MRI; Magnetresonanz Spektroskopie; Schlaf; Hirn; Glutamat; Datenverarbeitung; Bewegungskorrektur; Quantifizierung; Metabolite Mapping; Methodik; Glukose
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Background: Magnetic resonance imaging (MRI) and spectroscopy (MRS) provide versatile tools to investigate human anatomy, function and metabolism non-invasively. MRS is established as biomedical research tool to investigate the chemical composition of the human body, but it still lacks the robustness and sensitivity needed for broad clinical applicability. Ultrahigh magnetic fields (>=7T) can overcome some of the limitations with better resolution and signal-to-noise; however, additional methodological developments are necessary to make MRS robust and reliable enough to serve as clinical decision-maker. This includes motion-insensitivity in general since MRS examinations are time-consuming, but in particular in special patient groups or situations such as pediatric patients or examinations during sleep. The latter is an inviting situation for MR investigations since recent research suggests that a major role of sleep is detoxification, given that interstitial space was found to be increased by 60% in sleep and appears to enable flushing by CSF, which could explain the recently found relationship in Alzheimer’s patients between sleep reduction/disorders and cerebral amyloid deposition. In addition to increased robustness, quantitative accessibility of additional metabolites will foster the relevance of MRS. Chemical exchange saturation transfer (CEST) MRI has been developed to map specific classes of meta¬bolites, in particular also glucose - though so far in animals at very high field only. Given the importance of cerebral glucose metabolism, the relevance of an adaptation of these techniques to clinical MR systems is obvious.Working Hypotheses:A) The robustness and reliability of MRS and CEST methods can be enhanced enough by combination with external motion tracking or real-time field correction to extend their use in the clinic to novel patient groups and in research to extend to unconventional applications, like sleep research or glucose mapping in pathologic situations. B) Changes in interstitial volume during sleep are amenable to exploration by MR in humans and the determined diffusion constants could turn out to serve as a proxy for assessing state dependent changes in amyloid accumulation.Main Specific Aims:The proposal aims at improving existing MR methods and devising new MR tools, both by combining existing techniques, but also by realizing new ideas.1) Methods for clinical MRS and sleep-research: Improve robustness of MRS using a fast motion correction scheme, simultaneous recording of reference data, and novel methods for absolute quantification. Among other clinical situations, observation of MRS and MRI during sleep shall benefit from the achieved motion insensitivity.2) Methods for extended MRS and CEST-based metabolite mapping: Improve stability of CEST MRI by combination with real-time field corrections at 7T and elucidate exchange mechanisms as well as target molecules with downfield MRS. CEST shall be optimized for glucose and glutamate mapping in the brain.Methods: Thanks to an extended network and collaboration of two MR sites, hardware as well as sophisticated acquisition and processing methods are available. This includes 3T and 7T whole body MR systems, unique locally developed field probes and an MR-compatible EEG system, a general model fitting tool for interrelated datasets, and schemes for MRS without water saturation. CEST sequences and motion correction methods are provided by pioneers in these fields.1) Clinical MRS and sleep-research: Non water suppressed MRS with external motion tracking and real-time shimming, as well as optimized methods for absolute quantification will be developed. Tests will be performed in moving phantoms and volunteers. Changes of interstitial space during sleep will be evaluated in 15 healthy volunteers in MR sessions of 5 hours with sleep states monitored by EEG while scanning. Because of their differing compartment distribution, we expect inverse changes in diffusion constants of metabolites and water.2) Extended MRS and CEST-based metabolite mapping: Downfield resonances and exchange mechanisms will be elucidated with novel MRS methods. Robustness of the available CEST sequence will be improved by prevention of variability of direct water saturation using field monitoring and optimization of acquisition parameters based on improved local B1 and B0 shimming. Optimized CEST MRI will be applied for glutamate in healthy subjects and to corre-late glucose CEST with brain glucose levels from MRS in Type 1 diabetes patients during a eu-/hyper-glycemic clamp.Expected Value of the Proposed Project: The proposal aims at more robust MR methods on one side and extended uses of MR on the other. It includes appli-cations that are only possible with the novel robust technology: investigation of sleeping subjects thanks to motion tracking on one hand and brain glucose mapping thanks to robust CEST on the other. MR methodology is advanced by elucidation of exchange phenomena and spectral composition at 7T. A much broader impact is expected from motion-corrected MRS for clinical neuro-investigations - e.g. by enabling diagnostic MR investigations in non-sedated children and prevention of motion-related misdiagnoses in focal lesions. Even wider impact is expected from a demon¬stration of increased interstitial volume in sleep, with potential implications for effects of sleep and sleep disturbances on the accumulation of amyloids in human brain. Very similarly, a range of impact can be expected for the proposed progress in CEST methodology: combination of CEST with field correction will provide a clear advancement in technology. However, if the implementation of human brain glucose mapping succeeds with good reliability, we expect that this technique may have tremendous impact on future mapping of glucose by MR vs. by FDG-PET.