Background and Objective: Alcohol use disorder (AUD) can be a treatable condition, but relapse rates are still high and new therapeutic targets important to the pathophysiology need to be identified. Emerging pre- clinical and human postmortem data implicate astroglia, the most abundant glial cell in brain, in AUD behavior and associated brain damage. Although controversial, we believe that the astroglial response to chronic brain insult (e.g., in AUD) is largely and normally protective (i.e., not harmful) by supporting neuronal metabolic function and integrity. Since the status of astroglia in brain of persons with AUD is uncertain, and may even be compromised, our overall Objective is to establish whether the astroglial cell is deficient, or not, in living brain of persons with AUD. We expect that the obtained results will help guide therapeutic efforts.
Specific Aims and Hypotheses:
We aim to establish whether brain levels of an astroglial marker, the enzyme monoamine oxidase B (MAO-B), are lower in AUD than those in healthy control subjects (and may recover during protracted abstinence). Our directional working hypothesis is based on some postmortem human brain data suggesting that brain astroglial integrity might be lower than normal in AUD. Design: To measure astroglial status we will measure binding of [11C]SL25.1188, a third generation PET (positron emission tomography) radiotracer selective for MAO-B, which we recently developed for use in the human. 25 persons with AUD in early abstinence (3-7 days) 15 of which are estimated to completed a scan during protracted abstinence (~21 days) and 25 matched control subjects will be enrolled. We will also examine the relationship between astroglial activation (inferred from PET data) and peripheral blood measures of immune markers and explore whether these might be related to behaviour (e.g. relapse, craving, withdrawal). Relevance: Our team is unique in combining extensive experience in measuring glial proteins in both postmortem and living brain of persons with substance use disorders and in developing/using (to our knowledge) the only third generation radiolabeled astroglial marker in human PET brain imaging investigations. The obtained results will represent the first step in guiding therapeutic efforts targeted at the brain astroglial cell in AUD while at the same time exploring the relationship between brain and peripheral (blood) markers in this condition. The latter effort is innovative and will address the unmet need for identification of simple, noninvasive and inexpensive pathophysiologically relevant peripheral biomarkers of CNS ?damage?.
Alcohol use disorder may be associated with a brain immune response involving the most abundant glial cell, the astrocyte; and which is suspected to contribute to clinical symptomatology and brain damage. We will use a neuroimaging strategy to address whether alcohol use disorder is indeed associated with a change in the status of astrocyte. This will help understand the role of these non-neuronal cells in the pathophysiology of alcohol use disorder and may lead to better treatments.
