Amide proton transfer-weighted (APTw) MR imaging shows promise as a biomarker of brain tumor status. Currently used APTw MRI pulse sequences and protocols vary substantially among different institutes, and there are no agreed-on standards in the imaging community. Therefore, the results acquired from different research centers are difficult to compare, which hampers uniform clinical application and interpretation. This paper reviews current clinical APTw imaging approaches and provides a rationale for optimized APTw brain tumor imaging at 3 T, including specific recommendations for pulse sequences, acquisition protocols, and data processing methods. We expect that these consensus recommendations will become the first broadly accepted guidelines for APTw imaging of brain tumors on 3 T MRI systems from different vendors. This will allow more medical centers to use the same or comparable APTw MRI techniques for the detection, characterization, and monitoring of brain tumors, enabling multi-center trials in larger patient cohorts and, ultimately, routine clinical use. K E Y W O R D APTw standardization, APT-weighted imaging, brain tumor, CEST imaging How to cite this article: Zhou J, Zaiss M, Knutsson L, et al. Review and consensus recommendations on clinical APT-weighted imaging approaches at 3T: Application to brain tumors.

Experimental myocardial infarction (MI) in mice is an important disease model, in part due to the ability to study genetic manipulations. MRI has been used to assess cardiac structural and functional changes after MI in mice, but changes in myocardial perfusion after acute MI have not previously been examined. Arterial spin labeling noninvasively measures perfusion but is sensitive to respiratory motion and heart rate variability and is difficult to apply after acute MI in mice. To account for these factors, a cardiorespiratory-gated arterial spin labeling sequence using a fuzzy C-means algorithm to retrospectively reconstruct images was developed. Using this method, myocardial perfusion was measured in remote and infarcted regions at 1, 7, 14, and 28 days post-MI. Baseline perfusion was 4.9 6 0.5 mL/gÁmin and 1 day post-MI decreased to 0.9 6 0.8 mL/gÁmin in infarcted myocardium (P < 0.05 versus baseline) while remaining at 5.2 6 0.8 mL/gÁmin in remote myocardium. During the subsequent 28 days, perfusion in the remote zone remained unchanged, while a partial recovery of perfusion in the infarct zone was seen. This technique, when applied to genetically engineered mice, will allow for the investigation of the roles of specific genes in myocardial perfusion during infarct healing. Magn Reson Med 63:648-657, 2010. V C 2010 Wiley-Liss, Inc.Key words: arterial spin labeling; myocardial perfusion; myocardial infarction; fuzzy C-means; mouse Mice are widely used as models of human disease in biomedical research. Similarities in the cardiovascular systems of mice and humans, the low cost of mouse studies, the relative ease of genetic manipulation of mice, and improved surgical techniques have led to increased use of mouse models of myocardial infarction (MI) (1-3). Cardiac MRI has been used to study structural and functional left ventricular (LV) remodeling in mice following MI (3-5). However, measurement of myocardial perfusion in mice by MRI during acute MI and subsequently during the processes of infarct healing and post-MI LV remodeling has not previously been performed.Arterial spin labeling (ASL) provides quantitative measurements of blood flow and has been used for quantification of cerebral blood flow (6,7) and myocardial perfusion (8-11) in humans. In small animals, ASL has been performed in both mice (12-15) and rats (16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Prior murine studies have examined myocardial perfusion at baseline (12-15), with differing anesthesia (13), in response to a vasodilator (13,15), and for phenotyping of genetically altered mice (14,15). Only two prior studies have measured perfusion after MI in mice, and those measurements were restricted only to the remote myocardium at 4 weeks following MI (12,14). ASL has been more widely used in rats (22) and has been used to assess changes in myocardial perfusion in response to dobutamine (17), adenosine (25), methods of anesthesia (23,24), diabetes (18,19) and following coronary stenosis (20,21) and MI (20,21). Similar to mouse studies, measurements...

Loss of beta-cell function in type 1 and type 2 diabetes leads to metabolic dysregulation and inability to maintain normoglycemia. Noninvasive imaging of beta-cell function in vivo would therefore provide a valuable diagnostic and research tool for quantifying progression to diabetes and response to therapeutic intervention. Because manganese (Mn(2+)) is a longitudinal relaxation time (T1)-shortening magnetic resonance imaging (MRI) contrast agent that enters cells such as pancreatic beta-cells through voltage-gated calcium channels, we hypothesized that Mn(2+)-enhanced MRI of the pancreas after glucose infusion would allow for noninvasive detection of beta-cell function in vivo. To test this hypothesis, we administered glucose and saline challenges intravenously to normal mice and mice given high or low doses of streptozotocin (STZ) to induce diabetes. Serial inversion recovery MRI was subsequently performed after Mn(2+) injection to probe Mn(2+) accumulation in the pancreas. Time-intensity curves of the pancreas (normalized to the liver) fit to a sigmoid function showed a 51% increase in signal plateau height after glucose stimulation relative to saline (P < 0.01) in normal mice. In diabetic mice given a high dose of STZ, only a 9% increase in plateau signal intensity was observed after glucose challenge (P = not significant); in mice given a low dose of STZ, a 20% increase in plateau signal intensity was seen after glucose challenge (P = 0.02). Consistent with these imaging findings, the pancreatic insulin content of high- and low-dose STZ diabetic mice was reduced about 20-fold and 10-fold, respectively, compared with normal mice. We conclude that Mn(2+)-enhanced MRI demonstrates excellent potential as a means for noninvasively monitoring beta-cell function in vivo and may have the sensitivity to detect progressive decreases in function that occur in the diabetic disease process.

MRI provides non-invasive in vivo evidence that nNOS does not play a role in basal contractile function or myocardial perfusion, but is required for increasing cardiac inotropy and lusitropy upon beta-adrenergic stimulation.

The move from reading to writing the human genome offers new opportunities to improve human health. The United States National Institutes of Health (NIH) Somatic Cell Genome Editing (SCGE) Consortium aims to accelerate the development of safer and more-effective methods to edit the genomes of disease-relevant somatic cells in patients, even in tissues that are difficult to reach. Here we discuss the consortium’s plans to develop and benchmark approaches to induce and measure genome modifications, and to define downstream functional consequences of genome editing within human cells. Central to this effort is a rigorous and innovative approach that requires validation of the technology through third-party testing in small and large animals. New genome editors, delivery technologies and methods for tracking edited cells in vivo, as well as newly developed animal models and human biological systems, will be assembled—along with validated datasets—into an SCGE Toolkit, which will be disseminated widely to the biomedical research community. We visualize this toolkit—and the knowledge generated by its applications—as a means to accelerate the clinical development of new therapies for a wide range of conditions.

Molecular imaging strives to detect molecular events at the level of the whole organism. In some cases, the molecule of interest can be detected either directly, or through the use of targeted contrast media. However many genes and proteins, and particularly those located in intracellular compartments, are not accessible for targeted agents. The transcriptional regulation of these genes can never the less be detected, though indirectly, through the use of reporter genes encoding for readily detectable proteins. Such reporter proteins can be expressed in the tissue of interest by genetically introducing the reporter gene in the target cells. Imaging of reporter genes has become a powerful tool in modern biomedical research. Typically, expression of fluorescent or bioluminescent proteins, or the reaction product of expressed enzymes and exogenous substrates, are examined using in vitro histological methods, or in vivo whole body imaging methods. Recent advances in MRI reporter gene methods raise the possibility that MRI could become a powerful tool for concomitant high resolution anatomical and functional imaging and for imaging of reporter gene activity. An immediate application of MRI reporter gene methods is for monitoring gene expression patterns in gene therapy and for in vivo imaging of the survival, proliferation, migration, and differentiation of pluripotent or multipotent cells used in cell based regenerative therapies for cancer, myocardial infarction, and neural degeneration. In this review, we characterize the variety of MRI reporter gene methods based on their applicability to report cell survival/proliferation, cell migration, and cell differentiation. In particular, we discuss which methods are best suited for translation to clinical use in regenerative therapies.

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An improved pre-clinical cardiac chemical exchange saturation transfer (CEST) pulse sequence (cardioCEST) was used to selectively visualize paramagnetic CEST (paraCEST)-labeled cells following intramyocardial implantation. In addition, cardioCEST was used to examine the effect of diet-induced obesity upon myocardial creatine CEST contrast. CEST pulse sequences were designed from standard turbo-spin-echo and gradient-echo sequences, and a cardiorespiratory-gated steady-state cine gradient-echo sequence. In vitro validation studies performed in phantoms composed of 20mM Eu-HPDO3A, 20mM Yb-HPDO3A, or saline demonstrated similar CEST contrast by spin-echo and gradient-echo pulse sequences. Skeletal myoblast cells (C2C12) were labeled with either Eu-HPDO3A or saline using a hypotonic swelling procedure and implanted into the myocardium of C57B6/J mice. Inductively coupled plasma mass spectrometry confirmed cellular levels of Eu of 2.1 × 10−3 ng/cell in Eu-HPDO3A-labeled cells and 2.3 × 10−5 ng/cell in saline-labeled cells. In vivo cardioCEST imaging of labeled cells at ±15ppm was performed 24 h after implantation and revealed significantly elevated asymmetric magnetization transfer ratio values in regions of Eu-HPDO3A-labeled cells when compared with surrounding myocardium or saline-labeled cells. We further utilized the cardioCEST pulse sequence to examine changes in myocardial creatine in response to diet-induced obesity by acquiring pairs of cardioCEST images at ±1.8 ppm. While ventricular geometry and function were unchanged between mice fed either a high-fat diet or a corresponding control low-fat diet for 14 weeks, myocardial creatine CEST contrast was significantly reduced in mice fed the high-fat diet. The selective visualization of paraCEST-labeled cells using cardioCEST imaging can enable investigation of cell fate processes in cardioregenerative medicine, or multiplex imaging of cell survival with imaging of cardiac structure and function and additional imaging of myocardial creatine.