Periodic Reporting for period 1 - GLU-IMAGE (Glutamate dynamics during visual stimulation and ketamine challenge in the human brain)
Reporting period: 2019-07-01 to 2021-06-30
Impaired glucose homeostasis and mitochondrial dysfunction are key components of neurodegenerative, metabolic, and psychiatric diseases, such as Alzheimer’s, schizophrenia, and depression. Therefore, an affordable, reliable, and easy-to-apply method to measure brain glucose metabolism is emergently needed. The development of the noninvasive technique, which allows objective, dynamic and longitudinal tracking of brain alterations in health, disease, and aging was a primary goal of our work. To date, techniques such as PET allow to solely measure glucose consumption but do not allow to quantify the downstream metabolism of glucose, affected in the brain diseases. To address this issue, we have focused on developing novel quantitative and noninvasive glutamate MR measures. Glutamate (Glu) is the most abundant neurotransmitter and the downstream component of the Glc metabolism thus considered a key marker of oxidative brain metabolism. Indeed, glutamatergic impairments are fundamentally involved in the pathophysiology of several neurological and neuropsychiatric disorders and are a significant target of emerging therapies. A novel ground-breaking accelerated method for ultra-short echo time proton (1H) MRS imaging (UTE-MRSI), developed and fine-tuned for the project by our team at the High-field MR Centre, Medical University of Vienna, indeed offers critical sensitivity improvements for Glu quantification compared to conventional SV-MRS and previous MRSI approaches. Hence, the proposed improved version of the UTE-MRSI technique will allow image-based multi-slice measurements of baseline Glu concentration and tracking Glu responses to brain activation. These measures are essential for accurate mapping of metabolic changes and treatment responses in severe neurological and psychiatric brain diseases such as depression, schizophrenia, epilepsy, and Alzheimer’s disease. In the current project, we established a highly reproducible MRSI technique to map and visualize endogenous Glu in the resting and activated human brain regions. We significantly improved an innovative noninvasive UTE-MRSI method that provided superior spatial resolution and coverage compared to SV-MRS, and we validated its feasibility to detect Glu oscillations in the resting and activated human brain.
Our initial studies gained from the high sensitivity of ultra-high field (7 Tesla) MR scanner to detect functional glutamate oscillations. We tested and optimized functional MRSI acquisition protocol and sensorimotor and visual stimulation paradigms on 20 subjects. We utilized the navigator images to assure the stable position of MRSI slab during the sessions. We acquired 14 functional MRSI sessions during sensorimotor tasks that consisted of 3 stimulation and 3 resting periods. Under my supervision, a master student Dario Goranovic, MSc, implemented a new approach to suppress unwanted signals of lipids called “channel-wise L2 regularization”. Our tests revealed an impressive impact of the lipid suppression method on the within-session coefficients of variations in metabolite concentrations and the positive effect on the detectability of functional metabolite changes. The feasibility of functional MRSI during the sensorimotor paradigm was presented at the Meeting of the International Society for Magnetic Resonance in Medicine (ISMRM). We also conducted a pilot study (10 subjects) proving the feasibility to detect functional metabolite oscillations with fine-tuned semi-LASER single-voxel MRS methodology developed and fine-tuned for clinical 3T scanners at the CMRR, University of Minnesota. Functional MRS/MRSI methodologies were utilized for pharmacological spectroscopy at a 3T scanner and published in the Frontiers in Psychiatry and Frontiers in Neuroscience journals. We investigated the impact of ketamine infusion on brain neurochemistry by comparing MRS acquired before and after ketamine infusion in 2 separate sessions in several brain regions. This extension of our project provided valuable information on clinical 3 Tesla scanners, which will interest the clinicians. The limitation of the current functional spectroscopy methods is assessing only relative functional metabolite changes (stimulation minus rest). To overcome the inability to quantify metabolite rates, we developed a novel methodology utilizing the functional 1H-MRSI measured after peroral administration of the deuterated glucose in humans. The method benefits from incorporating deuterons (2H) in the 2H-labeled glucose molecule into the downstream glucose metabolites, e.g. glutamate, and yields quantitative information about the speed of related metabolic cycles in the resting or activated human brain. Since the deuterons provide no signal at 1H-MRS, the increased concentration of deuterated metabolites is detected as a decaying signal in the 1H-MR spectrum. The beneficiary will seek the commercialization of indirect deuterium imaging. Overall, the study outcomes were well received by the scientific community and were awarded several distinctions, such as the ISMRM Merit Award and Early Career Poster Award (Minnesota spectroscopy workshop). The method of indirect deuterium imaging has been submitted to a high-ranked journal.
The first human application of indirect deuterium detection with 1H-MRSI revealed a great potential to image the brain cycles involved in oxidative glucose consumption (Glu) and neurotransmitter synthesis (Glu and GABA). These novel, ground-breaking methodologies provide quantitative information about the glutamate turnover obtained with high spatial resolution. The method is non-invasive and clearly showed promise to replace 18F-fluorodeoxyglucose (FDG) positron emission tomography, the current gold standard in the imaging of brain glucose metabolism, with broad implications in clinical and diagnostic imaging. While FDG-PET utilizes unstable radioactive tracers, which are potentially harmful and their preparation requires expensive on-site equipment such as cyclotrons, the deuterated tracers needed for 2H-to-1H-MRSI have negligible health risks and can be prepared off-site. FDG-PET provides measures of the brain Glc uptake, but the FDG is not further incorporated into the downstream Glc metabolites. Thus 2H-to-1H-MRSI quantitates several metabolic pathways of anaerobic and aerobic combustion via dynamic quantification of several neurochemicals and neurotransmitters. In addition, deuterated neurochemicals can be detected with broadly clinically available MR scanners. The noninvasive nature predetermines the methodology for utilization in clinical trials, which require multiple scans to track treatment effects and disease progression. The potential applications involve most severe neurological and neuropsychiatric diseases, particularly states with mitochondrial dysfunction and impaired glucose oxidation such as brain tumors, brain insulin resistance, and Alzheimer’s dementia, as well as diseases with impaired glutamatergic neurotransmission such as depression. Robustly detection of downstream glucose metabolism utilizing clinically available MR hardware without the need for radioactive tracers and PET promises to improve the development of therapies and healthcare in patients with neurological a psychiatric disorders.