Brain Inflammation and Function in Alcoholism
Condition: Alcohol Use Disorder (AUD)
MeSH terms: Infectious Encephalitis; Encephalitis; Inflammation; Alcoholism; Alcohol Drinking
Study type: Interventional
Phase: Early Phase 1

Summary: 
      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.
    

Detailed description: 
      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 at least 3 weeks of
      abstinence as compared between groups (alcoholic vs. healthy volunteers). 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 (AUD) as per DSM IV or DSM
      5 AUD 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
      (AUD subjects) or as outpatient (AUD 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 AUD
      over a 3 month follow-up period.

      [1] Collste K, Forsberg A, Varrone A, Amini N, Aeinehband S, Yakushev I, Halldin C, Farde L,
      Cervenka S. Test-retest reproducibility of [(11)C]PBR28 binding to TSPO in healthy control
      subjects. Eur J Nucl Med Mol Imaging. 2016 Jan;43(1):173-83. doi: 10.1007/s00259-015-3149-8.
      Epub 2015 Aug 22.
    

Intervention name(s): connectivity; neuroinflammation; neurofunction
Intervention type(s): Other; Drug; Other
Intervention description(s): Magnetic resonance imaging (MRI) scans will be done to assess brain structure, functional reactivity and functional connectivity.; The use of [11C]PBR28 will allow us to assess for the first time in vivo if there is neuroinflammation in the brain of alcoholics. It will also allow us to assess if it recovers with alcohol detoxification.; To assess regional brain glucose metabolism.
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Imaging Studies; Alcohol Use Disorder (AUD); Inflammation