Zhongliang Zu

Multi-angle ratiometric approach to measure chemical exchange in amide proton transfer imaging

Amide proton transfer imaging, a specific form of chemical exchange saturation transfer imaging, has previously been applied to studies of acute ischemic acidosis, stroke, and cancer. However, interpreting the resulting contrast is complicated by its dependence on the exchange rate between amides and water, the amide concentration, amide and water relaxation, and macromolecular magnetization transfer. Hence, conventional chemical exchange saturation transfer contrast is not specific to changes such as reductions in pH due to tissue acidosis. In this article, a multi‐angle ratiometric approach based on several pulsed‐chemical exchange saturation transfer scans at different irradiation flip angles is proposed to specifically reflect exchange rates only. This separation of exchange effects in pulsed‐chemical exchange saturation transfer experiments is based on isolating rotation vs. saturation contributions, and such methods form a new subclass of chemical exchange rotation transfer (CERT) experiments. Simulations and measurements of creatine/agar phantoms indicate that a newly proposed imaging metric isolates the effects of exchange rate changes, independent of other sample parameters. Magn Reson Med, 2012.

Optimizing pulsed-chemical exchange saturation transfer imaging sequences

Chemical exchange saturation transfer (CEST) provides a new imaging contrast mechanism sensitive to labile proton exchange. Pulsed‐CEST imaging is better suited to the hardware constraints on clinical imaging systems when compared with traditional continuous wave‐CEST imaging methods. However, designing optimum pulsed‐CEST imaging sequences entails complicated and time‐consuming numerical integrations. In this work, a simplified and computationally efficient technique is provided to optimize the pulsed‐CEST imaging sequence. An analysis was performed of the optimal average irradiation power and the optimal irradiation flip angle as a function of the acquisition parameters and sample properties in both a two‐pool model and a three‐pool model of endogenous amine exchange. Key simulated and experimental results based on a creatine/agar tissue phantom show that ( 1 ) the average irradiation power is a more meaningful sequence metric than is the average irradiation field amplitude, ( 2 ) the optimal average powers for continuous wave and pulsed‐CEST imaging are approximately equal to each other for a relevant range of solute frequency offsets, exchange rates, and concentrations, ( 3 ) an irradiation flip angle of 180° is optimal or near optimal, independent of the other acquisition parameters and the sample properties, and ( 4 ) higher duty cycles yield higher CEST contrast. Magn Reson Med, 2011.

On the origins of chemical exchange saturation transfer (CEST) contrast in tumors at 9.4 T

Chemical exchange saturation transfer (CEST) provides an indirect means to detect exchangeable protons within tissues through their effects on the water signal. Previous studies have suggested that amide proton transfer (APT) imaging, a specific form of CEST, detects endogenous amide protons with a resonance frequency offset 3.5 ppm downfield from water, and thus may be sensitive to variations in mobile proteins/peptides in tumors. However, as CEST measurements are influenced by various confounding effects, such as spillover saturation, magnetization transfer (MT) and MT asymmetry, the mechanism or degree of increased APT signal in tumors is not certain. In addition to APT, nuclear Overhauser enhancement (NOE) effects upfield from water may also provide distinct information on tissue composition. In the current study, APT, NOE and several other MR parameters were measured and compared comprehensively in order to elucidate the origins of APT and NOE contrasts in tumors at 9.4 T. In addition to conventional CEST methods, a new intrinsic inverse metric was applied to correct for relaxation and other effects. After corrections for spillover, MT and T1 effects, corrected APT in tumors was found not to be significantly different from that in normal tissues, but corrected NOE effects in tumors showed significant decreases compared with those in normal tissues. Biochemical measurements verified that there was no significant enhancement of protein contents in the tumors studied, consistent with the corrected APT measurements and previous literature, whereas quantitative MT data showed decreases in the fractions of immobile macromolecules in tumors. Our results may assist in the better understanding of the contrast depicted by CEST imaging in tumors, and in the development of improved APT and NOE measurements for cancer imaging. Copyright

A new method for detecting exchanging amide protons using chemical exchange rotation transfer

In this study, we introduce a new method for amide proton transfer imaging based on chemical exchange rotation transfer. It avoids several artifacts that plague conventional chemical exchange saturation transfer approaches by creating label and reference scans based on varying the irradiation pulse rotation angle (π and 2π radians) instead of the frequency offset (3.5 and −3.5 ppm). Specifically, conventional analysis is sensitive to confounding contributions from magnetic field (B0) inhomogeneities and, more problematically, inherently asymmetric macromolecular resonances. In addition, the lipid resonance at −3.5 ppm complicates the interpretation of the reference scan and decreases the resulting contrast. Finally, partial overlap of the amide signal by nearby amines and hydroxyls obscure the results. By avoiding these issues, our new method is a promising approach for imaging endogenous protein and peptide content and mapping pH. Magn Reson Med, 2013.

The radial diffusivity and magnetization transfer pool size ratio are sensitive markers for demyelination in a rat model of type III multiple sclerosis (MS) lesions.

Determining biophysical sensitivity and specificity of quantitative magnetic resonance imaging is essential to develop effective imaging metrics of neurodegeneration. Among these metrics, apparent pool size ratio (PSR) from quantitative magnetization transfer (qMT) imaging and radial diffusivity (RD) from diffusion tensor imaging (DTI) are both known to relate to histological measure of myelin density and integrity. However their relative sensitivities towards quantitative myelin detection are unknown. In this study, we correlated high-resolution quantitative magnetic resonance imaging measures of subvoxel tissue structures with corresponding quantitative myelin histology in a lipopolysaccharide (LPS) mediated animal model of MS. Specifically, we acquired quantitative magnetization transfer (qMT) and diffusion tensor imaging (DTI) metrics (on the same tissue sample) in an animal model system of type III oligodendrogliopathy which lacked prominent lymphocytic infiltration, a system that had not been previously examined with quantitative MRI. We find that the qMT measured apparent pool size ratio (PSR) showed the strongest correlation with a histological measure of myelin content. DTI measured RD showed the next strongest correlation, and other DTI and relaxation parameters (such as the longitudinal relaxation rate (R1f) or fractional anisotropy (FA)) showed considerably weaker correlations with myelin content.

A combined analytical solution for chemical exchange saturation transfer and semi-solid magnetization transfer

Off‐resonant RF irradiation in tissue indirectly lowers the water signal by saturation transfer processes: on the one hand, there are selective chemical exchange saturation transfer (CEST) effects originating from exchanging endogenous protons resonating a few parts per million from water; on the other hand, there is the broad semi‐solid magnetization transfer (MT) originating from immobile protons associated with the tissue matrix with kilohertz linewidths. Recently it was shown that endogenous CEST contrasts can be strongly affected by the MT background, so corrections are needed to derive accurate estimates of CEST effects. Herein we show that a full analytical solution of the underlying Bloch–McConnell equations for both MT and CEST provides insights into their interaction and suggests a simple means to isolate their effects. The presented analytical solution, based on the eigenspace solution of the Bloch–McConnell equations, extends previous treatments by allowing arbitrary lineshapes for the semi‐solid MT effects and simultaneously describing multiple CEST pools in the presence of a large MT pool for arbitrary irradiation. The structure of the model indicates that semi‐solid MT and CEST effects basically add up inversely in determining the steady‐state Z‐spectrum, as previously shown for direct saturation and CEST effects. Implications for existing previous CEST analyses in the presence of a semi‐solid MT are studied and discussed. It turns out that, to accurately quantify CEST contrast, a good reference Z‐value, the observed longitudinal relaxation rate of water, and the semi‐solid MT pool size fraction must all be known. Copyright

Amide proton transfer imaging of the human breast at 7T: Development and reproducibility

Chemical exchange saturation transfer (CEST) can offer information about protons associated with mobile proteins through the amide proton transfer (APT) effect, which has been shown to discriminate tumor from healthy tissue and, more recently, has been suggested as a prognosticator of response to therapy. Despite this promise, APT effects are small (only a few percent of the total signal), and APT imaging is often prone to artifacts resulting from system instability. Here we present a procedure that enables the detection of APT effects in the human breast at 7T while mitigating these issues. Adequate signal‐to‐noise ratio (SNR) was achieved via an optimized quadrature RF breast coil and 3D acquisitions. To reduce the influence of fat, effective fat suppression schemes were developed that did not degrade SNR. To reduce the levels of ghosting artifacts, dummy scans have been integrated into the scanning protocol. Compared with results obtained at 3T, the standard deviation of the measured APT effect was reduced by a factor of four at 7T, allowing for the detection of APT effects with a standard deviation of 1% in the human breast at 7T. Together, these results demonstrate that the APT effect can be reliably detected in the healthy human breast with a high level of precision at 7T. Copyright

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.

Optimized inversion recovery sequences for quantitative T1 and magnetization transfer imaging.

Inversion recovery sequences that vary the inversion time (ti) have been employed to determine T1 and, more recently, quantitative magnetization transfer parameters. Specifically, in previous work, the inversion recovery pulse sequences varied ti only while maintaining a constant delay (td) between repetitions. T1 values were determined by fitting to a single exponential function, and quantitative magnetization transfer parameters were then determined by fitting to a biexponential function with an approximate solution. In the current study, new protocols are employed, which vary both ti and td and fit the data with minimal approximations. Cramer‐Rao lower bounds are calculated to search for acquisition schemes that will maximize the precision efficiencies of T1 and quantitative magnetization transfer parameters. This approach is supported by Monte Carlo simulations. The optimal T1 schemes are verified by measurements on MnCl2 samples. The optimal quantitative magnetization transfer schemes are confirmed by measurements on a series of cross‐linked bovine serum albumin phantoms of varying concentrations. The effects of varying the number of sampling data points are also explored, and a rapid acquisition scheme is demonstrated in vivo. These new optimized quantitative imaging methods provide an improved means for determining T1 and magnetization transfer parameter values compared to previous inversion recovery based methods. Magn Reson Med, 2010.

A new NOE-mediated MT signal at around −1.6 ppm for detecting ischemic stroke in rat brain

In the present work, we reported a new nuclear Overhauser enhancement (NOE)-mediated magnetization transfer (MT) signal at around -1.6ppm (NOE(-1.6)) in rat brain and investigated its application in the detection of acute ischemic stroke in rodent model. Using continuous wave (CW) MT sequence, the NOE(-1.6) is reliably detected in rat brain. The amplitude of this new NOE signal in rat brain was quantified using a 5-pool Lorentzian Z-spectral fitting method. Amplitudes of amide, amine, NOE at -3.5ppm (NOE(-3.5)), as well as NOE(-1.6) were mapped using this fitting method in rat brain. Several other conventional imaging parameters (R1, R2, apparent diffusion coefficient (ADC), and semi-solid pool size ratio (PSR)) were also measured. Our results show that NOE(-1.6), R1, R2, ADC, and APT signals from stroke lesion have significant changes at 0.5-1h after stroke. Compared with several other imaging parameters, NOE(-1.6) shows the strongest contrast differences between stroke and contralateral normal tissues and stays consistent over time until 2h after onset of stroke. Our results demonstrate that this new NOE(-1.6) signal in rat brain is a new potential contrast for assessment of acute stroke in vivo and might provide broad applications in the detection of other abnormal tissues.