The distortions of the free water model for diffusion MRI data when assuming single compartment relaxometry and proton density.

Objective.To document the bias of thesimplifiedfree water model of diffusion MRI (dMRI) signal vis-à-vis aspecificmodel which, in addition to diffusion, incorporates compartment-specific proton density (PD), T1 recovery during repetition time (TR), and T2 decay during echo time (TE).Approach.Both models assume that volume fractionfof the total signal in any voxel arises from the free water compartment (fw) such as cerebrospinal fluid or edema, and the remainder (1-f) from hindered water (hw) which is constrained by cellular structures such as white matter (WM). Thespecificandsimplifiedmodels are compared on a synthetic dataset, using a range of PD, T1 and T2 values. We then fit the models to anin vivohealthy brain dMRI dataset. For bothsyntheticandin vivodata we use experimentally feasible TR, TE, signal-to-noise ratio (SNR) and physiologically plausible diffusion profiles.Main results.From the simulations we see that the difference between the estimatedsimplified fandspecific fis largest for mid-range ground-truthf, and it increases as SNR increases. The estimation of volume fractionfis sensitive to the choice of model,simplifiedorspecific, but the estimated diffusion parameters are robust to small perturbations in the simulation.Specific fis more accurate and precise thansimplified f. In the white matter (WM) regions of thein vivoimages,specific fis lower thansimplified f.Significance.In dMRI models for free water, accounting for compartment specific PD, T1 and T2, in addition to diffusion, improves the estimation of model parameters. This extra model specification attenuates the estimation bias of compartmental volume fraction without affecting the estimation of other diffusion parameters.

Distribution of brain iron accrual in adolescence: Evidence from cross-sectional and longitudinal analysis.

To track iron accumulation and location in the brain across adolescence, we repurposed diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) data acquired in 513 adolescents and validated iron estimates with quantitative susceptibility mapping (QSM) in 104 of these subjects. DTI and fMRI data were acquired longitudinally over 1 year in 245 male and 268 female, no-to-low alcohol-consuming adolescents (12-21 years at baseline) from the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) study. Brain region average signal values were calculated for susceptibility to nonheme iron deposition: pallidum, putamen, dentate nucleus, red nucleus, and substantia nigra. To estimate nonheme iron, the corpus callosum signal (robust to iron effects) was divided by regional signals to generate estimated R2 (edwR2 for DTI) and R2 * (eR2 * for fMRI). Longitudinal iron deposition was measured using the normalized signal change across time for each subject. Validation using baseline QSM, derived from susceptibility-weighted imaging, was performed on 46 male and 58 female participants. Normalized iron deposition estimates from DTI and fMRI correlated with age in most regions; both estimates indicated less iron in boys than girls. QSM results correlated highly with DTI and fMRI results (adjusted R2 = 0.643 for DTI, 0.578 for fMRI). Cross-sectional and longitudinal analyses indicated an initial rapid increase in iron, notably in the putamen and red nucleus, that slowed with age. DTI and fMRI data can be repurposed for identifying regional brain iron deposition in developing adolescents as validated with high correspondence with QSM.

Simultaneous imaging of 13C metabolism and 1H structure: technical considerations and potential applications.

Real-time imaging of (13)C metabolism in vivo has been enabled by recent advances in hyperpolarization. As a result of the inherently low natural abundance of endogenous (13)C nuclei, hyperpolarized (13)C images lack structural information that could be used to aid in motion detection and anatomical registration. Motion before or during the (13)C acquisition can therefore result in artifacts and misregistration that may obscure measures of metabolism. In this work, we demonstrate a method to simultaneously image both (1)H and (13)C nuclei using a dual-nucleus spectral-spatial radiofrequency excitation and a fully coincident readout for rapid multinuclear spectroscopic imaging. With the appropriate multinuclear hardware, and the means to simultaneously excite and receive on both channels, this technique is straightforward to implement requiring little to no increase in scan time. Phantom and in vivo experiments were performed with both Cartesian and spiral trajectories to validate and illustrate the utility of simultaneous acquisitions. Motion compensation of dynamic metabolic measurements acquired during free breathing was demonstrated using motion tracking derived from (1)H data. Simultaneous multinuclear imaging provides structural (1)H and metabolic (13)C images that are correlated both spatially and temporally, and are therefore amenable to joint (1)H and (13)C analysis and correction of structure-function images.

Application of a whole-body pharmacokinetic model for targeted radionuclide therapy to NM404 and FLT.

We have previously developed a model that provides relative dosimetry estimates for targeted radionuclide therapy (TRT) agents. The whole-body and tumor pharmacokinetic (PK) parameters of this model can be noninvasively measured with molecular imaging, providing a means of comparing potential TRT agents. Parameter sensitivities and noise will affect the accuracy and precision of the estimated PK values and hence dosimetry estimates. The aim of this work is to apply a PK model for TRT to two agents with different magnitudes of clearance rates, NM404 and FLT, explore parameter sensitivity with respect to time and investigate the effect of noise on parameter precision and accuracy. Twenty-three tumor bearing mice were injected with a 'slow-clearing' agent, (124)I-NM404 (n = 10), or a 'fast-clearing' agent, (18)F-FLT (3'-deoxy-3'-fluorothymidine) (n = 13) and imaged via micro-PET/CT pseudo-dynamically or dynamically, respectively. Regions of interest were drawn within the heart and tumor to create time-concentration curves for blood pool and tumor. PK analysis was performed to estimate the mean and standard error of the central compartment efflux-to-influx ratio (k(12)/k(21)), central elimination rate constant (k(el)), and tumor influx-to-efflux ratio (k(34)/k(43)), as well as the mean and standard deviation of the dosimetry estimates. NM404 and FLT parameter estimation results were used to analyze model accuracy and parameter sensitivity. The accuracy of the experimental sampling schedule was compared to that of an optimal sampling schedule found using Cramer-Rao lower bounds theory. Accuracy was assessed using correlation coefficient, bias and standard error of the estimate normalized to the mean (SEE/mean). The PK parameter estimation of NM404 yielded a central clearance, k(el) (0.009 ± 0.003 h(-1)), normal body retention, k(12)/k(21) (0.69 ± 0.16), tumor retention, k(34)/k(43) (1.44 ± 0.46) and predicted dosimetry, D(tumor) (3.47 ± 1.24 Gy). The PK parameter estimation of FLT yielded a central elimination rate constant, k(el) (0.050 ± 0.025 min(-1)), normal body retention, k(12)/k(21) (2.21 ± 0.62) and tumor retention, k(34)/k(43) (0.65 ± 0.17), and predicted dosimetry, D(tumor) (0.61 ± 0.20 Gy). Compared to experimental sampling, optimal sampling decreases the dosimetry bias and SEE/mean for NM404; however, it increases bias and decreases SEE/mean for FLT. For both NM404 and FLT, central compartment efflux rate constant, k(12), and central compartment influx rate constant, k(21), possess mirroring sensitivities at relatively early time points. The instantaneous concentration in the blood, C(0), was most sensitive at early time points; central elimination, k(el), and tumor efflux, k(43), are most sensitive at later time points. A PK model for TRT was applied to both a slow-clearing, NM404, and a fast-clearing, FLT, agents in a xenograft murine model. NM404 possesses more favorable PK values according to the PK TRT model. The precise and accurate measurement of k(12), k(21), k(el), k(34) and k(43) will translate into improved and precise dosimetry estimations. This work will guide the future use of this PK model for assessing the relative effectiveness of potential TRT agents.

In vivo imaging and spectroscopy of dynamic metabolism using simultaneous 13C and 1H MRI.

Hyperpolarized (HP) (13)C-labeled pyruvate studies with magnetic resonance (MR) have been used to observe the kinetics of metabolism in vivo. Kinetic modeling to measure metabolic rates in vivo is currently limited because of nonspecific hyperpolarized signals mixing between vascular, extravascular, and intracellular compartments. In this study, simultaneous acquisition of both (1)H and (13)C signals after contrast agent injection is used to resolve specific compartments to improve the accuracy of the modeling. We demonstrate a novel technique to provide contrast to the intracellular compartments by sequential injection of HP [1-(13)C] pyruvate followed by gadolinium-chelate to provide T(1)-shortening to extra-cellular compartments. A kinetic model that distinguishes the intracellular space and includes the T(1)-shortening effect of the gadolinium chelate can then be used to directly measure the intracellular (13)C kinetics.

Measurement of lung airways in three dimensions using hyperpolarized helium-3 MRI.

Large airway measurement is clinically important in cases of airway disease and trauma. The gold standard is computed tomography (CT), which allows for airway measurement. However, the ionizing radiation dose associated with CT is a major limitation in longitudinal studies and trauma. To avoid ionizing radiation from CT, we present a method for measuring the large airway diameter in humans using hyperpolarized helium-3 (HPHe) MRI in conjunction with a dynamic 3D radial acquisition. An algorithm is introduced which utilizes the significant airway contrast for semi-automated segmentation and skeletonization which is used to derive the airway lumen diameter. The HPHe MRI method was validated with quantitative CT in an excised and desiccated porcine lung (linear regression R(2) = 0.974 and slope = 0.966 over 32 airway segments). The airway lumen diameters were then compared in 24 human subjects (22 asthmatics and 2 normals; linear regression R(2) value of 0.799 and slope = 0.768 over 309 airway segments). The feasibility for airway path analysis to areas of ventilation defect is also demonstrated.

Dynamic nuclear polarization system output volume reduction using inert fluids.

PURPOSE: To present a method for significantly increasing the concentration of a hyperpolarized compound produced by a commercial dynamic nuclear polarization (DNP) polarizer, enabling the polarization process to be more suitable for preclinical applications. MATERIALS AND METHODS: Using a HyperSense DNP polarizer, we investigated the combined use of perfluorocarbon and water to warm and dissolve the hyperpolarized material from the polarization temperature of 1.4K to produce material at temperatures suitable for injection. RESULTS: By replacing 75% of the water in the dissolution volume with a chemically and biologically inert liquid that is immiscible with water, the injection volume can be reduced 4-fold. Rapid separation of the water and perfluorocarbon mixture enables the aqueous layer containing polarized material to be easily and rapidly collected. CONCLUSION: The approach provides a significantly increased concentration of compound in a volume for injection that is more appropriate for small animal studies. This is demonstrated for (13) C-labeled pyruvic acid and (13) C-labeled succinate, but may be applied to the majority of nuclei and compounds hyperpolarized by the DNP method.

Hyperpolarized 13carbon MR.

Hyperpolarized (HP) (13)C labeled compounds can be used as MR contrast agents to investigate metabolic pathways in vivo in almost real time. To date, a high proportion of reported studies have utilized HP 1-(13)C pyruvate to investigate intracellular metabolism in tumors and other tissues. The long T(1) relaxation time of the carboxylate carbon enables the (13)C signal of the pyruvate to be followed for nearly 2 minutes following injection. During this time, pyruvate is rapidly metabolized to generate observable metabolites such as alanine and lactate. HP (13)C labeled compounds have, for example, also been used to non-invasively probe physiological parameters such as pH, which emphasizes the expanding potential of the technique. The commercial availability of dynamic nuclear polarization (DNP) systems to generate hyperpolarized material for injection has made the technique available to researchers worldwide. As a consequence, DNP (13)C MR has become a rapidly expanding area of research. The technique, with its specific strengths and weaknesses, has incredible potential coupled with inherent limitations, and this review aims to both present background to the technique and describe some of the necessary hardware and software essential to perform hyperpolarized (13)C studies. An overview of the current and future role of HP (13)C based molecular imaging is presented.

Evaluation of structure-function relationships in asthma using multidetector CT and hyperpolarized He-3 MRI.

RATIONALE AND OBJECTIVES: Although multiple detector computed tomography (MDCT) and hyperpolarized gas magnetic resonance imaging (HP MRI) have demonstrated ability to detect structural and ventilation abnormalities in asthma, few studies have sought to exploit or cross-validate the regional information provided by these techniques. The purpose of this work is to assess regional disease in asthma by evaluating the association of sites of ventilation defect on HP MRI with other regional markers of airway disease, including air trapping on MDCT and inflammatory markers on bronchoscopy. MATERIALS AND METHODS: Both HP MRI using helium-3 and MDCT were acquired in the same patients. Supervised segmentation of the lung lobes on MRI and MDCT facilitated regional comparisons of ventilation abnormalities in the lung parenchyma. The percentage of spatial overlap was evaluated between regions of ventilation defect on HP MRI and hyperlucency on MDCT to determine associations between obstruction and likely regions of gas trapping. Similarly, lung lobes with high defect volume were compared to lobes with low defect volume for differences in inflammatory cell number and percentage using bronchoscopic assessment. RESULTS: There was significant overlap between sites of ventilation defect on HP MRI and hyperlucency on MDCT suggesting that sites of airway obstruction and air trapping are associated in asthma. The percent (r=0.68; P= .0039) and absolute (r=0.61; P= .0125) number of neutrophils on bronchoalveolar lavage for the sampled lung lobe also directly correlated with increased defect volume. CONCLUSIONS: These results show promise for using image guidance to assess specific regions of ventilation defect or air trapping in heterogeneous obstructive lung diseases such as asthma.