Inflammation plays a central pathophysiological role in a large number of diseases. While conventional magnetic resonance imaging (MRI) can depict gross tissue alterations due to proton changes, specific visualization of inflammation is an unmet task in clinical medicine. (19) F/(1) H MRI is a novel technology that allows tracking of stem and immune cells in experimental disease models after labelling with perfluorocarbon (PFC) emulsions. (19) F markers such as PFC compounds provide a unique signal in vivo due to the negligible (19) F background signal of the body. Concomitant acquisition of (1) H images places the labelled cells into their anatomical context. This novel imaging technique has been applied to monitor immune cell responses in myocardial infarction, pneumonia, bacterial abscess formation, peripheral nerve injury, and rejection of donor organs after transplantation. Upon systemic application PFC nanoparticles are preferentially phagozytosed by circulating monocytes/macrophages and, thus, the fluorine signal in inflamed organs mainly reflects macrophage infiltration. Moreover, attenuation of the inflammatory response after immunosuppressive or antibiotic treatments could be depicted based on (19) F/(1) H-MRI. Compared to other organ systems (19) F-MRI of neuroinflammation is still challenging, mainly because of lack in sensitivity. In focal cerebral ischemia early application of PFCs revealed ongoing thrombotic vessel occlusion rather than cell migration indicating that timing of contrast agent application is critical. Current restrictions of (19) F/(1) H-MRI in sensitivity may be overcome by improved imaging hardware, imaging sequences and reconstruction techniques, as well as improved label development and cell labelling procedures in the future.

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BackgroundDuring the last years, 19F-MRI and perfluorocarbon nanoemulsion (PFC) emerged as a powerful contrast agent based MRI methodology to track cells and to visualize inflammation. We applied this new modality to visualize deep tissue abscesses during acute and chronic phase of inflammation caused by Staphylococcus aureus infection.Methodology and Principal FindingsIn this study, a murine thigh infection model was used to induce abscess formation and PFC or CLIO (cross linked ironoxides) was administered during acute or chronic phase of inflammation. 24 h after inoculation, the contrast agent accumulation was imaged at the site of infection by MRI. Measurements revealed a strong accumulation of PFC at the abscess rim at acute and chronic phase of infection. The pattern was similar to CLIO accumulation at chronic phase and formed a hollow sphere around the edema area. Histology revealed strong influx of neutrophils at the site of infection and to a smaller extend macrophages during acute phase and strong influx of macrophages at chronic phase of inflammation.Conclusion and SignificanceWe introduce 19F-MRI in combination with PFC nanoemulsions as a new platform to visualize abscess formation in a murine thigh infection model of S. aureus. The possibility to track immune cells in vivo by this modality offers new opportunities to investigate host immune response, the efficacy of antibacterial therapies and the influence of virulence factors for pathogenesis.

Background— Monocytes and macrophages are indispensable in the healing process after myocardial infarction (MI); however, the spatiotemporal distribution of monocyte infiltration and its correlation to prognostic indicators of reperfused MI have not been well described. Methods and Results— With combined fluorine 19/proton ( 1 H) magnetic resonance imaging, we noninvasively visualized the spatiotemporal recruitment of monocytes in vivo in a rat model of reperfused MI. Blood monocytes were labeled by intravenous injection of 19 F-perfluorocarbon emulsion 1 day after MI. The distribution patterns of monocyte infiltration were correlated to the presence of microvascular obstruction (MVO) and intramyocardial hemorrhage. In vivo, 19 F/ 1 H magnetic resonance imaging performed in series revealed that monocyte infiltration was spatially inhomogeneous in reperfused MI areas. In the absence of MVO, monocyte infiltration was more intense in MI regions with serious ischemia-reperfusion injuries, indicated by severe intramyocardial hemorrhage; however, monocyte recruitment was significantly impaired in MVO areas accompanied by severe intramyocardial hemorrhage. Compared with MI with isolated intramyocardial hemorrhage, MI with MVO resulted in significantly worse pump function of the left ventricle 28 days after MI. Conclusions— Monocyte recruitment was inhomogeneous in reperfused MI tissue. It was highly reduced in MVO areas defined by magnetic resonance imaging. The impaired monocyte infiltration in MVO regions could be related to delayed healing and worse functional outcomes in the long term. Therefore, monocyte recruitment in MI with MVO could be a potential diagnostic and therapeutic target that could be monitored noninvasively and longitudinally by 19 F/ 1 H magnetic resonance imaging in vivo.

BackgroundRecent studies have shown that human ferritin can be used as a reporter of gene expression for magnetic resonance imaging (MRI). Bacteria also encode three classes of ferritin-type molecules with iron accumulation properties.Methods and FindingsHere, we investigated whether these bacterial ferritins can also be used as MRI reporter genes and which of the bacterial ferritins is the most suitable reporter. Bacterial ferritins were overexpressed in probiotic E. coli Nissle 1917. Cultures of these bacteria were analyzed and those generating highest MRI contrast were further investigated in tumor bearing mice. Among members of three classes of bacterial ferritin tested, bacterioferritin showed the most promise as a reporter gene. Although all three proteins accumulated similar amounts of iron when overexpressed individually, bacterioferritin showed the highest contrast change. By site-directed mutagenesis we also show that the heme iron, a unique part of the bacterioferritin molecule, is not critical for MRI contrast change. Tumor-specific induction of bacterioferritin-expression in colonized tumors resulted in contrast changes within the bacteria-colonized tumors.ConclusionsOur data suggest that colonization and gene expression by live vectors expressing bacterioferritin can be monitored by MRI due to contrast changes.

Background 19F magnetic resonance imaging (MRI) was recently introduced as a promising technique for in vivo cell tracking. In the present study we compared 19F MRI with iron-enhanced MRI in mice with photothrombosis (PT) at 7 Tesla. PT represents a model of focal cerebral ischemia exhibiting acute vessel occlusion and delayed neuroinflammation.Methods/Principal FindingsPerfluorocarbons (PFC) or superparamagnetic iron oxide particles (SPIO) were injected intravenously at different time points after photothrombotic infarction. While administration of PFC directly after PT induction led to a strong 19F signal throughout the entire lesion, two hours delayed application resulted in a rim-like 19F signal at the outer edge of the lesion. These findings closely resembled the distribution of signal loss on T2-weighted MRI seen after SPIO injection reflecting intravascular accumulation of iron particles trapped in vessel thrombi as confirmed histologically. By sequential administration of two chemically shifted PFC compounds 0 and 2 hours after illumination the different spatial distribution of the 19F markers (infarct core/rim) could be visualized in the same animal. When PFC were applied at day 6 the fluorine marker was only detected after long acquisition times ex vivo. SPIO-enhanced MRI showed slight signal loss in vivo which was much more prominent ex vivo indicative for neuroinflammation at this late lesion stage.ConclusionOur study shows that vessel occlusion can be followed in vivo by 19F and SPIO-enhanced high-field MRI while in vivo imaging of neuroinflammation remains challenging. The timing of contrast agent application was the major determinant of the underlying processes depicted by both imaging techniques. Importantly, sequential application of different PFC compounds allowed depiction of ongoing vessel occlusion from the core to the margin of the ischemic lesions in a single MRI measurement.

A novel method for B þ 1 mapping based on the Bloch-Siegert (BS) shift was recently presented. This method applies offresonant pulses before signal acquisition to encode B 1 information into the signal phase. BS-based methods possess significant advantages in measurement time and accuracy compared to magnitude-based B þ 1 methods. This study extends the idea of BS B þ 1 mapping to Carr, Purcell, Meiboom, Gill (CPMG)-based multi-spin-echo (BS-CPMG-MSE) and turbo-spin-echo (BS-CPMG-TSE) imaging. Compared to BSbased spin echo imaging (BS-SE), faster acquisition of the B þ 1 information was possible using the BS-CPMG-TSE sequence. Furthermore, signal loss by T 2 * effects could be minimized using these spin echo-based techniques. These effects are critical for gradient echo-based BS methods at high field strengths. However, multi-spin-echo-based BS B 1 methods inherently possess high specific absorption rates. Thus, the relative specific absorption rate of BS-CPMG-TSE sequences was estimated and compared with the specific absorption rate produced by BS-SE sequences. A novel method for fast B þ 1 mapping was recently proposed (1). The authors demonstrated that a B 1 dependent phase shift is introduced by applying off-resonant pulses after signal excitation and before signal acquisition. This phase shift is named after Bloch-Siegert (BS), who gave the theoretical description of this phenomenon in 1940 (2). If certain requirements are met, the BS shift is directly proportional to (B 1 ) 2 , the duration of the off-resonant BS pulse, and inversely proportional to the off-resonance (v off ) of the BS pulse (1). The phase-based BS method is robust, contrary to magnitude-based B 1 methods, to biases caused by several parameters such as TR, T 1 relaxation, and magnetization transfer (1). Due to the robustness to TR and T 1 relaxation fast B 1 mapping is enabled. For B 1 mapping, a gradient echo-based BS (BS-FLASH) as well as a spin echo-based BS sequence (BS-SE) were introduced in (1). Several initial studies showed the wide applicability of these BS-based B 1 mapping methods (1,3-7).This work extends the idea of using the BS shift for B þ 1 mapping to multi/turbo-spin-echo-based (MSE/TSE) MRI. To avoid image artifacts inherent to MSE/TSE sequences, the same phase must be present before every refocusing pulse. This scenario is referred to as Carr, Purcell, Meiboom, Gill (CPMG)-based conditions (8-10). Alternatives for avoiding image artifacts introduced by uncorrelated echoes are either crushing the unwanted echo pathway (11) or separating the pathways by adding an unbalanced read gradient (12,13). When compared against CPMG MSE/TSE imaging, however, these solutions would lead to a signal loss.With the proposed sequences, simultaneous B 1 and T 2 mapping can be performed using BS-based MSE (BS-CPMG-MSE) sequences when the produced magnetization transfer is negligible. To demonstrate the applicability of the proposed BS-CPMG-MSE sequence, 2D phantom and in vivo T 2 and B 1 maps were simultaneously acquired. Using the BS CPMG...

BS-gradients were demonstrated as a feasible option for spatial phase encoding. Furthermore, undistorted BS-SET images could be obtained using the proposed reconstruction method.