Daniel F. Gochberg

Characterization of 1H NMR Signal in Human Cortical Bone for Magnetic Resonance Imaging

Recent advancements in MRI have enabled clinical imaging of human cortical bone, providing a potentially powerful new means for assessing bone health with molecular‐scale sensitivities unavailable to conventional X‐ray‐based diagnostics. In human cortical bone, MRI is sensitive to populations of protons (1H) partitioned among water and protein sources, which may be differentiated according to intrinsic NMR properties such as chemical shift and transverse and longitudinal relaxation rates. Herein, these NMR properties were assessed in human cortical bone donors from a broad age range, and four distinct 1H populations were consistently identified and attributed to five microanatomical sources. These findings show that modern human cortical bone MRI contrast will be dominated by collagen‐bound water, which can also be exploited to study human cortical bone collagen via magnetization transfer. Magn Reson Med, 2010.

Inverse Z-spectrum analysis for spillover-, MT-, and T1-corrected steady-state pulsed CEST-MRI – application to pH-weighted MRI of acute stroke

Endogenous chemical exchange saturation transfer (CEST) effects are always diluted by competing effects, such as direct water proton saturation (spillover) and semi‐solid macromolecular magnetization transfer (MT). This leads to unwanted T2 and MT signal contributions that lessen the CEST signal specificity to the underlying biochemical exchange processes. A spillover correction is of special interest for clinical static field strengths and protons resonating near the water peak. This is the case for all endogenous CEST agents, such as amide proton transfer, –OH‐CEST of glycosaminoglycans, glucose or myo‐inositol, and amine exchange of creatine or glutamate. All CEST effects also appear to be scaled by the T1 relaxation time of water, as they are mediated by the water pool. This forms the motivation for simple metrics that correct the CEST signal.

Multiexponential T2, magnetization transfer, and quantitative histology in white matter tracts of rat spinal cord.

Quantitative MRI measures of multiexponential T2 relaxation and magnetization transfer were acquired from six samples of excised and fixed rat spinal cord and compared with quantitative histology. MRI and histology data were analyzed from six white matter tracts, each of which possessed unique microanatomic characteristics (axon diameter and myelin thickness, in particular) but a relatively constant volume fraction of myelin. The results indicated that multiexponential T2 relaxation characteristics varied substantially with variation of microanatomy, while the magnetization transfer characteristics remained close to constant. The most‐often‐cited multiexponential T2 relaxation metric, myelin water fraction, varied by almost a factor of 2 between two regions with myelin volume fractions that differed by only ≈ 12%. Based on the quantitative histology, the proposed explanation for this variation was intercompartmental water exchange, which caused the underestimation of myelin water fraction and T2 values and is, presumably, a greater factor in white matter regions where axons are small and myelin is thin. In contrast to the multiexponential T2 relaxation observations, magnetization transfer metrics were relatively constant across white matter tracts and concluded to be relatively insensitive to intercompartmental water exchange. Magn Reson Med 63:902–909, 2010.

Quantitative magnetization transfer imaging via selective inversion recovery with short repetition times.

Quantitative magnetization transfer imaging (qMTI) methods are able to estimate fundamental sample parameters, such as the relative size of the solid‐like macromolecular proton pool and the spin exchange rate between this pool and the directly measured free water protons. One such method is selective inversion recovery (SIR), in which the free water protons are selectively inverted and the signal is fit to a biexponential function of the inversion time (TI). SIR uses only low‐power pulses and requires no separate RF (B1) or static field (B0) field maps, and the analysis is largely independent of the macromolecular pool lineshape. These are all advantages over steady‐state off‐resonance saturation qMTI methods. However, up to now, SIR has been implemented only with repetition times TR ≫ T1. This paper describes a modification of SIR with smaller TR values and a greater signal‐to‐noise ratio (SNR) efficiency. Magn Reson Med 57:437–441, 2007.

Quantitative imaging of magnetization transfer using an inversion recovery sequence.

A new imaging method has been developed for quantitatively measuring magnetization transfer (MT). It uses a simple inversion recovery sequence, although one with very short (milliseconds) inversion times, and thus can be implemented on clinical imaging systems with little modification to existing pulse sequences. The sequence requires an inversion pulse with a length much longer than T2m (typically 10 μs) and much shorter than T2f (typically tens of ms) and 1/kmf (typically tens of ms), where T2m and T2f are the transverse relaxation times of the immobile macromolecular and free water protons, respectively, and kmf is the rate of MT between these populations. The resultant NMR signal is sensitive to MT when this inversion pulse affects the mobile and immobile proton pools to different degrees and by appropriate analysis of the signals obtained for different inversion times, quantitative information can be derived on the macromolecular content and exchange rates within the sample. The method has been used in conjunction with echo planar imaging to produce maps of the spatial distribution of the macromolecular content and MT rate in cross‐linked bovine serum albumin. Comparisons between this method and other quantitative MT techniques are discussed. Magn Reson Med 49:501–505, 2003.

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.

Non-invasive Predictors of Human Cortical Bone Mechanical Properties: T2-Discriminated 1H NMR Compared with High Resolution X-ray

Recent advancements in magnetic resonance imaging (MRI) have enabled clinical imaging of human cortical bone, providing a potentially powerful new means for assessing bone health with molecular-scale sensitivities unavailable to conventional X-ray-based diagnostics. To this end, 1H nuclear magnetic resonance (NMR) and high-resolution X-ray signals from human cortical bone samples were correlated with mechanical properties of bone. Results showed that 1H NMR signals were better predictors of yield stress, peak stress, and pre-yield toughness than were the X-ray derived signals. These 1H NMR signals can, in principle, be extracted from clinical MRI, thus offering the potential for improved clinical assessment of fracture risk.