Dual-frequency irradiation CEST-MRI of endogenous bulk mobile proteins

• Applicant: Professor Dr. Mark E. Ladd, since 12/2021
• Subject Area: Medical Physics, Biomedical Technology
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 413716733

• Final Report Year: 2022

Final Report Abstract

Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) is an emerging molecular imaging technique enabling the detection of key biomolecules like proteins or glucose with a resolution comparable to conventional MRI. However, in living tissue the CEST signals of the different biomolecules are difficult to separate, impeding the selective detection of one specific compound of interest. The improvement of specificity has become one of the most important issues in the research field of CEST-MRI. In this project, we established a novel CEST-based technique – dualCEST – which overcomes this limitation and enables the selective detection of endogenous bulk mobile proteins in vivo. Substantial improvement of the MR pulse sequence now allows high-resolution dualCEST examinations of the human brain with 3D coverage and good-to-excellent repeatability. Key steps for the improvement were the extension of the MRI readout to a 3D acquisition mode, the implementation of a cosine-modulated pre-saturation scheme, the application of a novel denoising technique, the use of a weighted acquisition scheme, and the correction of motioninduced artifacts. Taken together, a final improvement in the image quality (i.e. signal-to-noise ratio, SNR) of about 800% could be achieved. Comparison of the mobile-protein-specific dualCEST signal with conventional multi-pool CEST-MRI in brain tumor and Alzheimer’s patients verified that also the conventional rNOE-CEST signal is mainly associated with bulk mobile proteins. In Alzheimer’s patients, the rNOE-CEST signal enabled differentiation from age-matched heathy volunteers. This provides evidence for a potential diagnostic tool for Alzheimer’s disease based on the non-invasive methodology of CEST-MRI, and thus, the possibility for more frequent follow-ups, allowing an improved level of patient care. In addition, monitoring of the heat-shock response of an organotypic 3D cell culture in a cuttingedge bioreactor system verified the detectability of physiologically relevant proteomic changes, such as chaperone-induced refolding of protein aggregates, in vivo using CEST-MRI. This implies that the protein folding state is, along with concentration changes, a relevant physiological parameter for the interpretation of CEST signal changes in diseases like Alzheimer’s that are associated with pathological changes in protein expression. The ability to visualize denaturation processes of proteins in living organisms as an MR image significantly expands the potential clinical value of CEST-MRI beyond the scope of this project.

Publications

• A novel normalization for amide proton transfer CEST MRI to correct for fat signal–induced artifacts: application to human breast cancer imaging. Magnetic Resonance in Medicine, 83(3), 920-934.
  Zimmermann, Ferdinand; Korzowski, Andreas; Breitling, Johannes; Meissner, Jan‐Eric; Schuenke, Patrick; Loi, Lisa; Zaiss, Moritz; Bickelhaupt, Sebastian; Schott, Sarah; Schlemmer, Heinz‐Peter; Paech, Daniel; Ladd, Mark E.; Bachert, Peter & Goerke, Steffen
  
• Dynamic glucose‐enhanced (DGE) MRI in the human brain at 7 T with reduced motion‐induced artifacts based on quantitative R1ρ mapping. Magnetic Resonance in Medicine, 84(1), 182-191.
  Boyd, Philip S.; Breitling, Johannes; Zimmermann, Ferdinand; Korzowski, Andreas; Zaiss, Moritz; Schuenke, Patrick; Weinfurtner, Nina; Schlemmer, Heinz‐Peter; Ladd, Mark E.; Bachert, Peter; Paech, Daniel & Goerke, Steffen
  
• Optimized dualCEST‐MRI for imaging of endogenous bulk mobile proteins in the human brain. NMR in Biomedicine, 33(5).
  Breitling, Johannes; Meissner, Jan‐Eric; Zaiss, Moritz; Paech, Daniel; Ladd, Mark E.; Bachert, Peter & Goerke, Steffen
  
• Protein-sensitive CEST-MRI of Alzheimer’s patients at 3 T. Proceedings of the 28th Annual Scientific Meeting ISMRM, virtual meeting. 2020; P#3093.
  Goerke S., Breitling J., Kubera K. M., Zaiss M., Hirjak D., Wolf R. C., Tavakoli A. A., Schlemmer H.-P., Paech D., Ladd M. E. & Bachert P.
  
• The cellular heat shock response monitored by chemical exchange saturation transfer MRI. Scientific Reports, 10(1).
  Kleimaier, Dennis; Goerke, Steffen; Nies, Cordula; Zaiss, Moritz; Kunz, Patrick; Bachert, Peter; Ladd, Mark E.; Gottwald, Eric & Schad, Lothar R.
  
• Clinical routine acquisition protocol for 3D relaxation‐compensated APT and rNOE CEST‐MRI of the human brain at 3T. Magnetic Resonance in Medicine, 86(1), 393-404.
  Goerke, Steffen; Breitling, Johannes; Korzowski, Andreas; Paech, Daniel; Zaiss, Moritz; Schlemmer, Heinz‐Peter; Ladd, Mark E. & Bachert, Peter
  
• Mapping intracellular pH in tumors using amide and guanidyl CEST‐MRI at 9.4 T. Magnetic Resonance in Medicine, 87(5), 2436-2452.
  Boyd, Philip S.; Breitling, Johannes; Korzowski, Andreas; Zaiss, Moritz; Franke, Vanessa L.; Mueller‐Decker, Karin; Glinka, Andrey; Ladd, Mark E.; Bachert, Peter & Goerke, Steffen
  
• Motion correction for three‐dimensional chemical exchange saturation transfer imaging without direct water saturation artifacts. NMR in Biomedicine, 35(7).
  Breitling, Johannes; Korzowski, Andreas; Kempa, Neele; Boyd, Philip S.; Paech, Daniel; Schlemmer, Heinz‐Peter; Ladd, Mark E.; Bachert, Peter & Goerke, Steffen