A hybrid numeric-analytic solution for pulsed CEST.

Chemical exchange saturation transfer (CEST) methods measure the effect of magnetization exchange between solutes and water. While CEST methods are often implemented using a train of off-resonant shaped RF pulses, they are typically analyzed as if the irradiation were continuous. This approximation does not account for exchange of rotated magnetization, unique to pulsed irradiation and exploited by chemical exchange rotation transfer methods. In this work, we derive and test an analytic solution for the steady-state water signal under pulsed irradiation by extending a previous work to include the effects of pulse shape. The solution is largely accurate at all offsets, but this accuracy diminishes at higher exchange rates and when applying pulse shapes with large root-mean-squared to mean ratios (such as multi-lobe sinc pulses).

Chemical exchange rotation transfer imaging of phosphocreatine in muscle.

In chemical exchange saturation transfer (CEST) imaging, the signal at 2.6 ppm from the water resonance in muscle has been assigned to phosphocreatine (PCr). However, this signal has limited specificity for PCr since the signal is also sensitive to exchange with protein and macromolecular protons when using some conventional quantification methods, and will vary with changes in the water longitudinal relaxation rate. Correcting for these effects while maintaining reasonable acquisition times is challenging. As an alternative approach to overcome these problems, here we evaluate chemical exchange rotation transfer (CERT) imaging of PCr in muscle at 9.4 T. Specifically, the CERT metric, AREXdouble,cpw at 2.6 ppm, was measured in solutions containing the main muscle metabolites, in tissue homogenates with controlled PCr content, and in vivo in rat leg muscles. PCr dominates CERT metrics around 2.6 ppm (although with nontrivial confounding baseline contributions), indicating that CERT is well-suited to PCr specific imaging, and has the added benefit of requiring a relatively small number of acquisitions.

Relayed nuclear Overhauser enhancement sensitivity to membrane Cho phospholipids.

PURPOSE: Phospholipids are key constituents of cell membranes and serve vital functions in the regulation of cellular processes; thus, a method for in vivo detection and characterization could be valuable for detecting changes in cell membranes that are consequences of either normal or pathological processes. Here, we describe a new method to map the distribution of partially restricted phospholipids in tissues. METHODS: The phospholipids were measured by signal changes caused by relayed nuclear Overhauser enhancement-mediated CEST between the phospholipid Cho headgroup methyl protons and water at around -1.6 ppm from the water resonance. The biophysical basis of this effect was examined by controlled manipulation of head group, chain length, temperature, degree of saturation, and presence of cholesterol. Additional experiments were performed on animal tumor models to evaluate potential applications of this novel signal while correcting for confounding contributions. RESULTS: Negative relayed nuclear Overhauser dips in Z-spectra were measured from reconstituted Cho phospholipids with cholesterol but not for other Cho-containing metabolites or proteins. Significant contrast was found between tumor and contralateral normal tissue signals in animals when comparing both the measured saturation transfer signal and a more specific imaging metric. CONCLUSION: We demonstrated specific relayed nuclear Overhauser effects in partially restricted phospholipid phantoms and similar effects in solid brain tumors after correcting for confounding signal contributions, suggesting possible translational applications of this novel molecular imaging method, which we name restricted phospholipid transfer.

Chemical exchange rotation transfer (CERT) on human brain at 3 Tesla.

PURPOSE: To test the ability of a novel pulse sequence applied in vivo at 3 Tesla to separate the contributions to the water signal from amide proton transfer (APT) and relayed nuclear Overhauser enhancement (rNOE) from background direct water saturation and semisolid magnetization transfer (MT). The lack of such signal source isolation has confounded conventional chemical exchange saturation transfer (CEST) imaging. METHODS: We quantified APT and rNOE signals using a chemical exchange rotation transfer (CERT) metric, MTRdouble . A range of duty cycles and average irradiation powers were applied, and results were compared with conventional CEST analyses using asymmetry (MTRasym ) and extrapolated magnetization transfer (EMR). RESULTS: Our results indicate that MTRdouble is more specific than MTRasym and, because it requires as few as 3 data points, is more rapid than methods requiring a complete Z-spectrum, such as EMR. In white matter, APT (1.5 ± 0.5%) and rNOE (2.1 ± 0.7%) were quantified by using MTRdouble with a 30% duty cycle and a 0.5-µT average power. In addition, our results suggest that MTRdouble is insensitive to B0 inhomogeneity, further magnifying its speed advantage over CEST metrics that require a separate B0 measurement. However, MTRdouble still has nontrivial sensitivity to B1 inhomogeneities. CONCLUSION: We demonstrated that MTRdouble is an alternative metric to evaluate APT and rNOE, which is fast, robust to B0 inhomogeneity, and easy to process.

Towards an analytic solution for pulsed CEST.

Chemical exchange saturation transfer (CEST) is an imaging method based on magnetization exchange between solutes and water. This exchange generates changes in the measured signal after off-resonance radiofrequency irradiation. Although the analytic solution for CEST with continuous wave (CW) irradiation has been determined, most studies are performed using pulsed irradiation. In this work, we derive an analytic solution for the CEST signal after pulsed irradiation that includes both short-time rotation effects and long-time saturation effects in a two-pool system corresponding to water and a low-concentration exchanging solute pool. Several approximations are made to balance the accuracy and simplicity of the resulting analytic form, which is tested against numerical solutions of the coupled Bloch equations and is found to be largely accurate for amides at high fields, but less accurate at the higher exchange rates, lower offsets and typically higher irradiation powers of amines.

Propagation of error from parameter constraints in quantitative MRI: Example application of multiple spin echo T2 mapping.

PURPOSE: Quantitative MRI may require correcting for nuisance parameters which can or must be constrained to independently measured or assumed values. The noise and/or bias in these constraints propagate to fitted parameters. For example, the case of refocusing pulse flip angle constraint in multiple spin echo T2 mapping is explored. METHODS: An analytical expression for the mean-squared error of a parameter of interest was derived as a function of the accuracy and precision of an independent estimate of a nuisance parameter. The expression was validated by simulations and then used to evaluate the effects of flip angle (θ) constraint on the accuracy and precision of T⁁2 for a variety of multi-echo T2 mapping protocols. RESULTS: Constraining θ improved T⁁2 precision when the θ-map signal-to-noise ratio was greater than approximately one-half that of the first spin echo image. For many practical scenarios, constrained fitting was calculated to reduce not just the variance but the full mean-squared error of T⁁2, for bias in θ⁁≲6%. CONCLUSION: The analytical expression derived in this work can be applied to inform experimental design in quantitative MRI. The example application to T2 mapping provided specific cases, depending on θ⁁ accuracy and precision, in which θ⁁ measurement and constraint would be beneficial to T⁁2 variance or mean-squared error. Magn Reson Med 79:673-682, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Fast T2 mapping with multiple echo, Caesar cipher acquisition and model-based reconstruction.

PURPOSE: Fast, quantitative T2 mapping is of value to both clinical and research environments. However, many protocols utilizing fast spin echo (FSE) pulse sequences contain acceleration-induced artifacts that are compounded when fitting parameter maps, especially in the presence of imperfect refocusing. This work presents a B1 -corrected, model-based reconstruction and associated Cartesian FSE phase-encode ordering that provides enhanced accuracy in T2 estimates compared with other common accelerated protocols. THEORY AND METHODS: The method, known as multiple echo, Caesar cipher acquisition and model-based reconstruction (ME-CAMBREC), directly fitted T2 , flip angle, and proton density maps on a row-by-row basis to k-space data using the extended phase graph model. Regularization was enforced in order to minimize noise amplification effects. ME-CAMBREC was evaluated in computational and physical phantoms, as well as human brain, and compared with other FSE-based T2 mapping protocols, DESPOT2, and parallel imaging acceleration. RESULTS: In computational, phantom, and human experiments, ME-CAMBREC provided T2 maps with fewer artifacts and less or similar error compared with other methods tested at moderate-to-high acceleration factors. In vivo, ME-CAMBREC provided error rates approximately one-half those of other methods. CONCLUSION: Directly fitting multi-echo data to k-space using the extended phase graph can increase fidelity of T2 maps significantly, especially when using an appropriate phase-encode ordering.

On the inherent precision of mcDESPOT.

A statistical analysis of the mcDESPOT protocol for characterizing two exchanging water proton pools--a seven-dimensional problem that fits to multiple flip angle measurements of both spoiled and refocused gradient echoes--is presented. Theoretical calculations of the Cramér-Rao lower bounds of the variance of fitted model parameters were made using a variety of model system parameters, meant to mimic those expected in human white matter. The results, validated by Monte Carlo simulations, indicated that mcDESPOT signals acquired at feasibly attainable signal-to-noise ratios cannot provide parameter estimates with useful levels of precision. Precision can be greatly improved by constraining solutions with a priori model information, although this will generally lead to biased parameter estimates with less specificity. These results indicate that previous, apparently successful applications of mcDESPOT to human white matter may have used data fitting methods that implicitly constrained parameter solutions, or that the two-pool model of white matter may not be sufficient to describe the observed water proton signal in mcDESPOT acquisitions. In either case, mcDESPOT-derived estimates of two-pool model parameters cannot yet be unambiguously related to specific tissue characteristics.