Aggregation‐induced changes in the chemical exchange saturation transfer (CEST) signals of proteins

Published on Jan 1, 2017in NMR in Biomedicine3.221
· DOI :10.1002/NBM.3665
Steffen Goerke14
Estimated H-index: 14
(DKFZ: German Cancer Research Center),
Katharina S. Milde1
Estimated H-index: 1
(DKFZ: German Cancer Research Center)
+ 9 AuthorsMoritz Zaiss28
Estimated H-index: 28
(DKFZ: German Cancer Research Center)
Sources
Abstract
Chemical exchange saturation transfer (CEST) is an MRI technique that allows mapping of biomolecules (small metabolites, proteins) with nearly the sensitivity of conventional water proton MRI. In living organisms, several tissue-specific CEST effects have been observed and successfully applied to diagnostic imaging. In these studies, particularly the signals of proteins showed a distinct correlation with pathological changes. However, as CEST effects depend on various properties that determine and affect the chemical exchange processes, the origins of the observed signal changes remain to be understood. In this study, protein aggregation was identified as an additional process that is encoded in the CEST signals of proteins. Investigation of distinct proteins that are involved in pathological disorders, namely amyloid beta and huntingtin, revealed a significant decrease of all protein CEST signals upon controlled aggregation. This finding is of particular interest with regard to diagnostic imaging of patients with neurodegenerative diseases that involve amyloidogenesis, such as Alzheimer's or Huntington's disease. To investigate whether the observed CEST signal decrease also occurs in heterogeneous mixtures of aggregated cellular proteins, and thus prospectively in tissue, heat-shocked yeast cell lysates were employed. Additionally, investigation of different cell compartments verified the assignment of the protein CEST signals to the soluble part of the proteome. The results of in vitro experiments demonstrate that aggregation affects the CEST signals of proteins. This observation can enable hypotheses for CEST imaging as a non-invasive diagnostic tool for monitoring pathological alterations of the proteome in vivo.
📖 Papers frequently viewed together
115 Citations
777 Citations
40 Citations
References33
Newest
#1Dong-Hoon Lee (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 18
#2Hye Young Heo (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 20
Last. Jinyuan Zhou (ICSCI: Kennedy Krieger Institute)H-Index: 54
view all 7 authors...
Purpose To quantify pure chemical exchange–dependent saturation transfer (CEST) related amide proton transfer (APT) and nuclear Overhauser enhancement (NOE) signals in a rat glioma model and to investigate the mixed effects of water content and water T1 on APT and NOE imaging signals. Methods Eleven U87 tumor-bearing rats were scanned at 4.7 T. A relatively accurate mathematical approach, based on extrapolated semisolid magnetization-transfer reference signals, was used to remove the concurrent ...
47 CitationsSource
#1Moritz ZaissH-Index: 28
#2Johannes WindschuhH-Index: 15
Last. Alexander RadbruchH-Index: 41
view all 13 authors...
Purpose The chemical exchange saturation transfer (CEST) effect observed in brain tissue in vivo at the frequency offset 3.5 ppm downfield of water was assigned to amide protons of the protein backbone. Obeying a base-catalyzed exchange process such an amide-CEST effect would correlate with intracellular pH and protein concentration, correlations that are highly interesting for cancer diagnosis. However, recent experiments suggested that, besides the known aliphatic relayed-nuclear Overhauser ef...
75 CitationsSource
#1E DemetriouH-Index: 1
#2M TachrountH-Index: 1
Last. X GolayH-Index: 1
view all 7 authors...
1 Citations
#1Steffen Goerke (DKFZ: German Cancer Research Center)H-Index: 14
#2Moritz Zaiss (DKFZ: German Cancer Research Center)H-Index: 28
Last. Peter Bachert (DKFZ: German Cancer Research Center)H-Index: 36
view all 9 authors...
Chemical exchange saturation transfer (CEST) allows the detection of metabolites of low concentration in tissue with nearly the sensitivity of MRI with water protons. With this spectroscopic imaging approach, several tissue-specific CEST effects have been observed in vivo. Some of these originate from exchanging sites of proteins, such as backbone amide protons, or from aliphatic protons within the hydrophobic protein core. In this work, we employed CEST experiments to detect global protein unfo...
40 CitationsSource
#1Moritz ZaissH-Index: 28
#2Johannes WindschuhH-Index: 15
Last. Alexander Radbruch (Heidelberg University)H-Index: 41
view all 14 authors...
Abstract Endogenous chemical exchange saturation transfer (CEST) effects of protons resonating near to water protons are always diluted by competing effects such as direct water saturation and semi-solid magnetization transfer (MT). This leads to unwanted T2 and MT signal contributions that contaminate the observed CEST signal. Furthermore, all CEST effects appear to be scaled by the T1 relaxation time of the mediating water pool. As MT, T1 and T2 are also altered in tumor regions, a recently pu...
121 CitationsSource
#1Moritz ZaissH-Index: 28
#2Zhongliang Zu (Vandy: Vanderbilt University)H-Index: 22
Last. Peter BachertH-Index: 36
view all 8 authors...
Off-resonant RF irradiation in tissue indirectly lowers the water signal by saturation transfer processes: on the one hand, there are selective chemical exchange saturation transfer (CEST) effects originating from exchanging endogenous protons resonating a few parts per million from water; on the other hand, there is the broad semi-solid magnetization transfer (MT) originating from immobile protons associated with the tissue matrix with kilohertz linewidths. Recently it was shown that endogenous...
73 CitationsSource
#1Kun Yan (WHU: Wuhan University)H-Index: 10
#2Zongming Fu (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 13
Last. Jinyuan Zhou (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 54
view all 11 authors...
Purpose To investigate the biochemical origin of the amide photon transfer (APT)-weighted hyperintensity in brain tumors.
65 CitationsSource
#1Dario Livio Longo (UNITO: University of Turin)H-Index: 28
#2Enza Di Gregorio (UNITO: University of Turin)H-Index: 16
Last. Silvio Aime (UNITO: University of Turin)H-Index: 91
view all 7 authors...
A versatile method for assessing protein properties via magnetic resonance imaging (MRI) through chemical exchange saturation transfer (CEST) modality is described. The observed CEST signal changes allow monitoring of protein aggregation processes, protein folding/unfolding steps and interaction with lipid membranes.
17 CitationsSource
#1Jiadi Xu (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 34
#2Nirbhay N. Yadav (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 20
Last. Peter C.M. van Zijl (ICSCI: Kennedy Krieger Institute)H-Index: 109
view all 9 authors...
Purpose Chemical exchange saturation transfer (CEST) imaging is a new MRI technology allowing the detection of low concentration endogenous cellular proteins and metabolites indirectly through their exchangeable protons. A new technique, variable delay multi-pulse CEST (VDMP-CEST), is proposed to eliminate the need for recording full Z-spectra and performing asymmetry analysis to obtain CEST contrast. Methods The VDMP-CEST scheme involves acquiring images with two (or more) delays between radiof...
81 CitationsSource
#1Junzhong Xu (Vandy: Vanderbilt University)H-Index: 27
#2Moritz Zaiss (DKFZ: German Cancer Research Center)H-Index: 28
Last. John C. GoreH-Index: 137
view all 8 authors...
Chemical exchange saturation transfer (CEST) provides an indirect means to detect exchangeable protons within tissues through their effects on the water signal. Previous studies have suggested that amide proton transfer (APT) imaging, a specific form of CEST, detects endogenous amide protons with a resonance frequency offset 3.5 ppm downfield from water, and thus may be sensitive to variations of mobile proteins/peptides in tumors. However, since CEST measurements are influenced by various confo...
105 CitationsSource
Cited By32
Newest
#1Harri Merisaari (UTU: University of Turku)H-Index: 16
#2Christian Federau (UZH: University of Zurich)H-Index: 18
Intravoxel incoherent motion (IVIM) is a method that can provide quantitative information about perfusion in the human body, in vivo, and without contrast agent. Unfortunately, the IVIM perfusion parameter maps are known to be relatively noisy in the brain, in particular for the pseudo-diffusion coefficient, which might hinder its potential broader use in clinical applications. Therefore, we studied the conditions to produce optimal IVIM perfusion images in the brain. IVIM imaging was performed ...
Source
#1Andrea Crețu (Technische Universität Ilmenau)
#2Carlos Mattea (Technische Universität Ilmenau)H-Index: 19
Last. Siegfried Stapf (Technische Universität Ilmenau)H-Index: 26
view all 0 authors...
Osteoarthritis (OA) as the main degenerative disease of articular cartilage in joints is accompanied by structural and compositional changes in the tissue. Degeneration is a consequence of a reduction of the amount of macromolecules, the so-called proteoglycans, and of a corresponding increase in water content, both leading to structural weakening of cartilage. NMR investigations of cartilage generally address only the relaxation properties of water. In this study, two-dimensional (T1-T2) measur...
Source
#1Kevin D. Harkins (Vandy: Vanderbilt University)H-Index: 12
#2Mark D. Does (Vandy: Vanderbilt University)H-Index: 49
Abstract Accurate measurement of gradient waveform errors can often improve image quality in sequences with time varying readout and excitation waveforms. Self-encoding or offset-slice sequences are commonly used to measure gradient waveforms. However, the self-encoding method requires a long scan time, while the offset-slice method is often low precision, requiring the thickness of the excited slice to be small compared to the maximal k-space encoded by the test waveform. This work introduces a...
Source
#1Saeed Jerban (UCSD: University of California, San Diego)H-Index: 12
#2Yajun Ma (UCSD: University of California, San Diego)H-Index: 18
Last. Christine B. Chung (UCSD: University of California, San Diego)H-Index: 60
view all 13 authors...
Abstract Purpose The development of ultrashort echo time (UTE) MRI sequences has led to improved imaging of tissues with short T2 relaxation times, such as the deep layer cartilage and meniscus. UTE combined with adiabatic T1ρ preparation (UTE-Adiab-T1ρ) is an MRI measure with low sensitivity to the magic angle effect. This study aimed to investigate the sensitivity of UTE-Adiab-T1ρ to mechanical load-induced deformations in the tibiofemoral cartilage and meniscus of human cadaveric knee joints....
Source
#1Jang Hoon Oh (Kyung Hee University)
#2Bo Guem Choi (Kyung Hee University)
Last. Geon Ho Jahng (Kyung Hee University)H-Index: 5
view all 11 authors...
Objective Chemical exchange-dependent saturation transfer (CEST) MRI is sensitive for detecting solid-like proteins and may detect changes in the levels of mobile proteins and peptides in tissues. The objective of this study was to evaluate the characteristics of chemical exchange proton pools using the CEST MRI technique in patients with dementia. Materials and methods Our institutional review board approved this cross-sectional prospective study and informed consent was obtained from all parti...
Source
#1Henrik Lundell (Copenhagen University Hospital)H-Index: 16
#2Chloe Najac (LUMC: Leiden University Medical Center)H-Index: 13
Last. Itamar Ronen (LUMC: Leiden University Medical Center)H-Index: 27
view all 6 authors...
Abstract Double diffusion encoding (DDE) of the water signal offers a unique ability to separate the effect of microscopic anisotropic diffusion in structural units of tissue from the overall macroscopic orientational distribution of cells. However, the specificity in detected microscopic anisotropy is limited as the signal is averaged over different cell types and across tissue compartments. Performing side-by-side water and metabolite DDE spectroscopic (DDES) experiments provides complementary...
2 CitationsSource
#1Wynton B Overcast (IU: Indiana University)H-Index: 1
#2Korbin M. Davis (IU: Indiana University)H-Index: 3
Last. Michael C. Veronesi (IU: Indiana University)H-Index: 6
view all 7 authors...
PURPOSE OF REVIEW This review will explore the latest in advanced imaging techniques, with a focus on the complementary nature of multiparametric, multimodality imaging using magnetic resonance imaging (MRI) and positron emission tomography (PET). RECENT FINDINGS Advanced MRI techniques including perfusion-weighted imaging (PWI), MR spectroscopy (MRS), diffusion-weighted imaging (DWI), and MR chemical exchange saturation transfer (CEST) offer significant advantages over conventional MR imaging w...
3 CitationsSource
#1Steffen Goerke (DKFZ: German Cancer Research Center)H-Index: 14
#2Johannes Breitling (DKFZ: German Cancer Research Center)H-Index: 5
Last. P Bachert (Heidelberg University)
view all 8 authors...
PURPOSE The value of relaxation-compensated amide proton transfer (APT) and relayed nuclear Overhauser effect (rNOE) chemical exchange saturation transfer (CEST)-MRI has already been demonstrated in various neuro-oncological clinical applications. Recently, we translated the approach from 7T to a clinically relevant magnetic field strength of 3T. However, the overall acquisition time was still too long for a broad application in the clinical setting. The aim of this study was to establish a shor...
1 CitationsSource
#1T Borbath (University of Tübingen)H-Index: 4
#2Saipavitra Murali‐Manohar (University of Tübingen)H-Index: 3
Last. Anke Henning (MPG: Max Planck Society)H-Index: 33
view all 4 authors...
Purpose Relaxation times are a valuable asset when determining spectral assignments. In this study, apparent T2 relaxation times ( T 2 app ) of downfield peaks are reported in the human brain at 9.4 T and are used to guide spectral assignments of some downfield metabolite peaks. Methods Echo time series of downfield metabolite spectra were acquired at 9.4 T using a metabolite-cycled semi-LASER sequence. Metabolite spectral fitting was performed using LCModel V6.3-1L while fitting a pH sweep to e...
1 CitationsSource
#1Petra J. van Houdt (NKI-AVL: Netherlands Cancer Institute)H-Index: 11
#2Yingli Yang (UCLA: University of California, Los Angeles)H-Index: 16
Last. Uulke A. van der Heide (NKI-AVL: Netherlands Cancer Institute)H-Index: 21
view all 3 authors...
MRI-guided radiotherapy systems have the potential to bring two important concepts in modern radiotherapy together: adaptive radiotherapy and biological targeting. Based on frequent anatomical and functional imaging, monitoring the changes that occur in volume, shape as well as biological characteristics, a treatment plan can be updated regularly to accommodate the observed treatment response. For this purpose, quantitative imaging biomarkers need to be identified that show changes early during ...
7 CitationsSource