Metabolism in the human brain following oral consumption of a keto-ester for applications in alcohol use disorder (AUD) with 1H-MRSI

AbstractIntroduction Magnetic Resonance Spectroscopy (MRS) is a technique that provides chemical information by detecting metabolite concentrations in tissues unlike MRI, which focuses on structural and functional imaging. MR spectroscopic imaging (MRSI) is an extension of MRS, capable of mapping the metabolic profile over a large brain region. Detecting metabolites through MRS is significant because it allows non-invasive assessment of the biochemical environment within the central nervous system. Certain metabolites serve as biomarkers, reflecting the physiological or pathological state of brain tissue. As such, through the detection and quantification of metabolites, MRS and MRSI are powerful tools that have seen applications in the diagnose and assessment of neurological and psychiatric disorders through biochemical changes in the brain. Building on this knowledge, our study aims to explore brain ketone-body metabolism in alcohol use disorder (AUD), enabling us to examine BHB transport as a marker of disease severity and gain insights into craving mechanisms associated with AUD. AUD is a complex, relapsing brain disorder resulting from prolonged alcohol use, often linked to metabolic disruptions in brain function and an increased susceptibility to other illnesses. Research indicates that individuals with AUD experience a substantial decrease in brain glucose metabolism, leading to a dependency on alternative energy sources, specifically acetate. This has led to interest in exploring ketone bodies as potential therapeutic agents for AUD due to their shared transport mechanisms across the blood-brain barrier with acetate. Detecting ketone bodies in the brain, particularly beta-hydroxybutyrate (BHB), could provide insights into therapeutic responses and help monitor disease severity. Emerging studies have documented elevated levels of BHB, detected through proton magnetic resonance (1H-MR) spectroscopy following the intake of ketone esters. This current study aims to build on this knowledge by evaluating BHB metabolism in individuals with AUD compared to healthy controls after ingesting a keto-ester. The study’s objectives include assessing the reliability of BHB detection and understanding metabolic changes related to AUD severity and cravings. Methods In this pilot study, four individuals with AUD and eight healthy controls participated. Magnetic resonance spectroscopy imaging (MRSI) scans were performed on each participant using a 4 T Medspec MRI system. Before consuming the keto-ester (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate (HBHB), baseline scans were obtained. Each participant then consumed HBHB orally at a dose of 0.4 g/kg, followed by post-consumption BHB-edited MRSI scans. Upon ingestion, HBHB metabolizes to BHB and 1,3-butanediol (BDO) in the body. Since BDO can further convert to BHB in the liver, detection in the brain is anticipated, as evidenced in previous studies. NMR spectral analysis was employed to differentiate BHB from BDO in the MRSI data. Results and Discussion The data demonstrated high-quality metabolic maps for lactate and BHB+BDO, though isolating BHB from BDO proved challenging due to the overlap of co-edited resonances. Enhancing signal-noise-ratio and refining post-processing techniques is expected to improve BHB and BDO differentiation. Advanced selective editing at specific resonances could further refine BHB detection, potentially enhancing the understanding of ketone metabolism in AUD and facilitating the development of targeted metabolic therapies