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      Diagnostic value of alternative techniques to gadolinium-based contrast agents in MR neuroimaging—a comprehensive overview

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          Abstract

          Gadolinium-based contrast agents (GBCAs) increase lesion detection and improve disease characterization for many cerebral pathologies investigated with MRI. These agents, introduced in the late 1980s, are in wide use today. However, some non-ionic linear GBCAs have been associated with the development of nephrogenic systemic fibrosis in patients with kidney failure. Gadolinium deposition has also been found in deep brain structures, although it is of unclear clinical relevance. Hence, new guidelines from the International Society for Magnetic Resonance in Medicine advocate cautious use of GBCA in clinical and research practice. Some linear GBCAs were restricted from use by the European Medicines Agency (EMA) in 2017.

          This review focuses on non-contrast-enhanced MRI techniques that can serve as alternatives for the use of GBCAs. Clinical studies on the diagnostic performance of non-contrast-enhanced as well as contrast-enhanced MRI methods, both well established and newly proposed, were included. Advantages and disadvantages together with the diagnostic performance of each method are detailed. Non-contrast-enhanced MRIs discussed in this review are arterial spin labeling (ASL), time of flight (TOF), phase contrast (PC), diffusion-weighted imaging (DWI), magnetic resonance spectroscopy (MRS), susceptibility weighted imaging (SWI), and amide proton transfer (APT) imaging.

          Ten common diseases were identified for which studies reported comparisons of non-contrast-enhanced and contrast-enhanced MRI. These specific diseases include primary brain tumors, metastases, abscess, multiple sclerosis, and vascular conditions such as aneurysm, arteriovenous malformation, arteriovenous fistula, intracranial carotid artery occlusive disease, hemorrhagic, and ischemic stroke.

          In general, non-contrast-enhanced techniques showed comparable diagnostic performance to contrast-enhanced MRI for specific diagnostic questions. However, some diagnoses still require contrast-enhanced imaging for a complete examination.

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          MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset

          Under current guidelines, intravenous thrombolysis is used to treat acute stroke only if it can be ascertained that the time since the onset of symptoms was less than 4.5 hours. We sought to determine whether patients with stroke with an unknown time of onset and features suggesting recent cerebral infarction on magnetic resonance imaging (MRI) would benefit from thrombolysis with the use of intravenous alteplase.
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            Using the amide proton signals of intracellular proteins and peptides to detect pH effects in MRI.

            In the past decade, it has become possible to use the nuclear (proton, 1H) signal of the hydrogen atoms in water for noninvasive assessment of functional and physiological parameters with magnetic resonance imaging (MRI). Here we show that it is possible to produce pH-sensitive MRI contrast by exploiting the exchange between the hydrogen atoms of water and the amide hydrogen atoms of endogenous mobile cellular proteins and peptides. Although amide proton concentrations are in the millimolar range, we achieved a detection sensitivity of several percent on the water signal (molar concentration). The pH dependence of the signal was calibrated in situ, using phosphorus spectroscopy to determine pH, and proton exchange spectroscopy to measure the amide proton transfer rate. To show the potential of amide proton transfer (APT) contrast for detecting acute stroke, pH effects were noninvasively imaged in ischemic rat brain. This observation opens the possibility of using intrinsic pH contrast, as well as protein- and/or peptide-content contrast, as diagnostic tools in clinical imaging.
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              A new class of contrast agents for MRI based on proton chemical exchange dependent saturation transfer (CEST).

              It has been previously shown that intrinsic metabolites can be imaged based on their water proton exchange rates using saturation transfer techniques. The goal of this study was to identify an appropriate chemical exchange site that could be developed for use as an exogenous chemical exchange dependent saturation transfer (CEST) contrast agent under physiological conditions. These agents would function by reducing the water proton signal through a chemical exchange site on the agent via saturation transfer. The ideal chemical exchange site would have a large chemical shift from water. This permits a high exchange rate without approaching the fast exchange limit at physiological pH (6.5-7.6) and temperature (37 degrees C), as well as minimizing problems associated with magnetic field susceptibility. Numerous candidate chemicals (amino acids, sugars, nucleotides, heterocyclic ring chemicals) were evaluated in this preliminary study. Of these, barbituric acid and 5, 6-dihydrouracil were more fully characterized with regard to pH, temperature, and concentration CEST effects. The best chemical exchange site found was the 5.33-ppm indole ring -NH site of 5-hydroxytryptophan. These data demonstrate that a CEST-based exogenous contrast agent for MRI is feasible.
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                Author and article information

                Contributors
                +46851770000 , anna.falk-delgado@neuroradkarolinska.se
                Journal
                Insights Imaging
                Insights Imaging
                Insights into Imaging
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                1869-4101
                23 August 2019
                23 August 2019
                December 2019
                : 10
                : 84
                Affiliations
                [1 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, Clinical neurosciences, , Karolinska Institutet, ; Stockholm, Sweden
                [2 ]ISNI 0000 0000 9241 5705, GRID grid.24381.3c, Department of Neuroradiology, , Karolinska University Hospital, ; Eugeniavägen 3, Solna, Stockholm, Sweden
                [3 ]ISNI 0000 0001 0930 2361, GRID grid.4514.4, Department of Clinical Sciences/Radiology, Faculty of Medicine, , Lund University, ; Lund, Sweden
                [4 ]ISNI 0000 0001 0930 2361, GRID grid.4514.4, Department of Medical Radiation Physics, , Lund University, ; Lund, Sweden
                [5 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Russell H. Morgan Department of Radiology and Radiological Science, School of Medicine, , Johns Hopkins University, ; Baltimore, MD USA
                [6 ]ISNI 0000000086837370, GRID grid.214458.e, Department of Radiology, , University of Michigan, ; Ann Arbor, MI USA
                [7 ]ISNI 0000 0004 1936 9457, GRID grid.8993.b, Department of Surgical Sciences, Radiology, , Uppsala University, ; Uppsala, Sweden
                Article
                771
                10.1186/s13244-019-0771-1
                6708018
                31444580
                3d79474e-bc50-485d-8ea9-dcdc2aabb822
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 7 February 2019
                : 12 July 2019
                Categories
                Critical Review
                Custom metadata
                © The Author(s) 2019

                Radiology & Imaging
                non-contrast-enhanced,gadolinium,area under curve,diagnostic performance,brain
                Radiology & Imaging
                non-contrast-enhanced, gadolinium, area under curve, diagnostic performance, brain

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