, depression, and symptoms of BPD in a large sample of young adults (age 18-30) with varying lifetime alcohol-related problems. The results showed that the correlation between trait anxiety and alcohol problems was significantly stronger in men than women, regardless of depression and BPD symptoms. These findings suggest sex-specific mechanisms underlying the relationship between trait anxiety and alcohol problems.
“Intravenous Administration of Ghrelin Increases Serum Cortisol and Aldosterone Concentrations in Heavy-Drinking Alcohol-Dependent Individuals: Results from a Double-Blind, Placebo-Controlled Human Laboratory Study” was published in Neuropharmacology (2019 Jul 13:107711) by CL Haass-Koffler, VM Long, M Farokhnia, M Magill, GA Kenna, RM Swift RM, and L Leggio. Effects of ghrelin administration on cortisol and aldosterone, two corticosteroid hormones involved in the neurobiology of AUD, have been observed in previous studies. In this study, serum concentrations of cortisol and aldosterone were used to develop a model to predict the effect of exogenous ghrelin administration on alcohol craving in individuals with AUD. Ghrelin-induced changes in aldosterone (but not cortisol) predicted craving. These findings provide initial evidence of a link between ghrelin and glucocorticoids/mineralocorticoids in the context of AUD, thereby providing additional information on how the ghrelin system may play a role in alcohol-related behaviors.
“Alcohol Rehabilitation Within 30 Days of Hospital Discharge Is Associated With Reduced Readmission, Relapse, and Death in Patients With Alcoholic Hepatitis” was published in Clinical Gastroenterology and Hepatology (2019 Apr 28. pii: S1542-3565(19)30438-0) by TB Peeraphatdit, PS Kamath, VM Karpyak, B Davis, V Desai, S Liangpunsakul, A Sanyal, N Chalasani, VH Shah, and DA Simonetto. Patients who have recovered from alcoholic hepatitis (AH) remain at risk of hospital readmission and death, outcomes generally attributed to alcohol relapse. This analysis of two patient cohorts evaluated rates of hospital readmission, alcohol relapse, and mortality in AH patients. Participation in early alcohol rehabilitation (within 30 days of discharge) was associated with decreased 30-day readmission and alcohol relapse in both cohorts, as well as reduced mortality. These results suggest that all patients with AH should be formally evaluated by addiction specialists during their hospital stay and referred for treatment within 30 days of hospital discharge.
“Health Care Use Over 3 Years After Adolescent SBIRT” was published in Pediatrics (2019 May; 143. pii: e20182803) by S Sterling, AH Kline-Simon, A Jones, L Hartman, K Saba, C Weisner, and S Parthasarathy. This study used electronic health data to examine subsequent health care use among adolescents from a randomized clinical trial comparing usual care to two modalities of delivering Screening, Brief Intervention, and Referral to Treatment (SBIRT) in pediatric primary care (either pediatrician- or behavioral clinician-delivered). Adolescents in the SBIRT group were likely to have had more substance use treatment visits and fewer psychiatry department visits and total outpatient visits over a 3-year period compared with those in usual care. These findings suggest that providing SBIRT in primary care may reduce health care use and improve adolescent health.
“The Relationship Between the U.S. State Alcohol Policy Environment and Individuals' Experience of Secondhand Effects: Alcohol Harms Due to Others' Drinking” was published in Alcoholism: Clinical and Experimental Research (2019 Jun; 43(6):1234-1243) by TK Greenfield, WK Cook, KJ Karriker-Jaffe, D Patterson, WC Kerr, Z Xuan, and TS Naimi. This study examined the prevalence of alcohol’s secondhand effects and whether the prevalence of these effects differed based on the strength of a state’s policies. Secondhand harms in three categories (aggression-related, family- or financial-related, and driving-related) were experienced by 16.8 percent of people under age 40 and 7.8 percent of people over age 40. Researchers then modeled the effects of a 10 percent increase in alcohol policy restrictiveness, which was linked with lower levels of aggression-related harms and drunk driving-related harms for individuals under age 40. These findings suggest that state policies known to reduce binge drinking and impaired driving might also reduce the secondhand harms of alcohol, particularly among individuals under age 40.
Council Member Presentation: Cerebral and Cerebellar Targets of Hazardous Drinking from Adolescence to Senescence
Dr. Koob introduced Council member Edith V. Sullivan, Ph.D., Stanford University School of Medicine, whose presentation focused on what structural magnetic resonance imaging (MRI) reveals about neurodevelopment, aging, and alcohol, specifically impacts on the cerebrum and cerebellum. Her presentation addressed both older adults and adolescents.
Older Adults: Results of the National Health Interview Survey between 1997-2014 reveal declining abstention from alcohol and increasing levels of drinking and binge drinking among older adults. These increases are greater for women than for men. Another study using data from the U.S. National Survey on Drug Use and Health from 2015-2017 found that more than a tenth of adults age 65 and older engaged in binge drinking. As the percentage of the U.S. population 65 and older continues to expand, there is concern about the increasing potential for age-related dementias, age-alcohol interactions, and alcohol-related dementia.
Brain weight increases fourfold from birth to about 10 years of age. Gray matter volume starts declining during adolescence and continues to decline across the adult years. To understand how aging and hazardous drinking affect brain structure, researchers need to detect and measure neuropathology in the context of normal development and aging. In a study led by Dr. Sullivan, cross-sectional and longitudinal data were collected over 14 years from 222 individuals with alcohol use disorder (AUD) and 199 healthy control subjects. Each study participant was scanned with MRI up to eight times during the study. The results indicated an anterior distribution of cortical volume deficits in the brains of participants with AUD. The greatest differences were in regions of the frontal cortex and the insula, which has been considered a site of addiction. Additional volume deficits were detected in limbic structures, including the hippocampus and thalamus, both known to subserve episodic memory processes. The gray matter volume of the controls declined significantly with aging; the alcohol group, however, experienced a steeper decline. Accelerated aging was notable in the precentral and superior frontal cortices of the older adults with AUD, putting older adults at heightened risk for age-related neuro-compromise, even if alcohol misuse was initiated later in life. In fact, a large number of individuals had a relatively late onset of AUD (i.e., after age 45) and this later-onset group, who advanced into the age range of dementia over the course of the study, had the greatest frontal volume deficits, despite age correction.
Alcohol-related dementia (ARD) represents 10 percent of all early onset dementias, but little more than one percent of late-onset dementias. ARD patients are typically less cognitively impaired than those with other dementias. Notably, 82 percent of ARD cases are men, but only 14 percent of men comprise patients with other dementias, raising the possibility that occult AUD may be present with greater prevalence than previously thought in early onset cases of dementia. Further, the noted sex differences may be an artifact of the higher incidence of alcohol misuse by men than women. Given the new epidemiological data on alcohol use, however, the sex-ARD distribution may now include more women.
The cerebellum, which is the major portion of the infratentorial volume, is only 13 percent of the total intracranial volume (ICV), but contains 3.6 times the number of neurons as the rest of the brain. Like the cortex, cerebellar gray matter volumes decline with aging in healthy adults and do so more in those with AUD. Together, accelerated volume decline in frontal and cerebellar regions, which have many functional connections, may be a source of accelerated functional decline in older adults with AUD that could masquerade as dementia.
Adolescents: How does initiation of heavy alcohol drinking divert the normal aging trajectory of regional brain growth in adolescents? To address this question, NIH (primarily NIAAA) funded the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) about seven years ago to prospectively track brain development in adolescents annually before and then after a segment of youth initiated alcohol consumption. NCANDA follows a cohort sequential design that recruited youth in three age bands: 12-14, 15-17, and 18-21, with entry criteria based on a participant’s age, e.g., 12-year-olds should have almost no alcohol exposure whereas 20-year-olds could have initiated modest but not heavy drinking. The study designates such participants as "no-to-low" drinkers and recruited 647 of them, plus 134 who exceeded the criteria.
In determining the developmental trajectories of the youth who remained no-to-low drinkers, the researchers observed the expected decline in cortical gray matter volume with age at one-year follow-up and continued volumetric decline at the two-year follow-up. At the two-year follow-up when most youth had had three scans, 356 remained at the no-low drinking level, 65 transitioned into moderate alcohol consumption, and 62 transitioned into heavy drinking. Among those in the moderate alcohol consumption group, a modestly faster than normal volume decline was observed and an even faster decline was observed among youth in the heavy drinking group. Measurement of the entire cortical mantle revealed a frontal and parietal distribution of accelerated cortical volume decline in drinking adolescents. These are regions that subserve critical cognitive functions of decision-making, inhibition, and information integration. There was some evidence for a dose effect in these negative correlations, with faster volume loss in youth who had reported having more maximum drinks on an occasion over the past year.
The normal growth trajectory observed in the gray matter of the cerebrum in the NCANDA boys and girls was also evident in their cerebellar gray matter. The NCANDA researchers analyzed the cerebellum following 3-year follow-up, with 2043 MRIs acquired on 220 drinkers and 328 youth who remained as no-low drinkers. In no/low drinking adolescents, gray matter volumes declined in the boys and girls, whereas cerebrospinal fluid (CSF)-filled spaces and white matter volumes expanded, yet all three volumes showed decelerating slopes of change with approaching adulthood. A novel contribution of this longitudinal study was to establish the pattern of development by cerebellar lobule and tissue type in no/low drinking youth. Parcellation of this complex brain structure revealed sexual dimorphism in different lobules and by different tissue type in growth patterns for gray matter, white matter, and CSF-filled spaces. Youth who transitioned to moderate or heavy drinking exhibited accelerated enlargement of CSF volumes and accelerated declines of gray matter volume that were greater in heavy than in moderate drinkers. In the cerebellum there is a horizontal fissure that separates the anterior-superior lobules from the inferior lobules, the former commonly affected in adult AUD. That horizontal fissure showed marked acceleration of CSF volume in the drinking youth who also showed accelerated enlargement of CSF volumes in the anterior superior and vermian regions and accelerated shrinkage of cerebellar gray matter volumes in this constellation of regions, providing evidence that the cerebellum is affected in youth who initiate appreciable drinking.
Dr. Sullivan acknowledged the responsibility that clinical researchers have who use structural MRIs to investigate otherwise unseen development—both normal and anomalous. The NCANDA adolescents were screened to be healthy and developing normally. Yet clinical neuroradiological readings revealed a significant number of "incidental findings"—some serious enough to warrant clinical follow-up. Clinical review identified 11.5 percent incidence of visually detectable anomalies in the 833 NCANDA youth at baseline MRI. Most findings were benign and required no intervention. However, several findings were serious enough to require clinical follow-up.
In summary, structural MRI is a powerful clinical and research tool with excellent translational opportunities. The alcohol-related cortical decline in youth involved fronto-cerebellar systems commonly affected in adult AUD, raising testable hypotheses expressed here as questions: 1) Does early drinking cause selective vulnerability in this brain network in adults who go on to develop AUD? 2) Can high-drinking youth who reduce consumption and sustain abstinence or low drinking re-establish normal growth trajectories? 3) Does an identifiable segment of early onset dementia have an AUD component, which unlike classical dementia is a treatable and potentially reversible condition?
Discussion: Dr. Koob asked Dr. Sullivan her thoughts about whether high-drinking youth who reduce consumption can re-establish normal growth trajectories. Dr. Sullivan responded that NCANDA is conducting studies to address this question with youth who started heavy drinking but are undergoing treatment. She speculated that the polio model may apply, i.e., if one drinks early on, he or she may have a vulnerability later in life, e.g., greater interaction with aging and AUD and thus an increased risk for dementia. Louis Baxter, M.D., inquired about the impact of genetics on the outcomes that Dr. Sullivan described. Dr. Sullivan explained that family history of alcohol is one of many potentially confounding variables that the researchers have evaluated, and for which they have not yet seen a significant impact. Similarly, they have not found significant sex differences; usually, when they correct for intra-cranial volume, sex differences disappear. In the research on adolescent development she presented that showed some differences between boys and girls, those differences disappeared when they looked at the individual lobules or the entire cerebellum. As researchers develop more refined approaches to parcellation of the brain, they might find that some areas are more genetically determined and where family history may play a role. Arun Sanyal, M.D., asked if Dr. Sullivan or others have looked at interactions of alcohol with obesity, inflammation, or diabetes. Dr. Sullivan noted that body mass index (BMI) of study participants is routinely recorded and some relationship between high BMI and alcohol intake has been noted, but it is one of several dynamic relationships that are not stable. David Goldman, M.D., inquired about differences between the youth who did not drink and those who did before the onset of alcohol use, as well as about any subsequent neurofunctional outcomes between the drinkers and non-drinkers. Dr. Sullivan responded that when NCANDA researchers looked at the “big” differences among participants before some began drinking, they did not find any that were statistically significant. Regarding outcomes, it is commonly difficult to find relations between quantitative measures of a specific brain region and quantitative measures of selective neuropsychological functions in healthy individuals, especially within restricted age ranges. Such structure-function relations are more forthcoming in situations in which a group spans the full age range of adulthood or has a frank lesion and impaired performance. In those conditions, the ideal is to seek and find a double dissociation, which would provide some assurance for the selectivity and causality of observed correlations. An additional point to be made with respect to adolescent development and finding differences in brain structure or function related to initiation of moderate to heavy drinking is the following: longitudinally-determined, alcohol-related volume declines or neuropsychological test performance detected in normally developing youth examined before and after initiating appreciable drinking provides unique evidence for untoward effects of drinking, even if it is short of establishing specific brain structure-function relations.
Council Member Presentation: Immune Mechanisms of Depression
Dr. Koob introduced Council member Scott Russo, Ph.D., who described preclinical research that the Laboratory of Neural and Immune Mechanisms of Psychiatric Illness at the Icahn School of Medicine has conducted to investigate immune mechanisms related to psychiatric issues. Traditionally, scientists believed that mental health disorders are caused by pathologies in the circuits or nerve cells within the brain. The reality, however, is that the body is coordinating many different functions simultaneously and that functions at the periphery can impact the brain and behavior. This thinking emerged from a prominent theory in psychopharmacology that suggested that various brain-related issues were related to disruptions in the immune system. The earliest data supporting this theory were epidemiological. Classic immune- or inflammatory-based illnesses are associated with increased risk of depression among those with every major illness. For example, the world-wide prevalence of depression in healthy individuals is 3.2 percent, compared to patients with arthritis (10.7 percent), angina (15 percent), and asthma (18.1 percent). These epidemiological studies led the field to think about brain diseases as follows: an illness or injury causes the immune system to cordon off the injury or infection by enhancing the secretion of molecules such as peripheral cytokines and chemokines. Under these conditions over time, people may exhibit behavioral symptoms that are associated with depression. Therefore, scientists theorized that under conditions of chronic stress, this cytokine activation doesn’t shut off, leading to a state of chronic sickness and increasing the likelihood of a diagnosis of depression. The first functional evidence of this phenomenon appeared in a 2002 study led by Michael Maes, M.D., Ph.D., in which a large percentage of at-risk individuals developed depression while being treated with interferon-alpha for hepatitis C. A 2010 meta-analysis of 24 studies focused on cytokines in major depression reported significantly higher concentrations of proinflammatory cytokines TNF- and IL-6 in depressed subjects compared to controls.
The field has generally been reluctant to accept this model, believing that heightened levels of cytokines might be a response to being chronically stressed out and depressed or an unrelated biomarker of the condition, but that the inflammatory molecules at the periphery themselves had no bearing on the disease. A 2014 study led by Gotam Khandaker, Ph.D., discredited that belief; these investigators obtained biospecimens from children prior to the development of any psychiatric syndrome and followed them to look for the development of depression or psychosis. They found that youngsters who had elevated levels of cytokines at age eight or nine were at much greater risk of developing depression or psychosis later on.
These studies, however, did not provide information that Dr. Russo’s group sought to address, i.e., does the peripheral immune system play a causal role in stress vulnerability? Dr. Russo and his colleagues adopted the social defeat stress model to approach the design of their animal studies. This model posits that chronic social defeat causes anxiety-like symptoms, hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, disrupted circadian rhythms, metabolic syndrome, greater addiction liability, anhedonia-like symptoms (decreased interest in pleasurable activities), and profound social avoidance. In their experiments using the model, they paired a male aggressor mouse with a socially subordinate mouse, keeping them together five minutes per day for two weeks, then housing the aggressor mouse in the same cage separated by a lucite divider. The subordinate mouse developed physiological characteristics similar to depression, such as disrupted sleep, overeating, insulin-sensitivity, anhedonia, use of drugs of abuse (e.g., cocaine, opiates), and reduced interest in social interaction.
Roughly one-third of the defeated mice were resilient and did not develop social avoidance syndrome. Resilience for social avoidance is associated with resilience for other symptoms of chronic social defeat (e.g., anhedonia, metabolic syndrome), but not all symptoms (e.g., anxiety). Early studies conducted by Dr. Russo’s lab sought to establish systemic changes in inflammation. They found no difference between circulating immune cells in a resilient and a susceptible mouse, but those under chronic stress showed massive changes in the immune system, i.e., immune-suppression in the adaptive compartments such that B cells and T cells were reduced. They also found reductions in memory B cells, suggesting this might be a potential life stress making the individual more vulnerable to a variety of infectious agents. But the opposite effect was observed within the innate compartments for the early responders to an infection, i.e., inflammatory cells that secrete inflammatory molecules. Chronic stress significantly enhanced both neutrophils and monocytes, innate immune cell sub-types. Yet despite the fact that there are no differences in the frequency of circulating cells, the reactivity of these cells may be the difference between the resilient and susceptible mice, i.e., there may be cells that are ready to respond and, in particularly vulnerable individuals, those cells might start secreting more inflammatory molecules. For example, social stress dramatically increases peripheral IL-6 in susceptible mice and it stays elevated for a significant amount of time. It is also predictive, as it was in humans. Researchers can take naïve mice, isolate their peripheral blood mononuclear cells, stimulate them ex-vivo with an endotoxin, lipopolysaccharide (LPS), and predict which animals will become susceptible. The susceptible mice with the most elevated IL-6 were also the most likely to be socially isolated.
Most compounds that are used to inhibit inflammation cross the blood-brain barrier and affect central immune cells. To address this challenge, the researchers generated mice with chimeric immune systems by irradiating a naïve mouse to remove the bone marrow-derived stem cells that produce leukocytes, and then graft in stem cells from a host mouse that has some genetic manipulation or experiential difference. This creates an animal with a normal central immune system, but circulating immune cells from the host mouse. The first experiment they conducted was to make the naïve mouse more susceptible. They were also able to graft in bone marrow-derived cells from Il-6 knockout mice and showed that those who lacked IL-6 in their peripheral immune cells were far more resilient to the effects of chronic defeat stress similar to those who had IL-6 knocked out of all cells in their bodies, because IL-6 is produced by many different cells in the body, e.g., muscle cells and brain neurons. Thus, stress vulnerability seems to be significantly regulated by the bone-marrow-derived peripheral cells, providing strong support for the theory that peripheral immune cells influence behavior.
Understanding the underlying biology of how this happens could provide the basis for the development of more targeted medications or better stratification of patients. Upon examination of the brain neurovasculature of the stressed mice, it became clear that the stressed mice have a large number of irregular and discontinuous tight junction breaks in the nucleus accumbens (NAC) endothelia compared to healthy mice. These suggest an impairment in the blood-brain barrier. The researchers undertook a number of functional assays to examine blood-brain barrier permeability and integrity. In one experiment, they took IL-6 protein and tagged it with biotin, allowing them to track the protein in the brain. They wanted to find out if peripheral IL-6 injected through the blood stream could push into the brain parenchyma through the damaged vessels that had been observed at the histological level. Large amounts of biotin were tracked in the brains of the susceptible mice, but not in the healthy animals nor the resilient ones. Thus, the damaged endothelium, at least at the correlative level, seems to be driving a brain permeability event that leads to direct infiltration of IL-6. This hypothesis may be affected by the animal’s age, which could turn out to be a significant variable.
The researchers demonstrated causality in this experiment: by injecting IL-6 into the accumbens, they produced behavioral effects indicative of 10 days of chronic stress in the naïve animals, i.e., social avoidance. They hypothesized that stress was causing impairment by breaking the tight junctions in the NAC endothelia. They considered a number of substances that are involved in the health of blood vessels, both in the periphery and in the neurovasculature or factors involved in the formation of the blood-brain barrier. Using mRNA analysis, they identified a protein for the CLAUDIN 5 (CLDN 5) gene, a tight junction protein that is selectively expressed in the endothelium of the adult brain. If scientists virally manipulated or downregulated this tight junction protein, could they change infiltration and thus change behavior? Dr. Russo’s lab collaborated with Matthew Campbell, Ph.D., at Trinity College Dublin who developed an adeno-associated viral vector (AAV) that expressed a shRNA to downregulate CLDN 5 in the ventral striatum and was infused with biotin-laden IL-6. If the animal had the shRNA expressed in the accumbens, the infiltration of the IL-6 was visible in ways that were not seen in the control condition. The investigators then examined behavioral outcomes. They learned that CLDN5 downregulation significantly promoted the avoidant phenotype, even in an animal that has only experienced an acute social stressor. Similar effects were also found across other endpoints.
In humans, there is some evidence that vascular damage is associated with unipolar depression. In one study, investigators found elevated CSF proteins in male patients with depression, suggesting significant vascular damage. In a histological study, the second layer of blood-brain barrier, the astrocyte layer of the brain that typically wraps the vessels with their end feet, was lost with major depressive disorder (MDD). Dr. Russo’s lab is now starting a program to study this in humans, beginning to translate the tools they’ve developed in mice to people. The first published data is from post-mortem DNA analysis of CLDN5. When the researchers looked at the NAC of depressed patients after death, they saw reduced CLDN5 expression whether the individual was on antidepressants or not. These patients largely died by suicide, so even if they were on antidepressants, the medications were likely not therapeutically effective because they were not taking them correctly or were resistant. Looking at this situation under more controlled circumstances in a mouse, the scientists induced depression-like behavior in the animals by subjecting them to 10 days of social stress, and then observed social avoidance that is restored by 30 days of imipramine treatment and the normalization of CLDN5. This suggests that antidepressants could have health-promoting effects i.e., effectively reducing or reversing stress vulnerability and depression. Dr. Russo’s laboratory has developed assays such as gadolinium contrast imaging that allows the researchers to look at functional permeability in the human brain. They have some early evidence that unipolar depression is associated with vascular damage and greater permeability of gadolinium.
In summary, Dr. Russo’s work suggests that stress and depression is a two-fold disease in some patients whereby they have predisposition to being more inflamed by stress exposure; they release more pro-inflammatory factors into the blood stream, and these factors then access brain parenchyma tissue to alter behavior through damaged blood vessels that lose integrity of tight junctions.
Discussion: Dr. Koob inquired if there are strains of mice that are depressed; if so, do they show the phenotype and CLDN change? Dr. Russo responded that some strains do appear more vulnerable with a heightened inflammatory response, but the researchers have yet to look at the blood-brain barrier. Dr. Koob observed that John Crabbe, Ph.D., developed two strains of mice from diverse backgrounds that drink a lot in the dark; they have the same phenotype but the reasons why they drink are completely different. Dr. Russo commented that his laboratory has started to consider the development of the right protocols and mouse lines to address alcohol-related issues because it is a good drug to study in regard to neurovasculature damage and immune infiltration. Vijay Shah, M.D., inquired about how peripheral immune factors influences affect neurotransmitters and, ultimately, neurons in the brain. Dr. Russo responded that there are two ways such impact could occur: 1) these factors are directly involved in synaptic plasticity, e.g., if one chronically stresses an animal, certain cells and striatum start to sprout more excited synapses and certain cells in the prefrontal cortex start to remove excited synapses in a process that is completely dependent on IL-6; 2) immune factors affect metabolism mechanisms in the mesolimbic dopamine system. Andrew Miller, M.D., Emory University School of Medicine, has data spanning species from mice to humans that indicate TNF and other inflammatory molecules can directly impact the metabolism and breakdown of dopamine, leading to a hypo-dopaminergic state that results in the anhedonic response during depression. Alex Dopico, M.D., Ph.D., asked if there is a way to move the system in the opposite direction by increasing CLDN5 to improve the integrity of the barrier and then examine the behavioral change. Dr. Russo noted that over-expression of CLDN5 becomes toxic so the scientists are having a hard time gauging the correct amount to use. He used an adeno-associated viral vector (AAV) to express a shRNA against CLDN5 to reduce levels in the brain. Expression of the shRNA was under the control of a doxycycline regulated promoter. When given Dox, the shRNA is expressed and CLDN5 is reduced. However, the expression of CLDN5 comes back when it is removed. His team would welcome ideas about pharmacological solutions.
Consideration of COUNCIL SOP, NCAA & CRAN MAY 14-15, 2019 Minutes/Future Meeting Dates
Council members voted unanimously to approve the Council Standard Operating Procedures (SOP) and the minutes of the NIAAA Advisory Council and Collaborative Research on Addiction at NIH (CRAN) meetings held on May 14-15, 2019.
Dr. Bautista announced upcoming meeting dates for 2020-2024. In 2020, the Council will meet on February 6, May 12, and September 10; the CRAN Council will meet in 2020 on May 13. In 2021, the Council will meet on February 4, May 11, and September 9; the CRAN Council will meet on May 12, 2021. In 2022, Council will meet on February 20, May 10 and September 8; the CRAN meeting will be on May 11. In 2023, Council will meet on February 9, May 9, and September 7; the CRAN Council will meet on May 10. In 2024, Council will meet on February 8, May 14, and September 12; the CRAN Council meeting will meet on May 15.
Council broke for lunch at 12:10 p.m. and reconvened at 1:10 p.m. for the afternoon session.
Pathogenesis and Therapeutic Targets of Alcoholic-related Liver Disease
Dr. Koob introduced Bin Gao, M.D., Ph.D., Chief, NIAAA Laboratory of Liver Diseases, who described current intramural research on how binge drinking, obesity, and aging affect alcohol-related liver disease (ALD). In ALD, daily or near-daily heavy drinking leads to the development of steatosis in 90-95 percent of individuals, then to alcoholic-related steatohepatitis/inflammation in some individuals (20-40 percent). The alcohol- induced liver disease may then advance to cirrhosis, and eventually to hepatocellular carcinoma (HCC). Many patients have the underlying disease, but do not have any symptoms. Some do develop acute alcoholic hepatitis (AH) which is associated with high short-term mortality. Inflammation is believed to play a major role in the progression of ALD, but what causes the inflammation is not well understood. NIAAA’s and others’ research over the past five to ten years suggests that excessive binge drinking and fat play an important role in the development of the inflammation, especially neutrophil infiltration.
Several animal models of ALD that were previously used did not include binge drinking and had not demonstrated neutrophil infiltration in the liver. NIAAA developed a simple mouse model of alcoholic liver injury by chronic ethanol feeding (10-day ad libitum oral feeding with the Lieber-DeCarli ethanol liquid diet) plus a single binge ethanol feeding. This protocol for chronic-plus-single-binge ethanol feeding synergistically induces liver injury, inflammation and fatty liver in mice, which mimics acute-on-chronic alcoholic liver injury in humans. By using this model (chronic feeding plus binge), the researchers found that such chronic-plus-binge feeding induced neutrophil recruitment (Ly6G and myeloperoxidase expression, both are specific markers for neutrophils]) in the liver; neutrophils were not observed in the chronic or binge drinking only comparison groups. Thus, using this animal model, the intramural researchers demonstrated several mechanisms by which excessive binge drinking induced neutrophil infiltration, i.e., up-regulation of CXCL1, E-selectin, and mitochondrial DNA.
To address the issue in humans, the NIAAA researchers collaborated with Suthat Liangpunsakul, M.D., Indiana University School of Medicine, to study 300 individuals with AUD from a detoxification center who were divided into two groups: 160 without recent drinking in the past 10 days (chronic alcohol drinkers) and 140 who had had excessive intake in the past 10 days (chronic + binge drinkers). Their blood samples were compared to those of 45 healthy controls. The researchers found that the chronic + binge drinkers had higher levels of liver enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST)than the chronic drinkers, whose levels were higher than the controls. These elevated ALT and AST levels indicated liver injury in the drinkers. The same pattern of elevation was also observed for circulating neutrophils, as well as for mitochondrial DNA extracellular vesicles. They also found that the circulating neutrophil numbers correlated positively with the serum ALT and AST, indicating the elevated levels of neutrophils may contribute to the injury. Thus, the NIAAA researchers believe that binge ethanol intake strongly promotes liver neutrophil infiltration, which is a hallmark of alcoholic steatohepatitis in patients.
Since it was first published in 2013, the NIAAA model has been widely used to identify therapeutic pathways and testing of therapeutic compounds. Interleukin-22 (IL-22) is the first drug that has been tested with the model. IL-22 is a key survival factor for epithelial cells, such as hepatocytes, and protects against liver injury. In 2010, NIAAA researchers published the first preclinical study documenting that Il‐22 treatment ameliorated alcoholic hepatitis (as indicated in levels of AST, ALT, and steatohepatits) in the NIAAA model. In a Phase 1 trial with healthy volunteers, it was found to have minimal side effects. A Phase 2b trial at the Mayo Clinic under the leadership of Dr. Shah on moderate to severe AH patients concluded that IL-22-Fc is safe and associated with improvements in the model for end-stage liver disease (MELD) score, as well as with reductions in serum and plasma markers of inflammation and increases in markers in liver regeneration. A larger trial is now under discussion. IL-22 holds similar promise for other organs, including the pancreas, kidney, thymus, lung, and gut, and thus could be useful in treating pancreatitis, kidney failure, and lung fibrosis
NIAAA’s studies have also demonstrated that fat, especially visceral fat, interacts with binge drinking to increase inflammation in the liver and promote neutrophil infiltration. To study this, the investigators created a model in which mice were fed a high-fat diet for three days or three months and then given a single or multiple binges. The binges induced severe steatohepatitis, elevated levels of ALT, mild fibrosis, and neutrophil infiltration in these high-fat diet-fed mice. To study how the model induced high neutrophil infiltration, they examined various chemokines in the liver and found that hepatic CXCL1 played a critical role. Hepatic CXCL1 was upregulated 30-fold after only three days of the high fat diet and one binge. It was not elevated in other tissues.
The fatty tissue in a normal liver is 1.5-1.8 liters. Non-obese individuals normally have about 24 liters of fatty tissue, compared to obese individuals whose fatty tissue may exceed 80 liters. Visceral fat in the body is located so closely to the liver that blood drains from the fat into the liver via the portal vein, carrying fatty acids and inflammatory mediators. Current thinking is that when the obese individual binge drinks, it causes adipocyte deaths and lipolysis, which induces fatty acid release and in turn, upregulates the CXCL1 expression. CXCL1 is a key cytokine for neutrophil infiltration, causing steatohepatitis. However, fatty acid itself can also activate the peroxisome proliferator-activated receptor PPAR which can strongly suppress CXCL1 up-regulation. Binge ethanol, however, can completely block the PPAR. Thus, binge ethanol plus the high fat diet highly elevated the CXCL1, causing neutrophil infiltration and steatohepatitis. The NIAAA data also suggested another model. The binge drinking activates the adipocyte death and lipolysis, as noted above, which, in turn, can cause inflammation in the visceral fat and lead to the activation of macrophages which may directly drain into the liver to cause inflammation and liver injury. The NIAAA researchers are currently working to better understand this model.
Ethanol is metabolized by enzymes into acetaldehyde via the alcohol dehydrogenase I (ADH1) enzyme and acetaldehyde into acetate via the aldehyde dehydrogenase 2 (ALDH2). To determine which process affects the interaction of binge drinking and fat on inflammation, the NIAAA researchers compared ADH1 knockout mice with ALDH2-deficient mice. The results were surprising. Compared to the wild-type mice, the ADH1 mice had acute liver injury as measured by AST and ALT levels. In the ALHD2-deficient mice, the acetaldehyde was elevated compared to the wild-type mice, but the acute liver injury was lower. This was surprising because acetaldehyde is considered very toxic. To further confirm that it is ethanol and not acetaldehyde that causes liver injury, the researchers performed the experiment using intraperitoneal (IP) injections of ethanol or acetaldehyde. The results confirmed the earlier findings.
These studies suggest that it is ethanol that promotes acute hepatocellular damage. There are two possible metabolic pathways through which this occurs: oxidative and non-oxidative. NIAAA researchers are currently testing the hypothesis that it is the non-oxidative metabolism of ethanol using multiple enzymes that induces acute liver injury via fatty acid ethyl esters (FAEE) that are toxic to hepatocytes.
Finally, NIAAA researchers published an article titled “Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression” in the Journal of Hepatology (2017 Mar; 66(3):601-609) about their research demonstrating that aging mice are very susceptible to alcohol-induced inflammation fibrosis.
In summary, NIAAA researchers believe that excessive binge drinking, fat, and aging are three significant factors in the development of alcohol-related liver disease and inflammation. The goal is that their studies will lead to the identification of novel therapeutic targets for the treatment of alcohol-related liver disease in the future.
Discussion: Dr. Koob asked how IL-22 is administered to human patients. Dr. Shah responded that it is injected by vein using a 2-3 dose protocol. Dr. Albizu-Garcia asked if IL-22 could have a protective effect on the gut of heavy drinkers whose liver function tests are fairly normal. Dr. Gao replied that IL-22 may have a protective effect in the gut. Hendrikx T et al., (Gut. 2019 Aug;68(8):1504-1515), demonstrated that IL-22 prevented translocation of bacteria to the liver, thereby ameliorating ALD. Dr. Sanyal mentioned that heavy drinkers have a different gut biodome than those with alcoholic steatosis. Eighty percent of people who drink heavily do not develop liver problems; some of the impact is genetic. Dr. Koob noted that liver disease is only one bad outcome of heavy drinking; car accidents, for example, are another. Susan M. Smith, Ph.D., inquired about sex differences, noting that females and males have different levels of adiposity. Dr. Gao commented that female mice are resistant to obesity so the data he presented was only for males.
Concept Clearance: Medications Development
Dr. Koob introduced Joanne Fertig, Ph.D., who asked Council to consider the reissue of an earlier 2019 Request for Applications (RFA) to expand it to include candidate compounds to treat alcohol-related organ damage. The RFA’s purpose is to advance candidate compounds towards U.S. Food & Drug Administration (FDA) approval. To be considered, studies must have defined entry and exit points. Acceptable study phases include: Lead optimization; Investigational New Drug (IND) enabling; Phase 1 (safety, tolerability, dose ranging); or Phase 2 (efficacy, safety). Phase 2 studies may be human laboratory or small clinical trials. This RFA is expansive and open to academic sites and to small businesses. The NIAAA FOA will not be restricted by Small Business Innovation Research (SBIR) regulations as described in other solicitations. These awards will be cooperative agreements, so NIAAA will work with awardees on the applications to facilitate FDA approval.
Entry requirements are as follows: the candidate compound must be adequately characterized; compound must be patentable and have a plausible path to commercialization; applicant must show ownership or agreement (i.e. license agreement, Memorandum of Understanding) of intellectual property rights to propose compound; new chemical entities are highest priority; and repurposed drugs are acceptable if reformulation is eligible for FDA approval.
High priority targets addressed by the RFA, not in order, include: Vasopressin 1b antagonists; corticotrophin releasing factor (CRF1) antagonists; orexin 1 & 2 receptor antagonists; kappa opioid receptor antagonists; glucocorticoid receptor antagonists; cannabinoid receptor antagonists (CB1 & CB2); nicotinic α3 /β4 partial agonist; GABA B receptor positive allosteric modulator, agonist;
neuropeptide Y1, Y2 antagonist; and oxytocin receptor agonist. Other targets are acceptable, if validated.
The new part of this RFA is the alcohol-related organ damage targets, including liver, lung, muscle, bone, pancreas, cardiovascular system, immune system, and fetal development. Potential targets include inflammation, cell damage, oxidative stress, and tissue repair. Dual gut-brain targets are also acceptable.
Kathy Jung, Ph.D., commented that the major goal is to get products to market to alleviate suffering, rather than discovery. It’s important that efficacy has been shown in animals, and that the applicant has ownership. The goal is to cover the “valley of death” between early stages and Phase 3 clinical trials. IND studies are very costly; this RFA can help support them.
Dr. Koob asked Dr. Fertig to explain where the funding comes from and how the application process works. She responded that the awards are cooperative agreements. NIAAA assigns a project scientist, in addition to a project officer, and no deliverables are specified at the beginning. Dr. Koob noted that the funding mechanism is a U01, which allows more input from staff and specific goals. Dr. Fertig commented that NIAAA is happy to discuss applications, but the applicant must initiate the contact. She also noted that not having an IND has been a failure point for many applicants; once the IND is in hand, other companies will want to work with the applicant to further develop the compound. Daniel Calac, M.D., asked when Council should consider the costs of new medications for people who can’t afford them--now or further down the road? Dr. Fertig responded that this issue is best considered later in the drug development process. These studies will have annual costs that NIAAA has been able to estimate, but marketing and related costs are still unknown. Dr. Koob observed that Phase 3 and 4 trials are needed to address the issue, but those are beyond the current budget. Nonetheless, the issue is an important one to keep in mind.
Concept Clearance: Alcohol, and HIV-AIDS Comorbidities, Coinfections, and Complications Research-- Intervention and Cross-Cutting Foundational Research
Dr. Koob introduced Kendall Bryant, Ph.D., NIAAA Director HIV/AIDS and Alcohol Research, who provided an overview of a concept statement about intervention and cross-cutting foundational research on alcohol and HIV-AIDS comorbidities, coinfections, and complications. It is a re-issue of a past RFA that established centers of excellence and multi-disciplinary studies. Research funded under the FOA should serve as the foundation for a next generation of intervention studies and inform implementation efforts to improve provision of alcohol-related interventions and treatments for people living with HIV (PLWH) in healthcare and community settings.
Specifically, this future FOA will continue NIAAA-supported programs that will advance operations or implementation research in the context of alcohol and HIV/AIDS (RFA AA-16-001): 1) to continue to develop a broader systems approach for monitoring complex HIV and alcohol-related morbidity, and 2) to intervene to reduce the impact of alcohol and HIV disease progression and transmission. This proposed research initiative is aligned with the research priorities set forth in the NIH Strategic Plan for HIV and HIV-Related Research. NIH’s new priorities for HIV and HIV-related research include reducing the incidence, researching a cure, engaging cross-cutting areas, developing next-gen HIV therapies, and addressing comorbidities, coinfections, and complications. NIAAA is already carrying out research in the last domain through a variety of existing multi-disciplinary research platforms and collaborations with different Institutes/Centers (ICs). This research addresses coinfections, neurological complications, malignancies, cardiovascular complications, mental health and substance abuse, and metabolic disorders, all addressed within a lifespan framework. To establish viral control, alcohol use remains a complicating factor, with both behavioral and biological issues such as non-adherence to medication or systemic inflammation. Research on patterns of alcohol use is needed to understand how levels of alcohol consumption complicate HIV treatment. These issues are best addressed in large-scale studies. Such research—including epidemiological and population studies, pathogenesis research, syndemics, clinical research, and implementation science research--will facilitate achievement of a national goal, ending the HIV-AIDS epidemic.
The goals for interventions and implementation research within this priority area are to develop interventions that combine behavioral and biological strategies; discover innovative approaches to measure and treat HIV and alcohol misuse in diverse populations; develop strategies to prevent HIV and common alcohol-associated coinfections; and support and advance novel research to address and mitigate underlying alcohol and HIV-associated medical and social inequalities.
The goals for foundational and preclinical research are to pursue innovative research methods and the use of new and improved technologies; use emerging new methodologies focused on analysis and representation of large/complex datasets; advance the understanding of how the severity of alcohol use (including AUD) impacts clinical outcomes for people living with HIV (PLWH); and examine the additive or synergistic impact for specific comorbidities in determining clinical outcomes for PLWH who have sustained organ and tissue damage.
Outcomes include monitoring progress to improve the health of PLWH, i.e., improving linkage to care and retention in HIV and alcohol care; accelerating reductions in alcohol use resulting in increased viral suppression; identifying mitigating social determinants of poor outcomes such as homelessness; reducing frailty and subsequent mortality related to aging; reducing the incidence of new Infections; and reducing HIV and alcohol disparities in key populations of men and women and in the Southern U.S. and other high-incidence locations.
Resources will be focused on the 48 highest burden counties in the United States; Washington, D.C.; San Juan, Puerto Rico; and the seven states with a substantial rural HIV burden.
Discussion: Constance Horgan, Sc.D., commented positively on the emphasis on implementation research, a pathway to health services research. Dr. Bryant noted that all NIAAA divisions are participating in this FOA.
Council Roundtable Discussion
Council Discussion: Dr. Koob invited Council member comments on topics important to them. Dr. Smith expressed concerns that NIAAA has signed on to an RFA titled “Pragmatic Randomized Controlled Trial of Acupuncture for Management of Chronic Low Back Pain in Older Adults” because carefully controlled studies have demonstrated that acupuncture is no more effective than a placebo and has no basis in biology. Dr. Bautista asked Antonio Noronha, Ph.D. to confirm that this RFA is part of the Helping to End Addiction Long-Term (HEAL) initiative, which he did. Dr. Koob asked Dr. Smith to share research on the topic with him; he can raise the issue with his fellow IC directors. Dr. Sanyal thanked Dr. Koob for the opportunity to serve on Council, noting that he had learned a lot, especially about the behavioral aspects of the population he serves. He encouraged NIAAA to find ways to combine behavioral and clinical research, noting that two-thirds of his patients drink and two-thirds of the U.S. population is obese. Dr. Koob reported that NIAAA is now collaborating with NIDDK on liver disease research, and that he is excited about any new efforts in obesity research. Constance Weisner, D.R.P.H., seconded Dr. Sanyal’s point, noting that the field will do a better job of getting alcohol addressed in health care if it addresses the whole person. She hopes the next generation of alcohol trainees/scholars will learn to be conversational about other areas of research; this should be a focus of NIAAA training grants. Dr. Koob observed that former Council member Howard Becker, Ph.D., had raised this point about the training grants for the past two years. He suggested NIAAA could address the issue in part with information in the core clinician’s resource, i.e., the information that both clinicians and the general public should know, that is currently under development. Carmen Albizu-Garcia, M.D., expressed her gratitude for learning a great deal as a Council member before reinforcing Dr. Weisner’s comments. She emphasized the importance of social factors that impact alcohol-related behaviors and can hinder access to care. She recommended a move toward more interdisciplinary arenas of research as well as adoption of a population health perspective. Frank Sloan, Ph.D., commented that he has great enjoyed learning about other Council members’ areas of expertise, acknowledging that people in the field may need more exposure to other content areas but shouldn’t be expected to become an expert in all of them. Dr. Koob concurred, noting that he is seeing more “cross-talk” generally within NIH. He also commented that he has dedicated 2019 to getting everything that NIAAA knows about alcohol out to the public via a wide array of mechanisms such as CollegeAIM and the Alcohol Treatment Navigator. Dr. Sloan raised a general concern about the underutilization of treatment by those with AUD. Dr. Koob agreed on the importance of this issue, noting that the lack of universal healthcare is an obstacle to achieving better treatment utilization. Tatiana Foroud, Ph.D., reinforced previous comments about considering alcohol in conjunction with other comorbidities. She noted that NIAAA is a small Institute so that getting its message out is critical. She identified what Council members have learned about issues and priorities as important experiences, and encouraged NIAAA to use retiring Council members as ambassadors to the field. Dr. Koob responded that there were opportunities for Council members to serve as ambassadors through Friends of NIAAA; he also encouraged retiring Council members to advocate about alcohol issues. One issue, for example, is addiction training for physicians which is not well addressed in medical education. Dr. Baxter commented, as past president of the American Society of Addiction Medicine (ASAM), that ASAM has worked hard with other disciplines to encourage greater attention to alcohol issues in the medical school curriculum; some progress has been made. Dr. Weisner commented that Patrice Harris, M.D., the new president of the American Medical Association, is very interested in addiction, including alcohol. She encouraged Friends of NIAAA to get in touch with Dr. Harris. Dr. Koob noted that alcohol is the most widespread of substances used, e.g., 2 million people suffer from an opioid use disorder compared to 14-15 million with an AUD. Dr. Sanyal commented that there is a need to increase understanding of the critical factors required to translate findings from preclinical to clinical studies; there is a significant translational gap. Dr. Koob acknowledged the need for the development of translational criteria; he noted that the alcohol field probably has better animal models than other disciplines. Dr. Russo commented that researchers are increasingly not waiting for preclinical findings, but instead starting with human pathology and conducting animal and clinical studies in tandem. The National Institute of Mental Health has a number of consortia that provide access to biologicals from humans. The more these are available to basic scientists, the better the translation process will be. Dr. Koob responded that NIAAA funds some resources, such as a brain bank in Australia and a collection of livers from monkeys with significant alcohol exposure; he asked Bridget Williams-Simmons, Ph.D., if these resources are listed on the NIAAA website. She responded that there is a list of consortia. Dr. Russo asked how easy it would be for a naïve researcher to access such resources. Dr. Noronha responded that the researcher interested in access should send a one-page proposal to the Principal Investigator (PI). Dr. Koob said that the NIAAA website needs a section on “Resources Available for Research.” Dr. Bautista commented that NIAAA has several R24-funded resources from multiple divisions. There is a plan to develop a website where someone can click a link to instructions on how to access resources from the several NIAAA-funded banks. There is a requirement within the R24 grant that awardees must support investigators from at least two institutions or organizations that are external to their institution in order to support the extramural community. Dr. Williams-Simmons commented that the website includes the list of R24s, but does not provide information on how to access them. Dr. Bautista suggested that R24 grantees can be asked to post their procedures for access on their websites. Dr. Koob noted that NIAAA has multiple resources similar to the R24s, such as mice with specific alcohol-related phenotypes.
Robert Huebner, Ph.D., Chair of the Friends of NIAAA, provided an overview of this nonprofit organization. It is comprised of organizations that promote and disseminate research supported by NIAAA, primarily through sponsorship of events on Capitol Hill to raise the scientific literacy about alcohol. He told Council members that he may someday ask them to speak about their areas of expertise at such an event.
Dr. Koob adjourned the meeting at 2:40 p.m.
I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.
George F. Koob, Ph.D.
National Institute on Alcohol Abuse and Alcoholism
National Advisory Council on Alcohol Abuse and Alcoholism
Abraham P. Bautista, Ph.D.
Office of Extramural Activities
National Advisory Council on Alcohol Abuse and Alcoholism