Dynamic Metabolic and functional brain Imaging at 7T in Glioblastoma, Epilepsy and Healthy volunteers

This thesis significantly enhances our understanding of the complex relationship between brain metabolism, particularly glucose metabolism, and neural function, leveraging advanced MRI techniques including 13C-Magnetic Resonance Spectroscopy (13C-MRS), functional Magnetic Resonance Imaging (fMRI), and Deuterium Metabolic Imaging (DMI). By systematically investigating glucose metabolism’s influence on brain activity, the research illuminates crucial mechanisms underlying normal neural functionality and their alterations in neurological diseases such as glioblastoma and epilepsy.
Initially, the thesis demonstrates the importance of methodological precision by examining the reproducibility of metabolic measurements using [U-13C]-labeled glucose to track 13C-labeling of glutamate (Glu) and glutamine (Gln). The findings establish a reliable baseline for brain metabolism studies, highlighting that although reproducibility is generally robust, the lower concentration and slower kinetics of 13C-labeling of Gln introduce greater variability. Understanding such variability is essential for accurately comparing healthy states against disease conditions and evaluating therapeutic interventions in future studies.
Further investigations reveal how glucose infusion impacts neuronal activity after overnight fasting, as evidenced by alterations in resting-state BOLD-fMRI signal fluctuations. Significant alterations in low-frequency amplitudes, persisting beyond the immediate availability of glucose, indicate that glucose administration can have sustained effects on brain physiology. This underscores the intricate relationship between neuronal metabolic activity and systemic physiological processes, enhancing our insight into metabolic influences on neurological functions.
Employing Deuterium Metabolic Imaging (DMI), the thesis identifies optimal dosing strategies of [6,6’-2H2]glucose, demonstrating that a reduced dose (0.50 g/kg) effectively captures brain metabolic signals, improving accessibility and patient compliance. This methodological advancement positions DMI as an increasingly viable tool for clinical use, capable of simultaneously visualizing multiple critical metabolites, thereby offering comprehensive metabolic insights.
The application of dynamic DMI in glioblastoma further reveals metabolic alterations consistent with the Warburg effect—a hallmark of cancer metabolism characterized by increased glycolysis and lactate production despite adequate oxygen availability. These findings illustrate distinct metabolic reprogramming within tumor tissues, evidenced by reduced glutamate/glutamine production and elevated lactate-to-glutamate/glutamine ratios, highlighting DMI’s potential as a valuable, non-invasive biomarker for diagnosing and monitoring tumor metabolism.
Expanding the clinical applicability of DMI, this thesis investigates metabolic abnormalities in MRI-negative epilepsy patients. Results showed elevated glutamate/glutamine metabolism in both hippocampi, with higher levels in the hippocampus-EZ (epileptogenic zone). This pattern is consistent with the hippocampus vulnerability to glutamatergic excitotoxicity, but robust conclusions about epilepsy-specific alterations cannot be drawn in the absence of healthy control data. Unlike static imaging modalities such as FDG-PET, dynamic DMI captures temporal changes in metabolic fluxes, highlighting its potential for providing novel insights into epileptic pathophysiology, though its role in presurgical planning requires further validation.
Collectively, this research advances our comprehension of brain metabolism’s pivotal role in neural health and pathology. The insights gained from these advanced metabolic imaging techniques provide a robust framework for future investigations, offering substantial potential to improve diagnostic accuracy and therapeutic outcomes in various brain disorders. Ultimately, these findings lay the groundwork for ongoing innovations in clinical neuroscience, promising enhanced patient care and improved quality of life.