Nuclear Overhauser Enhancement Signals Research Articles

NOE-weighted imaging in tumors using low-duty-cycle 2π-CEST.

Nuclear Overhauser enhancement (NOE)-mediated CEST imaging at -3.5 ppm has shown clinical interest in diagnosing tumors. Multiple-pool Lorentzian fit has been used to quantify NOE, which, however, requires a long scan time. Asymmetric analysis of CEST signals could be a simple and fast method to quantify this NOE, but it has contamination from the amide proton transfer (APT) at 3.5 ppm. This work proposes a new method using an asymmetric analysis of a low-duty-cycle pulsed-CEST sequence with a flip angle of 360°, termed 2π-CEST, to reduce the contribution from APT. Simulations were used to evaluate the capability of the 2π-CEST to reduce APT. Experiments on animal tumor models were performed to show its advantages compared with the conventional asymmetric analysis. Samples of reconstituted phospholipids and proteins were used to evaluate the molecular origin of this NOE. The 2π-CEST has reduced contribution from APT. In tumors where we show that the NOE is comparable to the APT effect, reducing the contamination from APT is crucial. The results show that the NOE signal obtained with 2π-CEST in tumor regions appears more homogeneous than that obtained with the conventional method. The phantom study showed that both phospholipids and proteins contribute to the NOE at -3.5 ppm. The NOE at -3.5 ppm has a different contrast mechanism from APT and other CEST/NOE effects. The proposed 2π-CEST is more accurate than the conventional asymmetric analysis in detecting NOE, and requires much less scan time than the multiple-pool Lorentzian fit.

Molecular imaging of cancer by glucosamine chemical exchange saturation transfer MRI: A preclinical study.

Glucosamine (GlcN) was recently proposed as an agent with an excellent safety profile to detect cancer with the chemical exchange saturation transfer (CEST) MRI technique. Translation of the GlcN CEST method to the clinical application requires evaluation of its sensitivity to the different frequency regions of irradiation. Hence, imaging of the GlcN signal was established for the full Z spectra recorded following GlcN administration to mice bearing implanted 4T1 breast tumors. Significant CEST effects were observed at around 1.5, 3.6 and -3.4 ppm, corresponding to the hydroxyl, amine/amide exchangeable protons and for the Nuclear Overhauser Enhancement (NOE), respectively. The sources of the observed CEST effects were investigated by identifying the GlcN metabolic products as observed by 13 C NMR spectroscopy studies of extracts from the same tumor model following treatment with [UL-13 C] -GlcN·HCl. The CEST contribution can be attributed to several phosphorylated products of GlcN, including uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc), which is a substrate for the O-linked and N-linked glycosylated proteins that may be associated with the increase of the NOE signal. The observation of a significant amount of lactate among the metabolic products hints at acidification as one of the sources of the enhanced CEST effect of GlcN. The proposed method may offer a new approach for clinical molecular imaging that enables the detection of metabolically active tumors and may play a role in other diseases.

Age-related differences in myeloarchitecture measured at 7 T

We have used the magnetisation transfer (MT) MRI measure as a primary measure of myelination in both the gray matter (GM) of the 78 cortical automated anatomical labeling (AAL) regions of the brain, and the underlying white matter in each region, in a cohort of healthy adults (aged 19–62 year old). The results revealed a significant quadratic trend in myelination with age, with average global myelination peaking at 42.9 year old in gray matter, and at 41.7 year old in white matter. We also explored the possibility of using the Nuclear Overhauser Enhancement (NOE) effect, which is acquired in a similar method to MT, as an additional measure of myelination. We found that the MT and NOE signals were strongly correlated in the brain and that the NOE effects displayed similar (albeit weaker) parabolic trends with age. We also investigated differences in cortical thickness with age, and confirmed a previous result of a linear decline of 4.5 ± 1.2 μm/y.

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.

Toward more reliable measurements of NOE effects in CEST spectra at around -1.6 ppm (NOE (-1.6)) in rat brain.

Recently, a new relayed nuclear Overhauser enhancement (NOE) saturation transfer effect at around -1.6 parts per million, termed NOE(-1.6), and its potential applications in tumor and stroke were reported by several institutes. However, there is a concern of the reproducibility of NOE(-1.6) measurements because it is not reported by many other publications. This paper aims to study the influence of typically overlooked experimental settings on the NOE(-1.6) signal and to build a framework for more reliable measurements of NOE(-1.6) at 9.4T. Z-spectra were obtained in rat brains. A fitting approach was performed to quantify all known saturation transfer effects except NOE(-1.6). Residual signals were obtained by removing these confounding effects from Z-spectra and were then used to quantify NOE(-1.6). Multislice imaging was performed to study the NOE(-1.6) dependence on brain regions. The influences of euthanasia, anesthesia, breathing gases, and RF irradiation power were also evaluated. Results demonstrate that the NOE(-1.6) signal contributions are often not clearly observable in raw Z-spectra at relatively high irradiation powers due to, for example, the direct water saturation effect, but they can be visualized after removing other nonspecific effects. In addition, the NOE(-1.6) effect depends on brain region, decreases postmortem, shifts after long-duration anesthesia, and may be enhanced by increasing O2 and N2 O breathing air concentrations. Because the NOE(-1.6) effect is more susceptible to the direct water saturation effect and more sensitive to physiological conditions than are other CEST effects, incorporating known sensitivities into the experimental design and data analysis is necessary to ensure more reliable NOE(-1.6) results.

The z-spectrum from human blood at 7T

Chemical Exchange Saturation Transfer (CEST) has been used to assess healthy and pathological tissue in both animals and humans. However, the CEST signal from blood has not been fully assessed. This paper presents the CEST and nuclear Overhauser enhancement (NOE) signals detected in human blood measured via z-spectrum analysis. We assessed the effects of blood oxygenation levels, haematocrit, cell structure and pH upon the z-spectrum in ex vivo human blood for different saturation powers at 7T. The data were analysed using Lorentzian difference (LD) model fitting and AREX (to compensate for changes in T1), which have been successfully used to study CEST effects in vivo. Full Bloch-McConnell fitting was also performed to provide an initial estimate of exchange rates and transverse relaxation rates of the various pools. CEST and NOE signals were observed at 3.5 ppm, −1.7 ppm and −3.5 ppm and were found to originate primarily from the red blood cells (RBCs), although the amide proton transfer (APT) CEST effect, and NOEs showed no dependence upon oxygenation levels. Upon lysing, the APT and NOE signals fell significantly. Different pH levels in blood resulted in changes in both the APT and NOE (at −3.5 ppm), which suggests that this NOE signal is in part an exchange relayed process. These results will be important for assessing in vivo z-spectra.

Imaging of nuclear Overhauser enhancement at 7 and 3T.

Nuclear Overhauser enhancement (NOE) is a type of magnetization transfer using cross-relaxation. It originates from mobile macromolecules, which may have relevance to the evaluation of tumor features. We studied the value of NOE imaging at 7 and 3T and suggest a utility for diagnosing human brain tumors. Two types of protein solution at different concentrations and pH values, and six normal Sprague Dawley (SD) rats, were used to detect NOE signal with a 7T scanner. Then, six healthy volunteers and 11 patients with brain tumors (six gliomas and five meningiomas) were included at 3T. Z-spectra were measured and NOE weighted (NOE*) images were acquired with a three-offset measurement. Wide spectral separation was shown at both 7T and 3T delineating the NOE peak in the Z-spectrum. The concentration dependence and pH independence of NOE were confirmed in phantom experiments, and NOE values were greater in white matter than in gray matter in vivo. At 3T, data indicated that NOE* maps were slightly hypointense in gliomas and were not obviously different from meningiomas. Thus, NOE imaging may help distinguish benign from malignant tumors, and as such may contribute to diagnosing brain tumors.

Nuclear Overhauser Enhancement-Mediated Magnetization Transfer Imaging in Glioma with Different Progression at 7 T.

Glioma is a malignant neoplasm affecting the central nervous system. The conventional approaches to diagnosis, such as T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), and contrast-enhanced T1WI, give an oversimplified representation of anatomic structures. Nuclear Overhauser enhancement (NOE) imaging is a special form of magnetization transfer (MT) that provides a new way to detect small solute pools through indirect measurement of attenuated water signals, and makes it possible to probe semisolid macromolecular protons. In this study, we investigated the correlation between the effect of NOE-mediated imaging and progression of glioma in a rat tumor model. We found that the NOE signal decreased in tumor region, and signal of tumor center and peritumoral normal tissue markedly decreased with growth of the glioma. At the same time, NOE signal in contralateral normal tissue dropped relatively late (at about day 16-20 after implanting the glioma cells). NOE imaging is a new contrast method that may provide helpful insights into the pathophysiology of glioma with regard to mobile proteins, lipids, and other metabolites. Further, NOE images differentiate normal brain tissue from glioma tissue at a molecular level. Our study indicates that NOE-mediated imaging is a new and promising approach for estimation of tumor progression.

Quantitative assessment of the effects of water proton concentration and water T1 changes on amide proton transfer (APT) and nuclear overhauser enhancement (NOE) MRI: The origin of the APT imaging signal in brain tumor.

To quantify pure chemical exchange-dependent saturation transfer (CEST) related amide proton transfer (APT) and nuclear Overhauser enhancement (NOE) signals in a rat glioma model and to investigate the mixed effects of water content and water T1 on APT and NOE imaging signals. Eleven U87 tumor-bearing rats were scanned at 4.7 T. A relatively accurate mathematical approach, based on extrapolated semisolid magnetization-transfer reference signals, was used to remove the concurrent effects of direct water saturation and semisolid magnetization-transfer. Pure APT and NOE signals, in addition to the commonly used magnetization-transfer-ratio asymmetry at 3.5 ppm, MTRasym (3.5ppm), were assessed. The measured APT signal intensity of the tumor (11.06%, much larger than the value reported in the literature) was the major contributor (approximately 80.6%) to the MTRasym (3.5ppm) contrast between the tumor and the contralateral brain region. Both the water content ([water proton]) and water T1 (T1w ) were increased in the tumor, but there were no significant correlations among APT, NOE, or MTRasym (3.5ppm) signals and T1w /[water proton]. The effect of increasing T1w on the CEST signal in the tumor was mostly eliminated by the effect of increasing water content, and the observed APT-weighted hyperintensity in the tumor should be dominated by the increased amide proton concentration. Magn Reson Med 77:855-863, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Whole-brain amide proton transfer (APT) and nuclear overhauser enhancement (NOE) imaging in glioma patients using low-power steady-state pulsed chemical exchange saturation transfer (CEST) imaging at 7T.

To explore the relationship of amide proton transfer (APT) and nuclear Overhauser enhancement (NOE) signal intensities with respect to different World Health Organization (WHO) brain tumor grades (II to IV) at 7T. APT-based and NOE-based signals at 7T using low-power steady-state chemical exchange saturation transfer (CEST) were compared among de novo primary gliomas of different WHO grades (II to IV). The quantitative APT and NOE signals, calculated by fitting approach using extrapolated semisolid MT reference (EMR) signals, were compared with the magnetization transfer ratio asymmetry (MTRasym ) analysis, commonly used in APT-weighted MRI. The observed NOE signals of all glioma grades were significantly lower than normal brain tissue (P < 0.01). NOE signals significantly differed between low-grade (II) gliomas and high-grade (III, IV) gliomas (P < 0.05). APT signals showed no difference between the tumor regions for any glioma grades (M = 3.08%, 2.64%, and 3.10%, 95% confidence interval [CI] = 2.81% ∼ 3.33%, 2.36% ∼ 2.91%, and 2.85% ∼ 3.36% for grade II, III, and IV, respectively), and between normal brain tissue and all glioma grades (P = 0.08, M = 4.29% and 2.94%, 95% CI = 3.57% ∼ 4.99% and 2.47% ∼ 3.41% for normal and average grade II, III, and IV), while MTRasym differed significantly between normal tissue and all glioma grades (P < 0.05). NOE contributes substantially to APT-weighted MRI at 7T at low RF saturation power and provides a promising biomarker for glioma grading.J. Magn. Reson. Imaging 2016;44:41-50.

Quantitative assessment of amide proton transfer (APT) and nuclear overhauser enhancement (NOE) imaging with extrapolated semi-solid magnetization transfer reference (EMR) signals: Application to a rat glioma model at 4.7 Tesla.

To quantify amide proton transfer (APT) and nuclear Overhauser enhancement (NOE) contributions to in vivo chemical exchange saturation transfer MRI signals in tumors. Two-pool (free water and semi-solid protons) and four-pool (free water, semi-solid, amide, and upfield NOE-related protons) tissue models combined with the super-Lorentzian lineshape for semi-solid protons were used to fit wide and narrow frequency-offset magnetization-transfer (MT) data, respectively. Extrapolated semi-solid MT signals at 3.5 and -3.5 ppm from water were used as reference signals to quantify APT and NOE, respectively. Six glioma-bearing rats were scanned at 4.7 Tesla. Quantitative APT and NOE signals were compared at three saturation power levels. The observed APT signals were significantly higher in the tumor (center and rim) than in the contralateral normal brain tissue at all saturation powers, and were the major contributor to the APT-weighted image contrast (based on MT asymmetry analysis) between the tumor and the normal brain tissue. The NOE (a positive confounding factor) enhanced this APT-weighted image contrast. The fitted amide pool sizes were significantly larger, while the NOE-related pool sizes were significantly smaller in the tumor than in the normal brain tissue. The extrapolated semi-solid magnetization transfer reference provides a relatively accurate approach for quantitatively measuring pure APT and NOE signals.

Observation of true and pseudo NOE signals using CEST-MRI and CEST-MRS sequences with and without lipid suppression.

To investigate the characteristics of nuclear Overhauser enhancement (NOE) imaging signals in the brain at 7T. Fresh hen eggs, as well as six healthy, and six C6 glioma-bearing Wistar rats were scanned using chemical exchange saturation transfer-magnetic resonance imaging (CEST-MRI) and chemical exchange saturation transfer-magnetic resonance spectroscopy (CEST-MRS) sequences (saturation duration 3 s, power 1.47 µT) with and without lipid suppression. CEST data were acquired over an offset range of -6 to +6 ppm relative to the water resonance in 0.5 ppm steps. The water signals were not disrupted by other protons during the CEST-MRS sequences, and true NOE signals could be observed. Using the CEST-MRI sequence without lipid suppression, pseudo NOE imaging signals were observed in the lipid-containing regions (egg yolk, scalp, and even white matter). These pseudo NOE signals were almost (but incompletely) removed with the lipid suppression. Egg yolk results indicated the presence of the NOE to olefinic protons overlapping with the water signal. In vivo experiments showed that the amide proton transfer signal was larger in the tumor, whereas the NOE signal was larger in the normal white matter. True NOE signals can be detected using MRS sequences, and considerable pseudo NOE imaging signals may be observed using MRI sequences.

Imaging amide proton transfer and nuclear overhauser enhancement using chemical exchange rotation transfer (CERT)

This study investigates amide proton transfer (APT) and nuclear overhauser enhancement (NOE) in phantoms and 9L tumors in rat brains at 9.4 Tesla, using a recently developed method that can isolate different contributions to exchange. Chemical exchange rotation transfer (CERT) was used to quantify APT and NOEs through subtraction of signals acquired at two irradiation flip angles, but with the same average irradiation power. CERT separates and quantifies specific APT and NOE signals without contamination from other proton pools, and thus overcomes a key shortcoming of conventional CEST asymmetry approaches. CERT thus has increased specificity, though at the cost of decreased signal strength. In vivo experiments show that the APT effect acquired with CERT in 9L rat tumors (3.1%) is relatively greater than that in normal tissue (2.5%), which is consistent with previous CEST asymmetry analysis. The NOE effect centered at -1.6 ppm shows substantial image contrast within the tumor and between the tumor and the surrounding tissue, while the NOE effect centered at -3.5 ppm shows little contrast. CERT provides an image contrast that is more specific to chemical exchange than conventional APT by means of asymmetric CEST Z-spectra analysis.

High‐resolution imaging of magnetisation transfer and nuclear Overhauser effect in the human visual cortex at 7 T

The aim of this study was to optimise a pulse sequence for high-resolution imaging sensitive to the effects of conventional macromolecular magnetisation transfer (MT(m)) and nuclear Overhauser enhancement (NOE), and to use it to investigate variations in these parameters across the cerebral cortex. A high-spatial-resolution magnetisation transfer-prepared turbo field echo (MT-TFE) sequence was designed to have high sensitivity to MT(m) and NOE effects, whilst being robust to B0 and B1 inhomogeneities, and producing a good point spread function across the cortex. This was achieved by optimising the saturation and imaging components of the sequence using simulations based on the Bloch equations, including exchange and an image simulator. This was used to study variations in these parameters across the cortex. Using the sequence designed to be sensitive to NOE and MT(m), a variation in signals corresponding to a variation in MT(m) and NOE across the cortex, consistent with a reduction in myelination from the white matter surface to the pial surface of the cortex, was observed. In regions in which the stria was visible on T2*-weighted images, it could also be detected in signals sensitive to MT(m) and NOE. There was greater variation in signals sensitive to NOE, suggesting that the NOE signal is more sensitive to myelination. A sequence has been designed to image variations in MT(m) and NOE at high spatial resolution and has been used to investigate variations in contrast in these parameters across the cortex.

Nuclear Overhauser enhancement (NOE) imaging in the human brain at 7T

Chemical exchange saturation transfer (CEST) is a magnetization transfer (MT) technique to indirectly detect pools of exchangeable protons through the water signal. CEST MRI has focused predominantly on signals from exchangeable protons downfield (higher frequency) from water in the CEST spectrum. Low power radiofrequency (RF) pulses can slowly saturate protons with minimal interference of conventional semi-solid based MT contrast (MTC). When doing so, saturation-transfer signals are revealed upfield from water, which is the frequency range of non-exchangeable aliphatic and olefinic protons. The visibility of such signals indicates the presence of a relayed transfer mechanism to the water signal, while their finite width reflects that these signals are likely due to mobile solutes. It is shown here in protein phantoms and the human brain that these signals build up slower than conventional CEST, at a rate typical for intramolecular nuclear Overhauser enhancement (NOE) effects in mobile macromolecules such as proteins/peptides and lipids. These NOE-based saturation transfer signals show a pH dependence, suggesting that this process is the inverse of the well-known exchange-relayed NOEs in high resolution NMR protein studies, thus a relayed-NOE CEST process. When studying 6 normal volunteers with a low-power pulsed CEST approach, the relayed-NOE CEST effect was about twice as large as the CEST effects downfield and larger in white matter than gray matter. This NOE contrast upfield from water provides a way to study mobile macromolecules in tissue. First data on a tumor patient show reduction in both relayed NOE and CEST amide proton signals leading to an increase in magnetization transfer ratio asymmetry, providing insight into previously reported amide proton transfer (APT) effects in tumors.