Brain Inflammation and Function in Alcoholism
Brain Inflammation and Function in Alcoholism
Background:

 - Brain inflammation due to high alcohol intake may affect thinking, memory, and
 concentration. Researchers want to measure this using positron emission tomography (PET).

 Objective:

 - To study how excessive alcohol consumption affects brain function.

 Eligibility:

 -  Adults 30-75 years old who are moderate or severe alcohol drinkers.

 -  Healthy volunteers.

 Design:

 -  Participants will be screened with medical history, physical exam, interview, and blood
 and urine tests. Their breath will be tested for alcohol and recent smoking.

 -  Phase 1:

 -  Participants will stay in the hospital 3 days. They will have blood and heart tests and
 daily urine tests.

 -  A small plastic tube will be inserted by needle in each arm. One will go in a vein, the
 other in an artery.

 -  Participants will have 2 PET scans with 2 different radioactive compounds. Participants
 will lie on a bed that slides in and out of the scanner with a cap on their head.

 -  Participants will have magnetic resonance imaging (MRI) scans. Participants will lie in
 the scanner either resting with their eyes open or while performing an attention task.

 -  Participants will have tests of memory, attention, concentration, and thinking. They may
 answer questions, take tests, and perform simple actions.

 -  Phase 2 of the study will only be done if Phase 1 results show brain inflammation.

 -  Phase 2 will repeat Phase 1.

 -  For healthy volunteers, Phase 2 will begin 3 weeks after Phase 1.

 -  Other volunteers must not have alcohol for at least 3 weeks and stay in a hospital up to
 4-6 weeks between Phase 1 and Phase 2. After Phase 2, they will have 5 follow-up calls
 over 3 months.
The abuse of high doses of alcohol is associated with cognitive impairment that in extreme
 cases can result in dementia. However, the mechanisms underlying the neurotoxic effects of
 alcohol to the human brain are poorly understood. Here we test the hypothesis that
 alcohol-induced neuroinflammation contributes to its neurotoxic effects in humans

 Objectives: The primary objectives in Phase I are to assess if there is inflammation in the
 brain of alcoholics and if present to determine if it recovers after 3 weeks of abstinence as
 compared between groups (alcoholic vs. healthy volunteers) in Phase II. Phase II objectives
 are to assess between group differences in inflammation in the brain of AUD subjects who
 either abstain from alcohol for at least 3 weeks or relapse (continue to drink alcohol) for
 at least 3 weeks. Secondary outcomes are to evaluate the functional consequences of
 inflammation as assessed by: regional brain glucose metabolism, functional brain activation
 to cognitive tasks, structural brain imaging, resting functional connectivity and
 neuropsychological tests.

 Study population: Participants diagnosed with alcohol use disorder (AD) as per DSM IV or DSM
 5 AD and healthy controls. Males and females ages 30-75 will be included

 Design: This study has two phases (phase I and II). The two phases can be done as inpatient
 (AD subjects) or as outpatient (AD and healthy controls) over a 2-3 day period. In phase I
 participants will undergo two positron emission tomography (PET) scans, one with [11C]PBR28
 (marker of neuroinflammation) and one with 18FDG (marker of brain glucose metabolism) and
 magnetic resonance imaging (MRI) scans to assess brain structure, functional reactivity and
 functional connectivity. In parallel we will perform neuropsychological tests (NP). Phase II
 will include the same procedures as Phase I but it will be done at least 3 weeks later over a
 2-3 day period only in AUD participants who successfully completed phase I who either
 abstained from alcohol or relapsed/continued to drink alcohol after Phase I.

 Relapsers would be eligible for Phase II if they continued to drink for at least 3 weeks

 prior scheduled imaging studies. We will complete Phase II studies on up to 24 additional AUD
 subjects (n=12 abstainers and n=12 relapsers) to assess whether [11C]PBR28 uptake recovers
 after abstinence. Since there are not much differences between test/retest studies in healthy
 volunteers in the literature [1], there is no need to complete Phase II studies in controls.

 Outcome parameters: Main outcome measure is to assess if there is neuroinflammation with
 alcoholism and if it recovers with detoxification. Secondary outcome measures are: to assess
 if neuroinflammation is associated with markers of brain function, which include (1) regional
 brain glucose metabolism; (2) MRI based voxel-based morphometry (VBM) to assess cortical
 atrophy; (3) blood-oxygenation level-dependent (BOLD) activation to a cognitive task, (4)
 brain functional connectivity, (5) myo-inositol (mI) concentration, and (6) NP testing to
 assess cognitive performance, and to evaluate if neuroinflammation predicts relapse in AD
 over a 3 month follow-up period.
-INCLUSION CRITERIA:

 -All Participants

 1. Between 30 and 75 years of age.

 2. Ability to provide written informed consent as determined by physical examination and
 verbal communication. Capacity to consent will be determined by those giving the
 informed consent.

 3. Females: Negative urine pregnancy test and not currently breastfeeding.
 Post-menopausal or surgically sterile (tubal ligation or hysterectomy); or not
 sexually active with a male partner and able to get pregnant; or documented agreement
 to use an effective form of birth control. Acceptable forms of contraception include:
 hormonal contraceptives (birth-control pills, injectable hormones, vaginal-ring
 hormones); IUD; diaphragm with spermicide; condom with spermicide.

 -Specific For AD Participants

 4. DSM-IV diagnosis of alcohol dependence or alcohol abuse or DSM-5 diagnosis of moderate
 or severe alcohol use disorder (established through history and clinical exam). We
 include subjects that drink high doses of alcohol since alcohol's detrimental effects
 are greater with larger doses and particularly with binge drinking.

 5. Participants seeking treatment for their AD as well as those not seeking treatment for
 their AD will be included.

 6. Minimum 5 year history of heavy drinking (self-report).

 7. Must consume at least 20 alcoholic drinks per week (male) or 15 per week (female)
 (self-report).

 8. Must have had the last drinking episode (females 3 or more drinks; and males 4 or more
 drinks) within 1 week of baseline PET scan (self-report).

 9. Alcohol specified as the preferred drug (self-report).

 EXCLUSION CRITERIA:

 -  All Participants

 1. Unwilling or unable to refrain from use within 24 hours of scheduled study
 procedures: psychoactive medications or medication that may affect study results
 (e.g., analgesics [non narcotic], antibiotics (must finish course at least 24
 hours prior to a scheduled procedure), antidiarrheal preparations,
 anti-inflammatory drugs (systemic corticosteroids are exclusionary),
 antinauseants, cough/cold preparations) (self-report, medical history). The
 following medications are allowable for entry on this study: analgesics
 (non-narcotic); antacids; antiasthma agents that are not systemic
 corticosteroids; antifungal agents for topical use; antihistamines
 (non-sedating); H2-Blockers/PPI (proton pump inhibitors); laxatives. The use of
 antihyperlipidemics and/or diuretics are permitted as long as they have been
 taken for at least 1 month before procedure visits and dose has been stabilized.
 The use of benzodiazepines such as alprazolam (( )Xanax), diazepam (( )Valium)
 and lorazepam (( )Ativan), will not exclude participants from this study.

 2. Current or past DSM-IV or DSM-5 diagnosis of a psychiatric disorder (other than
 alcohol in AD participants and nicotine/caffeine use disorders) that required
 hospitalization (any length), or chronic medication management (more than 4
 weeks) and that could impact brain function at the time of the study as
 determined by history and clinical exam. The following chronically used
 medications are exclusionary from the study: analgesics containing narcotics;
 anorexics (sibuteramine); antianginal agents; antiarrhythmics; antiasthma agents
 that are systemic corticosteroids; antibiotics; anticholinergics; anticoagulants;
 anticonvulsants; antidepressants; antidiarrheal preparations; antifungal agents
 (systemic); antihistamines (sedating); antihypertensives; anti-inflammatory drugs
 (systemic); antineoplastics; antiobesity; antipsychotics; antivirals (except for
 treatment of HSV with agents without CNS activity, e.g. acyclovir, ganciclovir,
 famciclovir, valacyclovir); anxiolytics; cough/cold preparations
 (dextromethorphan preparations, pseudoephedrine); hormones (exceptions: thyroid
 hormone replacement, oral contraceptives, and estrogen replacement therapy);
 insulin; lithium; muscle relaxants; psychotropic drugs not otherwise specified
 (nos) including herbal products (no drugs with psychomotor effects or with
 anxiolytics, stimulant, antipsychotic, or sedative properties);
 sedatives/hypnotics. Note that nicotine and/or caffeine use will not exclude
 participants.

 3. Major medical problems that can permanently impact brain function (e.g., CNS,
 cardiovascular, metabolic, autoimmune, endocrine) as determined by history and
 clinical exam.

 4. Any clinically significant laboratory finding as determined during the screening
 procedures that could impact brain function or study procedures (evidenced from
 clinical laboratory results).

 5. Have had previous radiation exposure (from X-rays, PET scans, or other exposure)
 that with the exposure from this study, would exceed NIH annual research limits
 (self-report, medical history)

 6. Head trauma with loss of consciousness for more than 30 minutes (self-report,
 medical history);

 7. Positive test for alcohol on the day of the PET, the MRI or the NP tests
 (clinical laboratory results).

 8. Urine positive for psychoactive drugs (clinical laboratory results) on study days
 involving imaging (PET and MRI) and neuropsychological testing.

 9. Pregnant or breast feeding (self-report)

 10. History of coagulation disorder (clinical laboratory results, medical history)

 11. Have a history of allergic reaction to lidocaine (self-report, medical history)

 12. Presence of ferromagnetic objects in the body that are contraindicated for MRI of
 the head, fear of enclosed spaces, or other standard contraindication to MRI
 (self-report checklist).

 13. Cannot lie comfortably flat on your back for up to 2 hours in the PET and MRI
 scanners (self-report).

 14. Body weight > 250 kg. The MR scanner bed is tested to a weight limit of 250 kg
 (~550 lbs).

 15. Have a positive HIV test (clinical laboratory results, medical history).

 16. Homozygosity for the rs6971 polymorphism on TSPO that results in LB (Owen et al
 2011) (genotyping results).

 17. NIH employees who meet criteria as AD subjects. Although we will include NIH
 employees as healthy volunteers, study investigators and their superiors,
 subordinates and immediate family members (adults children, spouses, parents,
 siblings) will be excluded.

 EXCLUSION CRITERIA SPECIFIC FOR CONTROL PARTICIPANTS:

 -  Consumption of moderate to high levels of alcohol. That includes if female, currently
 (within past 6 months) consuming more than 2 drinks on a given episode and if male,
 consuming more than 3 drinks on a given episode; and/or consuming if female, more than
 a total of 7 drinks a week or if male, more than 10 drinks a week (self-report).