Superparamagnetic iron oxide (SPIO) nanoparticles with optimized and well-characterized properties are critical for Magnetic Particle Imaging (MPI). MPI is a novel in vivo imaging modality that promises to integrate the speed of CT, safety of MRI and sensitivity of PET. Since SPIOs are the source of MPI signal, both the core and surface properties must be optimized to enable efficient in vivo imaging with pharmacokinetics tailored for specific imaging applications. Existing SPIOs like Resovist (ferucarbotran) provide suboptimal MPI signal, and further limit MPI's in vivo utility due to rapid systemic clearance. An SPIO agent with a long blood half-life (t1/2) would be a versatile MPI tracer with widespread applications. Here we show a long circulating polyethylene glycol (PEG)-coated SPIO tracer, LS-008, provides excellent colloidal stability and persistent intravascular MPI signal, showing potential as the first blood pool tracer optimized for MPI. We evaluated variations of the PEG coating and found that colloidal stability of tracers improved with increasing PEG molecular weight (keeping PEG loading constant). Blood circulation in mice, evaluated using Magnetic Particle Spectrometry (MPS), showed that t1/2 of SPIO tracers varied with both PEG molecular weight and loading. LS-008, coated with 20 kDa PEG at 18.8% loading capacity, provided the most promising long-term colloidal stability with a t1/2 of about 105 minutes in mice. In vivo MPI imaging with LS-008 in a 7 T/m/μ0 3D x-space MPI mouse scanner revealed a prolonged intravascular signal (3-5 hours) post-injection. Our results show the optimized magnetic properties a nd long systemic retention of LS-008 make it a promising blood pool MPI tracer, with potential to enable MPI imaging in cardio - and cerebrovascular disease models, and solid tumor quantification and imaging via enhanced permeation and retention.

Magnetic Particle Imaging (MPI) is an emerging tracer-based medical imaging modality that images non-radioactive, kidney-safe superparamagnetic iron oxide (SPIO) tracers. MPI offers quantitative, high-contrast and high-SNR images, so MPI has exceptional promise for applications such as cell tracking, angiography, brain perfusion, cancer detection, traumatic brain injury and pulmonary imaging. In assessing MPI's utility for applications mentioned above, it is important to be able to assess tracer short-term biodistribution as well as long-term clearance from the body. Here, we describe the biodistribution and clearance for two commonly used tracers in MPI: Ferucarbotran (Meito Sangyo Co., Japan) and LS-oo8 (LodeSpin Labs, Seattle, WA). We successfully demonstrate that 3D MPI is able to quantitatively assess short-term biodistribution, as well as long-term tracking and clearance of these tracers in vivo.

The development of hyperpolarized technology utilizing dynamic nuclear polarization (DNP) has enabled the rapid measurement of 13C metabolism in vivo with very high SNR. However, with traditional DNP equipment, consecutive injections of a hyperpolarized compound in an animal have been subject to a practical minimum time between injections governed by the polarization build-up time, which is on the order of an hour for [1-13C]pyruvate. This has precluded the monitoring of metabolic changes occurring on a faster time scale. In this study, we demonstrated the ability to acquire in vivo dynamic magnetic resonance spectroscopy (MRS) and 3D magnetic resonance spectroscopic imaging (MRSI) data in normal rats with a 5 minute interval between injections of hyperpolarized [1-13C]pyruvate using a prototype, sub-Kelvin dynamic nuclear polarizer with the capability to simultaneously polarize up to 4 samples and dissolve them in rapid succession. There were minimal perturbations in the hyperpolarized spectra as a result of the multiple injections, suggesting that such an approach would not confound the investigation of metabolism occurring on this time scale. As an initial demonstration of the application of this technology and approach for monitoring rapid changes in metabolism as a result of a physiological intervention, we investigated the pharmacodynamics of the anti-cancer agent dichloroacetate (DCA), collecting hyperpolarized data before administration of DCA, 1 minute after administration, and 6 minutes after administration. Dramatic increases in 13C-bicarbonate were detected just 1 minute (as well as 6 minutes) after DCA administration.

Decline in executive function is the most common age-associated cognitive deficit and may be a risk factor for neurodegenerative disease. The antisaccade (AS) task involves inhibition of a prepotent visuomotor response and is a well-validated executive function test in aging and neurodegeneration. We investigated the functional connectivity of the cortical oculomotor network during successful AS performance in healthy elders. Elevated BOLD activity in the right lateral frontal eye field (rlatFEF), a region linked to volume loss in individuals with impaired AS performance, was associated with worse AS performance and weaker network efficiency. In contrast, hub integrity of the right dorsolateral prefrontal cortex (rDLPFC) and anterior cingulate cortex (rACC) was associated with better AS performance. These data suggest that while several right lateral frontal regions are central nodes in the oculomotor network, the rlatFEF demonstrates early neural aberrations and the rDLPFC and rACC continue to support inhibitory cognitive control in healthy elders. We conclude that alterations in AS task functional connectivity, quantified as hub and network efficiency, may be clinically-relevant biomarkers of cognitive decline in executive functioning.

Computational models are widely used during the design and characterization of microwave ablation (MWA) devices, and have been proposed for pretreatment planning. Our objective was to assess three-dimensional (3D) transient temperature and ablation profiles predicted by MWA computational models with temperature profiles measured experimentally using magnetic resonance (MR) thermometry in ex vivo bovine liver. Materials and methods: We performed MWA in ex vivo tissue under MR guidance using a custom, 2.45 GHz water-cooled applicator. MR thermometry data were acquired for 2 min prior to heating, during 5-10 min microwave exposures, and for 3 min following heating. Fiber-optic temperature sensors were used to validate the accuracy of MR temperature measurements. A total of 13 ablation experiments were conducted using 30-50 W applied power at the applicator input. MWA computational models were implemented using the finite element method, and incorporated temperature-dependent changes in tissue physical properties. Model-predicted ablation zone extents were compared against MRI-derived Arrhenius thermal damage maps using the Dice similarity coefficient (DSC). Results: Prior to heating, the observed standard deviation of MR temperature data was in the range of 0.3-0.7°C. Mean absolute error between MR temperature measurements and fiber-optic temperature probes during heating was in the range of 0.5-2.8°C. The mean DSC between model-predicted ablation zones and MRI-derived Arrhenius thermal damage maps for 13 experimental setups was 0.95. When comparing simulated and experimentally (i.e. using MRI) measured temperatures, the mean absolute error (MAE %) relative to maximum temperature change was in the range 5%-8.5%. Conclusion: We developed a system for characterizing 3D transient temperature and ablation profiles with MR thermometry during MWA in ex vivo liver tissue, and applied the system for experimental validation of MWA computational models.

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Despite higher rates of hospitalization and mortality following traumatic brain injury (TBI) in patients over 65 years old, older patients remain underrepresented in drug development studies. Worse outcomes in older individuals compared to younger adults could be attributed to exacerbated injury mechanisms including oxidative stress, inflammation, blood-brain barrier disruption, and bioenergetic dysfunction. Accordingly, pleiotropic treatments are attractive candidates for neuroprotection. Taurine, an endogenous amino acid with antioxidant, anti-inflammatory, anti-apoptotic, osmolytic, and neuromodulator effects, is neuroprotective in adult rats with TBI. However, its effects in the aged brain have not been evaluated. We subjected aged male rats to a unilateral controlled cortical impact injury to the sensorimotor cortex, and randomized them into four treatment groups: saline or 25 mg/kg, 50 mg/kg, or 200 mg/kg i.p. taurine. Treatments were administered 20 min post-injury and daily for 7 days. We assessed sensorimotor function on post-TBI days 1-14 and tissue loss on day 14 using T-weighted magnetic resonance imaging. Experimenters were blinded to the treatment group for the duration of the study. We did not observe neuroprotective effects of taurine on functional impairment or tissue loss in aged rats after TBI. These findings in aged rats are in contrast to previous reports of taurine neuroprotection in younger animals. Advanced age is an important variable for drug development studies in TBI, and further research is required to better understand how aging may influence mechanisms of taurine neuroprotection.

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