Haifeng Zeng^1,2, Nirbhay N. Yadav^1,2, Xiang Xu^1,2, Kannie W.Y. Chan^1,2, Guanshu Liu^1,2, Michael T. McMahon^1,2, Peter C.M. van Zijl^1,2, and Jiadi Xu^1,2
1Kirby Center, Kennedy Krieger Institute, Baltimore, MD, United States, ²Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Amide Proton Transfer (APT) and relayed NOE CEST (rNOE-CEST) images of endogenous mobile protein in vivo can be used to detect pH changes as well as tumors. However, the precise mechanisms underlying the magnetization transfer contributions among water, amide protons and aliphatic protons in mobile proteins is still under debate. Using a series of NMR experiments on egg white, we confirmed that the magnetization transfer from water to aliphatic protons is relayed through amide protons.

Jochen Keupp¹, Mariya Doneva¹, Julien Sénégas¹, Silke Hey², and Holger Eggers^1
1Philips Research Europe, Hamburg, Germany, ²Philips Healthcare, Best, Netherlands

Amide proton transfer (APT), an endogenous saturation transfer contrast, has recently gained attention as a molecular imaging approach in oncology and neurology. For clinical applications, 3D coverage of the whole tumor or whole brain within acceptable acquisition time as well as a robust field homogeneity correction is essential. In this work, we combined previous approaches for fast-spin echo APT MRI with radial phase encoding and intrinsic 3-point spin-echo Dixon B₀ mapping and homogeneity correction. The volunteer study (N=9) demonstrates the ability to obtain homogeneous and high SNR 3D APT images in the brain using a single examination in less than 5 minutes.

Jing Yuan¹, Ann D King¹, Shuzhong Chen¹, Kunwar S Bhatia¹, Qinwei Zhang¹, Tom Wing Cheung Yuen¹, Yi-Xiang J Wang¹, David Ka Wai Yeung¹, Juan Wei², and Jinyuan Zhou^3
1Imaging and Interventional Radiology, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, ²Philips Research China, Shanghai, China, ³Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States

This study for the first time explored the use of APT-MRI for the head and neck (HN) at 3T, which is challenging due to tissue heterogeneity, pronounced susceptibility and various motions. We successfully demonstrated the feasibility of APT-MRI for the HN at clinical field strengths by adopting various approaches for image acquisition and data processing to mitigate the technical challenges. Z-spectra and of magnetization transfer ratio asymmetry of HN tissues were recorded. Preliminary results of APT-MRI on HN tumor patients showed that APT effect would be promising to be used as a sensitive biomarker for tumor delineation and characterization.

Jan-Eric Meissner¹, Johannes Windschuh¹, Moritz Zaiss¹, Daniel Paech^2,3, Alexander Radbruch^2,3, and Peter Bachert^1
1Department of Medical Physics in Radiology, German Cancer Research Center, Heidelberg, Germany, ²Department of Neuroradiology, University of Heidelberg Medical Center, Heidelberg, Germany, ³Neurooncologic Imaging, Department of Radiology, German Cancer Research Center, Heidelberg, Germany

Chemical Exchange Saturation Transfer (CEST) enables indirect imaging of metabolites in vivo via magnetization transfer between exchanging protons of functional groups and water protons. We propose and evaluate a 2D-CEST sequence with high spectral sampling which allows for pixel-wise detection and separation of NOE-, amides-, and amine-mediated CEST effects and MT simultaneously by the use of a multi Lorentzian fit. Especially isolated amide and NOE mapping allowed insights into glioblastoma substructure.

Xiang Xu^1,2, Jiadi Xu^1,2, Nirbhay N. Yadav^1,2, Craig K. Jones^1,2, Michael T. McMahon^1,2, Alexej Jerschow³, and Peter C. M. van Zijl^1,2
1Radiology Department, Johns Hopkins University School of Medicine, Baltimore, MD, United States, ²F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Research Institute, Baltimore, MD, United States, ³Chemistry Department, New York University, New York, NY, United States

Recently we reported an ultrafast method to obtain a Z-spectrum over a large range of frequency offsets from only two signal excitations. In this study we extend the spectroscopic method into imaging that enables screening multiple samples at the same time. Furthermore, by interleaving a number of saturation and readout periods within the TR, a series of images with different saturation times can be acquired allowing quantification of the exchange rates using variable saturation time (QUEST) approach. Since only two images are needed, the method reduces time required to acquire Z-spectra and enables high throughput screening of CEST contrast agents.

Jiadi xu^1,2, Kannie W. Y. Chan^1,2, Xiang Xu^1,2, Nirbhay Yadav^1,2, Guanshu Liu^1,2, Michael T. McMahon^1,2, and Peter C. M. van Zijl^1,2
1Radiology Department, Johns Hopkins University, Baltimore, MD, United States, ²Kennedy Krieger Institute, Baltimore, MD, United States

A new CEST scheme was developed using the variable delay multi-pulse train CEST (VDMP-CEST) in which the semi-solid magnetization transfer contrast (MTC) contribution was removed based on its exchange rate. The scheme requires acquisition of two images: one at zero inter-pulse delay and a second with an inter-pulse delay at which the MTC signal is comparable to that at zero delay. Consequently, subtracting the two images removes MTC. In addition, direct saturation is reduced, while CEST contrast in different exchange rate regimes remains preserved. The new method is demonstrated on phantoms and on normal mouse brain.

Nirbhay N Yadav^1,2, Jiadi Xu^1,2, Xiang Xu^1,2, Michael T McMahon^1,2, and Peter C M van Zijl^1,2
1Radiology, The Johns Hopkins University, Baltimore, MD, United States, ²FM Kirby Research Center, Kennedy Krieger Institute, Baltimore, MD, United States

Measurement of chemical exchange is important for characterizing many biological processes. Current methods for detecting exchange in spectroscopy are classified based on whether exchange is slow, intermediate, or fast on the NMR time scale. Here we demonstrate a pulse sequence with solute proton frequency encoding and water detection that has the ability to distinguish exchange contributions over a large range of exchange rates (slow-intermediate-fast). When exchange is slow-intermediate, solute protons are labeled and detected with enhanced sensitivity. At higher exchange rates, changes in the water line shape are detected. This principle is demonstrated for the metabolites creatine, myo-inositol, and glutamate.

Zheng Liu^1,2, Ivan E. Dimitrov^2,3, Robert E. Lenkinski^1,2, and Elena Vinogradov^1,2
1Radiology, University of Texas Southwestern Medical Center, Dallas, Texas, United States, ²Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas, United States, ³Philips Medical Systems, Highland Heights, Ohio, United States

Chemical Exchange Saturation Transfer often utilizes acquisition of multi-point Z-spectra, which can be time consuming. Recently an ultrafast Z-spectroscopy method was introduced, employing frequency-encoding gradient during saturation and readout-gradient, thus collecting the whole data with two scans. Here we combine the method with PRESS to achieve localized ultrafast Z-spectroscopy (UCEPR). The sequence is straightforward to implement on clinical scanner and provides CEST effects comparable to the standard Z-spectra UCERP provides localized CEST information on a time scale currently unattainable and we anticipate that it will complement conventional imaging and spectroscopy methods in-vivo.

Ying Cheng^1,2, Kilian Weiss³, Peter van Zijl^1,4, Kathleen Zackowski^5,6, and Craig Jones^1,4
1Neurosection, Div. of MRI Research, Dept. of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States, ²Dept. of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United States, ³Dept. of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States,⁴F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States, ⁵Motion Analysis, Kennedy Krieger Institute, Baltimore, MD, United States, ⁶Dept. of Physical Medicine & Rehab, Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Magnetic resonance spectroscopy (MRS) techniques have been applied to study skeletal muscle energetics. However they suffer from poor spatial resolution and low sensitivity. Chemical exchange saturation transfer (CEST) is a new MRI method that can indirectly detect endogenous cellular substances (e.g. creatine, glycogen) and proteins and metabolites through their exchangeable protons. Here, we applied the CEST technique in human calf muscle at 3T to a previously described exercise regime reported to be glycogen depleting only without a change in phosphocreatine. We demonstrate the potential of detecting exercise-induced changes in CEST signal, which could include glycogen, creatine, and/or T2 changes.

Tao Jin¹, Hunter Mehrens¹, and Seong-Gi Kim^1,2
1Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States, ²Center for Neuroscience Imaging Research, Department of Biological Sciences, SKKU, Suwon, Korea

With chemical exchange dependent saturation transfer (CEST) MRI, recent animal studies administering natural D-glucose demonstrated results comparable to PET, and showed wide potential applications in diseases such as cancer. However, this gluco-CEST approach has low sensitivity, low temporal resolution, and is highly susceptible to B0 shifts. Furthermore, the CEST signal is strongly affected by other relaxation effects such as T1, T2 and magnetization transfer, and lacks a reliable means to quantify glucose concentration. In this study we showed that spin-lock MRI is highly sensitive to the administration of D-glucose and 2-deoxy-D-glucose, and is able to quantify concentration changes.

Stephen J Bawden¹, Olivier Mougin¹, Karl Hunter², Luca Marciani³, and Penny Gowland^1
1SPMMRC, University of Nottingham, Nottingham, United Kingdom, ²Unilever Discover, Bedford, United Kingdom, ³NDDC Biomedical Research Unit, University of Nottingham, Nottingham, United Kingdom

Glycogen and Lipid levels are measured simultaneously using localised GlycoCEST proton MRS. Phantoms with glycogen, glucose and coconut milk were scanned using frequency stepped pre-saturation pulses and PRESS localization for MRS acquisition. Individual spectra were averaged in saturated and non-saturated regions to determine lipid-to-water peak ratios, and the asymmetry of off-resonance saturation water peak heights used to determine the CEST effect. This sequence was tested in vivo in the liver for varying off resonance saturations, and for varying pulse powers. This pilot study offers a promising new technique for reducing study time and costs whilst simultaneously measuring multiple metabolic pathways.

Liu Qi Chen¹, Christine M. Howison², Amanda F. Baker³, and Mark D. Pagel^2
1Chemistry & Biochemistry, University of Arizona, Tucson, AZ, United States, ²Biomedical Engineering, University of Arizona, Tucson, AZ, United States, ³The University of Arizona Cancer Center, University of Arizona, Tucson, AZ, United States

Extracelluar pH (pHe) is a hallmark for tumor microenvironment. A non-invasive MRI method, term “acidoCEST MRI”, was used to accurately measure pHe and assess tumor acidosis. The pixel-wise pHe mapping allows us to access spatial heterogeneity and also contrast agent uptake. We have applied acidoCEST MRI to monitor effects of tumor growth in lymphoma tumor model, Raji, Ramos and Granta519. Our results showed mildly acidic pHe in all 3 tumor models. Granta519 pHe decreased over the course of 3 weeks. The % contrast agent uptake evaluated using acidoCEST MRI correlated with ex vivo VEGF-A score.

Francisco Torrealdea¹, Marilena Rega¹, Joanne Lau¹, Jessica Broni¹, Sebastian Brandner¹, Simon Walker-Samuel², David L Thomas¹, and Xavier Golay^1
1Institute of Neurology, UCL, London, London, United Kingdom, ²Centre for Advance Biomedical Imaging, UCL, London, London, United Kingdom

Upregulated aerobic glycolysis in tumours causes acidic extracellular pH. Changes in pH can be detected in-vivo by CEST MRI. The goal of this study is to assess the CEST signal response of brain gliomas following the administration of an intra-peritoneal (IP) bolus of sodium bicarbonate. This preliminary study shows the potential of bicarbonate as a theragnostic CEST agent for the treatment and early assessment of gliomas.

Yee Kai Tee¹, George Harston², Nicholas Blockley³, Thomas Okell³, Jacob Levman¹, Martino Cellerini⁴, Fintan Sheerin⁴, Peter Jezzard³, James Kennedy², Stephen Payne¹, and Michael Chappell^1
1Department of Engineering Science, Institute of Biomedical Engineering, University of Oxford, Oxford, Oxfordshire, United Kingdom, ²Acute Stroke Programme, Radcliffe Department of Medicine, University of Oxford, Oxfordshire, United Kingdom, ³FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxfordshire, United Kingdom, ⁴Department of Neuroradiology, Oxford University Hospitals NHS Trust, Oxfordshire, United Kingdom

Amide proton transfer (APT) imaging is a variant of chemical exchange saturation transfer (CEST) that has potential for assessing ischemic tissue at risk for infarction. In this study, APT data in healthy subjects and hyper-acute stroke patients within 6 hours of onset were acquired. A quantitative model-based analysis, where the modified Bloch equations were fitted to measured data using Bayesian algorithm, was used to quantify the APT effect. Based on the quantified APT effect and a previously published pH versus amide proton exchange rate relationship, quantitative pH maps in healthy subjects and stroke patients were generated.

Patrick Kunz¹, Moritz Zaiss², Steffen Goerke², Alexander Radbruch^3,4, and Peter Bachert^2
1Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany, ²Dept. Medical Physics in Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany, ³Dept. of Neuroradiology, University of Heidelberg, Heidelberg, Germany, ⁴Section Neuro–oncologic Imaging, German Cencer Research Center (DKFZ), Heidelberg, Germany

Urea–dependent unfolding of BSA, which can be monitored by fluorescence spectroscopy, affects saturation transfer between water and aliphatic protons of the protein mediated by dipole–dipole couplings (NOE). We show that the NOE imaging contrast of the BSA solution is a function of protein structure and propose that, besides concentration, temperature, and pH, protein folding/unfolding generates an additional contrast mechanism of CEST MR imaging. First outcomes of application in human glioblastoma patients are presented and discussed.

Kannie WY Chan^1,2, Antje Arnold^1,3, Ali Fatemi⁴, Michael Porambo⁴, Peter CM van Zjil^1,2, Jeff WM Bulte^1,3, Piotr Walczak^1,3, and Michael T McMahon^1,2
1Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States, ²Kennedy Krieger Institute, Baltimore, MD, United States, ³Institute for Cell Engineering, MD, United States, ⁴Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD, United States

Cell therapy has shown promise for treating neurological disorders, e.g. stroke, spinal cord injury and multiple sclerosis. Primary challenges include protection and support of cell grafts after transplantation, along with methods to determine cell functionality. These would be important in refinement of treatments, allowing early evaluation of the success of cell therapy for restoring the lost function. Hydrogels have been used to protect and support therapeutic cells in such therapies, here, we show that CEST MRI allow imaging of the microenvironments, including pH, for specific injectable hydrogels suited for glial restricted precursor cells (GRPs).

Kristian Rink¹, Moritz C. Berger¹, Andreas Korzowski¹, Peter Bachert¹, and Armin M. Nagel^1
1German Cancer Research Center (DKFZ), Heidelberg, Germany

Phosphorus plays a crucial role in the energy metabolism of the human body but in comparison to ¹H MRI the in-vivo signal is four orders of magnitude smaller. In this work phosphocreatine images of the human calf muscle at 3T were acquired using a frequency selective 3D imaging sequence amplified by Nuclear Overhauser Effect (NOE) pulses. Implementing the NOE yields an SNR gain of up to 1.4 in-vivo and 1.7 in phantom studies with an isotropic resolution of 1cm (TA=33min).

Xu Jiang¹, Peter van Gelderen¹, Jacco A de Zwart¹, and Jeff H Duyn^1
1AMRI, LFMI, NINDS, National Institutes of Health, Bethesda, MD, United States

A novel approach is presented to indirectly image brain myelin content. The proposed method is based on a pulsed saturation transfer experiment, in which water with short T₂ (including myelin water) is selectively saturated, after which the delayed effect on long T₂ water is studied. Experiments performed at 7T confirm sensitivity and specificity of the method.

Mathieu Boudreau¹, Nikola Stikov¹, and G. Bruce Pike^1,2
1Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada, ²Hotchkiss Brain Institute, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada

Quantitative magnetization transfer (qMT) requires several additional measurements to correct for instrumental biases (B₀, B₁) and to constrain parameters in the fitting model (T₁). When using variable flip angle (VFA) T₁ maps, B₁ is used twice before fitting the qMT parameters: to correct T₁, and the MT saturation powers. Inaccuracies in B₁ would propagate to the fitting of the qMT parameters through two pathways – through errors in T₁ and MT saturation powers. This work demonstrates that for the Sled and Pike qMT model, certain qMT parameters (F, T_2f) are insensitive to a large range of B₁ inaccuracies when using VFA.

Jae-Woong Kim¹, Janggeun Cho², Chulhyun Lee², and Sung-Hong Park^1
1Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea, ²Korea Basic Science Institute, Ochang, Korea

Imaging myelin is important for studies related to white matter (WM) diseases. We investigated the feasibility of mapping WM characteristics using interslice MT asymmetry and MT ratio using a recent method termed Alternate Ascending/Descending Directional Navigation (ALADDIN). The WM contrast (compared to gray matter and muscle) was much higher in MT asymmetry images than in MT ratio images, and the two images showed slightly different WM information in subcortical regions, indicating that combination of MT ratio and MT asymmetry may be a promising tool for better understanding of WM characteristics.

Juyoung Lee¹, Paul Kyu Han¹, Seung-Hong Choi², Sung-Hong Park¹, and Jong Chul Ye^1
1Department of Bio and Brain Engineering, KAIST, Daejeon, Yuseong-gu, Korea, ²Department of Radiology, Seoul National University Hospital, Seoul, Korea

CEST can be combined with 3D gradient echo imaging to minimize distortion and avoid slice-dependent saturation frequency variations, but the spatial coverage may be limited. One potential approach to overcome this limitation is to use compressed sensing (CS). In this study, we successfully obtained in vivo 3D CEST images using k-t FOCUSS at 3T. Experimental results show that CS acceleration by a factor of 4 works well for both 3D CEST-bSSFP and 3D CEST-FISP and improves the z-spectrum compared to parallel imaging method, which confirms that combination of CS may be a good solution for 3D- CEST imaging.