Shaokuan Zheng

The development and expression of physical nicotine dependence corresponds to structural and functional alterations in the anterior cingulate-precuneus pathway.

Perturbations in neural function provoked by a drug are thought to induce neural adaptations, which, in the absence of the drug, give rise to withdrawal symptoms. Previously published structural data from this study indicated that the progressive development of physical dependence is associated with increasing density of white matter tracts between the anterior cingulum bundle and the precuneus.

Chemical exchange saturation transfer effect in blood

In this report, the feasibility of using blood as an agent for Chemical Exchange Saturation Transfer (CEST) effect is investigated.

MRI investigation of the linkage between respiratory motion of the heart and markers on patient's abdomen and chest: Implications for respiratory amplitude binning list-mode PET and SPECT studies

Respiratory motion of the heart impacts the diagnostic accuracy of myocardial-perfusion emission-imaging studies. Amplitude binning has come to be the method of choice for binning list-mode based acquisitions for correction of respiratory motion in PET and SPECT. In some subjects respiratory motion exhibits hysteretic behavior similar to damped non-linear cyclic systems. The detection and correction of hysteresis between the signals from surface movement of the patients body used in binning and the motion of the heart within the chest remains an open area for investigation. This study reports our investigation in nine volunteers of the combined MRI tracking of the internal respiratory motion of the heart using Navigators with stereo-tracking of markers on the volunteers chest and abdomen by a visual-tracking system (VTS). The respiratory motion signals from the internal organs and the external markers were evaluated for hysteretic behavior analyzing the temporal correspondence of the signals. In general, a strong, positive correlation between the external marker motion (AP direction) and the internal heart motion (SI direction) during respiration was observed. The average ± standard deviation in the Spearmans ranked correlation coefficient (ρ) over the nine volunteer studied was 0.92±0.1 between the external abdomen marker and the internal heart, and 0.87±0.2 between the external chest marker and the internal heart. However despite the good correlation on average for the nine volunteers, in three studies a poor correlation was observed due to hysteretic behavior between inspiration and expiration for either the chest marker and the internal motion of the heart, or the abdominal marker and the motion of the heart. In all cases we observed a good correlation of at least either the abdomen or the chest with the heart. Based on this result, we propose the use of marker motion from both the chest and abdomen regions when estimating the internal heart motion to detect and address hysteresis when binning list-mode emission data.

MR Imaging of Myeloperoxidase Activity in a Model of the Inflamed Aneurysm Wall

BACKGROUND AND PURPOSE: Although myeloperoxidase activity in vivo can be visualized by using noninvasive imaging, successful clinical translation requires further optimization of the imaging approach. We report a motion-sensitized driven-equilibrium MR imaging approach for the detection of a myeloperoxidase activity–specific gadolinium-containing imaging agent in experimental aneurysm models, which compensates for irregular blood flow, enabling vascular wall imaging in the aneurysm. MATERIALS AND METHODS: A phantom was built from rotational angiography of a rabbit elastase aneurysm model and was connected to a cardiac pulse duplicator mimicking rabbit-specific flow conditions. A T1-weighted turbo spin-echo–based motion-sensitized driven-equilibrium pulse sequence was optimized in vitro, including the addition of fat suppression and the selection of the velocity-encoding gradient parameter. The optimized sequence was applied in vivo to rabbit aneurysm models with and without inflammation in the aneurysmal wall. Under each condition, the aneurysms were imaged before and after intravenous administration of the imaging agent. The signal-to-noise ratio of each MR imaging section through the aneurysm was calculated. RESULTS: The motion-sensitized driven-equilibrium sequence was optimized to reduce flow signal, enabling detection of the myeloperoxidase imaging agent in the phantom. The optimized imaging protocol in the rabbit model of saccular aneurysms revealed a significant increase in the change of SNR from pre- to post-contrast MR imaging in the inflamed aneurysms compared with naïve aneurysms and the adjacent carotid artery (P < .0001). CONCLUSIONS: A diagnostic MR imaging protocol was optimized for molecular imaging of a myeloperoxidase-specific molecular imaging agent in an animal model of inflamed brain aneurysms.

Diagnostic Magnetic Resonance Imaging of Atherosclerosis in Apolipoprotein E Knockout Mouse Model Using Macrophage-Targeted Gadolinium-Containing Synthetic Lipopeptide Nanoparticles

Cardiovascular disease is the leading cause of death in Western cultures. The vast majority of cardiovascular events, including stroke and myocardial infarction, result from the rupture of vulnerable atherosclerotic plaques, which are characterized by high and active macrophage content. Current imaging modalities including magnetic resonance imaging (MRI) aim to characterize anatomic and structural features of plaques rather than their content. Previously, we reported that macrophage-targeted delivery of gadolinium (Gd)-based contrast agent (GBCA-HDL) using high density lipoproteins (HDL)-like particles significantly enhances the detection of plaques in an apolipoprotein (apo) E knockout (KO) mouse model, with an atherosclerotic wall/muscle normalized enhancement ratio (NER) of 120% achieved. These particles are comprised of lipids and synthetic peptide fragments of the major protein of HDL, apo A-I, that contain a naturally occurring modification which targets the particles to macrophages. Targeted delivery minimizes the Gd dose and thus reduces the adverse effects of Gd. The aims of the current study were to test whether varying the GBCA-HDL particle shape and composition can further enhance atherosclerotic plaque MRI and control organ clearance of these agents. We show that the optimized GBCA-HDL particles are efficiently delivered intracellularly to and uptaken by both J774 macrophages in vitro and more importantly, by intraplaque macrophages in vivo, as evidenced by NER up to 160% and higher. This suggests high diagnostic power of our GBCA-HDL particles in the detection of vulnerable atherosclerotic plaques. Further, in contrast to discoidal, spherical GBCA-HDL exhibit hepatic clearance, which could further diminish adverse renal effects of Gd. Finally, activated macrophages are reliable indicators of any inflamed tissues and are implicated in other areas of unmet clinical need such as rheumatoid arthritis, sepsis and cancer, suggesting the expanded diagnostic and prognostic use of this method.

Creation of 3D Digital Anthropomorphic Phantoms which Model Actual Patient Non-rigid Body Motion as Determined from MRI and Position Tracking Studies of Volunteers

Patient motion can cause artifacts, which can lead to difficulty in interpretation. The purpose of this study is to create 3D digital anthropomorphic phantoms which model the location of the structures of the chest and upper abdomen of human volunteers undergoing a series of clinically relevant motions. The 3D anatomy is modeled using the XCAT phantom and based on MRI studies. The NURBS surfaces of the XCAT are interactively adapted to fit the MRI studies. A detailed XCAT phantom is first developed from an EKG triggered Navigator acquisition composed of sagittal slices with a 3 x 3 x 3 mm voxel dimension. Rigid body motion states are then acquired at breath-hold as sagittal slices partially covering the thorax, centered on the heart, with 9 mm gaps between them. For non-rigid body motion requiring greater sampling, modified Navigator sequences covering the entire thorax with 3 mm gaps between slices are obtained. The structures of the initial XCAT are then adapted to fit these different motion states. Simultaneous to MRI imaging the positions of multiple reflective markers on stretchy bands about the volunteers chest and abdomen are optically tracked in 3D via stereo imaging. These phantoms with combined position tracking will be used to investigate both imaging-data-driven and motion-tracking strategies to estimate and correct for patient motion. Our initial application will be to cardiacperfusion SPECT imaging where the XCAT phantoms will be used to create patient activity and attenuation distributions for each volunteer with corresponding motion tracking data from the markers on the body-surface. Monte Carlo methods will then be used to simulate SPECT acquisitions, which will be used to evaluate various motion estimation and correction strategies.

Development of a high resolution MRI intracranial atherosclerosis imaging phantom

Background and purpose Currently, there is neither a standard protocol for vessel wall MR imaging of intracranial atherosclerotic disease (ICAD) nor a gold standard phantom to compare MR sequences. In this study, a plaque phantom is developed and characterized that provides a platform for establishing a uniform imaging approach for ICAD. Materials and methods A patient specific injection mold was 3D printed to construct a geometrically accurate ICAD phantom. Polyvinyl alcohol hydrogel was infused into the core shell mold to form the stenotic artery. The ICAD phantom incorporated materials mimicking a stenotic vessel and plaque components, including fibrous cap and lipid core. Two phantoms were scanned using high resolution cone beam CT and compared with four different 3 T MRI systems across eight different sites over a period of 18 months. Inter-phantom variability was assessed by lumen dimensions and contrast to noise ratio (CNR). Results Quantitative evaluation of the minimum lumen radius in the stenosis showed that the radius was on average 0.80 mm (95% CI 0.77 to 0.82 mm) in model 1 and 0.77 mm (95% CI 0.74 to 0.81 mm) in model 2. The highest CNRs were observed for comparisons between lipid and vessel wall. To evaluate manufacturing reproducibility, the CNR variability between the two models had an average absolute difference of 4.31 (95% CI 3.82 to 5.78). Variation in CNR between the images from the same scanner separated by 7 months was 2.5–6.2, showing reproducible phantom durability. Conclusions A plaque phantom composed of a stenotic vessel wall and plaque components was successfully constructed for multicenter high resolution MRI standardization.

Modeling Unstable Brain Aneurysms: MR Molecular Imaging of Myeloperoxidase in Vascular Wall and Correlation With Human Pathology

Brain aneurysm bleeding is associated with high rates of fatality or permanent neurological impairment. Despite the low risk of bleeding of an unruptured cerebral aneurysm (UCA) [1,2], the dismal outcome of aneurysmal rupture has led to the aggressive treatment of these aneurysms. In 2008, approximately 60,000 UCAs were treated in the USA [3]. The rate of morbidity and mortality from treatment is high: approximately 5 and 14% for coil embolization and surgical clipping, respectively [3]. The risk-benefit analysis does not support treatment of all UCAs and in an era of significant attention to healthcare economics, considerable expense for treatment of unruptured aneurysms may not be justified. Thus, there is a strong clinical need to identify asymptomatic patients with UCA who would benefit from preventative interventional or surgical procedures.Copyright

E-023 Towards Non-Invasive Flow-Insensitive Magnetic Resonance Angiography Using AngioCEST - A Preliminary Study

Purpose Non-contrast-enhanced magnetic resonance angiography (MRA) is a widely accepted diagnostic imaging method. However, neurovascular diseases that present with slow or complex flow (eg, aneurysms) may not be fully appreciated due to flow artifacts1. In this report, the feasibility of using Chemical Exchange Transfer Saturation (CEST)2 for angiography is investigated (angioCEST). Since contrast in CEST imaging is generated by the exchangeable protons in solute and not by blood flow, it is hypothesised that angioCEST will be less sensitive to slow/complex flow. Materials and Methods To evaluate generated CEST contrast from blood, experiments were performed using cylindrical tubes filled with porcine blood in acid citrate dextrose (ACD) that were emerged in saline. Imaging was performed on a 3.0T whole-body scanner using a custom-made solenoid T/R coil. CEST data was acquired using a single slice parallel to the short axis of the cylindrical tube and was corrected for B0-inhomogeneities using a WASSR3 method. To provide proof-of-principle, angioCEST was performed on the intracranial vasculature of a healthy volunteer. Single axial WASSR and CEST slices were acquired of the brain superior to the ICA siphon using an 8-channel SENSE head coil. Regions of interest (ROIs) were manually drawn in WASSR data and automatically copied to corresponding CEST data (figure 1). Normalised Z-spectra were generated using the mean values per ROI and were filtered for noise and corrected for B0 inhomogeneities using WASSR. To quantify the generated CEST contrast, MTRasym was used2. Results MTRasym analysis of the porcine blood samples showed a CEST effect of approximately 12% relative to surrounding saline at 2.5 ppm offset frequency. CEST experiments were performed on ACD confirmed that the observed CEST effect was due to blood and not generated by the anticoagulant. MTRasym plots (figure 1) of arterial blood (solid line) and white matter (dashed line) are shown in the bottom panel. Corresponding ROIs were drawn in WASSR data (top left) and copied to CEST data (top right) for analysis. Arterial blood shows a clear CEST effect of approximately 8% with respect to surrounding brain tissue. Conclusion In-vitro and in-vivo experiments have shown feasibility to obtain CEST contrast from blood, which may enable development of a novel method for MR angiography that is less sensitive to flow artifacts than currently available non-invasive techniques. Disclosures I. van der Bom: None. S. Zheng: None. M. Gounis: None. References Bernstein et al. Magn Reson Med 2001;46:955–962. van Zijl et al. Magn Reson Med. 2011;65:927–948. Kim et al. Magn Reson Med. 2009;61:1441–1450. Abstract E-023 Figure 1

O-014 Modelling Unstable Brain Aneurysms: MR Molecular Imaging of Myeloperoxidase in the Aneurysm Wall and Correlation with Human Pathology

Introduction An imaging approach identifying patients who benefit from treatment of unruptured intracranial aneurysms (UIA) is desired. We investigate a potential biomarker of UIA instability, myeloperoxidase (MPO), in human aneurysm tissue and in parallel develop a MPO molecular imaging approach in experimental models. Materials and Methods We harvested 20 aneurysms from 17 patients during surgical clipping. Angiograms were evaluated for: 1. maximum diameter, 2. blebs, 3. surface architecture (berry/irregular), and 4. single-lobe or multilobular. The tissue samples were stained against human MPO. MRI sequence insensitive to complex intra-aneurysmal flow was optimised in vitro. A silicone vascular replica of a rabbit elastase aneurysm was built1 and embedded in coconut oil. Flow was generated by a pulsatile pump simulating the rabbit aortic waveform1 using a blood analogue matching T1- and viscosity of blood. At 3T, we acquired motion-sensitised driven-equilibrium (MSDE) (TE=10ms, variable TR and FA) and optimised the flow velocity encoded gradient echo imaging parameter (VENC, 1–8cm/s), while using spectral pre-saturation inversion recovery (SPIR) fat suppression. Saccular aneurysm model in white New Zealand rabbits (n=8) was created2. The animals were imaged using the MRI protocol optimised in-vitro. Naïve aneurysms were imaged before and 3 hours after injecting MPO-specific contrast agent. Animals returned to the surgical suite 1-week later for lipopolysaccharide (LPS)-induced inflammation of the aneurysm wall3. Two-days after the LPS administration, the MRI study was repeated before and after MPO-specific contrast agent infusion. The animals were euthanised and the aneurysms explanted for histology. Results Ten human aneurysms were positive for MPO. All ruptured aneurysms (n=3) were positive for MPO. UIAs described as irregular/complex had a positive trend for MPO infiltration (p=0.087). Aneurysms were more likely to be positive for MPO in patients who had a family history of subarachnoid haemorrhage (p<0.05). Aneurysms with MPO were 39% larger. All UIAs that were negative for MPO were described as berry aneurysms. In the phantom experiment we confirmed that the MSDE sequence with VENC of 1 cm/s and SPIR eliminated the signal from blood flow and adjacent fat, respectively, yet provided sufficient contrast to image a representative amount of the MPO-contrast. The optimised MSDE sequence was used in the rabbit aneurysm model. Significant motion artifact required respiratory-triggering. Consequently, T1-weighting was lost. An inversion pulse was added to the sequence as to gain T1-sensitivity by inversion recovery (IR, IR delay optimised to 800ms). As compared to the naïve aneurysm, there was a 40-fold increase in the SNR change from pre to post-contrast MSDE imaging in the inflamed aneurysm model (p<0.0001). Histologically, LPS-induced inflammation demonstrated a large infiltration of MPO within the aneurysm wall. Conclusion Human aneurysms with associated risk factors for rupture or that have ruptured contain MPO within the aneurysm wall; suggesting that MPO could be a valuable biomarker for assessment of aneurysm propensity for rupture. A diagnostic MR imaging protocol has been optimised in vitro and applied for detection of an MPO-specific contrast agent in an animal model of aneurysms. Disclosures M. Gounis: 1; C; NIH. I. van der Bom: None. A. Wakhloo: None. S. Zheng: None. J. Weaver: None. A. Puri: None. A. Kuhn: None. A. Bogdanov: 1; C; NIH. References Seong, et al. Biorheology 2005;42:345–361 Cloft, et al. Radiology 1999;213:223–228 DeLeo, et al. Radiology 2009;252:696–703