Mirko I. Hrovat

Human pulmonary imaging and spectroscopy with hyperpolarized 129Xe at 0.2T.

RATIONALE AND OBJECTIVES Using a novel (129)Xe polarizer with high throughput (1-2 L/hour) and high polarization (approximately 55%), our objective was to demonstrate and characterize human pulmonary applications at 0.2T. Specifically, we investigated the ability of (129)Xe to measure the alveolar surface area per unit volume of gas, S(A)/V(gas). MATERIALS AND METHODS Variable spin echo time (TE) gradient and radiofrequency (RF) echoes were used to obtain estimates of the lungs contribution to both T(2)* and T(2). Standard multislice ventilation images were obtained and signal-to-noise ratio (SNR) determined. Whole-lung, time-dependent measurements of (129)Xe diffusion from gas to septal tissue were obtained with a chemical shift saturation recovery (CSSR) method. Four healthy subjects were studied, and the Butler et al CSSR formalism (J Phys Condensed Matter 2002; 14:L297-L304) was used to calculate S(A)/V(gas). A single-breath version of the xenon transfer contrast (SB-XTC) method was implemented and used to image (129)Xe diffusion between alveolar gas and septal tissue. A direct comparison of CSSR and SB-XTC was performed. RESULTS T(2)*=135+/-29 ms amd T(2)=326.2+/-9.5 ms. Maximum SNR=36 for ventilation images from inhalation of 1L 86% (129)Xe and voxel volume =0.225 mL. CSSR analysis showed S(A)/V(gas) decreased with increasing lung volume in a manner very similar to that observed from histology measurements; however, the absolute value of S(A)/V(gas) was approximately 40% smaller than histology values. SB-XTC images in different postures demonstrate gravitationally dependent values. Initial comparison of CSSR with XTC showed fairly good agreement with expected ratios. CONCLUSIONS Hyperpolarized (129)Xe human imaging and spectroscopy are very promising methods to provide functional information about the lung.

Diffusion of hyperpolarized 129Xe in the lung: a simplified model of 129Xe septal uptake and experimental results

We used hyperpolarized 129Xe NMR to measure pulmonary alveolar surface area per unit gas volume SA/Vgas, alveolar septal thickness h and capillary transit time ?, three critical determinants of the lungs primary role as a gas exchange organ. An analytical solution for a simplified diffusion model is described, together with a modification of the xenon transfer contrast imaging technique utilizing 90? radio-frequency pulses applied to the dissolved phase, rather than traditional 180? pulses. With this approach, three-dimensional (3D) maps of SA/Vgas were obtained. We measured global SA/Vgas, h and ? in four normal subjects, two subjects with mild interstitial lung disease (ILD) and two subjects with mild chronic obstructive pulmonary disease (COPD). In normals, SA/Vgas decreased with increasing lung volume from ~320 to 80?cm?1; both h~13??m and ?~1.5?s were relatively constant. For the two ILD subjects, h was, respectively, 36 and 97% larger than normal, quantifying an increased gas/blood tissue barrier; SA/Vgas and ? were normal. The two COPD subjects had SA/Vgas values ~25% that of normals, quantifying septal surface loss in emphysema; h and ? were normal. These are the first noninvasive, non-radiation-based, quantitative measurements of h and ? in patients with pulmonary disease.

Measuring surface-area-to-volume ratios in soft porous materials using laser-polarized xenon interphase exchange nuclear magnetic resonance

We demonstrate a minimally invasive nuclear magnetic resonance (NMR) technique that enables determination of the surface-area-to-volume ratio (S/V) of soft porous materials from measurements of the diffusive exchange of laser-polarized 129Xe between gas in the pore space and 129Xe dissolved in the solid phase. We apply this NMR technique to porous polymer samples and find approximate agreement with destructive stereological measurements of S/V obtained with optical confocal microscopy. Potential applications of laser-polarized xenon interphase exchange NMR include measurements of in vivo lung function in humans and characterization of gas chromatography columns.

3He lung imaging in an open access, very-low-field human magnetic resonance imaging system

The human lung and its functions are extremely sensitive to gravity; however, the conventional high‐field magnets used for most laser‐polarized 3He MRI of the human lung restrict subjects to lying horizontally. Imaging of human lungs using inhaled laser‐polarized 3He gas is demonstrated in an open‐access very‐low‐magnetic‐field (<5 mT) MRI instrument. This prototype device employs a simple, low‐cost electromagnet, with an open geometry that allows variation of the orientation of the imaging subject in a two‐dimensional plane. As a demonstration, two‐dimensional lung images were acquired with 4‐mm in‐plane resolution from a subject in two orientations: lying supine and sitting in a vertical position with one arm raised. Experience with this prototype device will guide optimization of a second‐generation very‐low‐field imager to enable studies of human pulmonary physiology as a function of subject orientation. Magn Reson Med 53:745–749, 2005.

Mitochondrial Function and Insulin Resistance in Overweight and Normal-Weight Children

BACKGROUND Obesity has become an epidemic in children, associated with an increase in insulin resistance and metabolic dysfunction. Mitochondrial function is known to be an important determinant of glucose metabolism in adults. However, little is known about the relationship between mitochondrial function and obesity, insulin resistance, energy expenditure, and pubertal development in children. METHODS Seventy-four participants, 37 overweight (> or = 85th percentile body mass index for age and sex) and 37 normal-weight (< 85th percentile) without personal or family history of diabetes mellitus were enrolled. Subjects were evaluated with an oral glucose tolerance test, metabolic markers, resting energy expenditure, Tanner staging, and (31)P magnetic resonance spectroscopy of skeletal muscle for mitochondrial function. RESULTS Overweight and normal-weight children showed no difference in muscle ATP synthesis [phosphocreatine (PCr) recovery after exercise] (32.4 +/- 2.3 vs. 34.1 +/- 2.1, P = 0.58). However, insulin-resistant children had significantly prolonged PCr recovery when compared with insulin-sensitive children, by homeostasis model assessment for insulin resistance quartile (ANOVA, P = 0.04). Similarly, insulin-resistant overweight children had PCr recovery that was prolonged compared with insulin-sensitive overweight children (P = 0.01). PCr recovery was negatively correlated with resting energy expenditure in multivariate modeling (P = 0.03). Mitochondrial function worsened during mid-puberty in association with insulin resistance. CONCLUSION Reduced skeletal muscle mitochondrial oxidative phosphorylation, assessed by PCr recovery, is associated with insulin resistance and an altered metabolic phenotype in children. Normal mitochondrial function may be associated with a healthier metabolic phenotype in overweight children. Further studies are needed to investigate the long-term physiological consequences and potential treatment strategies targeting children with reduced mitochondrial function.

Water- and fat-suppressed proton projection MRI (WASPI) of rat femur bone.

Investigators often study rats by μCT to investigate the pathogenesis and treatment of skeletal disorders in humans. However, μCT measurements provide information only on bone mineral content and not the solid matrix. CT scans are often carried out on cancellous bone, which contains a significant volume of marrow cells, stroma, water, and fat, and thus the apparent bone mineral density (BMD) does not reflect the mineral density within the matrix, where the mineral crystals are localized. Water‐ and fat‐suppressed solid‐state proton projection imaging (WASPI) was utilized in this study to image the solid matrix content (collagen, tightly bound water, and other immobile molecules) of rat femur specimens, and meet the challenges of small sample size and demanding submillimeter resolution. A method is introduced to recover the central region of k‐space, which is always lost in the receiver dead time when free induction decays (FIDs) are acquired. With this approach, points near the k‐space origin are sampled under a small number of radial projections at reduced gradient strength. The typical scan time for the current WASPI experiments was 2 hr. Proton solid‐matrix images of rat femurs with 0.4‐mm resolution and 12‐mm field of view (FOV) were obtained. This method provides a noninvasive means of studying bone matrix in small animals. Magn Reson Med 57:554–567, 2007.

Quantitative bone matrix density measurement by water- and fat-suppressed proton projection MRI (WASPI) with polymer calibration phantoms

The density of the organic matrix of bone substance is a critical parameter necessary to clinically evaluate and distinguish structural and metabolic pathological conditions such as osteomalacia in adults and rickets in growing children. Water‐ and fat‐suppressed proton projection MRI (WASPI) was developed as a noninvasive means to obtain this information. In this study, a density calibration phantom was developed to convert WASPI intensity to true bone matrix density. The phantom contained a specifically designed poly(ethylene oxide)/poly(methyl methacrylate) (PEO/PMMA) blend, whose MRI properties (T1, T2, and resonance linewidth) were similar to those of solid bone matrix (collagen, tightly bound water, and other immobile molecules), minimizing the need to correct for differences in T1 and/or T2 relaxation between the phantom and the subject. Cortical and trabecular porcine bone specimens were imaged using WASPI with the calibration phantom in the field of view (FOV) as a stable intensity reference. Gravimetric and amino acid analyses were carried out on the same specimens after WASPI, and the chemical results were found to be highly correlated (r2 = 0.98 and 0.95, respectively) to the WASPI intensity. By this procedure the WASPI intensity can be used to obtain the true bone matrix mass density in g cm–3. Magn Reson Med 60:1433–1443, 2008.

Quantitative 31P NMR spectroscopy and 1H MRI measurements of bone mineral and matrix density differentiate metabolic bone diseases in rat models

In this study, bone mineral density (BMD) of normal (CON), ovariectomized (OVX), and partially nephrectomized (NFR) rats was measured by (31)P NMR spectroscopy; bone matrix density was measured by (1)H water- and fat-suppressed projection imaging (WASPI); and the extent of bone mineralization (EBM) was obtained by the ratio of BMD/bone matrix density. The capability of these MR methods to distinguish the bone composition of the CON, OVX, and NFR groups was evaluated against chemical analysis (gravimetry). For cortical bone specimens, BMD of the CON and OVX groups was not significantly different; BMD of the NFR group was 22.1% (by (31)P NMR) and 17.5% (by gravimetry) lower than CON. For trabecular bone specimens, BMD of the OVX group was 40.5% (by (31)P NMR) and 24.6% (by gravimetry) lower than CON; BMD of the NFR group was 26.8% (by (31)P NMR) and 21.5% (by gravimetry) lower than CON. No significant change of cortical bone matrix density between CON and OVX was observed by WASPI or gravimetry; NFR cortical bone matrix density was 10.3% (by WASPI) and 13.9% (by gravimetry) lower than CON. OVX trabecular bone matrix density was 38.0% (by WASPI) and 30.8% (by gravimetry) lower than CON, while no significant change in NFR trabecular bone matrix density was observed by either method. The EBMs of OVX cortical and trabecular specimens were slightly higher than CON but not significantly different from CON. Importantly, EBMs of NFR cortical and trabecular specimens were 12.4% and 26.3% lower than CON by (31)P NMR/WASPI, respectively, and 4.0% and 11.9% lower by gravimetry. Histopathology showed evidence of osteoporosis in the OVX group and severe secondary hyperparathyroidism (renal osteodystrophy) in the NFR group. These results demonstrate that the combined (31)P NMR/WASPI method is capable of discerning the difference in EBM between animals with osteoporosis and those with impaired bone mineralization.

Generation of remote homogeneous magnetic fields

This paper presents a magnetic efficiency model for comparing efficiencies of various magnets for magnetic resonance imaging. It demonstrates that monohedral magnets, magnets with sources on one side, can generate remote saddle points in the field profile relatively efficiently. These magnets may be modeled by a minimum of two magnetic dipoles. The paper examines the field profile and magnetic dipole efficiency for the two-dipole model in detail, and develops some fundamental properties of homogeneous magnetic fields.

Bone matrix imaged in vivo by water‐ and fat‐suppressed proton projection MRI (WASPI) of animal and human subjects

To demonstrate water‐ and fat‐suppressed proton projection MRI (WASPI) in a clinical scanner to visualize the solid bone matrix in animal and human subjects.