Brain Inflammation and Function in Alcoholism

Summary

Participation Requirements

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 c...

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.

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