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Magnetic resonance techniques to determine metabolite levels: extending scope and clinical robustness

English title Magnetic resonance techniques to determine metabolite levels: extending scope and clinical robustness
Applicant Kreis Roland
Number 156952
Funding scheme Project funding (Div. I-III)
Research institution Abt. Magnetresonanz-Spektroskopie u. Method. Departement für Klinische Forschung Universität Bern
Institution of higher education University of Berne - BE
Main discipline Neurophysiology and Brain Research
Start/End 01.12.2014 - 30.11.2017
Approved amount 499'000.00
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All Disciplines (4)

Discipline
Neurophysiology and Brain Research
Biomedical Engineering
Pathophysiology
Biophysics

Keywords (11)

MRI; Magnetresonanz Spektroskopie; Schlaf; Hirn; Glutamat; Datenverarbeitung; Bewegungskorrektur; Quantifizierung; Metabolite Mapping; Methodik; Glukose

Lay Summary (German)

Lead
Magnetresonanz-Bildgebung (Magnetic Resonance Imaging, MRI) und MR-Spektroskopie (MRS) sind exzellente Werkzeuge um die Struktur, Funktion und den Metabolismus des menschlichen Körpers nicht-invasiv zu untersuchen. Die Empfindlichkeit und klinische Robustheit der Methoden könnend dauernd aufgrund technischer und methodischer Fortschritte verbessert werden. Zudem eröffnen sich immer wieder neue Anwendungsfelder.
Lay summary

Inhalt und Ziele des Forschungsprojekts

Die MRI und MRS Methodik soll in drei Hauptrichtungen erweitert werden:

1. Ein Hauptproblem der MRS ist die Bewegungsempfindlichkeit. In einer Zusammenarbeit mit Forschungsinstituten in Leipzig, Freiburg und Honolulu sollen spezielle MRS Techniken bewegungsunempfindlich gemacht werden. Davon erhoffen wir uns, dass auch Patienten untersucht werden können, die nicht längere Zeit still halten können, so etwa Kinder, demente Personen, oder auch schlafende Versuchspersonen.

2. Mittels neuer Methodik ist es kürzlich gelungen, Stoffwechselprodukte indirekt über das Wassersignal zu beobachten. Hier wird angestrebt, den Vorteil von hohen Untersuchungsfeldern (7 Tesla) zu nutzen und technische Beschränkungen zu eliminieren. Dabei ist ein Ziel, den Glukose-Stoffwechsel besser abbilden zu können.

3. Nachbearbeitungsmethoden sollen optimiert werden, sodass optimal Empfindlichkeit gewährleistet ist.

Wissenschaftlicher und Gesellschaftlicher Kontext des Projekts

Dieses Projekt zielt einerseits auf grundlagenwissenschaftlichen Fortschritt bei der Bereitstellung von neuen und verbesserten Methoden zur Untersuchung des menschlichen Hirns mittels nicht-invasiver Techniken. Andererseits wird auch angestrebt, die Anwendungsmöglichkeiten im klinischen Alltag und damit mit direktem Nutzen für den Patienten zu verbessern
Direct link to Lay Summary Last update: 17.11.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Fitting interrelated datasets: metabolite diffusion and general lineshapes
Adalid V., Döring A., Kyathanahally S. P., Bolliger C. S., Boesch C., Kreis R. (2017), Fitting interrelated datasets: metabolite diffusion and general lineshapes, in MAGMA, 30, 429-448.
Forecasting the quality of water-suppressed (1) H MR spectra based on a single-shot water scan
Kyathanahally S. P., Kreis R. (2017), Forecasting the quality of water-suppressed (1) H MR spectra based on a single-shot water scan, in Magn Reson Med, 78, 441-451.
In vivo characterization of the downfield part of (1) H MR spectra of human brain at 9.4 T: Magnetization exchange with water and relation to conventionally determined metabolite content
Fichtner N. D., Giapitzakis I. A., Avdievich N., Mekle R., Zaldivar D., Henning A., Kreis R. (2017), In vivo characterization of the downfield part of (1) H MR spectra of human brain at 9.4 T: Magnetization exchange with water and relation to conventionally determined metabolite content, in Magn Reson Med.
Metabolite-cycled STEAM and semi-LASER localization for MR spectroscopy of the human brain at 9.4T
Giapitzakis I. A., Shao T., Avdievich N., Mekle R., Kreis R., Henning A. (2017), Metabolite-cycled STEAM and semi-LASER localization for MR spectroscopy of the human brain at 9.4T, in Magn Reson Med.
Quality of clinical brain tumor MR spectra judged by humans and machine learning tools
Kyathanahally S. P., Mocioiu V., Pedrosa de Barros N., Slotboom J., Wright A. J., Julià-Sapé M., Arús C., Kreis R. (2017), Quality of clinical brain tumor MR spectra judged by humans and machine learning tools, in Magn Reson Med.
Test-retest analysis of multiple (31) P magnetization exchange pathways using asymmetric adiabatic inversion
Pouymayou B., Buehler T., Kreis R., Boesch C. (2017), Test-retest analysis of multiple (31) P magnetization exchange pathways using asymmetric adiabatic inversion, in Magn Reson Med, 78, 33-39.
The trouble with quality filtering based on relative Cramér-Rao lower bounds
Kreis Roland (2016), The trouble with quality filtering based on relative Cramér-Rao lower bounds, in Magnetic Resonance in Medicine, 75(1), 15-18.
Elucidation of the downfield spectrum of human brain at 7 T using multiple inversion recovery delays and echo times
Fichtner N. D., Henning A., Zoelch N., Boesch C., Kreis R. (2016), Elucidation of the downfield spectrum of human brain at 7 T using multiple inversion recovery delays and echo times, in Magn Reson Med, 78, 11-19.
Influence of muscle fiber orientation on water and metabolite relaxation times, magnetization transfer, and visibility in human skeletal muscle
MacMillan E. L., Bolliger C. S., Boesch C., Kreis R. (2016), Influence of muscle fiber orientation on water and metabolite relaxation times, magnetization transfer, and visibility in human skeletal muscle, in Magn Reson Med, 75, 1764-1770.
Does superficial fat affect metabolite concentrations determined by MR spectroscopy with water referencing?
Kyathanahally S. P., Fichtner N. D., Adalid V., Kreis R. (2015), Does superficial fat affect metabolite concentrations determined by MR spectroscopy with water referencing?, in NMR in Biomedicine, 28(11), 1543-1549.

Collaboration

Group / person Country
Types of collaboration
MPI, Human Cognitive and Brain Sciences, Leipzig , D, Prof HE Moeller Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Industry/business/other use-inspired collaboration
University Hospital of Psychiatry Bern, Dpt of Psychiatric Neurophysiology, Prof T. Koenig Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
University of Freiburg, D, Dr. M. Zaitsev Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
University Bern, Radiology & Clinical Research, Prof C Boesch Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Johns Hopkins University, Kennedy Krieger Institute, Baltimore, USA, Prof Peter van Zijl, C.Jones United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Max-Planck-Institut für biologische Kybernetik, Tübingen, D, Dr. A. Henning/Prof. K.Scheffler Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
University of Hawaii, USA, Prof T Ernst, Dr. B Keating United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
University Bern, Neuroradiology, Prof. R.Wiest. PD Dr J.Slotboom Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
34rd Annual Meeting ESMRMB Talk given at a conference Optimizing acquisition and fitting conditions for 1H-MRS investigations of global brain pathology 19.10.2017 Barcelona, Spain Kreis Roland; Höfemann Maike;
34rd Annual Meeting ESMRMB Talk given at a conference Simultaneous detection of water and metabolites alternations under visual stimulation in human visual cortex utilizing metabolite-cycled semi-LASER at 9.4T: preliminary results 19.10.2017 Barcelona, Spain Kreis Roland;
12th Annual Meeting, Clinical Neuroscience Bern Poster Metabolite diffusion measured by MR spectroscopy without water suppression yields an improved reproducibility 08.09.2017 Bern, Switzerland Adalid Lopez Victor; Döring André; Kreis Roland;
12th Annual Meeting, Clinical Neuroscience Bern Poster Optimizing acquisition and fitting conditions for 1H MRS investigations of global brain pathology 08.09.2017 Bern, Switzerland Kreis Roland; Adalid Lopez Victor; Höfemann Maike;
25th Meeting of ISMRM Poster Magnetization exchange between water and downfield metabolites in human brain at 9.4T. 22.04.2017 Honolulu, United States of America Fichtner Nicole Damara; Kreis Roland;
25th Meeting of ISMRM Poster Pinpointing differences in diffusion characteristics of metabolites determined in human gray matter using simultaneous spectral and diffusion modeling 22.04.2017 Honolulu, United States of America Adalid Lopez Victor; Döring André; Kreis Roland;
25th Meeting of ISMRM Poster Ghostbusters for MRS: Automatic detection of ghosting artifacts using deep learning: A Pilot Study 22.04.2017 Honolulu, United States of America Kyathanahally Sreenath Pruthviraj; Kreis Roland;
25th Meeting of ISMRM Talk given at a conference Functional Magnetic Resonance Spectroscopy (FMRS) using metabolite cycled semi-LASER at 9.4T: A Pilot Study 22.04.2017 Honolulu, United States of America Fichtner Nicole Damara; Kreis Roland;
33rd Annual Meeting ESMRMB Talk given at a conference Optimizing diffusion-weighted MR spectroscopy of the brain: Simultaneous modeling and correction for motion-related signal distortions 29.09.2016 Vienna, Austria Adalid Lopez Victor; Döring André; Kreis Roland;
ISMRM Workshop on "MR Spectroscopy: From Current Best Practice to Latest Frontiers" Poster Optimized estimation of apparent diffusion coefficients of metabolites. 14.08.2016 Constance, Germany Döring André; Kreis Roland; Adalid Lopez Victor;
ISMRM Workshop on "MR Spectroscopy: From Current Best Practice to Latest Frontiers" Talk given at a conference Assessing spectral quality: of man & machine. 14.08.2016 Constance, Germany Kreis Roland; Kyathanahally Sreenath Pruthviraj;
ISMRM Workshop on "MR Spectroscopy: From Current Best Practice to Latest Frontiers" Talk given at a conference Elucidation of the downfield spectrum of human brain at 7 T and at 9.4 T. 14.08.2016 Constance, Germany Fichtner Nicole Damara; Kreis Roland;
24th Meeting of ISMRM Poster Simultaneous modeling of spectra and apparent diffusion coefficients 07.05.2016 Singapore, Singapore Kreis Roland; Adalid Lopez Victor; Döring André;
24th Meeting of ISMRM Poster Downfield spectra of human brain obtained with and without water suppression at 9.4T. 07.05.2016 Singapore, Singapore Fichtner Nicole Damara; Kreis Roland;
24th Meeting of ISMRM Poster Elucidation of the downfield spectrum of human brain at 7T using multiple inversion recovery delays and echo times 07.05.2016 Singapore, Singapore Kreis Roland; Fichtner Nicole Damara;
24th Meeting of ISMRM Poster Diffusion weighted MR spectroscopy without water suppression allows to use water as inherent reference signal to correct for motion-related signal drop 07.05.2016 Singapore, Singapore Döring André; Kreis Roland; Adalid Lopez Victor;
24th Meeting of ISMRM Talk given at a conference Investigating machine learning approaches for quality control of brain tumor spectra 07.05.2016 Singapore, Singapore Kreis Roland; Kyathanahally Sreenath Pruthviraj;
57th ENC Talk given at a conference Getting More for Less in Clinical MRS? 10.04.2016 Pittsburgh, United States of America Kreis Roland;
11th Annual Meeting, Clinical Neuroscience Bern Poster Downfield MR Spectroscopy at Ultrahigh Magnetic Fields 31.03.2016 Bern, Switzerland Kreis Roland; Fichtner Nicole Damara;
11th Annual Meeting, Clinical Neuroscience Bern Poster Automatic Quality Filtering of MR Spectroscopy Data: A Common Trap 31.03.2016 Bern, Switzerland Kreis Roland; Kyathanahally Sreenath Pruthviraj;
32nd Annual Meeting ESMRMB Talk given at a conference Does superficial fat bias cerebral metabolite content determined by MRS? 01.10.2015 Edinburgh, Great Britain and Northern Ireland Fichtner Nicole Damara; Adalid Lopez Victor; Kyathanahally Sreenath Pruthviraj; Kreis Roland;
23rd Meeting of ISMRM Poster Potential effects of superficial fat on metabolite concentrations determined by water referencing studied with various acquisition settings! 30.05.2015 Toronto, Canada Kyathanahally Sreenath Pruthviraj; Adalid Lopez Victor; Kreis Roland; Fichtner Nicole Damara;
23rd Meeting of ISMRM Poster T2 estimation of downfield metabolites in human brain at 7 T! 30.05.2015 Toronto, Canada Fichtner Nicole Damara; Kreis Roland;
23rd Meeting of ISMRM Talk given at a conference Real-time tool to forecast the adequacy of shim and to define the number of acquisitions needed to answer the clinical question at hand with the prescribed 1H MR spectroscopy exam! 30.05.2015 Toronto, Canada Kyathanahally Sreenath Pruthviraj; Kreis Roland;
23rd Meeting of ISMRM Poster Lineshape compensation methods for modeling of 2DJ spectra 30.05.2015 Toronto, Canada Kreis Roland; Adalid Lopez Victor;
23rd Meeting of ISMRM Talk given at a conference Don’t use relative Cramer Rao lower bounds for elimination of low quality data! 30.05.2015 Toronto, Canada Kyathanahally Sreenath Pruthviraj; Kreis Roland;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Woche des Gehirns, Bern German-speaking Switzerland 2017

Associated projects

Number Title Start Funding scheme
135743 Magnetic Resonance Techniques to Investigate Human Brain Physiology: Acquisition and Postprocessing Tools to Advance Spectroscopy at Clinical and High Magnetic Fields 01.06.2011 Project funding (Div. I-III)
149779 Multi-nuclear magnetic resonance spectroscopy (MRS) and imaging (MRI) on a clinical whole-body MR-system: Lipid organelles and mitochondria 01.12.2013 Project funding (Div. I-III)
175984 Metabolic Fingerprints from Magnetic Resonance: Levels, Maps, and Microstructure 01.12.2017 Project funding (Div. I-III)
127359 Formal thought disorder: Pathophysiology and its implication for specific treatment 01.05.2010 Project funding (Div. I-III)

Abstract

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.
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