Whole-cerebrum guanidino and amide CEST mapping at 3 T by a 3D stack-of-spirals gradient echo acquisition.

PURPOSE: To develop a 3D, high-sensitivity CEST mapping technique based on the 3D stack-of-spirals (SOS) gradient echo readout, the proposed approach was compared with conventional acquisition techniques and evaluated for its efficacy in concurrently mapping of guanidino (Guan) and amide CEST in human brain at 3 T, leveraging the polynomial Lorentzian line-shape fitting (PLOF) method. METHODS: Saturation time and recovery delay were optimized to achieve maximum CEST time efficiency. The 3DSOS method was compared with segmented 3D EPI (3DEPI), turbo spin echo, and gradient- and spin-echo techniques. Image quality, temporal SNR (tSNR), and test-retest reliability were assessed. Maps of Guan and amide CEST derived from 3DSOS were demonstrated on a low-grade glioma patient. RESULTS: The optimized recovery delay/saturation time was determined to be 1.4/2 s for Guan and amide CEST. In addition to nearly doubling the slice number, the gradient echo techniques also outperformed spin echo sequences in tSNR: 3DEPI (193.8 ± 6.6), 3DSOS (173.9 ± 5.6), and GRASE (141.0 ± 2.7). 3DSOS, compared with 3DEPI, demonstrated comparable GuanCEST signal in gray matter (GM) (3DSOS: [2.14%-2.59%] vs. 3DEPI: [2.15%-2.61%]), and white matter (WM) (3DSOS: [1.49%-2.11%] vs. 3DEPI: [1.64%-2.09%]). 3DSOS also achieves significantly higher amideCEST in both GM (3DSOS: [2.29%-3.00%] vs. 3DEPI: [2.06%-2.92%]) and WM (3DSOS: [2.23%-2.66%] vs. 3DEPI: [1.95%-2.57%]). 3DSOS outperforms 3DEPI in terms of scan-rescan reliability (correlation coefficient: 3DSOS: 0.58-0.96 vs. 3DEPI: -0.02 to 0.75) and robustness to motion as well. CONCLUSION: The 3DSOS CEST technique shows promise for whole-cerebrum CEST imaging, offering uniform contrast and robustness against motion artifacts.

Exploring neurodegenerative disorders using advanced magnetic resonance imaging of the glymphatic system.

The glymphatic system, a macroscopic waste clearance system in the brain, is crucial for maintaining neural health. It facilitates the exchange of cerebrospinal and interstitial fluid, aiding the clearance of soluble proteins and metabolites and distributing essential nutrients and signaling molecules. Emerging evidence suggests a link between glymphatic dysfunction and the pathogenesis of neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's disease. These disorders are characterized by the accumulation and propagation of misfolded or mutant proteins, a process in which the glymphatic system is likely involved. Impaired glymphatic clearance could lead to the buildup of these toxic proteins, contributing to neurodegeneration. Understanding the glymphatic system's role in these disorders could provide insights into their pathophysiology and pave the way for new therapeutic strategies. Pharmacological enhancement of glymphatic clearance could reduce the burden of toxic proteins and slow disease progression. Neuroimaging techniques, particularly MRI-based methods, have emerged as promising tools for studying the glymphatic system in vivo. These techniques allow for the visualization of glymphatic flow, providing insights into its function under healthy and pathological conditions. This narrative review highlights current MRI-based methodologies, such as motion-sensitizing pulsed field gradient (PFG) based methods, as well as dynamic gadolinium-based and glucose-enhanced methodologies currently used in the study of neurodegenerative disorders.

Deep-learning-based super-resolution for accelerating chemical exchange saturation transfer MRI.

Chemical exchange saturation transfer (CEST) MRI is a molecular imaging tool that provides physiological information about tissues, making it an invaluable tool for disease diagnosis and guided treatment. Its clinical application requires the acquisition of high-resolution images capable of accurately identifying subtle regional changes in vivo, while simultaneously maintaining a high level of spectral resolution. However, the acquisition of such high-resolution images is time consuming, presenting a challenge for practical implementation in clinical settings. Among several techniques that have been explored to reduce the acquisition time in MRI, deep-learning-based super-resolution (DLSR) is a promising approach to address this problem due to its adaptability to any acquisition sequence and hardware. However, its translation to CEST MRI has been hindered by the lack of the large CEST datasets required for network development. Thus, we aim to develop a DLSR method, named DLSR-CEST, to reduce the acquisition time for CEST MRI by reconstructing high-resolution images from fast low-resolution acquisitions. This is achieved by first pretraining the DLSR-CEST on human brain T1w and T2w images to initialize the weights of the network and then training the network on very small human and mouse brain CEST datasets to fine-tune the weights. Using the trained DLSR-CEST network, the reconstructed CEST source images exhibited improved spatial resolution in both peak signal-to-noise ratio and structural similarity index measure metrics at all downsampling factors (2-8). Moreover, amide CEST and relayed nuclear Overhauser effect maps extrapolated from the DLSR-CEST source images exhibited high spatial resolution and low normalized root mean square error, indicating a negligible loss in Z-spectrum information. Therefore, our DLSR-CEST demonstrated a robust reconstruction of high-resolution CEST source images from fast low-resolution acquisitions, thereby improving the spatial resolution and preserving most Z-spectrum information.

Effect of inhaled oxygen level on dynamic glucose-enhanced MRI in mouse brain.

PURPOSE: To investigate the effect of inhaled oxygen level on dynamic glucose enhanced (DGE) MRI in mouse brain tissue and CSF at 3 T. METHODS: DGE data of brain tissue and CSF from mice under normoxia or hyperoxia were acquired in independent and interleaved experiments using on-resonance variable delay multi-pulse (onVDMP) MRI. A bolus of 0.15 mL filtered 50% D-glucose was injected through the tail vein over 1 min during DGE acquisition. MRS was acquired before and after DGE experiments to confirm the presence of D-glucose. RESULTS: A significantly higher DGE effect under normoxia than under hyperoxia was observed in brain tissue (p = 0.0001 and p = 0.0002 for independent and interleaved experiments, respectively), but not in CSF (p > 0.3). This difference is attributed to the increased baseline MR tissue signal under hyperoxia induced by a shortened T1 and an increased BOLD effect. When switching from hyperoxia to normoxia without glucose injection, a signal change of ˜3.0% was found in brain tissue and a signal change of ˜1.5% was found in CSF. CONCLUSIONS: DGE signal was significantly lower under hyperoxia than that under normoxia in brain tissue, but not in CSF. The reason is that DGE effect size of brain tissue is affected by the baseline signal, which could be influenced by T1 change and BOLD effect. Therefore, DGE experiments in which the oxygenation level is changed from baseline need to be interpreted carefully.

The effect of aquaporin-4 inhibition on cerebrospinal fluid-tissue water exchange in mouse brain detected by magnetization transfer indirect spin labeling MRI.

The fluid transport of cerebrospinal fluid (CSF) and interstitial fluid in surrounding tissues plays an important role in the drainage pathway that facilitates waste clearance from the brain. This pathway is known as the glymphatic or perivascular system, and its functions are dependent on aquaporin-4 (AQP4). Recently, magnetization transfer indirect spin labeling (MISL) magnetic resonance imaging (MRI) has been proposed as a noninvasive and noncontrast-enhanced method for detecting water exchange between CSF and brain tissue. In this study, we first optimized the MISL sequence at preclinical 3 T MRI, and then studied the correlation of MISL in CSF with magnetization transfer (MT) in brain tissue, as well as the altered water exchange under AQP4 inhibition, using C57BL/6 mice. Results showed a strong correlation of MISL signal with MT signal. With the AQP4 inhibitor, we observed a significant decrease in MISL value (P < 0.05), suggesting that the hampered AQP4 activity led to decreased water exchange between CSF and brain tissue or the impairment of the glymphatic function. Overall, our findings demonstrate the potential application of MISL in assessing brain water exchange at 3 T MRI and its potential clinical translation.

Simultaneous creatine and phosphocreatine mapping of skeletal muscle by CEST MRI at 3T.

PURPOSE: To confirm that CrCEST in muscle exhibits a slow-exchanging process, and to obtain high-resolution amide, creatine (Cr), and phosphocreatine (PCr) maps of skeletal muscle using a POlynomial and Lorentzian Line-shape Fitting (PLOF) CEST at 3T. METHODS: We used dynamic changes in PCr/CrCEST of mouse hindlimb before and after euthanasia to assign the Cr and PCr CEST peaks in the Z-spectrum at 3T and to obtain the optimum saturation parameters. Segmented 3D EPI was employed to obtain multi-slice amide, PCr, and Cr CEST maps of human skeletal muscle. Subsequently, the PCrCEST maps were calibrated using the PCr concentrations determined by 31 P MRS. RESULTS: A comparison of the Z-spectra in mouse hindlimb before and after euthanasia indicated that CrCEST is a slow-exchanging process in muscle (<150.7 s-1 ). This allowed us to simultaneously extract PCr/CrCEST signals at 3T using the PLOF method. We determined optimal B1 values ranging from 0.3 to 0.6 µT for CrCEST in muscle and 0.3-1.2 µT for PCrCEST. For the study on human calf muscle, we determined an optimum saturation time of 2 s for both PCr/CrCEST (B1 = 0.6 µT). The PCr/CrCEST using 3D EPI were found to be comparable to those obtained using turbo spin echo (TSE). (3D EPI/TSE PCr: (2.6 ± 0.3) %/(2.3 ± 0.1) %; Cr: (1.3 ± 0.1) %/(1.4 ± 0.07) %). CONCLUSIONS: Our study showed that in vivo CrCEST is a slow-exchanging process. Hence, amide, Cr, and PCr CEST in the skeletal muscle can be mapped simultaneously at 3T by PLOF CEST.

Boosting quantification accuracy of chemical exchange saturation transfer MRI with a spatial-spectral redundancy-based denoising method.

Chemical exchange saturation transfer (CEST) is a versatile technique that enables noninvasive detections of endogenous metabolites present in low concentrations in living tissue. However, CEST imaging suffers from an inherently low signal-to-noise ratio (SNR) due to the decreased water signal caused by the transfer of saturated spins. This limitation challenges the accuracy and reliability of quantification in CEST imaging. In this study, a novel spatial-spectral denoising method, called BOOST (suBspace denoising with nOnlocal lOw-rank constraint and Spectral local-smooThness regularization), was proposed to enhance the SNR of CEST images and boost quantification accuracy. More precisely, our method initially decomposes the noisy CEST images into a low-dimensional subspace by leveraging the global spectral low-rank prior. Subsequently, a spatial nonlocal self-similarity prior is applied to the subspace-based images. Simultaneously, the spectral local-smoothness property of Z-spectra is incorporated by imposing a weighted spectral total variation constraint. The efficiency and robustness of BOOST were validated in various scenarios, including numerical simulations and preclinical and clinical conditions, spanning magnetic field strengths from 3.0 to 11.7 T. The results demonstrated that BOOST outperforms state-of-the-art algorithms in terms of noise elimination. As a cost-effective and widely available post-processing method, BOOST can be easily integrated into existing CEST protocols, consequently promoting accuracy and reliability in detecting subtle CEST effects.

Creatine mapping of the brain at 3T by CEST MRI.

PURPOSE: To assess the feasibility of CEST-based creatine (Cr) mapping in brain at 3T using the guanidino (Guan) proton resonance. METHODS: Wild type and knockout mice with guanidinoacetate N-methyltransferase deficiency and low Cr and phosphocreatine (PCr) concentrations in the brain were used to assign the Cr and protein-based arginine contributions to the GuanCEST signal at 2.0 ppm. To quantify the Cr proton exchange rate, two-step Bloch-McConnell fitting was used to fit the extracted CrCEST line-shape and multi-B1 Z-spectral data. The pH response of GuanCEST was simulated to demonstrate its potential for pH mapping. RESULTS: Brain Z-spectra of wild type and guanidinoacetate N-methyltransferase deficiency mice show a clear Guan proton peak at 2.0 ppm at 3T. The CrCEST signal contributes ∼23% to the GuanCEST signal at B1 = 0.8 µT, where a maximum CrCEST effect of 0.007 was detected. An exchange rate range of 200-300 s-1 was estimated for the Cr Guan protons. As revealed by the simulation, an elevated GuanCEST in the brain is observed when B1 is less than 0.4 µT at 3T, when intracellular pH reduces by 0.2. Conversely, the GuanCEST decreases when B1 is greater than 0.4 µT with the same pH drop. CONCLUSIONS: CrCEST mapping is possible at 3T, which has potential for detecting intracellular pH and Cr concentration in brain.

Quantitative Assessment of Peripheral Oxidative Metabolism With a New Dynamic 1 H MRI Technique: A Pilot Study in People With and Without Diabetes Mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is linked to impaired mitochondrial function. Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) is a gadolinium-contrast-free 1 H method to assess mitochondrial function by measuring low-concentration metabolites. A CEST MRI-based technique may serve as a non-invasive proxy for assessing mitochondrial health. HYPOTHESIS: A 1 H CEST MRI technique may detect significant differences in in vivo skeletal muscle phosphocreatine (SMPCr) kinetics between healthy volunteers and T2DM patients undergoing standardized isometric exercise. STUDY TYPE: Cross-sectional study. SUBJECTS: Seven subjects without T2DM (T2DM-) and seven age, sex, and BMI-matched subjects with T2DM (T2DM+). FIELD STRENGTH/SEQUENCE: Single-shot rapid acquisition with refocusing echoes (RARE) and single-shot gradient-echo sequences, 3 T. ASSESSMENT: Subjects underwent a rest-exercise-recovery imaging protocol to dynamically acquire SMPCr maps in calf musculature. Medial gastrocnemius (MG) and soleus SMPCr concentrations were plotted over time, and SMPCr recovery time, τ $$ \tau $$ , was determined. Mitochondrial function index was calculated as the ratio of resting SMPCr to τ $$ \tau $$ . Participants underwent a second exercise protocol for imaging of skeletal muscle blood flow (SMBF), and its association with SMPCr was assessed. STATISTICAL TESTS: Unpaired t-tests and Pearson correlation coefficient. A P value <0.05 was considered statistically significant. RESULTS: SMPCr concentrations in MG and soleus displayed expected declines during exercise and returns to baseline during recovery. τ $$ \tau $$ was significantly longer in the T2DM+ cohort (MG 83.5 ± 25.8 vs. 54.0 ± 21.1, soleus 90.5 ± 18.9 vs. 51.2 ± 14.5). The mitochondrial function index in the soleus was significantly lower in the T2DM+ cohort (0.33 ± 0.08 vs. 0.66 ± 0.19). SMBF was moderately correlated with the SMPCr in T2DM-; this correlation was not significant in T2DM+ (r = -0.23, P = 0.269). CONCLUSION: The CEST MRI method is feasible for quantifying SMPCr in peripheral muscle tissue. T2DM+ individuals had significantly lower oxidative capacities than T2DM- individuals. In T2DM, skeletal muscle metabolism appeared to be decoupled from perfusion. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 1.

Learned spatiotemporal correlation priors for CEST image denoising using incorporated global-spectral convolution neural network.

PURPOSE: To develop a deep learning-based method, dubbed Denoising CEST Network (DECENT), to fully exploit the spatiotemporal correlation prior to CEST image denoising. METHODS: DECENT is composed of two parallel pathways with different convolution kernel sizes aiming to extract the global and spectral features embedded in CEST images. Each pathway consists of a modified U-Net with residual Encoder-Decoder network and 3D convolution. Fusion pathway with 1 × 1 × 1 convolution kernel is utilized to concatenate two parallel pathways, and the output of DECENT is noise-reduced CEST images. The performance of DECENT was validated in numerical simulations, egg white phantom experiments, and ischemic mouse brain and human skeletal muscle experiments in comparison with existing state-of-the-art denoising methods. RESULTS: Rician noise was added to CEST images to mimic a low SNR situation for numerical simulation, egg white phantom experiment, and mouse brain experiments, while human skeletal muscle experiments were of inherently low SNR. From the denoising results evaluated by peak SNR (PSNR) and structural similarity index (SSIM), the proposed deep learning-based denoising method (DECENT) can achieve better performance compared to existing CEST denoising methods such as NLmCED, MLSVD, and BM4D, avoiding complicated parameter tuning or time-consuming iterative processes. CONCLUSIONS: DECENT can well exploit the prior spatiotemporal correlation knowledge of CEST images and restore the noise-free images from their noisy observations, outperforming state-of-the-art denoising methods.

Toward accurate cerebral blood flow estimation in mice after accounting for anesthesia.

Purpose: To improve the accuracy of cerebral blood flow (CBF) measurement in mice by accounting for the anesthesia effects. Methods: The dependence of CBF on anesthesia dose and time was investigated by simultaneously measuring respiration rate (RR) and heart rate (HR) under four different anesthetic regimens. Quantitative CBF was measured by a phase-contrast (PC) MRI technique. RR was evaluated with a mouse monitoring system (MouseOX) while HR was determined using an ultrashort-TE MRI sequence. CBF, RR, and HR were recorded dynamically with a temporal resolution of 1 min in a total of 19 mice. Linear regression models were used to investigate the relationships among CBF, anesthesia dose, RR, and HR. Results: CBF, RR, and HR all showed a significant dependence on anesthesia dose (p < 0.0001). However, the dose in itself was insufficient to account for the variations in physiological parameters, in that they showed a time-dependent change even for a constant dose. RR and HR together can explain 52.6% of the variations in CBF measurements, which is greater than the amount of variance explained by anesthesia dose (32.4%). Based on the multi-parametric regression results, a model was proposed to correct the anesthesia effects in mouse CBF measurements, specifically C B F c o r r e c t e d = C B F + 0.58 R R - 0.41 H R - 32.66 D o s e . We also reported awake-state CBF in mice to be 142.0 ± 8.8 mL/100 g/min, which is consistent with the model-predicted value. Conclusion: The accuracy of CBF measurement in mice can be improved by using a correction model that accounts for respiration rate, heart rate, and anesthesia dose.

Sensitivity schemes for dynamic glucose-enhanced magnetic resonance imaging to detect glucose uptake and clearance in mouse brain at 3 T.

The article from this special issue was previously published in NMR In Biomedicine , Volume 35, Issue 3, 2022. For completeness we are including the title page of the article below. The full text of the article can be read in Issue 35:3 on Wiley Online Library: https://doi.org/10.1002/nbm.4640.

Interrogation of dynamic glucose-enhanced MRI and fluorescence-based imaging reveals a perturbed glymphatic network in Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disorder that presents with progressive motor, mental, and cognitive impairment leading to early disability and mortality. The accumulation of mutant huntingtin protein aggregates in neurons is a pathological hallmark of HD. The glymphatic system, a brain-wide perivascular network, facilitates the exchange of interstitial fluid (ISF) and cerebrospinal fluid (CSF), supporting interstitial solute clearance including abnormal proteins from mammalian brains. In this study, we employed dynamic glucose-enhanced (DGE) MRI to measure D-glucose clearance from CSF as a tool to assess CSF clearance capacity to predict glymphatic function in a mouse model of HD. Our results demonstrate significantly diminished CSF clearance efficiency in premanifest zQ175 HD mice. The impairment of CSF clearance of D-glucose, measured by DGE MRI, worsened with disease progression. These DGE MRI findings in compromised glymphatic function in HD mice were further confirmed with fluorescence-based imaging of glymphatic CSF tracer influx, suggesting an impaired glymphatic function in premanifest stage of HD. Moreover, expression of the astroglial water channel aquaporin-4 (AQP4) in the perivascular compartment, a key mediator of glymphatic function, was significantly diminished in both HD mouse brain as well as postmortem human HD brain. Our data, acquired using a clinically translatable MRI approach, indicate a perturbed glymphatic network in the HD brain as early as in the premanifest stage. Further validation of these findings in clinical studies should provide insights into potential of glymphatic clearance as a HD biomarker and for glymphatic functioning as a disease-modifying therapeutic target for HD.

The exchange rate of creatine CEST in mouse brain.

PURPOSE: To estimate the exchange rate of creatine (Cr) CEST and to evaluate the pH sensitivity of guanidinium (Guan) CEST in the mouse brain. METHODS: Polynomial and Lorentzian line-shape fitting (PLOF) were implemented to extract the amine, amide, and Guan CEST signals from the brain Z-spectrum at 11.7T. Wild-type (WT) and knockout mice with the guanidinoacetate N-methyltransferase deficiency (GAMT-/- ) that have low Cr and phosphocreatine (PCr) concentrations in the brain were used to extract the CrCEST signal. To quantify the CrCEST exchange rate, a two-step Bloch-McConnell (BM) fitting was used to fit the CrCEST line-shape, B1 -dependent CrCEST, and the pH response with different B1 values. The pH in the brain cells was altered by hypercapnia to measure the pH sensitivity of GuanCEST. RESULTS: Comparison between the Z-spectra of WT and GAMT-/- mice suggest that the CrCEST is between 20% and 25% of the GuanCEST in the Z-spectrum at 1.95 ppm between B1 = 0.8 and 2 µT. The CrCEST exchange rate was found to be around 240-480 s-1 in the mouse brain, which is significantly lower than that in solutions (∼1000 s-1 ). The hypercapnia study on the mouse brain revealed that CrCEST at B1 = 2 µT and amineCEST at B1 = 0.8 µT are highly sensitive to pH change in the WT mouse brain. CONCLUSIONS: The in vivo CrCEST exchange rate is slow, and the acquisition parameters for the CrCEST should be adjusted accordingly. CrCEST is the major contribution to the opposite pH-dependence of GuanCEST signal under different conditions of B1 in the brain.

Radiofrequency labeling strategies in chemical exchange saturation transfer MRI.

Chemical exchange saturation transfer (CEST) MRI has generated great interest for molecular imaging applications because it can image low-concentration solute molecules in vivo with enhanced sensitivity. CEST effects are detected indirectly through a reduction in the bulk water signal after repeated perturbation of the solute proton magnetization using one or more radiofrequency (RF) irradiation pulses. The parameters used for these RF pulses-frequency offset, duration, shape, strength, phase, and interpulse spacing-determine molecular specificity and detection sensitivity, thus their judicious selection is critical for successful CEST MRI scans. This review article describes the effects of applying RF pulses on spin systems and compares conventional saturation-based RF labeling with more recent excitation-based approaches that provide spectral editing capabilities for selectively detecting molecules of interest and obtaining maximal contrast.

Chemical exchange saturation transfer MRI detects myelin changes in cuprizone mouse model at 3T.

Chemical exchange saturation transfer (CEST) sensitively detects molecular alterations in the brain, such as relayed nuclear Overhauser effect (rNOE) CEST contrast at -3.5 ppm representing aliphatic protons in both lipids and proteins, and CEST contrast at 3.5 ppm correlating with amide proton in proteins. Myelin is rich in lipids and proteins, and therefore CEST can be explored as a biomarker for myelin pathology, which could contribute to the diagnosis and prognosis of multiple sclerosis (MS). In the current study, we investigate the specificity of aliphatic rNOE and the amide pool in myelin detection using the cuprizone (CPZ) mouse model, which recapitulates the demyelination and remyelination of MS. In this study, preclinical 3T MRI was performed in 19 male C57BL/6 mice. Mice in the normal control (NC) group (n = 9) were fed a normal diet for the whole course, while mice in the CPZ group (n = 10) were fed with CPZ for 10 weeks, followed by 4 weeks with a normal diet. The CEST contrast of rNOE (-3.5 ppm) and amide (3.5 ppm) in brain regions of the corpus callosum (CC) and the caudate putamen were compared. Statistical differences between the groups were calculated using two-way ANOVA. We observed significantly decreased rNOE (NC: 4.85% ± 0.09%/s vs. CPZ: 3.88% ± 0.18%/s, p = 0.007) and amide pool (NC: 3.20% ± 0.10%/s vs. CPZ: 2.46% ± 0.16%/s, p = 0.02) in the CC after 8 weeks on CPZ diet (p < 0.05). Moreover, the rNOE in the CPZ group recovered to a level comparable with the NC group at week 14 (p = 0.39), while amide remained at a level as low as that for the NC group (p = 0.051). Significant rNOE and amide changes, validated by immunohistochemistry results for demyelination and remyelination, demonstrate the huge potential of CEST for revealing myelin pathology, which has implications for MS identification at the clinical field strength of 3T.

Non-contrast assessment of blood-brain barrier permeability to water in mice: An arterial spin labeling study at cerebral veins.

Blood-brain barrier (BBB) plays a critical role in protecting the brain from toxins and pathogens. However, in vivo tools to assess BBB permeability are scarce and often require the use of exogenous contrast agents. In this study, we aimed to develop a non-contrast arterial-spin-labeling (ASL) based MRI technique to estimate BBB permeability to water in mice. By determining the relative fraction of labeled water spins that were exchanged into the brain tissue as opposed to those that remained in the cerebral veins, we estimated indices of global BBB permeability to water including water extraction fraction (E) and permeability surface-area product (PS). First, using multiple post-labeling delay ASL experiments, we estimated the bolus arrival time (BAT) of the labeled spins to reach the great vein of Galen (VG) to be 691.2 ± 14.5 ms (N = 5). Next, we investigated the dependence of the VG ASL signal on labeling duration and identified an optimal imaging protocol with a labeling duration of 1200 ms and a PLD of 100 ms. Quantitative E and PS values in wild-type mice were found to be 59.9 ± 3.2% and 260.9 ± 18.9 ml/100 g/min, respectively. In contrast, mice with Huntington's disease (HD) revealed a significantly higher E (69.7 ± 2.4%, P = 0.026) and PS (318.1 ± 17.1 ml/100 g/min, P = 0.040), suggesting BBB breakdown in this mouse model. Reproducibility studies revealed a coefficient-of-variation (CoV) of 4.9 ± 1.7% and 6.1 ± 1.2% for E and PS, respectively. The proposed method may open new avenues for preclinical research on pathophysiological mechanisms of brain diseases and therapeutic trials in animal models.

Chemical exchange saturation transfer imaging of creatine, phosphocreatine, and protein arginine residue in tissues.

Chemical exchange saturation transfer (CEST) MRI has become a promising technique to assay target proteins and metabolites through their exchangeable protons, noninvasively. The ubiquity of creatine (Cr) and phosphocreatine (PCr) due to their pivotal roles in energy homeostasis through the creatine phosphate pathway has made them prime targets for CEST in the diagnosis and monitoring of disease pathologies, particularly in tissues heavily dependent on the maintenance of rich energy reserves. Guanidinium CEST from protein arginine residues (i.e. arginine CEST) can also provide information about the protein profile in tissue. However, numerous obfuscating factors stand as obstacles to the specificity of arginine, Cr, and PCr imaging through CEST, such as semisolid magnetization transfer, fast chemical exchanges such as primary amines, and the effects of nuclear Overhauser enhancement from aromatic and amide protons. In this review, the specific exchange properties of protein arginine residues, Cr, and PCr, along with their validation, are discussed, including the considerations necessary to target and tune their signal effects through CEST imaging. Additionally, strategies that have been employed to enhance the specificity of these exchanges in CEST imaging are described, along with how they have opened up possible applications of protein arginine residues, Cr and PCr CEST imaging in the study and diagnosis of pathology. A clear understanding of the capabilities and caveats of using CEST to image these vital metabolites and mitigation strategies is crucial to expanding the possibilities of this promising technology.

Guanidinium and amide CEST mapping of human brain by high spectral resolution CEST at 3 T.

PURPOSE: To extract guanidinium (Guan) and amide CEST on the human brain at 3 T MRI with the high spectral resolution (HSR) CEST combined with the polynomial Lorentzian line-shape fitting (PLOF). METHODS: Continuous wave (cw) turbo spin-echo (TSE) CEST was implemented to obtain the optimum saturation parameters. Both Guan and amide CEST peaks were extracted and quantified using the PLOF method. The NMR spectra on the egg white phantoms were acquired to reveal the fitting range and the contributions to the amide and GuanCEST. Two types of CEST approaches, including cw gradient- and spin-echo (cwGRASE) and steady state EPI (ssEPI), were implemented to acquire multi-slice HSR-CEST. RESULTS: GuanCEST can be extracted with the PLOF method at 3 T, and the optimum B 1 = 0.6 µ T $$ {\mathrm{B}}_1=0.6\kern0.2em \upmu \mathrm{T} $$ was determined for GuanCEST in white matter (WM) and 1.0 µT in gray matter (GM). The optimum B1  = 0.8-1 µT was found for amideCEST. AmideCEST is lower in both WM and GM collected with ssEPI compared to those by cwGRASE (ssEPI = [1.27-1.63]%; cwGRASE = [2.19-2.25]%). The coefficients of variation (COV) of the amide and Guan CEST in both WM and GM for ssEPI (COV: 28.6-33.4%) are significantly higher than those of cwGRASE (COV: 8.6-18.8%). Completely different WM/GM contrasts for Guan and amide CEST were observed between ssEPI and cwGRASE. The amideCEST was found to have originated from the unstructured amide protons as suggested by the NMR spectrum of the unfolded proteins in egg white. CONCLUSION: Guan and amide CEST mapping can be achieved by the HSR-CEST at 3 T combing with the PLOF method.