Differential Laminar Activation Dissociates Encoding and Retrieval in the Human Medial and Lateral Entorhinal Cortex.

The hierarchically organized structures of the medial temporal lobe are critically important for episodic memory function. Accumulating evidence suggests dissociable information processing pathways are maintained throughout these structures including in the medial and lateral entorhinal cortex. Cortical layers provide an additional dimension of dissociation as the primary input to the hippocampus derives from layer 2 neurons in the entorhinal cortex, whereas the deeper layers primarily receive output from the hippocampus. Here, novel high-resolution T2-prepared functional MRI methods were successfully used to mitigate susceptibility artifacts typically affecting MRI signals in this region providing uniform sensitivity across the medial and lateral entorhinal cortex. During the performance of a memory task, healthy human subjects (age 25-33 years, mean age 28.2 ± 3.3 years, 4 female) showed differential functional activation in the superficial and deep layers of the entorhinal cortex associated with task-related encoding and retrieval conditions, respectively. The methods provided here offer an approach to probe layer-specific activation in normal cognition and conditions contributing to memory impairment.SIGNIFICANCE STATEMENT This study provides new evidence for differential neuronal activation in the superficial versus deep layers of the entorhinal cortex associated with encoding and retrieval memory processes, respectively, in cognitively normal adults. The study further shows that this dissociation can be observed in both the medial and the lateral entorhinal cortex. The study was achieved by using a novel functional MRI method allowing us to measure robust functional MRI signals in both the medial and lateral entorhinal cortex that was not possible in previous studies. The methodology established here in healthy human subjects lays a solid foundation for subsequent studies investigating layer-specific and region-specific changes in the entorhinal cortex associated with memory impairment in various conditions such as Alzheimer's disease.

Exploiting gradient-echo frequency evolution: Probing white matter microstructure and extracting bulk susceptibility-induced frequency for quantitative susceptibility mapping.

PURPOSE: This work is to investigate the microstructure-induced frequency shift in white matter (WM) with crossing fibers and to separate the microstructure-related frequency shift from the bulk susceptibility-induced frequency shift by model fitting the gradient-echo (GRE) frequency evolution for potentially more accurate quantitative susceptibility mapping (QSM). METHODS: A hollow-cylinder fiber model (HCFM) with two fiber populations was developed to investigate GRE frequency evolutions in WM voxels with microstructural orientation dispersion. The simulated and experimentally measured TE-dependent local frequency shift was then fitted to a simplified frequency evolution model to obtain a microstructure-related frequency difference parameter ( ∆ f $$ \Delta f $$ ) and a TE-independent bulk susceptibility-induced frequency shift ( C f $$ {C}_f $$ ). The obtained C f $$ {C}_f $$ was then used for QSM reconstruction. Reconstruction performances were evaluated using a numerical head phantom and in vivo data and then compared to other multi-echo combination methods. RESULTS: GRE frequency evolutions and ∆ f $$ \Delta f $$ -based tissue parameters in both parallel and crossing fibers determined from our simulations were comparable to those observed in vivo. The TE-dependent frequency fitting method outperformed other multi-echo combination methods in estimating C f $$ {C}_f $$ in simulations. The fitted ∆ f $$ \Delta f $$ , C f $$ {C}_f $$ , and QSM could be improved further by navigator-based B0 fluctuation correction. CONCLUSION: A HCFM with two fiber populations can be used to characterize microstructure-induced frequency shifts in WM regions with crossing fibers. HCFM-based TE-dependent frequency fitting provides tissue contrast related to microstructure ( ∆ f $$ \Delta f $$ ) and in addition may help improve the quantification accuracy of C f $$ {C}_f $$ and the corresponding QSM.

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.

Compartmental anisotropy of filtered exchange imaging (FEXI) in human white matter: What is happening in FEXI?

PURPOSE: To investigate the effects of compartmental anisotropy on filtered exchange imaging (FEXI) in white matter (WM). THEORY AND METHODS: FEXI signals were measured using multiple combinations of diffusion filter and detection directions in five healthy volunteers. Additional filters, including a trace-weighted diffusion filter with trapezoidal gradients, a spherical b-tensor encoded diffusion filter, and a T2 filter, were tested with trace-weighted diffusion detection. RESULTS: A large range of apparent exchange rates (AXR) and both positive and negative filter efficiencies (σ) were found depending on the mutual orientation of the filter and detection gradients relative to WM fiber orientation. The data demonstrated that the fast-diffusion compartment suppressed by diffusional filtering is not exclusively extra-cellular, but also intra-cellular. While not comprehensive, a simple two-compartment diffusion tensor model with water exchange was able to account qualitatively for the trends in positive and negative filtering efficiencies, while standard model imaging (SMI) without exchange could not. This two-compartment diffusion tensor model also demonstrated smaller AXR variances across subjects. When employing trace-weighted diffusion detection, AXR values were on the order of the R1 (=1/T1) of water at 3T for crossing fibers, while being less than R1 for parallel fibers. CONCLUSION: Orientation-dependent AXR and σ values were observed when using multi-orientation filter and detection gradients in FEXI, indicating that WM FEXI models need to account for compartmental anisotropy. When using trace-weighted detection, AXR values were on the order of or less than R1, complicating the interpretation of FEXI results in WM in terms of biological exchange properties. These findings may contribute toward better understanding of FEXI results in WM.

In vivo characterization of glycogen storage disease type III in a mouse model using glycoNOE MRI.

PURPOSE: Glycogen storage disease type III (GSD III) is a rare inherited metabolic disease characterized by excessive accumulation of glycogen in liver, skeletal muscle, and heart. Currently, there are no widely available noninvasive methods to assess tissue glycogen levels and disease load. Here, we use glycogen nuclear Overhauser effect (glycoNOE) MRI to quantify hepatic glycogen levels in a mouse model of GSD III. METHODS: Agl knockout mice (n = 13) and wild-type controls (n = 10) were scanned for liver glycogen content using glycoNOE MRI. All mice were fasted for 12 to 16 h before MRI scans. GlycoNOE signal was quantified by fitting the Z-spectrum using a four-pool Voigt lineshape model. Next, the fitted direct water saturation pool was removed and glycoNOE signal was estimated from the integral of the residual Z spectrum within -0.6 to -1.4 ppm. Glycogen concentration was also measured ex vivo using a biochemical assay. RESULTS: GlycoNOE MRI clearly distinguished Agl knockout mice from wild-type controls, showing a statistically significant difference in glycoNOE signals in the livers across genotypes. There was a linear correlation between glycoNOE signal and glycogen concentration determined by the biochemical assay. The obtained glycoNOE maps of mouse livers also showed higher glycogen levels in Agl knockout mice compared to wild-type mice. CONCLUSION: GlycoNOE MRI was used successfully as a noninvasive method to detect liver glycogen levels in mice, suggesting the potential of this method to be applied to assess glycogen storage diseases.

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.

On the optimization of 3D inflow-based vascular-space-occupancy (iVASO) MRI for the quantification of arterial cerebral blood volume (CBVa).

PURPOSE: The inflow-based vascular-space-occupancy (iVASO) MRI was originally developed in a single-slice mode to measure arterial cerebral blood volume (CBVa). When vascular crushers are applied in iVASO, the signals can be sensitized predominantly to small pial arteries and arterioles. The purpose of this study is to perform a systematic optimization and evaluation of a 3D iVASO sequence on both 3 T and 7 T for the quantification of CBVa values in the human brain. METHODS: Three sets of experiments were performed in three separate cohorts. (1) 3D iVASO MRI protocols were compared to single-slice iVASO, and the reproducibility of whole-brain 3D iVASO MRI was evaluated. (2) The effects from different vascular crushers in iVASO were assessed. (3) 3D iVASO MRI results were evaluated in arterial and venous blood vessels identified using ultrasmall-superparamagnetic-iron-oxides-enhanced MRI to validate its arterial origin. RESULTS: 3D iVASO scans showed signal-to-noise ratio (SNR) and CBVa measures consistent with single-slice iVASO with reasonable intrasubject reproducibility. Among the iVASO scans performed with different vascular crushers, the whole-brain 3D iVASO scan with a motion-sensitized-driven-equilibrium preparation with two binomial refocusing pulses and an effective TE of 50 ms showed the best suppression of macrovascular signals, with a relatively low specific absorption rate. When no vascular crusher was applied, the CBVa maps from 3D iVASO scans showed large CBVa values in arterial vessels but well-suppressed signals in venous vessels. CONCLUSION: A whole-brain 3D iVASO MRI scan was optimized for CBVa measurement in the human brain. When only microvascular signals are desired, a motion-sensitized-driven-equilibrium-based vascular crusher with binomial refocusing pulses can be applied in 3D iVASO.

Effect of motion, cortical orientation and spatial resolution on quantitative imaging of cortical R2* and magnetic susceptibility at 0.3 mm in-plane resolution at 7 T.

MR images of the effective relaxation rate R2* and magnetic susceptibility χ derived from multi-echo T2*-weighted (T2*w) MRI can provide insight into iron and myelin distributions in the brain, with the potential of providing biomarkers for neurological disorders. Quantification of R2* and χ at submillimeter resolution in the cortex in vivo has been difficult because of challenges such as head motion, limited signal to noise ratio, long scan time, and motion related magnetic field fluctuations. This work aimed to improve the robustness for quantifying intracortical R2* and χ and analyze the effects from motion, spatial resolution, and cortical orientation. T2*w data was acquired with a spatial resolution of 0.3 × 0.3 × 0.4 mm3 at 7 T and downsampled to various lower resolutions. A combined correction for motion and B0 changes was deployed using volumetric navigators. Such correction improved the T2*w image quality rated by experienced image readers and test-retest reliability of R2* and χ quantification with reduced median inter-scan differences up to 10 s-1 and 5 ppb, respectively. R2* and χ near the line of Gennari, a cortical layer high in iron and myelin, were as much as 10 s-1 and 10 ppb higher than the region at adjacent cortical depth. In addition, a significant effect due to the cortical orientation relative to the static field (B0) was observed in χ with a peak-to-peak amplitude of about 17 ppb. In retrospectively downsampled data, the capability to distinguish different cortical depth regions based on R2* or χ contrast remained up to isotropic 0.5 mm resolution. This study highlights the unique characteristics of R2* and χ along the cortical depth at submillimeter resolution and the need for motion and B0 corrections for their robust quantification in vivo.

Ultrafast Z-spectroscopic imaging in vivo at 3T using through-slice spectral encoding (TS-UFZ).

PURPOSE: Acquisition of high-resolution Z-spectra for CEST or magnetization transfer contrast (MTC) MRI requires excessive scan times. Ultrafast Z-spectroscopy (UFZ) has been proposed to address this; however, the quality of in vivo UFZ spectra has been insufficient. Here, we present a simple approach to improve this. THEORY AND METHODS: UFZ imaging acquires full Z-spectra by encoding the spectral dimension spatially via a gradient applied concurrently with the RF saturation pulse. Different from previous implementations, both this saturation gradient and its readout were applied in the slice direction, resulting in a relatively uniform voxel composition. Phase-encoding was applied in both in-plane directions, allowing additional under-sampling and acceleration. RESULTS: In phantoms, UFZ imaging with through-slice Z-spectral encoding (TS-UFZ) provided Z-spectra of salicylic acid and egg white in excellent agreement with conventional acquisitions. In vivo brain Z-spectra were influenced by flow through the imaging slice which affected the Z-spectral baseline. Still, CEST signals could be quantified after baseline fitting and mapping the residual CEST signal. Amide proton transfer (APT) contrast intensities obtained by TS-UFZ were on the same order of magnitude as conventional CEST but with different contrast across slice which likely is a result of different tissue regions contributing. CONCLUSION: TS-UFZ approach improves signal stability and spectral uniformity over previous implementations and allows high spectral-resolution imaging of saturation transfer effects in the human brain at 3T. This implementation allows for further acceleration by reducing phase encoding steps and thus opens up the possibility of mapping dynamic CEST signals in vivo with a practical temporal resolution.

Evaluation of 3D stack-of-spiral turbo FLASH acquisitions for pseudo-continuous and velocity-selective ASL-derived brain perfusion mapping.

PURPOSE: The most-used 3D acquisitions for ASL are gradient and spin echo (GRASE)- and stack-of-spiral (SOS)-based fast spin echo, which require multiple shots. Alternatively, turbo FLASH (TFL) allows longer echo trains, and SOS-TFL has the potential to reduce the number of shots to even single-shot, thus improving the temporal resolution. Here we compare the performance of 3D SOS-TFL and 3D GRASE for ASL at 3T. METHODS: The 3D SOS-TFL readout was optimized with respect to fat suppression and excitation flip angles for pseudo-continuous ASL- and velocity-selective (VS)ASL-derived cerebral blood flow (CBF) mapping as well as for VSASL-derived cerebral blood volume (CBV) mapping. Results were compared with 3D GRASE readout on healthy volunteers in terms of perfusion quantification and temporal SNR (tSNR) efficiency. CBF and CBV mapping derived from 3D SOS-TFL-based ASL was demonstrated on one stroke patient, and the potential for single-shot acquisitions was exemplified. RESULTS: SOS-TFL with a 15° flip angle resulted in adequate tSNR efficiency with negligible image blurring. Selective water excitation was necessary to eliminate fat-induced artifacts. For pseudo-continuous ASL- and VSASL-based CBF and CBV mapping, compared to the employed four-shot 3D GRASE with an acceleration factor of 2, the fully sampled 3D SOS-TFL delivered comparable performance (with a similar scan time) using three shots, which could be further undersampled to achieve single-shot acquisition with higher tSNR efficiency. SOS-TFL had reduced CSF contamination for VSASL-CBF. CONCLUSION: 3D SOS-TFL acquisition was found to be a viable substitute for 3D GRASE for ASL with sufficient tSNR efficiency, minimal relaxation-induced blurring, reduced CSF contamination, and the potential of single-shot, especially for VSASL.

A numerical human brain phantom for dynamic glucose-enhanced (DGE) MRI: On the influence of head motion at 3T.

PURPOSE: Dynamic glucose-enhanced (DGE) MRI relates to a group of exchange-based MRI techniques where the uptake of glucose analogues is studied dynamically. However, motion artifacts can be mistaken for true DGE effects, while motion correction may alter true signal effects. The aim was to design a numerical human brain phantom to simulate a realistic DGE MRI protocol at 3T that can be used to assess the influence of head movement on the signal before and after retrospective motion correction. METHODS: MPRAGE data from a tumor patient were used to simulate dynamic Z-spectra under the influence of motion. The DGE responses for different tissue types were simulated, creating a ground truth. Rigid head movement patterns were applied as well as physiological dilatation and pulsation of the lateral ventricles and head-motion-induced B0 -changes in presence of first-order shimming. The effect of retrospective motion correction was evaluated. RESULTS: Motion artifacts similar to those previously reported for in vivo DGE data could be reproduced. Head movement of 1 mm translation and 1.5 degrees rotation led to a pseudo-DGE effect on the order of 1% signal change. B0 effects due to head motion altered DGE changes due to a shift in the water saturation spectrum. Pseudo DGE effects were partly reduced or enhanced by rigid motion correction depending on tissue location. CONCLUSION: DGE MRI studies can be corrupted by motion artifacts. Designing post-processing methods using retrospective motion correction including B0 correction will be crucial for clinical implementation. The proposed phantom should be useful for evaluation and optimization of such techniques.

The relayed nuclear Overhauser effect in magnetization transfer and chemical exchange saturation transfer MRI.

Magnetic resonance (MR) is a powerful technique for noninvasively probing molecular species in vivo but suffers from low signal sensitivity. Saturation transfer (ST) MRI approaches, including chemical exchange saturation transfer (CEST) and conventional magnetization transfer contrast (MTC), allow imaging of low-concentration molecular components with enhanced sensitivity using indirect detection via the abundant water proton pool. Several recent studies have shown the utility of chemical exchange relayed nuclear Overhauser effect (rNOE) contrast originating from nonexchangeable carbon-bound protons in mobile macromolecules in solution. In this review, we describe the mechanisms leading to the occurrence of rNOE-based signals in the water saturation spectrum (Z-spectrum), including those from mobile and immobile molecular sources and from molecular binding. While it is becoming clear that MTC is mainly an rNOE-based signal, we continue to use the classical MTC nomenclature to separate it from the rNOE signals of mobile macromolecules, which we will refer to as rNOEs. Some emerging applications of the use of rNOEs for probing macromolecular solution components such as proteins and carbohydrates in vivo or studying the binding of small substrates are discussed.

Imaging of sugar-based contrast agents using their hydroxyl proton exchange properties.

The ability of CEST MRI to detect the presence of millimolar concentrations of non-metallic contrast agents has made it possible to study, non-invasively, important biological molecules such as proteins and sugars, as well as drugs already approved for clinical use. Here, we review efforts to use sugar and sugar polymers as exogenous contrast agents, which is possible based on the exchange of their hydroxyl protons with water protons. While this capability has raised early enthusiasm, for instance about the possibility of imaging D-glucose metabolism with MRI in a way analogous to PET, experience over the past decade has shown that this is not trivial. On the other hand, many studies have confirmed the possibility of imaging a large variety of sugar analogues, each with potentially interesting applications to assess tissue physiology. Some promising applications are the study of (i) sugar delivery and transport to assess blood-brain barrier integrity and (ii) sugar uptake by cells for their characterization (e.g., cancer versus healthy), as well as (iii) clearance of sugars to assess tissue drainage-for instance, through the glymphatic system. To judge these opportunities and their challenges, especially in the clinic, it is necessary to understand the technical aspects of detecting the presence of rapidly exchanging protons through the water signal in MRI, especially as a function of magnetic field strength. We expect that novel approaches in terms of MRI detection (both saturation transfer and relaxation based), MRI data analysis, and sugar design will push this young field forward in the next decade.

Tissue response curve-shape analysis of dynamic glucose-enhanced and dynamic contrast-enhanced magnetic resonance imaging in patients with brain tumor.

Dynamic glucose-enhanced (DGE) MRI is used to study the signal intensity time course (tissue response curve) after D-glucose injection. D-glucose has potential as a biodegradable alternative or complement to gadolinium-based contrast agents, with DGE being comparable with dynamic contrast-enhanced (DCE) MRI. However, the tissue uptake kinetics as well as the detection methods of DGE differ from DCE MRI, and it is relevant to compare these techniques in terms of spatiotemporal enhancement patterns. This study aims to develop a DGE analysis method based on tissue response curve shapes, and to investigate whether DGE MRI provides similar or complementary information to DCE MRI. Eleven patients with suspected gliomas were studied. Tissue response curves were measured for DGE and DCE MRI at 7 T and the area under the curve (AUC) was assessed. Seven types of response curve shapes were postulated and subsequently identified by deep learning to create color-coded "curve maps" showing the spatial distribution of different curve types. DGE AUC values were significantly higher in lesions than in normal tissue (p < 0.007). Furthermore, the distribution of curve types differed between lesions and normal tissue for both DGE and DCE. The DGE and DCE response curves in a 6-min postinjection time interval were classified as the same curve type in 20% of the lesion voxels, which increased to 29% when a 12-min DGE time interval was considered. While both DGE and DCE tissue response curve-shape analysis enabled differentiation of lesions from normal brain tissue in humans, their enhancements were neither temporally identical nor confined entirely to the same regions. Curve maps can provide accessible and intuitive information about the shape of DGE response curves, which is expected to be useful in the continued work towards the interpretation of DGE uptake curves in terms of D-glucose delivery, transport, and metabolism.

Concurrent measurement of perfusion parameters related to small blood vessels and cerebrospinal fluid circulation in the human brain using dynamic dual-spin-echo perfusion MRI.

Accumulating evidence from recent studies has indicated the importance of studying the interaction between the microvascular and lymphatic systems in the brain. To date, most imaging methods can only measure blood or lymphatic vessels separately, such as dynamic susceptibility contrast (DSC) MRI for blood vessels and DSC MRI-in-the-cerebrospinal fluid (CSF) (cDSC MRI) for lymphatic vessels. An approach that can measure both blood and lymphatic vessels in a single scan offers advantages such as a halved scan time and contrast dosage. This study attempts to develop one such approach by optimizing a dual-echo turbo-spin-echo sequence, termed "dynamic dual-spin-echo perfusion (DDSEP) MRI". Bloch simulations were performed to optimize the dual-echo sequence for the measurement of gadolinium (Gd)-induced blood and CSF signal changes using a short and a long echo time, respectively. The proposed method furnishes a T1-dominant contrast in CSF and a T2-dominant contrast in blood. MRI experiments were performed in healthy subjects to evaluate the dual-echo approach by comparing it with existing separate methods. Based on simulations, the short and long echo time were chosen around the time when blood signals show maximum difference between post- and pre-Gd scans, and the time when blood signals are completely suppressed, respectively. The proposed method showed consistent results in human brains as previous studies using separate methods. Signal changes from small blood vessels occurred faster than from lymphatic vessels after intravenous Gd injection. In conclusion, Gd-induced signal changes in blood and CSF can be detected simultaneously in healthy subjects with the proposed sequence. The temporal difference in Gd-induced signal changes from small blood and lymphatic vessels after intravenous Gd injection was confirmed using the proposed approach in the same human subjects. Results from this proof-of-concept study will be used to further optimize DDSEP MRI in subsequent studies.

Magnetic resonance imaging of glycogen using its magnetic coupling with water.

Glycogen plays a central role in glucose homeostasis and is abundant in several types of tissue. We report an MRI method for imaging glycogen noninvasively with enhanced detection sensitivity and high specificity, using the magnetic coupling between glycogen and water protons through the nuclear Overhauser enhancement (NOE). We show in vitro that the glycogen NOE (glycoNOE) signal is correlated linearly with glycogen concentration, while pH and temperature have little effect on its intensity. For validation, we imaged glycoNOE signal changes in mouse liver, both before and after fasting and during glucagon infusion. The glycoNOE signal was reduced by 88 ± 16% (n = 5) after 24 h of fasting and by 76 ± 22% (n = 5) at 1 h after intraperitoneal (i.p.) injection of glucagon, which is known to rapidly deplete hepatic glycogen. The ability to noninvasively image glycogen should allow assessment of diseases in which glucose metabolism or storage is altered, for instance, diabetes, cardiac disease, muscular disorders, cancer, and glycogen storage diseases.

CEST MRI and MALDI imaging reveal metabolic alterations in the cervical lymph nodes of EAE mice.

BACKGROUND: Multiple sclerosis (MS) is a neurodegenerative disease, wherein aberrant immune cells target myelin-ensheathed nerves. Conventional magnetic resonance imaging (MRI) can be performed to monitor damage to the central nervous system that results from previous inflammation; however, these imaging biomarkers are not necessarily indicative of active, progressive stages of the disease. The immune cells responsible for MS are first activated and sensitized to myelin in lymph nodes (LNs). Here, we present a new strategy for monitoring active disease activity in MS, chemical exchange saturation transfer (CEST) MRI of LNs. METHODS AND RESULTS: We studied the potential utility of conventional (T2-weighted) and CEST MRI to monitor changes in these LNs during disease progression in an experimental autoimmune encephalomyelitis (EAE) model. We found CEST signal changes corresponded temporally with disease activity. CEST signals at the 3.2 ppm frequency during the active stage of EAE correlated significantly with the cellular (flow cytometry) and metabolic (mass spectrometry imaging) composition of the LNs, as well as immune cell infiltration into brain and spinal cord tissue. Correlating primary metabolites as identified by matrix-assisted laser desorption/ionization (MALDI) imaging included alanine, lactate, leucine, malate, and phenylalanine. CONCLUSIONS: Taken together, we demonstrate the utility of CEST MRI signal changes in superficial cervical LNs as a complementary imaging biomarker for monitoring disease activity in MS. CEST MRI biomarkers corresponded to disease activity, correlated with immune activation (surface markers, antigen-stimulated proliferation), and correlated with LN metabolite levels.

T2 -oximetry-based cerebral venous oxygenation mapping using Fourier-transform-based velocity-selective pulse trains.

PURPOSE: To develop a T2 -oximetry method for quantitative mapping of cerebral venous oxygenation fraction (Yv ) using Fourier-transform-based velocity-selective (FT-VS) pulse trains. METHODS: The venous isolation preparation was achieved by using an FT-VS inversion plus a nonselective inversion (NSI) pulse to null the arterial blood signal while minimally affected capillary blood flows out into the venular vasculature during the outflow time (TO), and then applying an Fourier transform based velocity selective saturation (FT-VSS) pulse to suppress the tissue signal. A multi-echo readout was employed to obtain venous T2 (T2,v ) efficiently with the last echo used to detect the residual CSF signal and correct its contamination in the fitting. Here we compared the performance of this FT-VS-based venous isolation preparations with a traditional velocity-selective saturation (VSS)-based approach (quantitative imaging of extraction of oxygen and tissue consumption [QUIXOTIC]) with different cutoff velocities for Yv mapping on 6 healthy volunteers at 3 Tesla. RESULTS: The FT-VS-based methods yielded higher venous blood signal and temporal SNR with less CSF contamination than the velocity-selective saturation-based results. The averaged Yv values across the whole slice measured in different experiments were close to the global Yv measured from the individual internal jugular vein. CONCLUSION: The feasibility of the FT-VS-based Yv estimation was demonstrated on healthy volunteers. The obtained high venous signal as well as the mitigation of CSF contamination led to a good agreement between the T2,v and Yv measured in the proposed method with the values in the literature.

Detection of electrostatic molecular binding using the water proton signal.

PURPOSE: Saturation transfer MRI has previously been used to probe molecular binding interactions with signal enhancement via the water signal. Here, we detail the relayed nuclear overhauser effect (rNOE) based mechanisms of this signal enhancement, develop a strategy of quantifying molecular binding affinity, i.e., the dissociation constant ( KD$$ {K}_D $$ ), and apply the method to detect electrostatic binding of several charged small biomolecules. Another goal was to estimate the detection limit for transient receptor-substrate binding. THEORY AND METHODS: The signal enhancement mechanism was quantitatively described by a three-step magnetization transfer model, and numerical simulations were performed to verify this theory. The binding equilibria of arginine, choline, and acetyl-choline to anionic resin were studied as a function of ligand concentration, pH, and salt content. Equilibrium dissociation constants ( KD$$ {K}_D $$ ) were determined by fitting the multiple concentration data. RESULTS: The numerical simulations indicate that the signal enhancement is sufficient to detect the molecular binding of sub-millimolar (∼100 µM) concentration ligands to low micromolar levels of molecular targets. The measured rNOE signals from arginine, choline, and acetyl-choline binding experiments show that several magnetization transfer pathways (intra-ligand rNOEs and intermolecular rNOEs) can contribute. The rNOEs that arise from molecular ionic binding were influenced by pH and salt concentration. The molecular binding strengths in terms of KD$$ {K}_{\mathrm{D}} $$ ranged from 70-160 mM for the three cations studied. CONCLUSION: The capability to use MRI to detect the transient binding of small substrates paves a pathway towards the detection of micromolar level receptor-substrate binding in vivo.

Review and consensus recommendations on clinical APT-weighted imaging approaches at 3T: Application to brain tumors.

Amide proton transfer-weighted (APTw) MR imaging shows promise as a biomarker of brain tumor status. Currently used APTw MRI pulse sequences and protocols vary substantially among different institutes, and there are no agreed-on standards in the imaging community. Therefore, the results acquired from different research centers are difficult to compare, which hampers uniform clinical application and interpretation. This paper reviews current clinical APTw imaging approaches and provides a rationale for optimized APTw brain tumor imaging at 3 T, including specific recommendations for pulse sequences, acquisition protocols, and data processing methods. We expect that these consensus recommendations will become the first broadly accepted guidelines for APTw imaging of brain tumors on 3 T MRI systems from different vendors. This will allow more medical centers to use the same or comparable APTw MRI techniques for the detection, characterization, and monitoring of brain tumors, enabling multi-center trials in larger patient cohorts and, ultimately, routine clinical use.