Measuring the Neuroimmune Response to Alcohol

This study uses positron emission tomography imaging of the 18-kDa translocator protein to measure the brain's immune response to alcohol.

Alcohol Use Disorder affects nearly 14% of the population, accruing considerable cost to individual families and society. Much of this cost stems from alcohol's influence on the immune system. Alcohol impairs peripheral immune function, evidenced by increased susceptibility to infection related diseases such as liver cirrhosis and pancreatitis. The neuroimmune consequences of alcohol are subtler. Preclinically, alcohol triggers neuroimmune abnormalities that contribute to cognitive dysfunction, neurodegeneration, and alter alcohol drinking behaviors. Yet, limited experimental tools hamper translational efforts to study alcohol's effects on neuroimmune function in people. We propose to address this deficit by developing an innovative human imaging paradigm that measures neuroimmune response to alcohol.

Aim 1: A baseline PET scan with [11C]PBR28, a TSPO-specific radioligand, will be conducted with moderate drinkers. Next, subjects will drink a fixed alcohol dose, followed a post-alcohol [11C]PBR28 PET scan timed to capture acute neuroimmune response. [11C]PBR28 distribution volumes (VT), which are proportional to TSPO number, will be measured throughout the brain. We will test the hypothesis that acute alcohol robustly increases [11C]PBR28 VT, consistent with microglial activation. The percent change in [11C]PBR28 VT (ΔVT) from baseline will quantify the magnitude of neuroimmune response.

Aim 2: AUD subjects will participate in the study design described in Aim 1 (a baseline [11C]PBR28 PET scan, drink a fixed alcohol dose, followed by a post-alcohol [11C]PBR28 PET scans). The magnitude of neuroimmune response, quantified by ΔVT, will be compared between moderate drinkers and individuals with AUD to test the hypothesis that the neuroimmune response to alcohol is greater in those with AUD compared to moderate drinkers, consistent with the concept of alcohol 'priming microglia'.

This is the percent change in [11C]PBR28 distribution volume post-alcohol relative to baseline. As a percent change, it could range from -10% to 200%.

General Inclusion Criteria: Men and women, aged 21-50 years Willing and able to give voluntary written informed consent Able to read and write English and communicate effectively with the investigators, and comply with all study requirements, restrictions, and directions of the clinic staff AUD Subjects will meet DSM-5 criteria for current Alcohol Use Disorder Moderate Drinkers will report consuming alcohol on at least one occasion in the past three months that would result in an estimated blood alcohol level greater than 100 mg/dl but not meet DSM-5 criteria for AUD. This is to ensure that subjects have prior drinking exposure consistent with levels proposed in this study. Prospective subjects will be asked to recall the heaviest two days of drinking in the previous three months. Using this information, approximate BAC will be calculated for those prior episodes. Medically healthy upon physical examination and laboratory testing. General Exclusion Criteria: Individuals whom the investigators deem may not be able to comply with alcohol abstinence for 48 hours prior to study day. Current significant medical condition such as neurological, cardiovascular, endocrine, renal, liver, or thyroid pathology. History of or current neurological or significant psychiatric disorder such as schizophrenia or bipolar disorder (DSM-5 Axis 1). Other substance use disorder with the exception of nicotine dependence in smokers as assessed with the SCID or positive urine screen for drugs of abuse. Participants with any significant current medical conditions that would contraindicate the consumption of alcohol, such as history of neurological trauma or diseases, seizures, delirium or hallucinations, hepatic, or other unstable medical conditions. Current suicidal or homicidal intent or behavior, or history of suicidal or homicidal behavior. No barbiturates or other known microsomal enzyme induces or inhibitors in the past month. History of significant head trauma. Women who are pregnant or nursing or fail to use one of the following methods of birth control unless she or partner is surgically sterile or she is postmenopausal (hormone contraceptives [oral, implant, injection, patch, or ring], contraceptive sponge, double barrier [diaphragm or condom plus spermicide], or IUD). Regular or current significant use of any prescription, herbal or illegal psychotropic medications (e.g., antidepressants, antipsychotics, anxiolytics, ecstasy) in the past 6 mo, with no current illegal drug use confirmed by urine toxicology (except for cocaine and marijuana when relevant). Have MRI-incompatible implants and other contraindications for MRI, such as a pacemaker, artificial joints, non-removable body piercings, claustrophobia, etc. Subjects with history of prior radiation exposure for research purposes within the past year such that participation in this study would place them over FDA limits for annual radiation exposure. This guideline is an effective dose of 5 rem received per year. Subjects with current, past or anticipated exposure to radiation in the work place within one year of proposed research PET scans. Subjects with history of IV drug use which would prevent venous access for PET tracer injection. Blood donation within eight weeks of the start of the study History of blooding disorder or currently taking anticoagulants (such as Coumadin, Heparin, Pradaxa, Xarelto).