Chemical Exchange Saturation Transfer Research Articles

Angiopep-2, an MRI Biomarker, Dynamically Monitors Amyloid Deposition in Early Alzheimer's Disease.

The reliable and dynamic detection of amyloid β-protein (Aβ) deposition using imaging technology is necessary for preclinical Alzheimer's disease (AD), which may significantly improve prognosis. The present study aimed to evaluate the feasibility of applying angiopep-2 (ANG), a chemical exchange saturation transfer-magnetic resonance imaging (CEST-MRI) biomarker, for monitoring Aβ deposition in vivo. ANG exerted a good chemical exchange saturation transfer (CEST) effect and displayed a moderate binding affinity to Aβ1-42 in vitro. Six-month-old mice with AD injected with ANG exhibited a significantly enhanced CEST effect than controls in vivo; this effect gradually became more apparent at 8, 10, and 12 months. Spatial learning impairment caused by abundant Aβ deposition (representing mild cognitive impairment in AD patients) develops at 12 months in APPswe/PSEN1dE9 (line 85) AD mice. To conclude, the CEST of ANG could display very earlier age-related Aβ pathological progress in mice with AD, consistent with immunohistochemistry. ANG has extraordinary potential for clinical transformation as an imaging biomarker to diagnose early AD and track its progress dynamically and nonradiationally.

Glutamate alterations in the premature infant brain during different gestational ages with glutamate chemical exchange saturation transfer imaging: a pilot study.

To elucidate the change in glutamate levels in preterm infants at different gestational ages by glutamate chemical exchange saturated transfer (GluCEST) magnetic resonance imaging and to compare the difference in glutamate levels among different brain regions between very early preterm infants and middle and late preterm infants. Fifty-three preterm infants (59% males; median gestational age = 33.6 weeks) underwent MRI, including conventional MRI and GluCEST. The original data were postprocessed in MATLAB. Correlation analysis was used to determine the relationship between the MTRasym and gestational age. The differences in MTRasym signals among different ROIs were statistically analysed by one-way analysis of variance (ANOVA). The MTRasym difference of the bilateral hemispherical ROI was compared by a paired T test. In all ROIs, glutamate concentration was positively correlated with gestational age. The glutamate concentration in the thalamus was higher than that in the frontal lobe in very early, middle and late preterm infants. A difference in glutamate concentration was not found in the bilateral ROIs. The concentration of glutamate in the brains of preterm infants of different gestational ages increased with gestational age, which may be one of the factors contributing to the higher incidence of neurodevelopmental dysfunction in very early preterm infants compared to that in middle and late preterm infants. Meanwhile, the glutamate concentrations among different brain regions were also diverse. • The glutamate concentration was positively correlated with gestational age in preterm infants of the brain. • Glutamate concentrations were dissimilar in different brain regions of preterm infants. • Glutamate concentration during the process of brain development in premature infants was not found to be asymmetric.

Pathophysiology of Alzheimer’s disease revealed by chemical exchange saturation transfer MRI

Alzheimer’s disease (AD) is the most common neurodegenerative brain disorder that is characterized by the deposition of amyloid-β protein (Aβ) and neurofibrillary aggregates (tau). There is currently no cure for AD; however, early diagnosis and intervention may prevent progression to dementia. In addition to CSF and blood biomarkers, imaging techniques, such as PET, fMRI, volumetric MRI, and chemical exchange saturation transfer (CEST), have facilitated the early diagnosis of AD and provided essential information about the pathophysiology of AD. Indeed, CEST findings have helped clarify important aspects of the pathophysiology underlying AD. In this article we provide an in-depth review of different CEST applications, including endogenous CEST (APT, creatine-CEST, and glutamate-CEST) and exogenous CEST (angiopep2, glucose, and glymphatic system-related CEST), in further elucidating the pathophysiology of AD and discuss the potential of novel approaches.

Chemical Exchange Saturation Transfer MRI: What Neuro-Oncology Clinicians Need To Know.

Chemical exchange saturation transfer (CEST) is a relatively novel magnetic resonance imaging (MRI) technique with an image contrast designed for in vivo measurement of certain endogenous molecules with protons that are exchangeable with water protons, such as amide proton transfer commonly used for neuro-oncology applications. Recent technological advances have made it feasible to implement CEST on clinical grade scanners within practical acquisition times, creating new opportunities to integrate CEST in clinical workflow. In addition, the majority of CEST applications used in neuro-oncology are performed without the use gadolinium-based contrast agents which are another appealing feature of this technique. This review is written for clinicians involved in neuro-oncologic care (nonphysicists) as the target audience explaining what they need to know as CEST makes its way into practice. The purpose of this article is to (1) review the basic physics and technical principles of CEST MRI, and (2) review the practical applications of CEST in neuro-oncology.

Glucose exchange parameters in a subset of physiological conditions.

The chemical exchange of labile protons of the hydroxyl groups can be exploited in a variety of magnetic resonance experiments to gain information about the groups and their physicochemical environment. The exchangeable -OH protons provide important contributions to the T2 of water signals thus contributing to the T2-weighted contrast of MRI images. This exchange can be exploited more specifically and sensitively in chemical exchange saturation transfer (CEST) or longitudinal rotating frame relaxation (T1,ρ) experiments. Since glucose is omnipresent in living organisms, it may be seen as a rather universal probe. Even though the potential was first recognized many years ago, practical use has remained scarce due to numerous challenges. The major limitation is the rather low glucose concentration in most tissues. The other obstacles are related to multiple dependencies of the exchange parameters, such as temperature, pH, and concentration of various ions that are not known in sufficient detail for glucose. Thus, we embarked on evaluating the exchange parameters of a model that included every relevant chemical site for all -OH protons in both dominant enantiomers of glucose. We have (1) obtained conventional one-dimensional proton NMR spectra of glucose solutions in suitable temperature ranges, (2) we have iterated through several exchange models with various degrees of freedom determined by the number of distinguishable -OH proton sites and compared their performance, (3) we extrapolated the parameters of the best model of physiological temperature and (4) we demonstrated the use of the parameters in virtual experiments. As the main results, (1) we have obtained the temperature dependence of exchange parameters with reliable confidence intervals in three different pH values, with two of them reaching physiological temperature, and (2) we show how the parameters can be used in virtual experiments, helping to develop new applications for glucose as an NMR/MRI probe.

Effect of Saturation Pulse Duration and Power on pH-weighted Amide Proton Transfer Imaging: A Phantom Study.

Amide proton transfer (APT) imaging may detect changes in tissues' pH based on the chemical exchange saturation transfer (CEST) phenomenon, and thus it may be useful for identifying the penumbra in ischemic stroke patients. We investigated the effect of saturation pulse duration and power on the APT effect in phantoms with different pH values. Five samples were prepared from a 1:10 solution of egg-white albumin in phosphate-buffered saline at pH 6.53-7.65. The APT signal intensity (SI) was defined as asymmetry of the magnetization transfer ratio at 3.5 ppm. We measured the APT SIs in the egg-white albumin samples of different pH values with saturation pulse durations of 0.5, 1.0, 2.0, and 3.0 sec and saturation pulse powers of 0.5, 1.5, and 2.5 μT. The relative change in the APT SI in relation to the saturation duration and power at different pH values was defined as follows: (APT SI each saturation pulse - APT SI shortest or weakest pulse)/APT SIshortest or weakest pulse. The dependence of the APT SI on pH and the relative change in the APT SI were calculated as the slope of the linear regression. The lower the pH, the larger the relative change in the APT SI, due to the change in saturation pulse duration and power. The APT SI was highly correlated with the pH at all saturation pulse durations and powers. The influence of saturation duration and power on the APT effect was greater at lower pH than higher pH. The combination of saturation pulse ≥ 1.0 s and power ≥ 1.5 μT was useful for the sensitive detection of changes in APT effects in the egg-white albumin samples with different pH values.

Evaluation of the efficacy of creatine chemical exchange saturation transfer imaging in assessing testicular maturity.

Microscopic testicular sperm extraction is the most effective treatment for NOA, but the sperm retrieval rate is low and depends on testicular maturity. However, there are limited useful tests to assess testicular maturity. Chemical exchange saturation transfer (CEST) imaging is a new magnetic resonance imaging (MRI) technique that can image the distribution of trace substances in vivo. We focused on the potential role of creatine (Cr) in testes and hypothesized that Cr-CEST could indicate intratesticular spermatogenesis. We performed Cr-CEST by using 7T MRI on wild-type C57B6/J mice and several types of male infertility models such as Sertoli-cell only (SCO) (Kitw/Kitwv), maturation arrest (MA) (Zfp541 knockout mouse and Kctd19 knockout mouse), and teratozoospermia (Tbc1d21 knockout mouse). After performing Cr-CEST, histological analysis was performed. The SCO and MA models showed decreased CEST signal intensity (p < 0.05), while no reduction was observed in the teratozoospermia model (p=1.0). CEST signal intensity increased as the spermatogenesis stage progressed from the SCO model to the MA and teratozoospermia models. Furthermore, CEST signal intensity was reduced in 4-week-old wild-type mice with immature testes (p < 0.05). This study suggests that Cr-CEST evaluates intratesticular spermatogenesis noninvasively and provides a new therapeutic strategy for treating male infertility.

Tumor pH Imaging Using Chemical Exchange Saturation Transfer (CEST)-MRI.

Magnetic resonance imaging (MRI) is a noninvasive imaging technique that allows for physiological and functional studies of the tumor microenvironment. Within MRI, the emerging field of chemical exchange saturation transfer (CEST) has been largely exploited for assessing a salient feature of all solid tumors, extracellular acidosis. Iopamidol-based tumor pH imaging has been demonstrated to provide accurate and high spatial resolution extracellular tumor pH maps to elucidate tumor aggressiveness and for assessing response to therapy, with a high potential for clinical translation. Here, we describe the overall setup and steps for measuring tumor extracellular pH of tumor models in mice by exploiting MRI-CEST pH imaging with a preclinical MRI scanner following the administration of iopamidol. We address issues of pH calibration curve setup, animal handling, pH-responsive contrast agent injection, acquisition protocol, and image processing for accurate quantification and visualization of tumor acidosis.

Improving the potential of paraCEST through magnetic-coupling induced line sharpening

A paramagnetic chemical exchange saturation transfer (paraCEST) imaging agent based on a homodinuclear Ni(ii) complex exhibits enhanced CEST efficiency due to magnetic-coupling induced line sharpening effect.

Co(II) complexes of tetraazamacrocycles appended with amide or hydroxypropyl groups as paraCEST agents.

Co(II) complexes of 1,4,7,10-tetraazacyclododecane (CYCLEN) or 1,4,8,11-tetraazacyclotetradecane (CYCLAM) with 2-hydroxypropyl or carbamoylmethyl (amide) pendants are studied with the goal of developing paramagnetic chemical exchange saturation transfer (paraCEST) agents. Single-crystal X-ray diffraction studies show that two of the coordination cations with hexadentate ligands, [Co(DHP)]2+ and [Co(BABC)]2+, form six-coordinate complexes; whereas two CYCLEN-based complexes with potentially octadentate ligands, [Co(THP)]2+ and [Co(HPAC)]2+, are seven-coordinate with only three of the four pendant groups bound to the metal center. 1H NMR spectra of these complexes suggest that the six-coordinate complexes are present as a single isomer in aqueous solution. For the complexes which are seven-coordinate in the solid state, one is highly fluxional in aqueous solution on the NMR time scale ([Co(HPAC)]2+), whereas the NMR spectrum of [Co(THP)]2+ is consistent with an eight-coordinate complex with all pendants bound. Co(II) complexes of CYCLEN derivatives show CEST effects of low intensity that are assigned to NH or OH groups of the pendants. One complex, [Co(DHP)]2+, shows a highly-shifted CEST peak at 113 ppm versus bulk water, attributed to OH protons. However, the CEST effect is largest for two Co(II) CYCLAM-based complexes with coordinated amide groups that undergo NH proton exchange. All five complexes are inert towards dissociation in buffered solutions containing carbonate and phosphate and towards trans-metalation by excess Zn(II). These data give insight into the production of an intense CEST effect for tetraazamacrocyclic complexes with pendant groups containing NH or OH exchangeable protons. The intense and highly shifted CEST peak(s) of the CYCLAM-based complexes suggest that they are promising for further development as paraCEST agents.

Retracted: Angiopep-2 as an Exogenous Chemical Exchange Saturation Transfer Contrast Agent in Diagnosis of Alzheimer's Disease.

[This retracts the article DOI: 10.1155/2022/7480519.].

Accelerated and quantitative three-dimensional molecular MRI using a generative adversarial network.

To substantially shorten the acquisition time required for quantitative three-dimensional (3D) chemical exchange saturation transfer (CEST) and semisolid magnetization transfer (MT) imaging and allow for rapid chemical exchange parameter map reconstruction. Three-dimensional CEST and MT magnetic resonance fingerprinting (MRF) datasets of L-arginine phantoms, whole-brains, and calf muscles from healthy volunteers, cancer patients, and cardiac patients were acquired using 3T clinical scanners at three different sites, using three different scanner models and coils. A saturation transfer-oriented generative adversarial network (GAN-ST) supervised framework was then designed and trained to learn the mapping from a reduced input data space to the quantitative exchange parameter space, while preserving perceptual and quantitative content. The GAN-ST 3D acquisition time was 42-52 s, 70% shorter than CEST-MRF. The quantitative reconstruction of the entire brain took 0.8 s. An excellent agreement was observed between the ground truth and GAN-based L-arginine concentration and pH values (Pearson's r > 0.95, ICC > 0.88, NRMSE < 3%). GAN-ST images from a brain-tumor subject yielded a semi-solid volume fraction and exchange rate NRMSE of and , respectively, and SSIM of and , respectively. The mapping of the calf-muscle exchange parameters in a cardiac patient, yielded NRMSE < 7% and SSIM > 94% for the semi-solid exchange parameters. In regions with large susceptibility artifacts, GAN-ST has demonstrated improved performance and reduced noise compared to MRF. GAN-ST can substantially reduce the acquisition time for quantitative semi-solid MT/CEST mapping, while retaining performance even when facing pathologies and scanner models that were not available during training.

Grading of gliomas using 3D CEST imaging with compressed sensing and sensitivity encoding

PurposeWe evaluated the usefulness of three-dimensional (3D) chemical exchange saturation transfer (CEST) imaging with compressed sensing and sensitivity encoding (CS-SENSE) for differentiating low-grade gliomas (LGGs) from high-grade gliomas (HGGs). MethodsWe evaluated 28 patients (mean age 51.0 ± 13.9 years, 13 males, 15 females) including 12 with LGGs and 16 with HGGs, all acquired using a 3 T magnetic resonance (MR) scanner. Nine slices were acquired for 3D CEST imaging, and one slice was acquired for two-dimensional (2D) CEST imaging. Two radiological technologists each drew a region of interest (ROI) surrounding the high-signal-intensity area(s) on the fluid-attenuated inversion recovery image of each patient. We compared the magnetization transfer ratio asymmetry (MTRasym) at 3.5 ppm in the tumors among the (i) single-slice 2D CEST imaging (“2D”), (ii) all tumor slices of the 3D CEST imaging (3Dall), and (iii) a representative tumor slice of 3D CEST imaging (maximum signal intensity [3Dmax]). The relationship between the MTRasym at 3.5 ppm values measured by these three methods and the Ki-67 labeling index (LI) of the tumors was assessed. Diagnostic performance was evaluated with a receiver operating characteristic analysis. The Ki-67LI and MTRasym at 3.5 ppm values were compared between the LGGs and HGGs. ResultsA moderate positive correlation between the MTRasym at 3.5 ppm and the Ki-67LI was observed with all three methods. All methods proved a significantly larger MTRasym at 3.5 ppm for the HGGs compared to the LGGs. All methods showed equivalent diagnostic performance. The signal intensity varied depending on the slice position in each case. ConclusionsThe 3D CEST imaging provided the MTRasym at 3.5 ppm for each slice cross-section; its diagnostic performance was also equivalent to that of 2D CEST imaging.

WHO/ISUP grade and pathological T stage of clear cell renal cell carcinoma: value of ZOOMit diffusion kurtosis imaging and chemical exchange saturation transfer imaging.

To evaluate the value of ZOOMit diffusion kurtosis imaging (DKI) and chemical exchange saturation transfer (CEST) imaging in predicting WHO/ISUP grade and pathological T stage in clear cell renal cell carcinoma (ccRCC). Forty-six patients with ccRCC were included in this retrospective study. All participants underwent MRI including ZOOMit DKI and CEST. The non-Gaussian mean kurtosis (MK), mean diffusivity (MD), magnetization transfer ratio asymmetry (MTRasym (3.5 ppm)), and Ssat (3.5 ppm)/S0 were analyzed based on different WHO/ISUP grades and pT stages. Binary logistic regression was used to identify the best combination of the parameters. Pearson's correlation coefficients were calculated between CEST and diffusion-related parameters. The ADC, MD, and Ssat (3.5 ppm)/S0 values were significantly lower for higher WHO/ISUP grade tumors, whereas the MK and MTRasym (3.5 ppm) were higher in higher WHO/ISUP grade and higher pT stage tumors. MTRasym (3.5 ppm) combined with MD (AUC, 0.930; 95% CI, 0.858-1.000) showed the best diagnostic efficacy in evaluating the WHO/ISUP grade. MTRasym (3.5 ppm) and MK were mildly positively correlated (r = 0.324, p = 0.028). Ssat (3.5 ppm)/S0 wasmoderately positively correlated with ADC (r = 0.580, p < 0.001), mildly positively correlated with MD (r = 0.412, p = 0.005), and moderately negatively correlated with MK (r = -0.575, p < .001). The microstructural and biochemical assessment of ZOOMit DKI and CEST allowed for the characterization of different WHO/ISUP grades and pT stages in ccRCC. MTRasym (3.5 ppm) combined with MD showed the best diagnostic performance for WHO/ISUP grading. • Both diffusion kurtosis imaging (DKI) and chemical exchange saturation transfer (CEST) can be used to predict the WHO/ISUP grade and pathological T stage. • MTRasym (3.5 ppm) combined with MD showed the highest AUC (0.930; 95% CI, 0.858-1.000) in WHO/ISUP grading. • MTRasym at 3.5 ppm showed a positive correlation with mean kurtosis.

Amide Proton Transfer-Weighted Imaging Detects Hippocampal Proteostasis Disturbance Induced by Sleep Deprivation at 7.0 T MRI.

Sleep deprivation leads to hippocampal injury. Proteostasis disturbance is an important mechanism linking sleep deprivation and hippocampal injury. However, identifying noninvasive imaging biomarkers for hippocampal proteostasis disturbance remains challenging. Amide proton transfer-weighted (APTw) imaging is a chemical exchange saturation transfer technique based on the amide protons in proteins and peptides. We aimed to explore the ability of APTw imaging in detecting sleep deprivation-induced hippocampal proteostasis disturbance and its biological significance, as well as its biological basis. In vitro, the feasibility of APTw imaging in detecting changes of the protein state was evaluated, demonstrating that APTw imaging can detect alterations in the protein concentration, conformation, and aggregation state. In vivo, the hippocampal APTw signal declined with increased sleep deprivation time and was significantly lower in sleep-deprived rats than that in normal rats. This signal was positively correlated with the number of surviving neurons counted in Nissl staining and negatively correlated with the expression of glucose-regulated protein 78 evaluated in immunohistochemistry. Differentially expressed proteins in proteostasis network pathways were identified in the hippocampi of normal rats and sleep-deprived rats via mass spectrometry proteomics analysis, providing the biological basis for the change of the hippocampal APTw signal in sleep-deprived rats. These findings demonstrate that APTw imaging can detect hippocampal proteostasis disturbance induced by sleep deprivation and reflect the extent of neuronal injury and endoplasmic reticulum stress.

Enabling Characterisation of the NAD+ Biosynthesis Pathway via in vitro CEST MRI

AbstractBackgroundThe Chemical Exchange Saturation Transfer (CEST) MRI properties of six metabolites required for synthesis of coenzyme nicotinamide adenine dinucleotide (NAD+) and to evaluate the potential for clinical imaging of altered NAD+ regulation in neurodegenerative disordersMethodCEST images of metabolites in the NAD+ biosynthesis pathway were acquired at physiological temperature with high‐field MRI (9.4T) running a modified magnetisation transfer (MTR) prepared RARE sequence over a range of saturation powers and frequency ofsets, for pH values 5.5‐7.4. CEST data were fitted using spline interpolation, the exchange rate was calculated, and frequency specific MTR maps were generated using pixelwise analysis.ResultTryptophan, nicotinamide, nicotinic acid (NA), nicotinamide riboside (NR), nicotinamide mononucleotide (NMN) and NADH were evaluated. At pH 7.4, all molecules exhibited CEST contrast between 0.1 and 0.9 ppm, originating from the OH hydroxyl proton. NADH exhibited up to 15% CEST contrast in a B1 field of 2.4µT from its fast‐exchanging amine groups at 2 and 3 ppm, and showed a positive dependence of CEST efciency on pH. Tryptophan exhibited three independent peaks at 0.7, 2.6, and 5.4 ppm corresponding to pH 6.7, 5.5 and 7.4. NMN showed high CEST contrast at 0.7ppm originating from its phosphorous OH enabling higher CEST efciency due to enhanced charge delocalisation (Fig.1).ConclusionThis in vitro feasibility study demonstrates signal detection and characterization of NAD+ biosynthesis pathway precursor molecules over precise temperature, concentration and physiological pH ranges. All molecules exhibited a peak at 0.7 from the hydroxyl group with NMN showing highest CEST efficiency due to phosphate charge delocalisation. NADH showed a peak at 2 and 3ppm from amine group protons and a dependency on temperature and pH.

Low and asymmetrical hippocampal glutamate levels in healthy older adults

AbstractBackgroundGlutamate (Glu) is a critical molecule in cellular metabolism and the most abundant excitatory neurotransmitter in the brain. Glutamate dysfunction is common in neurodegenerative disorders—patients with Alzheimer’s disease (AD) have lower hippocampal glutamate—and likely contributes to age‐related declines in cognitive functioning. The extant literature on age‐related changes in brain Glu is small and all studies have employed proton spectroscopy. Thus, in this investigation we use a novel 7T magnetic resonanace imaging technique, Glutamate Chemical Exchange Saturation Transfer (GluCEST), to compare bilateral hippocampal brain Glu in between healthy old and young adults.MethodHippocampal GluCEST data were acquired from 14 healthy older adults [HOA; age: 71 (+/‐3)] and 10 young healthy adults [HYA; age: 21 (+/‐3)] using a Siemens 7T Terra. GluCEST data was acquired in axial slice positioned through bilateral hippocampus. Associations between MoCA scores and bilateral hippocampal GluCEST levels were investigated.ResultBilateral glutamate levels were 7% higher HYA as compared to HOA. HOA showed significant asymmetry (Left&gt;Right) within the hippocampus while GluCEST in HYA were equivalent across hemisphere (t(22)=2.37, p&lt;0.03). Within HOA, higher left hippocampal GluCEST levels were associated with higher performance on the MoCA [r(13)=0.55, p&lt;0.04].ConclusionGluCEST appears to be a marker of aging‐related neurological and cognitive change. The present findings are similar to previous findings in AD (Graff‐Radford et al., 2013) Moreover, the left‐right asymmetry in GluCEST aligns with recent translational studies indicating a left‐right dissociation in long‐term memory function, which may be partially mediated by asymmetries in glutamate receptor content (Shipton et al., 2014). This preliminary study is the first to compare GluCEST levels in young and older adults and is the first step towards elucidate age‐related trajectories of glutamatergic alterations and their relationship to clinical and cognitive phenotypes.

31P ParaCEST: 31P MRI-CEST Imaging Based on the Formation of a Ternary Adduct between Inorganic Phosphate and Eu-DO3A.

Development of the field of magnetic resonance imaging (MRI) chemical exchange saturation transfer (CEST) contrast agents is hampered by the limited sensitivity of the technique. In water, the high proton concentration allows for an enormous amplification of the exchanging proton pool. However, the 1H CEST in water implies that the number of nuclear spins of the CEST-generating species has to be in the millimolar range. The use of nuclei other than a proton allows exploitation of signals different from that of water, thus lowering the concentration of the exchanging pool as the source of the CEST effect. In this work, we report on the detection of a 31P signal from endogenous inorganic phosphate (Pifree) as the source of CEST contrast by promoting its exchange with the Pi bound to the exogenous complex 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (Pibound). The herein-reported results demonstrate that this approach can improve the detectability threshold by 3 orders of magnitude with respect to the conventional 1H CEST detection (considered per single proton). This achievement reflects the decrease of the bulk concentration of the detected signal from 111.2 M (water) to 10 mM (Pi). This method paves the way to a number of biological studies and clinically translatable applications, herein addressed with a proof-of-concept in the field of cellular imaging.

Simultaneous dynamic glucose-enhanced (DGE) MRI and fiber photometry measurements of glucose in the healthy mouse brain

Glucose is the main energy source in the brain and its regulated uptake and utilization are important biomarkers of pathological brain function. Glucose Chemical Exchange Saturation Transfer (GlucoCEST) and its time-resolved version Dynamic Glucose-Enhanced MRI (DGE) are promising approaches to monitor glucose and detect tumors, since they are radioactivity-free, do not require 13C labeling and are is easily translatable to the clinics. The main principle of DGE is clear. However, what remains to be established is to which extent the signal reflects vascular, extracellular or intracellular glucose. To elucidate the compartmental contributions to the DGE signal, we coupled it with FRET-based fiber photometry of genetically encoded sensors, a technique that combines quantitative glucose readout with cellular specificity. The glucose sensor FLIIP was used with fiber photometry to measure astrocytic and neuronal glucose changes upon injection of D-glucose, 3OMG and L-glucose, in the anaesthetized murine brain. By correlating the kinetic profiles of the techniques, we demonstrate the presence of a vascular contribution to the signal, especially at early time points after injection. Furthermore, we show that, in the case of the commonly used contrast agent 3OMG, the DGE signal actually anticorrelates with the glucose concentration in neurons and astrocytes.

Chemical Exchange Saturation Transfer Magnetic Resonance Imaging for Longitudinal Assessment of Intracerebral Hemorrhage and Deferoxamine Treatment at 3T in a Mouse Model.

Noninvasive imaging of molecular alterations after intracerebral hemorrhage (ICH) could provide valuable information to guide and monitor treatments. Chemical exchange saturation transfer (CEST) magnetic resonance imaging has demonstrated promises in identifying proliferation, necrosis, and changes in cellularity in brain tumors. Here, we applied CEST magnetic resonance imaging to monitor molecular changes in hematoma without and with treatment noninvasively over 2 weeks at 3T using endogenous contrast. CEST contrast related to proteins at 3.5 ppm (amide proton transfer) and proteins/lipids at -3.5 ppm (relayed nuclear overhauser effect [rNOE]) were examined over 14 days in a collagenase-induced ICH mouse model. Imaging findings were validated with immunohistochemistry based on the ICH neuropathology. We also examined iron-containing phantoms that mimicked iron concentrations in hematoma to ensure the iron will not attenuate the CEST contrast during disease progression. Based on the validity of the CEST contrast of hematoma, we further examined related molecular alterations under iron-chelation treatment with deferoxamine. We observed the temporal and spatial differences of CEST contrasts between rNOE at -3.5 ppm and amide proton transfer at 3.5 ppm, in which the core and perihematoma could be identified by rNOE on day 3 and day 14, and amide proton transfer on day 1, day 7, and day 14. Moreover, we observed a 25.7% significant reduction (P<0.05) of rNOE contrast after deferoxamine treatment to the ICH mice on day 3, which was not observable in amide proton transfer contrast. Our histology data indicated that rNOE primarily correlated with the myelin pathology, and amide proton transfer could reflect the cellularity increase at hematoma up to day 7. Significant rNOE changes correlated well with histologic findings, especially myelin lipids, and regional characteristics in hematoma indicate the uniqueness of CEST magnetic resonance imaging in monitoring molecular changes during ICH and treatment.