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The cellular heat shock response monitored by chemical exchange saturation transfer MRI.

ABSTRACT: CEST-MRI of the rNOE signal has been demonstrated in vitro to be closely linked to the protein conformational state. As the detectability of denaturation and aggregation processes on a physiologically relevant scale in living organisms has yet to be verified, the aim of this study was to perform heat-shock experiments with living cells to monitor the cellular heat-shock response of the rNOE CEST signal. Cancer cells (HepG2) were dynamically investigated after a mild, non-lethal heat-shock of 42 °C for 20 min using an MR-compatible bioreactor system at 9.4 T. Reliable and fast high-resolution CEST imaging was realized by a relaxation-compensated 2-point contrast metric. After the heat-shock, a substantial decrease of the rNOE CEST signal by 8.0?±?0.4% followed by a steady signal recovery within a time of 99.1?±?1.3 min was observed in two independent trials. This continuous signal recovery is in coherence with chaperone-induced refolding of heat-shock induced protein aggregates. We demonstrated that protein denaturation processes influence the CEST-MRI signal on a physiologically relevant scale. Thus, the protein folding state is, along with concentration changes, a relevant physiological parameter for the interpretation of CEST signal changes in diseases that are associated with pathological changes in protein expression, like cancer and neurodegenerative diseases.

SUBMITTER: Kleimaier D

PROVIDER: S-EPMC7338423 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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The cellular heat shock response monitored by chemical exchange saturation transfer MRI.

Kleimaier Dennis D Goerke Steffen S Nies Cordula C Zaiss Moritz M Kunz Patrick P Bachert Peter P Ladd Mark E ME Gottwald Eric E Schad Lothar R LR

Scientific reports 20200706 1

CEST-MRI of the rNOE signal has been demonstrated in vitro to be closely linked to the protein conformational state. As the detectability of denaturation and aggregation processes on a physiologically relevant scale in living organisms has yet to be verified, the aim of this study was to perform heat-shock experiments with living cells to monitor the cellular heat-shock response of the rNOE CEST signal. Cancer cells (HepG2) were dynamically investigated after a mild, non-lethal heat-shock of 42 ...[more]

PMID: 32632120

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Project description:Chemical exchange saturation transfer (CEST) has emerged as a novel MRI contrast mechanism that is well suited for molecular imaging studies. This new mechanism can be used to detect small amounts of contrast agent through the saturation of rapidly exchanging protons on these agents, allowing a wide range of applications. CEST technology has a number of indispensable features, such as the possibility of simultaneous detection of multiple 'colors' of agents and of changes in their environment (e.g. pH, metabolites, etc.) through MR contrast. Currently, a large number of new imaging schemes and techniques are being developed to improve the temporal resolution and specificity and to correct for the influence of B0 and B1 inhomogeneities. In this review, the techniques developed over the last decade are summarized with the different imaging strategies and post-processing methods discussed from a practical point of view, including the description of their relative merits for the detection of CEST agents. The goal of the present work is to provide the reader with a fundamental understanding of the techniques developed, and to provide guidance to help refine future applications of this technology. This review is organized into three main sections ('Basics of CEST contrast', 'Implementation' and 'Post-processing'), and also includes a brief Introduction and Summary. The 'Basics of CEST contrast' section contains a description of the relevant background theory for saturation transfer and frequency-labeled transfer, and a brief discussion of methods to determine exchange rates. The 'Implementation' section contains a description of the practical considerations in conducting CEST MRI studies, including the choice of magnetic field, pulse sequence, saturation pulse, imaging scheme, and strategies to separate magnetization transfer and CEST. The 'Post-processing' section contains a description of the typical image processing employed for B0 /B1 correction, Z-spectral interpolation, frequency-selective detection and improvement of CEST contrast maps.

Project description:ObjectiveChemical 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 methodsOur institutional review board approved this cross-sectional prospective study and informed consent was obtained from all participants. This study included 41 subjects (19 with dementia and 22 without dementia). Complete CEST data of the brain were obtained using a three-dimensional gradient and spin-echo sequence to map CEST indices, such as amide, amine, hydroxyl, and magnetization transfer ratio asymmetry (MTRasym) values, using six-pool Lorentzian fitting. Statistical analyses of CEST indices were performed to evaluate group comparisons, their correlations with gray matter volume (GMV) and Mini-Mental State Examination (MMSE) scores, and receiver operating characteristic (ROC) curves.ResultsAmine signals (0.029 for non-dementia, 0.046 for dementia, p = 0.011 at hippocampus) and MTRasym values at 3 ppm (0.748 for non-dementia, 1.138 for dementia, p = 0.022 at hippocampus), and 3.5 ppm (0.463 for non-dementia, 0.875 for dementia, p = 0.029 at hippocampus) were significantly higher in the dementia group than in the non-dementia group. Most CEST indices were not significantly correlated with GMV; however, except amide, most indices were significantly correlated with the MMSE scores. The classification power of most CEST indices was lower than that of GMV but adding one of the CEST indices in GMV improved the classification between the subject groups. The largest improvement was seen in the MTRasym values at 2 ppm in the anterior cingulate (area under the ROC curve = 0.981), with a sensitivity of 100 and a specificity of 90.91.ConclusionCEST MRI potentially allows noninvasive image alterations in the Alzheimer's disease brain without injecting isotopes for monitoring different disease states and may provide a new imaging biomarker in the future.

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The cellular heat shock response monitored by chemical exchange saturation transfer MRI.

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The cellular heat shock response monitored by chemical exchange saturation transfer MRI.

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