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1 17 Background: Indirect H-magnetic resonance (MR) imaging of O-labelled water allows imaging in vivo dynamic changes in water compartmentalisation. Our aim was to describe the feasibility of indirect H-MR methods to evaluate the effect of H O on the MR relaxation rates by using conventional a 3-T equipment and voxel-wise relaxation rates. Methods: MR images were used to calculate the R1, R2, and R2* relaxation rates in phantoms (19 vials with different H O concentrations, ranging from 0.039 to 5.5%). Afterwards, an experimental animal pilot study (8 rats) was designed to evaluate the in vivo relative R2 brain dynamic changes related to the intravenous administration of O-labelled water in rats. Results: There were no significant changes on the R1 and R2* values from phantoms. The R2 obtained with the −1 turbo spin-echo T2-weighted sequence with 20-ms echo time interval had the higher statistical difference (0.67 s , interquartile range 0.34, p < 0.001) and Spearman correlation (rho 0.79). The R2 increase was adjusted to a linear fit between 0.25 and 5.5%, represented with equation R2 = 0.405 concentration + 0.3215. The highest significant differences were obtained for the higher concentrations (3.1–5.5%). The rat brain MR experiment showed a mean 10% change in the R2 value after the H O injection with progressive normalisation. 1 17 Conclusions: Indirect H-MR imaging method is able to measure H O concentration by using R2 values and conventional 3-T MR equipment. Normalised R2 relative dynamic changes after the intravenous injection of a H O saline solution provide a unique opportunity to map water pathophysiology in vivo, opening the analysis of aquaporins status and modifications by disease at clinically available 3-T proton MR scanners. Keywords: Brain, Magnetic resonance imaging, Oxygen-17, Phantoms (imaging), Rats * Correspondence: marti_lui@gva.es Biomedical Imaging Research Group (GIBI230) at La Fe Health Research Institute and Imaging La Fe node at Distributed Network for Biomedical Imaging (ReDIB) Unique Scientific and Technical Infrastructures (ICTS), La Fe University and Polytechnic Hospital, Av. Fernando Abril Martorell, 106, Torre E, Planta 0, 46026 Valencia, Spain Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Martí-Bonmatí et al. European Radiology Experimental (2021) 5:56 Page 2 of 9 Key points due to its low gyromagnetic ratio and scarcity, which makes it difficult to quantify using direct techniques be- H O concentrations modify R2 values in cause of the poor signal-to-noise ratio and lower spatial conventional standard-of-care H 3-T magnetic resolution [2, 11]. The cost and complexity of these indir- resonance equipment. ect studies limit its widespread use. 17 1 Normalised R2 relative dynamic changes after the Fortunately, O slightly shortens the H-MR transver- intravenous injection of a H O saline solution sal relaxation times (T2) of water due to the coupling of 1 17 17 provide a unique opportunity to map water H and O spins [1, 10]. In this way, O can be also pathophysiology in vivo. detected by the widely used H-MR imaging T2 or T2* The relationship between R2 and H O sequences with greater overall sensitivity [10, 12]. To concentration was found to be linear with an initial further simplify the MR acquisition and open new in- threshold at 0.2%. sights, O can be incorporated within water molecules 17 17 17 A mean 10% change in the R2 value after the H O (H O, also known as O-labelled water), allowing im- 2 2 injection was shown in rats, with posterior aging human pathophysiology by the analysis of water stabilisation. compartmentalisation. The O-labelled water visualisa- tion can be achieved not only as the end product of the Background O inhalation and respiration process, as described pre- 16 17 18 17 Oxygen has three stable isotopes: O, O and O, viously, but also mainly after a H O bolus injection 16 17 17 being O by far the largest component. O natural [13]. As the amount of metabolically generated H O abundance is only 0.037% [1], being the only oxygen during O inhalation is small and variable [3], indirect 1 17 nuclei with gyromagnetic ratio (γ = 5.77 MHz/T) and a H-MR O-labelled water imaging remains the best op- half-integer spin of 5/2 [2]. These properties allow tion in clinical practice. Indirect H O MR imaging magnetic resonance (MR) experiments to detect O, might allow to visualise the dynamics of administered although the relaxation times of O are much shorter water distribution within tissues. 1 17 than those of the hydrogen isotope ( H) [3, 4]. Interest- H O MR images can be obtained using T2-weighted ingly, O molecules are not detectable by MR neither sequences [10, 14] although proton T2 relaxation ratio in gas form nor dissolved in water or within oxyhaemo- maps might also afford an objective quantitative approach. globin due to their strongly paramagnetic property [5]. This information might be crucial in many diseases, in- The direct observation of O has several limits for cluding oncology, inflammatory and degenerative diseases clinical implementation [1, 3]. Inhaled O administra- as aquaporins, a membrane water channels responsible for tion and distribution have been studied with special coils transmembrane water passage, are altered in these patho- adjusted to the precession frequency of O. Multinu- logical situations [15, 16]. clear MR units are restricted mainly for experimental The aim of the study is to verify, by means of both purposes, needing specific transmission-reception coils phantom and experimental animal studies, the feasibility 17 1 tuned to the O resonance frequency and ultrashort of indirect H-MR methods to evaluate the effect of 17 17 echo time pulse sequences [1]. The in vivo O-MR im- H O on the MR relaxation rates by using conventional ages are obtained at ultrahigh fields (B of 9.4 and 7 T) 3 Tesla MR imaging equipment and voxel-wise relax- [1, 3] but also at clinically used magnetic fields (B of 1.5 ation rates. and 3 T) [6, 7]. 17 1 O can be also detected by H-MR when it is bound Methods to protons such as in water molecules (H O). It is very First, different MR pulse sequences able to measure tis- useful because the metabolically derived H O could be sue relaxation times in standard-of-care MR clinical 1 17 indirectly quantified by H-MR [8]. The Oconsumption scanners were evaluated to select the one able to depict rate, i.e, cerebral metabolic rate of oxygen consumption H-MR relaxation rate changes related to the presence (CMRO ), can be determined by the inhalation of up to of H O in vials with different concentration samples. 2 2 70% enriched O via MR-compatible efficient ventilator Then, a pilot experimental animal study was performed devices. These indirect CMRO measurements from low- to in vivo evaluate the tissue dynamic changes related to resolution MR images with low signal-to-noise ratios have the intravenous administration of the labelled water in been already obtained in a small number of animal and rats. patients studies during experimental conditions [1, 7, 9]. In real practice, oxygenation has large uncertainties as the MR imaging chemical environment proportions are largely unknown, H-MR exams were performed on a 3-T Philips Achieva 17 1 introducing biases in Odetectability by H-MR [10]. TX standard-of-care clinical system (Philips Healthcare, 17 1 The MR signal induced by Oisweak compared to H Best, The Netherlands) within our experimental research Martí-Bonmatí et al. European Radiology Experimental (2021) 5:56 Page 3 of 9 platform. An eight-channel array receive surface coil was The rats were positioned on prone position inside the used for the phantom studies and an eight-channel vol- wrist coil. The multi-echo turbo spin-echo (TSE) ume wrist coil was employed for the rat studies. sequence with 20-ms echo time intervals was selected The T1, T2*, and T2 relaxation times and respective according to the phantom results (higher changes and relaxation rates were calculated from the H O phan- rho Spearman correlation coefficient) with the following toms. Details of the T1, T2*, and T2 MR sequences are 8 echo times: 20, 40, 60, 80, 100, 120, 140, and 160 ms. summarised in Table 1. A venous tail cannula was used to slowly inject H O to the rats after the baseline MR acquisition. The Phantom study volumes of the 70% H O saline solution were selected The in-house phantom consisted of a cylinder con- according to the weight of each rat to achieve an intra- taining 13 internal holes into which 50 mL vials vascular dose of 4.6%, assuming a rat blood volume of could be inserted. Different concentrations of 65 mL/kg and according to the phantom results and 17 17 enriched H O water were used to prepare the saline similar previous studies [13]. The H O concentration 2 2 solution by adding sodium chloride to 0.9% (Fig. 1). injected to the rats was the one with the highest statis- Nineteen vials were prepared with increasing H O tical differences with the saline solution (0.037%). The concentrations: 0.037 (natural abundance), 0.043, injection duration lasted 30 s plus a small bolus of 1 mL 0.045, 0.050, 0.074, 0.093, 0.145, 0.245, 0.491, 0.881, of standard saline, which also lasted 30 s. 1.270, 1.603, 2.0, 2.5, 3.1, 3.8, 4.6, 5.5, and 6.5%. Be- The concatenated dynamic multiecho MR acquisitions cause there were more vials than holes in the cylin- consisted of a baseline acquisition and 82 consecutive der, two phantoms were used, each one with a series immediately after the slow H O injection. Each different set of H O concentrations. dynamic series lasted 3 min and the overall sequence All prepared phantoms with the different set of H O duration was 246 min. concentrations had three tubes of standard saline fluid The experimental protocols were approved by the In- as control, representing the 0.037% natural abundance of stitutional Animal Ethics Committee of our Research In- H O (20.56 μmol/g of water) [3, 10]. The two phan- stitute and performed in accordance with our national toms were exam 30 times with the three MR sequences and institutional regulations. for the R1, R2*, and R2 calculations. The location of the phantom was slightly different in each acquisition, in Image analysis order to average the inhomogeneity of RF and coil sensi- MR images from phantoms and rats were acquired tivity in the acquired images. in Digital Imaging and Communications in Medicine, DICOM, format and converted into Neuroimaging Animal study Informatics Technology Initiative, NIFTI, format Eight female Wistar rats (mean weight, 292 ± 32 g, files. All images were processed and analysed using mean ± standard deviation) were initially anaesthe- an in-house software application developed in tised with isoflurane (5%) using an induction box. MATLAB release 2018b (Mathworks Inc., Natick, During the MR acquisition, rats kept anaesthetised MA, USA) to perform the quantitative R1, R2*, and with sevoflurane (3%) through a face mask. R2 analysis of each acquisition. Table 1 Magnetic resonance sequences used for the relaxation times calculations Sequences Echo time (TE); repetition time (TR) Flip angle Acquisition SENSE acceleration matrix; voxel factor; number of size (mm) acquisitions Three-dimensional TE = 4.6 ms; TR = 14 ms 5 different 192 × 192 × 15; 1.88 × 1.88 × 5 2; 1 T1-weighted (5°, 10°, 15°, 20° gradient-echo with and 45°) variable flip angle Two-dimensional TR = 13; 12 TEs. Two different acquisitions with 10° 96 × 96 × 13; 1.88 × 1.88 × 5 1.8; 1 T2*-weighted different echo time intervals (1, 2, 3, 4, 5, 6, 7, 8, gradient-echo 9, 10, 11, 12 ms; and 15, 17.8, 20.6, 23.4, 26.2, 29, 31.8, 34.6, 37.4, 40.2, 43, 45.8 ms) Two-dimensional TR = 800; 8 TEs. Four different acquisitions with 90° 96 × 96 × 1; 1.67 × 1.67 × 5 1; 1 T2-weighted turbo different echo time intervals (10, 20, 30, 40, 50, spin-echo 60, 70, 80 ms; 20, 40, 60, 80, 100, 120, 140, 160 ms; 40, 80, 120, 160, 200, 240, 280, 320 ms; 50, 100, 150, 200, 250, 300, 350, 400 ms) SENSE Sensitivity encoding parallel imaging method Martí-Bonmatí et al. European Radiology Experimental (2021) 5:56 Page 4 of 9 Fig. 1 Phantom (a), magnetic resonance images (b), and T2 parametric maps (c) obtained in the study with the automated regions-of-interest selection within the tubes Relaxation rates calculation from the in vitro phantom The in vivo image analysis of the rats’ brains was experiments were performed to demonstrate the influ- calculated only for the R2 relaxation rate, as this was 17 17 ence of different H O concentrations on the different the one with a relationship with H Opresenceand 2 2 magnetic relaxation rates (R1, R2*, and R2). The phan- quantity. The processing pipeline for all the rats in- tom processing pipeline included an automatic detection cluded a manual segmentation of the brain at the of a circular region of interest within the vials, with an central slice of the multi-echo T2-weighted sequence. area of 118 mm , located at the centred 5 slices (Fig. 1). The T2 relaxation time values were obtained voxel by The T1-weighted variable flip angles images were fitted voxel and the R2 (1/T2) parametric maps were to the signal intensity equation (Equation 1) for GRE calculated. Also, the relative R2 decay, expressed as sequences to extract the longitudinal relaxation T1 and the ratio between the R2 value before (PRE) and after derived R1 (1/T1) map [17]. The GRE equation function (POST) contrast administration and normalised to the was used to fit and extract T1 values. R2 PRE value, were obtained for all the time points after the contrast administration following the expres- TR 1 sion: (R2POST minus R2PRE)/R2PRE. Normalised ra- 1−e M ðÞ θ ¼ M sinðÞ θ ð1Þ z n 0 n TR − tios were also used to calculate the parametric maps 1− cosðÞ θ e for the first time point, obtained 3 min after the end of the intravenous labelled water administration, as M , magnetisation in balance when the net magnetisa- this was the one with a maximum change in the re- tion vector points in the direction of the applied mag- laxation ratio. netic field B ; T1, time elapsed until the difference between longitudinal magnetisation (M ) and its equilib- Statistical analysis rium value (M ) is reduced by an e factor; TR, repetition The statistical comparisons for signal change, O-la- time; θ , tilt angle. belled water concentration and MR sequences were On the other hand, an exponential model [18] was performed with SPSS®, version 24.0 (IBM, NY, USA). adjusted to pixel intensities echo by echo by curve fitting Results were obtained as the median and interquartile to generate the T2* and T2 maps (Fig. 1). All fitting range (IQR) of the ratios all over the concentration processes were obtained using the Levenberg-Marquardt values and for the different relaxation ratios. The nor- algorithm. The GRE and spin echo equation functions mality of the distributions was evaluated with the (Equation 2) were used to fit and extract T2* and T2 Shapiro-Wilk test. The Spearman rho correlation co- values, SI being the voxel signal intensity. For the accur- efficients between in vitro concentrations and relax- ate quantification of T2, all echoes were used. ation ratios were also calculated. A Games-Howell TE TE − − post hoc test to detect statistical differences for the T2 T2 SI ¼ ke and SI ¼ ke ð2Þ relaxation ratios values between concentrations was The R1, R2*, and R2 ratio values were then obtained used. A p value lower than 0.05 was considered indi- (1/relaxation time) by pixel wise averaging. cative of a statistically significance. Martí-Bonmatí et al. European Radiology Experimental (2021) 5:56 Page 5 of 9 Results TSE T2-weighted sequence with 20-ms echo time inter- MR sequence selection for the indirect H O imaging val. The first 9 lowest concentrations did not show a and quantitation statistical difference with the natural abundance 0.037% 17 17 The influence of the different H O concentrations on H O concentration. The highest significant R2 differ- 2 2 R1, R2 and R2* values were evaluated 30 times with all ences were obtained for the higher concentrations (3.1– the H O steps (from 0.037% to 6.5%). The distribu- 5.5%). The R2 reached the highest value at the higher tions were not normal for the R1, R2*, and R2 experi- 5.5% concentration. The R2 increase was adjusted to a ments (Shapiro-Wilk test, p < 0.001). linear fit between 0.25% and 5.5%, represented with the There were no statistically significant changes on the following equation: R1 values with increasing H O concentrations between −1 −1 any concentration (0.48 s , IQR 0.24 s ). The Spear- R2 ¼ 0:405 Concentration þ 0:3215 man correlation was low (rho = 0.148) with no signifi- cant changes on R1 with the different-labelled water concentrations (p = 0.075, Games-Howell post hoc test). Similar results were obtained for the R2* experiments H O concentration selection −1 and the two sequences having different echo time inter- Boxplots of the R2 relaxation rates (s ) obtained from −1 −1 vals. R2* values (17.31 s , IQR 27.87 s ) showed a low the multi-echo TSE sequence with 20-ms TE interval Spearman correlation coefficient (rho = 0.36) and no acquisitions of the two phantoms for all the labelled statistically significant changes between the different water concentration are shown in Fig. 2.The R2 relax- concentrations were observed (p = 0.739). ation ratios showed a linear signal adjustment as the However, the R2 relaxation rate values showed a statis- H O concentration increases between 0.25 and 5.5%. tically significant linear increase with increasing H O The concentrations with a highest statistical difference concentration. The R2 value obtained with the TSE se- (p values < 0.001) from the saline solution were from quence using 40 ms echo interval showed a significant 3.1 to 5.5%. In this sense, the pairwise comparisons also −1 change (p < 0.001) with concentration (0.57 s , IQR showed the highest significant difference (p values < −1 0.133 s ) and an increased in the Spearman correlation 0.001) between the five higher concentrations (3.1– coefficient (rho = 0.539). The R2 having the higher stat- 5.5%). Any of these five concentrations could therefore −1 −1 istical difference (0.67 s , IQR 0.34 s , p < 0.001) and be used in the rats’ experiments to measure the induced Spearman correlation (rho = 0.79) was obtained with the relaxation time R2 changes of the tissues. Fig. 2 Boxplot of the R2 relaxation rates and H O concentrations as measured with the phantom studies. The linear fitting and equation are shown 2 Martí-Bonmatí et al. European Radiology Experimental (2021) 5:56 Page 6 of 9 Animal studies Our phantom study demonstrates that an increased For the animal studies, the multi-echo TSE sequence concentration of H O results in an increase in the with 20-ms TE interval was selected for its highest sig- R2 relaxation rate, which was also confirmed in the nal. The H O selected dose was chosen according with experimental animal study. These results endorse the the weight of the rat to have a final intravascular solu- indirect correlation between the H O concentration tion of 4.6% (from an expected 20 mL of blood per rat). and R2 values [3] and the absence of R1 modifica- This dose and concentration were obtained by using the tions [14, 19, 20]. The non-significant correlation 70% enriched H O vial. This value was close to the found with R2* values was not published before. highest one in the phantom studies and was selected to Although R2 linear relationships were obtained in guarantee to observation of signal changes. No animal previous studies [19], the relationship found in this showed any clinically evident adverse effect related to study used a higher concentration range and showed the 70% enriched H O administration. a linear behaviour between 0.25 and 5.5%. This 0.25% In Fig. 3, the evolution curves of R2 value normalised threshold was not reported before [19]. to the baseline R2 value for each rat is shown. This Most research groups have used mainly T2-weighted curve shows a mean 10% change in the R2 value imme- steady-state free precession and echo-planar sequences, diately after the H O was injected into the rat to a with or without radiofrequency irradiation to remove 1 17 gradual decrease towards baseline R2 values. Figure 4 the residual H- O scalar coupling [20, 21]. However, shows R2 maps of a rat’s brain at baseline and after in- our multi-echo TSE T2-weighted sequences allow to jection of H O. In addition, it also shows the R2 values obtain high spatial resolution R2 relaxation rate normalised to the baseline. parametric maps and normalised R2 variation maps, probably improving more objective correlations. Other Discussion experiments using T1ρ weighted images for dynamic 17 1 Although not in clinical use, O is a natural magnetic H-MR analysis of perfusion have also been published, isotope that allows enriched labelled water to be traced but not replicated [22, 23]. by standard of care MR imaging. Our study shows that The R2 relaxation rate measurement allows to observe an indirect H-MR imaging method is able to measure the correlation to labelled water concentrations. The re- 17 17 H O-related changes by using R2 ratios from conven- lationship between the different H O concentrations 2 2 tional MR equipment and sequences. and R2 values allows a depiction of injected water in the Fig. 3 Mean relative normalised R2 values of the rat brain over the 246 min. Time 0 corresponds to the precontrast magnetic resonance images Martí-Bonmatí et al. European Radiology Experimental (2021) 5:56 Page 7 of 9 Fig. 4 R2 parametric maps of the rat brain before (PRE), after (3 min, POST1) and relative normalised change (R2POST1 minus R2PRE)/R2PRE). The normalised R2 changes reflect the local distribution of labelled water range between 0.25 and 5.5% by the change in the relax- Patients’ safety must be considered with this contrast 17 17 ation rate. The dependence of the H O concentration agent. O is a weak proton-relaxing agent that must be and R2 relaxation rate has also been experimentally used at relatively high concentrations (4–5%). As ex- proven in biological solutions up to 5% enrichment [3]. pected, there is no publication reflecting that H Ois Our results using the R2 relaxation rate can be more different in toxicity than ordinary water, being a natural consistent than previously published methods using bal- constituent of all living systems. anced steady state T2/T1 and T1ρ-weighted sequences. The relative R2 variations can be converted into Although balanced steady-state free precession and H O concentration changes in a voxel-by-voxel ap- echo-planar imaging sequences have been used in MR proach (see Fig. 4). The R2 dynamic acquisition would animal and human experiments, our R2 calculation allow the pharmacokinetic modelling analysis of the sig- approach by using a multi-echo TSE sequence seems to nal behaviour to assess the movement of labelled water be sensitive to small changes, being able to discriminate within the different compartments after H O-enriched between a range (0.25–5.5%) of concentrations at a cost physiological saline solution administration [14]. Mole- of a lower temporal resolution (3 min per dynamic cules that integrate living organisms, such as ions, sugars series) [20]. The signal change and spatial resolution of or proteins are dissolved in an aqueous medium. Cells R2 maps allow to evaluate water kinetics in different exchange molecules through their membranes using organs and structures with 3-T magnets [6, 12, 14]. mechanisms such as passive diffusion or specific trans- Assuming that humans have a 60% total body water, port and channel proteins. The movement of water into an intravascular concentration of H O around 4.5% and out of cells is a fundamental biological process that can be obtained by injecting 2 mL/kg body weight of is essential for life. The water molecule is neutral, water 70% enriched H O vial (38.43 molar), taking into con- movement across the cell membrane being not just by sideration a mean total body water volume of 42 L, 3 L simple diffusion but mainly by water channels. These of intravascular water, and 11 L of interstitial water. proteins were originally named CHIP28 (“channel-form- Therefore, R2 relaxation rate parametric images might ing integral protein”), but they are now known as aqua- allow to depict the injected water distribution dynamics porins (AQP) [15, 16]. These membrane water channels in clinical practice. To be used, the barrier to overcome have currently 13 different forms in mammals. AQP is the high cost of manufacturing H O. Unless a have a critical role in preserving cell stability and integ- cheaper process is available, close to 900€/mL of 70% rity all over the body [16, 25]. Functional in vivo studies enriched solution clearly limits its clinical use (data pro- of the AQP using a non-invasive technique, such as vided by NUKEM Isotopes GmbH, Germany). As an al- H O labelled MR imaging and R2 parametric maps, ternative, oxygen transfer by peroxides (H O ) has been could offer a unique relevant opportunity for the depiction 2 2 proposed as a low-cost method for O synthesis, of AQP changes resolved in space (R2 variation paramet- amongst others [24]. Relaxometry protocols are more ric maps) and time (dynamic and follow-up studies) [14]. sensitive so smaller changes in R2 will also allow to Although AQP can be histologically evaluated, in vivo measure lower H O concentrations. AQP dynamic kinetics modifications induced by disease, 2 Martí-Bonmatí et al. European Radiology Experimental (2021) 5:56 Page 8 of 9 including degeneration and cancer proliferation, cannot standard-of-care MR scanners without dedicated hard- be evaluated without the use of a water tracer [15, 16]. It ware. Detection of intravenous administered H O seems therefore reasonable to further improve the R2 dynamics could potentially provide new insights into maps methodology avoiding possible biases, providing im- water distribution. Normalised R2 dynamic changes after ages with even smaller voxel size, and sampling the water the intravenous injection of H O saline solution add dynamic changes faster. Expected areas of specific interest important insights into the in vivo evaluation of water for this analysis are related to a wide variety of diseases, kinetics modifications by disease at clinically available 3-T including cancer, renal dysfunction, neurological disorder, MR scanners. epilepsy, metabolic syndrome, infection, and cardiac dis- Abbreviations eases [25]. AQP: Aquaporins; CMRO : Cerebral metabolic rate of oxygen; GRE: Gradient- A possible bias in the quantitation of H O with the echo; IQR: Interquartile range; MR: Magnetic resonance; R1: Relaxation rate 1 17 T1; R2*: Relaxation rate T2*; R2: Relaxation rate T2; TE: Echo time; indirect method is that both H- O scalar coupling and TR: Repetition time; TSE: Turbo spin-echo 17 16 chemical exchange between H O and H O are sensi- 2 2 tive to pH and temperature [3]. However, the use of a Acknowledgements The authors thank NUKEM Isotopes GmbH, Alzenau, Germany, for providing normalised R2 change ratio minimised this bias. Also, as the enriched 20 and 70% H O vials. We also want to thank Grupo Juste, the rats in the in vivo experiment might change their Madrid, Spain, for kindly supporting this study. temperature by a few degrees, and this might slightly in- Authors’ contributions fluence R2, we do believe that this variation will have a Luis Marti-Bonmati: Conceptualisation, methodology, resources, writing ori- minimal impact on the calculated relaxation rates. One ginal draft, writing review and editing, supervision, project administration, main advantage of intravenous administrated H O funding acquisition. Alejandro Rodríguez-Ortega: Methodology, software, for- mal analysis, investigation, resources, data curation, writing—review and edit- over the inhalation of O is that the amount of ing. Amadeo Ten-Esteve: Formal analysis, investigation, writing—review and 17 17 metabolically generated H O from O inhalation is 2 2 editing. Angel Alberich-Bayarri: Conceptualisation, methodology, writing—re- unknown and usually less than the amount of adminis- view and editing. Bernardo Celda: Writing—review and editing. Eduardo Fer- rer: Conceptualisation, writing—review and editing, visualisation, supervision, trated H O[3]. Although field strength can be a limit- funding acquisition. The author(s) read and approved the final manuscript. ing factor, fortunately the use of indirect methods requires lower magnetics fields than direct methods to Funding Internal funding by the research group the quantification H O[3]. Also, the achieved spatial resolution can be considered sufficient (1.67 × 1.67 mm Availability of data and materials in plane) (see Fig. 4), but the temporal resolution was The data generated and/or analysed during the current study are not publicly available due institutional limitations but are available from the limited due to the long TR and TE multi-echo sequence. corresponding author on reasonable request. A much faster resolution might be required for a de- tailed examination of water kinetics in small structures. Declarations Maybe the use of accelerated artificial intelligence driven Ethics approval and consent to participate sequences will help to avoid this limitation. The experimental protocols were approved by the Institutional Animal Ethics This study had some other limitations that should be Committee of our Research Institute and performed in accordance with our national and institutional regulations. considered. First, the number of rats in this work is re- duced. Second, our study only evaluated relaxation rates Consent for publication using variable flip angles sequences, GRE and TSE for Not applicable. measure T1, T2*, and T2, respectively. Other alternative Competing interests methods, such as saturation/inversion recovery se- The authors declare that they have no competing interests. quences with variable TI, should be investigated. Unfor- tunately, estimating the H O concentrations from the Author details Biomedical Imaging Research Group (GIBI230) at La Fe Health Research change in R2 values is quite challenging. Although a Institute and Imaging La Fe node at Distributed Network for Biomedical change in R2 value can be extrapolated to a H O con- Imaging (ReDIB) Unique Scientific and Technical Infrastructures (ICTS), La Fe centration, we did prefer to normalise this change to the University and Polytechnic Hospital, Av. Fernando Abril Martorell, 106, Torre E, Planta 0, 46026 Valencia, Spain. Quantitative Imaging Biomarkers in precontrast R2 to standardise measurements. These nor- Medicine, QUIBIM SL, Valencia, Spain. Physical Chemistry Department, malised results will allow the validation with other MR University of Valencia, Valencia, Spain. Radiotherapy Department, Hospital equipment and vendors. It will be relevant to evaluate Clínico Universitario, Valencia, Spain. the best approach (normalised ratios versus concentra- Received: 23 June 2021 Accepted: 4 October 2021 tions) regarding reproducibility and explainability of results. References In summary, we have provided proof of concept that 1. Hoffmann SH, Begovatz P, Nagel AM, et al (2011) A measurement setup for 1 17 H-MR images allow to detect O-enriched H O mole- 17 direct O MRI at 7 T. Magn Reson Med 66:1109–1115. https://doi.org/10.1 cules by the induced changes in R2 of water protons at 002/mrm.22871 Martí-Bonmatí et al. European Radiology Experimental (2021) 5:56 Page 9 of 9 2. 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European Radiology Experimental – Springer Journals
Published: Dec 29, 2021
Keywords: Brain; Magnetic resonance imaging; Oxygen-17; Phantoms (imaging); Rats
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