Leveraging biomarkers for personalized treatment of alcohol use disorder comorbid with PTSD

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Summary The Blood Biomarkers Core (BBC) is led by Dr. Silvia Fossati. For Project 1, blood and brain samples from all mice will be collected at sacrifice to quantify: 1) molecular biomarkers in animals subjected to all alcohol and/or PTSD-like models after treatment with two doses of topiramate (TPM) or vehicle to clarify the mechanisms of TPM action, and 2) biomarkers for the neurobiological comparison of animal models of alcohol+PTSD with PTSD-like animal models alone, alcohol models alone, naïve control animals, and resilient animals. For Project 2, blood will be collected from all enrolled randomized clinical trial (RCT) participants at 2 time points (before randomization and at week 12), and processed to determine molecular biomarkers, predictors of therapeutic efficacy and GRIK1 genotype, following best practices for blood biomarker analysis developed by our group at the NYU Cohen Veterans Center. Using Simoa and ELISA assays, we will determine the blood concentration of the following molecules: 1) excitatory and inhibitory amino acids altered in AUD, PTSD and PTSD+AUD and central to the hypothesized mechanisms of action of TPM (gluatamate and GABA); 2) peptides and hormones regulating responses of the hypothalamic–pituitary–adrenal (HPA) axis (corticotrophin releasing factor (CRF), corticosterone/cortisol, neuropeptide Y, and brain-derived neurotrophic factor (BDNF)); 3) biomarkers implicated in neuroinflammation (IL6, IL10, IL1α, TNFα, and glial fibrillary acidic protein); and 4) apoptosis, oxidative stress and mitochondrial dysfunction markers (cytochrome C). Integration across projects will be achieved by two design elements and three analytic strategies. Integrative Design Elements include: 1) mice subjected to alcohol and/or PTSD-like models in Project 1 will be stratified and randomized to topiramate/vehicle and PTSD+AUD clinical trial participants in Project 2 will be stratified and randomized to topiramate/placebo, creating parallel designs to advance discovery of mechanisms of topiramate action and predictors of treatment response; and 2) all blood biomarkers in mice in Project 1 will be ascertained in clinical trial participants for Project 2 (cortisol will replace corticosterone). Integrative Analytic Strategies include: 1) blood biomarkers levels after topiramate/placebo treatment in Project 2 will be related to plasma biomarkers levels in alcohol+PTSD models after topiramate/vehicle treatment in Project 1; 2) blood biomarker values obtained in clinical trial participants in Project 2 will be related to their Project 2 clinical data and to fMRI, TMS/EEG and MRS markers derived from Project 3; and 3) gene expression and protein expression markers ascertained in PFC, amygdala, cingulate, insula, VTA and accumbens in mice in Project 1 will be related to circuit markers obtained in the same brain regions in clinical trial participants in Project 3. Further, because we will be able to collect a higher blood volume in humans than mice, we will bank plasma, serum, whole blood, DNA, and RNA for future systems biology analyses, including genomics, transcriptomics, DNA methylation, metabolomics and proteomics.