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5.  Nuclear Overhauser Enhancement (NOE) Imaging in the Human Brain at 7 T 
NeuroImage  2013;77:10.1016/j.neuroimage.2013.03.047.
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 an 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.
PMCID: PMC3848060  PMID: 23567889
CEST; nuclear overhauser enhancement; NOE; relay; exchange; high field; MRI; asymmetry analysis; Lorentzian Curve Fit
6.  Direct in vitro comparison of six 3D positive contrast methods for susceptibility marker imaging 
To compare different techniques for positive contrast imaging of susceptibility markers with MRI for 3D visualization. As several different techniques have been reported, the choice of the suitable method depends on its properties with regard to the amount of positive contrast and the desired background suppression, as well as other imaging constraints needed for a specific application.
Materials and methods
Six different positive contrast techniques are investigated for their ability to image at 3T a single susceptibility marker in vitro. The white marker method (WM), susceptibility gradient mapping (SGM), inversion recovery with on-resonant water suppression (IRON), frequency selective excitation (FSX), fast low flip-angle positive contrast SSFP (FLAPS), and iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) were implemented and investigated.
The different methods were compared with respect to the volume of positive contrast, the product of volume and signal intensity, imaging time, and the level of background suppression. Quantitative results are provided and strengths and weaknesses of the different approaches are discussed.
The appropriate choice of positive contrast imaging technique depends on the desired level of background suppression, acquisition speed, and robustness against artifacts, for which in vitro comparative data is now available.
PMCID: PMC3620818  PMID: 23281151
susceptibility imaging; off resonance; positive contrast
7.  A Spatially-selective Implementation of the Adiabatic T2Prep Sequence for Magnetic Resonance Angiography of the Coronary Arteries 
In coronary magnetic resonance angiography, a magnetization-preparation scheme for T2-weighting (T2Prep) is widely used to enhance contrast between the coronary blood-pool and the myocardium. This pre-pulse is commonly applied without spatial selection to minimize flow sensitivity, but the non-selective implementation results in a reduced magnetization of the in-flowing blood and a related penalty in signal-to-noise-ratio (SNR). It is hypothesized that a spatially-selective T2Prep would leave the magnetization of blood outside the T2Prep volume unaffected, and thereby lower the SNR penalty. To test this hypothesis, a spatially-selective T2Prep was implemented where the user could freely adjust angulation and position of the T2Prep slab to avoid covering the ventricular blood-pool and saturating the in-flowing spins. A time gap of 150ms was further added between the T2Prep and other pre-pulses to allow for in-flow of a larger volume of unsaturated spins. Consistent with numerical simulation, the spatially-selective T2Prep increased in vivo human coronary artery SNR (42.3±2.9 vs. 31.4±2.2, n=22, p<0.0001) and contrast-to-noise-ratio (18.6±1.5 vs. 13.9±1.2, p=0.009) as compared to those of the non-selective T2Prep. Additionally, a segmental analysis demonstrated that the spatially-selective T2Prep was most beneficial in proximal and mid segments where the in-flowing blood volume was largest compared to the distal segments.
PMCID: PMC3530637  PMID: 22915337
Coronary MR Angiography; Contrast Enhancement; T2Prep; Vessel Conspicuity; In-flowing Blood
Two approaches to high-resolution SENSE-encoded magnetic resonance spectroscopic imaging (MRSI) of the human brain at 7 Tesla (T) with whole-slice coverage are described. Both sequences use high-bandwidth radiofrequency pulses to reduce chemical shift displacement artifacts, SENSE-encoding to reduce scan time, and dual-band water and lipid suppression optimized for 7T. Simultaneous B0 and transmit B1 mapping was also used for both sequences to optimize field homogeneity using high order shimming and determine optimum radiofrequency (RF) transmit level, respectively. One sequence (‘Hahn-MRSI’) used reduced flip angle (90°) refocusing pulses for lower RF power deposition, while the other sequence used adiabatic fast passage (AFP) refocusing pulses for improved sensitivity and reduced signal dependence on the transmit-B1 level. In 4 normal subjects, AFP-MRSI showed a signal-to-noise ratio improvement of 3.2±0.5 compared to Hahn-MRSI at the same spatial resolution, TR, TE and SENSE-acceleration factor. An interleaved two-slice Hahn-MRSI sequence is also demonstrated to be experimentally feasible.
PMCID: PMC3443531  PMID: 22692894
Magnetic resonance spectroscopy; spectroscopic imaging; 7 Tesla; sensitivity-encoding; dual-band suppression; brain; adiabatic pulses
9.  Robust volume-targeted balanced steady-state free-precession coronary magnetic resonance angiography in a breathhold at 3.0 Tesla: a reproducibility study 
Transient balanced steady-state free-precession (bSSFP) has shown substantial promise for noninvasive assessment of coronary arteries but its utilization at 3.0 T and above has been hampered by susceptibility to field inhomogeneities that degrade image quality. The purpose of this work was to refine, implement, and test a robust, practical single-breathhold bSSFP coronary MRA sequence at 3.0 T and to test the reproducibility of the technique.
A 3D, volume-targeted, high-resolution bSSFP sequence was implemented. Localized image-based shimming was performed to minimize inhomogeneities of both the static magnetic field and the radio frequency excitation field. Fifteen healthy volunteers and three patients with coronary artery disease underwent examination with the bSSFP sequence (scan time = 20.5 ± 2.0 seconds), and acquisitions were repeated in nine subjects. The images were quantitatively analyzed using a semi-automated software tool, and the repeatability and reproducibility of measurements were determined using regression analysis and intra-class correlation coefficient (ICC), in a blinded manner.
The 3D bSSFP sequence provided uniform, high-quality depiction of coronary arteries (n = 20). The average visible vessel length of 100.5 ± 6.3 mm and sharpness of 55 ± 2% compared favorably with earlier reported navigator-gated bSSFP and gradient echo sequences at 3.0 T. Length measurements demonstrated a highly statistically significant degree of inter-observer (r = 0.994, ICC = 0.993), intra-observer (r = 0.894, ICC = 0.896), and inter-scan concordance (r = 0.980, ICC = 0.974). Furthermore, ICC values demonstrated excellent intra-observer, inter-observer, and inter-scan agreement for vessel diameter measurements (ICC = 0.987, 0.976, and 0.961, respectively), and vessel sharpness values (ICC = 0.989, 0.938, and 0.904, respectively).
The 3D bSSFP acquisition, using a state-of-the-art MR scanner equipped with recently available technologies such as multi-transmit, 32-channel cardiac coil, and localized B0 and B1+ shimming, allows accelerated and reproducible multi-segment assessment of the major coronary arteries at 3.0 T in a single breathhold. This rapid sequence may be especially useful for functional imaging of the coronaries where the acquisition time is limited by the stress duration and in cases where low navigator-gating efficiency prohibits acquisition of a free breathing scan in a reasonable time period.
PMCID: PMC4006454  PMID: 24758168
Coronary artery angiography; 3.0 T magnetic resonance imaging; Balanced steady-state free-precession; Reproducibility; Image-based shimming
11.  The Cement Prosthesis-Like Spacer: An Intermediate Halt on the Road to Healing 
The Scientific World Journal  2013;2013:763434.
Background. Periprosthetic infections remain a devastating problem in the field of joint arthroplasty. In the following study, the results of a two-stage treatment protocol for chronic periprosthetic infections using an intraoperatively molded cement prosthesis-like spacer (CPLS) are presented. Methods. Seventy-five patients with chronically infected knee prosthesis received a two-stage revision procedure with the newly developed CPLS between June 2006 and June 2011. Based on the microorganism involved, patients were grouped into either easy to treat (ETT) or difficult to treat (DTT) and treated accordingly. Range of motion (ROM) and the knee society score (KSS) were utilized for functional assessment. Results. Mean duration of the CPLS implant in the DTT group was 3.6 months (range 3–5 months) and in the ETT group 1.3 months (range 0.7–2.5 months). Reinfection rates of the final prosthesis were 9.6% in the ETT and 8.3% in the DTT group with no significant difference between both groups regarding ROM or KSS (P = 0.87, 0.64, resp.). Conclusion. The results show that ETT patients do not necessitate the same treatment protocol as DTT patients to achieve the same goal, emphasizing the need to differentiate between therapeutic regimes. We also highlight the feasibility of CLPS in two-stage protocols.
PMCID: PMC3806478  PMID: 24198728
12.  Regional Coronary Endothelial Function is Closely Related to Local Early Coronary Atherosclerosis in Patients with Mild Coronary Artery Disease: A Pilot Study 
Coronary endothelial function (endoFx) is abnormal in patients with established coronary artery disease (CAD) and was recently shown by MRI to relate to the severity of luminal stenosis. Recent advances in MRI now allow the non-invasive assessment of both anatomic and functional (endoFx) changes that previously required invasive studies. We tested the hypothesis that abnormal coronary endoFx is related to measures of early atherosclerosis such as increased coronary wall thickness (CWT).
Methods and Results
Seventeen arteries in fourteen healthy adults and seventeen arteries in fourteen patients with non-obstructive CAD were studied. To measure endoFx, coronary MRI was performed before and during isometric handgrip exercise, an endothelial-dependent stressor and changes in coronary cross-sectional area (CSA) and flow were measured. Black blood imaging was performed to quantify CWT and other indices of arterial remodeling. The mean stress-induced change in CSA was significantly higher in healthy adults (13.5%±12.8%, mean±SD, n=17) than in those with mildly diseased arteries (-2.2±6.8%, p<0.0001, n=17). Mean CWT was lower in healthy subjects (0.9±0.2mm) than in CAD patients (1.4±0.3mm, p<0.0001). In contrast to healthy subjects, stress-induced changes in CSA, a measure of coronary endoFx, correlated inversely with CWT in CAD patients (r= -0.73, p=0.0008).
There is an inverse relationship between coronary endothelial function and local CWT in CAD patients but not in healthy adults. These findings demonstrate that local endothelial-dependent functional changes are related to the extent of early anatomic atherosclerosis in mildly diseased arteries. This combined MRI approach enables the anatomic and functional investigation of early coronary disease.
PMCID: PMC3665274  PMID: 22492483
coronary disease; endothelium; magnetic resonance imaging
13.  Magnetic resonance Spectroscopy with Linear Algebraic Modeling (SLAM) for higher speed and sensitivity 
Speed and signal-to-noise ratio (SNR) are critical for localized magnetic resonance spectroscopy (MRS) of low-concentration metabolites. Matching voxels to anatomical compartments a priori yields better SNR than the spectra created by summing signals from constituent chemical-shift-imaging (CSI) voxels post-acquisition. Here, a new method of localized Spectroscopy using Linear Algebraic Modeling (SLAM) is presented, that can realize this additional SNR gain. Unlike prior methods, SLAM generates spectra from C signal-generating anatomic compartments utilizing a CSI sequence wherein essentially only the C central k-space phase-encoding gradient steps with highest SNR are retained. After MRI-based compartment segmentation, the spectra are reconstructed by solving a sub-set of linear simultaneous equations from the standard CSI algorithm. SLAM is demonstrated with one-dimensional CSI surface coil phosphorus MRS in phantoms, the human leg and the heart on a 3T clinical scanner. Its SNR performance, accuracy, sensitivity to registration errors and inhomogeneity, are evaluated. Compared to one-dimensional CSI, SLAM yielded quantitatively the same results 4-times faster in 24 cardiac patients and healthy subjects. SLAM is further extended with fractional phase-encoding gradients that optimize SNR and/or minimize both inter- and intra-compartmental contamination. In proactive cardiac phosphorus MRS of 6 healthy subjects, both SLAM and fractional-SLAM (fSLAM) produced results indistinguishable from CSI while preserving SNR gains of 36–45% in the same scan-time. Both SLAM and fSLAM are simple to implement and reduce the minimum scan-time for CSI, which otherwise limits the translation of higher SNR achievable at higher field strengths to faster scanning.
PMCID: PMC3381802  PMID: 22578557
spectral localization; chemical shift imaging (CSI); cardiac; constrained reconstruction; phosphorus; metabolism; heart
14.  Non-Invasive Detection of Coronary Endothelial Response to Sequential Handgrip Exercise in Coronary Artery Disease Patients and Healthy Adults 
PLoS ONE  2013;8(3):e58047.
Our objective is to test the hypothesis that coronary endothelial function (CorEndoFx) does not change with repeated isometric handgrip (IHG) stress in CAD patients or healthy subjects.
Coronary responses to endothelial-dependent stressors are important measures of vascular risk that can change in response to environmental stimuli or pharmacologic interventions. The evaluation of the effect of an acute intervention on endothelial response is only valid if the measurement does not change significantly in the short term under normal conditions. Using 3.0 Tesla (T) MRI, we non-invasively compared two coronary artery endothelial function measurements separated by a ten minute interval in healthy subjects and patients with coronary artery disease (CAD).
Twenty healthy adult subjects and 12 CAD patients were studied on a commercial 3.0 T whole-body MR imaging system. Coronary cross-sectional area (CSA), peak diastolic coronary flow velocity (PDFV) and blood-flow were quantified before and during continuous IHG stress, an endothelial-dependent stressor. The IHG exercise with imaging was repeated after a 10 minute recovery period.
In healthy adults, coronary artery CSA changes and blood-flow increases did not differ between the first and second stresses (mean % change ±SEM, first vs. second stress CSA: 14.8%±3.3% vs. 17.8%±3.6%, p = 0.24; PDFV: 27.5%±4.9% vs. 24.2%±4.5%, p = 0.54; blood-flow: 44.3%±8.3 vs. 44.8%±8.1, p = 0.84). The coronary vasoreactive responses in the CAD patients also did not differ between the first and second stresses (mean % change ±SEM, first stress vs. second stress: CSA: −6.4%±2.0% vs. −5.0%±2.4%, p = 0.22; PDFV: −4.0%±4.6% vs. −4.2%±5.3%, p = 0.83; blood-flow: −9.7%±5.1% vs. −8.7%±6.3%, p = 0.38).
MRI measures of CorEndoFx are unchanged during repeated isometric handgrip exercise tests in CAD patients and healthy adults. These findings demonstrate the repeatability of noninvasive 3T MRI assessment of CorEndoFx and support its use in future studies designed to determine the effects of acute interventions on coronary vasoreactivity.
PMCID: PMC3594224  PMID: 23536782
Magnetic resonance angiography (MRA) provides a noninvasive means to detect the presence, location and severity of atherosclerosis throughout the vascular system. In such studies, and especially those in the coronary arteries, the vessel luminal area is typically measured at multiple cross-sectional locations along the course of the artery. The advent of fast volumetric imaging techniques covering proximal to mid segments of coronary arteries necessitates automatic analysis tools requiring minimal manual interactions to robustly measure cross-sectional area along the three-dimensional track of the arteries in under-sampled and non-isotropic datasets. In this work, we present a modular approach based on level set methods to track the vessel centerline, segment the vessel boundaries, and measure transversal area using two user-selected endpoints in each coronary of interest. Arterial area and vessel length are measured using our method and compared to the standard Soap-Bubble reformatting and analysis tool in in-vivo non-contrast enhanced coronary MRA images.
PMCID: PMC3461337  PMID: 23032185
3D Centerline Tracking; 3D Segmentation; Level Set Methods; Non-contrast enhanced Magnetic Resonance Angiography; Coronary Arteries
20.  Coronary Artery Distensibility Assessed by 3.0 T Coronary Magnetic Resonance Imaging in Subjects With and Without Coronary Artery Disease 
The American journal of cardiology  2011;108(4):491-497.
Coronary vessel distensibility is reduced with atherosclerosis and normal aging but direct measurements have historically required invasive measurements at cardiac catheterization. Therefore, we sought to assess coronary artery distensibility non-invasively with 3.0T coronary magnetic resonance imaging (MRI) and to test the hypothesis that this non-invasive technique can detect differences in coronary distensibility between healthy and coronary artery disease (CAD) subjects. Thirty-eight healthy, adult subjects (23 men, mean age 31±10 years) and 21 patients with CAD defined on X-ray angiography (11 men, mean age 57±6 years) were studied on a commercial whole-body MR imaging system (Achieva 3.0 T; Philips, Best, The Netherlands). In each subject, the proximal segment of a coronary artery was imaged for cross-sectional area measurements using cine spiral MRI. Distensibility (mmHg−1*103) was determined as: (end-systolic lumen area–end-diastolic lumen area) / (pulse pressure multiplied by the end-diastolic lumen area). Pulse pressure was calculated as the difference between the systolic and diastolic brachial blood pressures. Thirty-four healthy subjects and nineteen patients had adequate image quality for coronary area measurements. Coronary artery distensibility was significantly higher in healthy subjects, than in the CAD patients (mean ± 1 SD: 2.4 ± 1.7 mmHg−1*103 vs. 1.1 ± 1.1 mmHg−1*103 respectively, p=0.007); (median: 2.2 vs. 0.9 mmHg−1*103). In a subgroup of 10 CAD patients we found a significant correlation between coronary artery distensibility measurements assessed with MRI and X-ray coronary angiography (R=0.65; p=0.003). In a group of 10 healthy subjects repeated distensibility measurements demonstrated a significant correlation (R=0.80; p=0.006). In conclusion, 3.0T MRI, a reproducible non-invasive means to assess human coronary artery vessel wall distensibility, is able to detect significant differences in distensibility between healthy subjects and CAD patients.
PMCID: PMC3159191  PMID: 21624552
coronary artery distensibility; non-invasive; cardiac magnetic resonance; 3.0 Tesla
21.  Practical Signal-to-Noise Ratio Quantification for Sensitivity Encoding: Application to Coronary MRA 
To develop and evaluate a practical method for the quantification of signal-to-noise ratio (SNR) on coronary magnetic resonance angiograms (MRA) acquired with parallel imaging.
Materials and Methods
To quantify the spatially varying noise due to parallel imaging reconstruction, a new method has been implemented incorporating image data acquisition followed by a fast noise scan during which radiofrequency pulses, cardiac triggering and navigator gating are disabled. The performance of this method was evaluated in a phantom study where SNR measurements were compared to those of a reference standard (multiple repetitions). Subsequently, SNR of myocardium and posterior skeletal muscle was determined on in vivo human coronary MRA.
In a phantom, the SNR measured using the proposed method deviated less than 10.1% from the reference method for small geometry factors (<=2). In-vivo, the noise scan for a 10 minutes coronary MRA acquisition was acquired in 30s. Higher signal and lower SNR, due to spatially varying noise, were found in myocardium compared to posterior skeletal muscle.
SNR quantification based on a fast noise scan is a validated and easy-to-use method when applied to 3D coronary MRA obtained with parallel imaging as long as the geometry factor remains low.
PMCID: PMC3098458  PMID: 21591001
SNR measurement; parallel imaging; coronary MRA; phased array coils; image noise
25.  Impaired ATP Kinetics in Failing in vivo Mouse Hearts 
The hypothesis that the failing heart may be energy starved is supported, in part, by observations of reduced rates of ATP synthesis through the creatine kinase (CK) reaction, the primary myocardial energy reservoir, in heart failure (HF) patients. Although murine models have been used to probe HF pathophysiology, it has not been possible to non-invasively measure the rate of ATP synthesis through CK in the in vivo mouse heart. The purpose of this work was to exploit non-invasive spatially-localized magnetic resonance spectroscopy (MRS) techniques to measure ATP flux through CK in in vivo mouse hearts and determine the extent of any reductions in murine HF.
Methods and Results
The Triple Repetition Time Saturation Transfer (TRiST) MRS method of measuring ATP kinetics was first validated in skeletal muscle, rendering similar results to conventional saturation transfer MRS. In normal mouse hearts the in vivo CK pseudo-first-order-rate constant, kf, was 0.32±0.03 s−1 (mean±SD) and the rate of ATP synthesis through CK was 3.16±0.47 µmol/g/s. Thoracic aortic constriction (TAC) reduced kf by 31% (0.23±0.03 s−1, p<0.0001) and ATP synthesis through CK by 51% (1.54±0.25 µmol/g/s, p<0.0001), analogous values to those in failing human hearts.
Despite the small size and high murine heart rate, the ATP synthesis rate through CK is similar in vivo in murine and human hearts and comparably reduced in HF. Because murine TAC shares fundamental energetic similarities with human HF, this model and new MRS approach promise a powerful means to non-invasively probe altered energetics in HF.
PMCID: PMC3066090  PMID: 20926788
energetics; CK flux; hypertrophy; in vivo mouse hearts; magnetic resonance spectroscopy

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