Penny L. Hubbard Cristinacce

Feasibility assessment of using oxygen-enhanced magnetic resonance imaging for evaluating the effect of pharmacological treatment in COPD

OBJECTIVES Oxygen-enhanced MRI (OE-MRI) biomarkers have potential value in assessment of COPD, but need further evaluation before treatment-induced changes can be interpreted. The objective was to evaluate how OE-MRI parameters of regional ventilation and oxygen uptake respond to standard pharmacological interventions in COPD, and how the response compares to that of gold standard pulmonary function tests. MATERIALS AND METHODS COPD patients (n=40), mean FEV1 58% predicted normal, received single-dose inhaled formoterol 9μg, or placebo, followed by 8 weeks treatment bid with a combination of budesonide and formoterol Turbuhaler(®) 320/9μg or formoterol Turbuhaler(®). OE-MRI biomarkers were obtained, as well as X-ray computed tomography (CT) biomarkers and pulmonary function tests, in a two-center study. An ANCOVA statistical model was used to assess effect size of intervention measurable in OE-MRI parameters of lung function. RESULTS OE-MRI data were successfully acquired at both study sites. 8-week treatment with budesonide/formoterol significantly decreased lung wash-out time by 31% (p<0.01), decreased the change in lung oxygen level upon breathing pure oxygen by 13% (p<0.05) and increased oxygen extraction from the lung by 58% (p<0.01). Single-dose formoterol increased both lung wash-out time (+47%, p<0.05) and lung oxygenation time (+47%, p<0.05). FEV1 was improved by single-dose formoterol (+12%, p<0.001) and 8 weeks of budesonide/formoterol (+ 18%, p<0.001), consistent with published studies. CONCLUSIONS In COPD, OE-MRI parameters showed response to both single-dose bronchodilatory effects of a β2-agonist, formoterol, and 8-week treatment with an inhaled corticosteroid, budesonide, and the measurements are feasible in a small-scale multi-center trial setting.

Biomimetic Phantom for Cardiac Diffusion MRI

Diffusion magnetic resonance imaging (MRI) is increasingly used to characterize cardiac tissue microstructure, necessitating the use of physiologically relevant phantoms for methods development. Existing phantoms are generally simplistic and mostly simulate diffusion in the brain. Thus, there is a need for phantoms mimicking diffusion in cardiac tissue.

COPD Patients Have Short Lung Magnetic Resonance T1 Relaxation Time.

Abstract Magnetic resonance imaging (MRI) may provide attractive biomarkers for assessment of pulmonary disease in clinical trials as it is free from ionizing radiation, minimally invasive and allows regional information. The aim of this study was to characterize lung MRI T1 relaxation time as a biomarker of chronic obstructive pulmonary disease (COPD); and specifically its relationship to smoking history, computed tomography (CT), and pulmonary function test (PFT) measurements in comparison to healthy age-matched controls. Lung T1 and inter-quartile range (IQR) of T1 maps from 24 COPD subjects and 12 healthy age-matched non-smokers were retrospectively analyzed from an institutional review board approved study. The subjects underwent PFTs and two separate MR imaging sessions at 1.5 tesla to test T1 repeatability. CT scans were performed on the COPD subjects. T1 repeatability (intraclass correlation coefficient) was 0.72 for repeated scans acquired on two visits. The lung T1 was significantly shorter (p < 0.0001) and T1 IQR was significantly larger (p = 0.0002) for the COPD subjects compared to healthy controls. Lung T1 significantly (p = 0.001) correlated with lung density assessed with CT. Strong significant correlations (p < 0.0001) between lung T1 and all PFT measurements were observed. Cigarette exposure did not correlate with lung T1 in COPD subjects. In conclusion, lung MRI T1 mapping shows potential as a repeatable, radiation free, non-invasive imaging technique in the evaluation of COPD.

MR Quantitative Equilibrium Signal Mapping: A Reliable Alternative to CT in the Assessment of Emphysema in Patients with Chronic Obstructive Pulmonary Disease

PURPOSE To compare magnetic resonance (MR) quantitative equilibrium signal (qS0) mapping with quantitative computed tomography (CT) in the estimation of emphysema in patients with chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS Written informed consent of the original study permitted future reanalysis of data. This study was a retrospective analysis of data from an institutional review board-approved study. Twenty-four patients with COPD and 12 healthy patients who did not smoke underwent spirometry and two separate 1.5-T MR imaging examinations. All patients with COPD underwent additional chest CT. Lung MR qS0 maps were generated from MR images obtained with multiple inversion times by fitting the inversion recovery signal equation. Mean, 15th percentile, and standard deviation of whole-lung qS0 and relative lung area with a qS0 value below 0.20 (RA0.20) were measured and compared between groups with an unpaired t test. Reproducibility between two examinations was tested with intraclass correlation coefficients (ICCs), and their associations with spirometry and CT measurements of 15th percentile attenuation (PA15) and relative lung area with attenuation below -950 HU (RA-950) were assessed with the Pearson correlation coefficient. RESULTS Whole-lung mean qS0 and 15th percentile of qS0 were significantly lower, whereas RA0.20 and standard deviation of qS0 were significantly higher in patients with COPD than in healthy control subjects (P = .014, P = .002, P = .005, and P < .001, respectively). Whole-lung mean qS0, the 15th percentile of qS0, and RA0.20 strongly correlated with RA-950 (r = -0.78, r = -0.81, and r = 0.86, respectively; P < .001) and PA15 (r = 0.78, r = 0.79, and r = -0.71, respectively; P < .001) and moderately correlated with the ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (r = 0.63, r = 0.67, and r = -0.60, respectively; P < .001) and percentage predicted FEV1 (r = 0.54, r = 0.62, and r = -0.56, respectively; P ≤ .001). Good reproducibility of qS0 readouts was found in both groups (ICC range, 0.89-0.98). CONCLUSION Lung MR qS0 mapping may be a reliable noncontrast nonradiation alternative to CT in the assessment of emphysema in patients with COPD.

Preparation and characterization of polycaprolactone microspheres by electrospraying

ABSTRACT The ability to reproducibly produce and effectively collect electrosprayed polymeric microspheres with controlled morphology and size in bulk form is challenging. In this study, microparticles were produced by electrospraying polycaprolactone (PCL) of various molecular weights and solution concentrations in chloroform, and by collecting materials on different substrates. The resultant PCL microparticles were characterized by optical and electron microscopy to investigate the effect of molecular weight, solution concentration, applied voltage, working distance, and flow rate on their morphology and size. The work demonstrates the key role of a moderate molecular weight and/or solution concentration in the formation of spherical PCL particles via an electrospraying process. Increasing the applied voltage was found to produce smaller and more uniform PCL microparticles. There was a relatively low increase in the particle average size with an increase in the working distance and flow rate. Four types of substrates were adopted to collect electrosprayed PCL particles: a glass slide, aluminium foil, liquid bath, and copper wire. Unlike 2D bulk structures collected on the other substrates, a 3D tubular structure of microspheres was formed on the copper wire which could find application in the construction of 3D tumor mimics.

Imaging atherosclerosis in rheumatoid arthritis: evidence for increased prevalence, altered phenotype and a link between systemic and localised plaque inflammation.

In rheumatoid arthritis (RA), chronic inflammation is thought to drive increased cardiovascular risk through accelerated atherosclerosis. It may also lead to a more high-risk plaque phenotype. We sought to investigate carotid plaque phenotype in RA patients using Dynamic Contrast-Enhanced MRI (DCE-MRI) and Fludeoxyglucose Positron Emission Tomography(FDG-PET). In this pilot study, RA patients and age/sex-matched controls were evaluated for cardiovascular risk factors and carotid plaque on ultrasound. Subjects with plaque >2 mm thick underwent DCE-MRI, and a subgroup of patients had FDG-PET. Comparison of MRI findings between groups and correlation between clinical, serological markers and imaging findings was undertaken. 130 patients and 62 controls were recruited. Plaque was more prevalent in the RA group (53.1% vs 37.0%, p = 0.038) and was independently associated with IL6 levels (HR[95%CI]: 2.03 [1.26, 3.26] per quartile). DCE-MRI data were available in 15 patients and 5 controls. Higher prevalence of plaque calcification was noted in RA, despite similar plaque size (73.3% vs 20%, p = 0.04). FDG-PET detected plaque inflammation in 12/13 patients scanned and degree of inflammation correlated with hs-CRP (r = 0.58, p = 0.04). This study confirms increased prevalence of atherosclerosis in RA and provides data to support the hypothesis that patients have a high-risk plaque phenotype.

Quantitative assessment of liver function using Gadoxetate-Enhanced Magnetic Resonance Imaging: Monitoring Transporter-Mediated processes in healthy volunteers

Objective The objective of this study was to use noninvasive dynamic contrast-enhanced magnetic resonance imaging (MRI) techniques to study, in vivo, the distribution and elimination of the hepatobiliary contrast agent gadoxetate in the human body and characterize the transport mechanisms involved in its uptake into hepatocytes and subsequent efflux into the bile using a novel tracer kinetic model in a group of healthy volunteers. Materials and Methods Ten healthy volunteers (age range, 18–29 years), with no history of renal or hepatic impairment, were recruited via advertisement. Participants attended 2 MRI visits (at least a week apart) with gadoxetate as the contrast agent. Dynamic contrast-enhanced MRI data were acquired for approximately 50 minutes with a 3-dimensional gradient-echo sequence in the axial plane, at a temporal resolution of 6.2 seconds. Data from regions of interest drawn in the liver were analyzed using the proposed 2-compartment uptake and efflux model to provide estimates for the uptake rate of gadoxetate in hepatocytes and its efflux rate into the bile. Reproducibility statistics for the 2 visits were obtained to examine the robustness of the technique and its dependence in acquisition time. Results Eight participants attended the study twice and were included into the analysis. The resulting images provided the ability to simultaneously monitor the distribution of gadoxetate in multiple organs including the liver, spleen, and kidneys as well as its elimination through the common bile duct, accumulation in the gallbladder, and excretion in the duodenum. The mean uptake (ki) and efflux (kef) rates in hepatocytes, for the 2 visits using the 50-minute acquisition, were 0.22 ± 0.05 and 0.017 ± 0.006/min, respectively. The hepatic extraction fraction was estimated to be 0.19 ± 0.04/min. The variability between the 2 visits within the group level (95% confidence interval; ki: ±0.02/min, kef: ±0.004/min) was lower compared with the individual variability (repeatability; ki: ±0.06/min, kef: ±0.012/min). Data truncation demonstrated that the uptake rate estimates retained their precision as well as their group and individual reproducibility down to approximately 10 minutes of acquisition. Efflux rate estimates were underestimated (compared with the 50-minute acquisition) as the duration of the acquisition decreased, although these effects were more pronounced for acquisition times shorter than approximately 30 minutes. Conclusions This is the first study that reports estimates for the hepatic uptake and efflux transport process of gadoxetate in healthy volunteers in vivo. The results highlight that dynamic contrast-enhanced MRI with gadoxetate can provide novel quantitative insights into liver function and may therefore prove useful in studies that aim to monitor liver pathology, as well as being an alternative approach for studying hepatic drug-drug interactions.

Diffusion tensor MRI phantom exhibits anomalous diffusion

This paper reports diffusion weighted MRI measurements of cyclohexane in a novel diffusion tensor MRI phantom composed of hollow coaxial electrospun fibers (average diameter 10.2 μm). Recent studies of the phantom demonstrated its potential as a calibration standard at low b values (less than 1000 s/mm<;sup>2<;/sup>) for mean diffusivity and fractional anisotropy. In this paper, we extend the characterization of cyclohexane diffusion in this heterogeneous, anisotropic material to high b values (up to 5000 s/mm<;sup>2<;/sup>), where the apparent diffusive motion of the cyclohexane exhibits anomalous behavior (i.e., the molecular mean squared displacement increases with time raised to the fractional power 2α/β). Diffusion tensor MRI was performed at 9.4 T using an Agilent imaging scanner and the data fit to a fractional order Mittag-Leffler (generalized exponential) decay model. Diffusion along the fibers was found to be Gaussian (2α/β=l), while diffusion across the fibers was sub-diffusive (2α/β<;l). Fiber tract reconstruction of the data was consistent with scanning electron micrograph images of the material. These studies suggest that this phantom material may be used to calibrate MR systems in both the normal (Gaussian) and anomalous diffusion regimes.

T1 Relaxation Time in Lungs of Asymptomatic Smokers

Purpose Interest in using T1 as a potential MRI biomarker of chronic obstructive pulmonary disease (COPD) has recently increased. Since tobacco smoking is the major risk factor for development of COPD, the aim for this study was to examine whether tobacco smoking, pack-years (PY), influenced T1 of the lung parenchyma in asymptomatic current smokers. Materials and Methods Lung T1 measurements from 35 subjects, 23 never smokers and 12 current smokers were retrospectively analyzed from an institutional review board approved study. All 35 subjects underwent pulmonary function test (PFT) measurements and lung T1, with similar T1 measurement protocols. A backward linear model of T1 as a function of FEV1, FVC, weight, height, age and PY was tested. Results A significant correlation between lung T1 and PY was found with a negative slope of -3.2 ms/year (95% confidence interval [CI] [-5.8, -0.6], p = 0.02), when adjusted for age and height. Lung T1 shortens with ageing among all subjects, -4.0 ms/year (95%CI [-6.3, -1.7], p = 0.001), and among the never smokers, -3.7 ms/year (95%CI [-6.0, -1.3], p = 0.003). Conclusions A correlation between lung T1 and PY when adjusted for both age and height was found, and T1 of the lung shortens with ageing. Accordingly, PY and age can be significant confounding factors when T1 is used as a biomarker in lung MRI studies that must be taken into account to detect underlying patterns of disease.

Axon mimicking hydrophilic hollow polycaprolactone microfibres for diffusion magnetic resonance imaging

Highly hydrophilic hollow polycaprolactone (PCL) microfibres were developed as building elements to create tissue-mimicking test objects (phantoms) for validation of diffusion magnetic resonance imaging (MRI). These microfibres were fabricated by the co-electrospinning of PCL-polysiloxane-based surfactant (PSi) mixture as shell and polyethylene oxide as core. The addition of PSi had a significant effect on the size of resultant electrospun fibres and the formation of hollow microfibres. The presence of PSi in both co-electrospun PCL microfibre surface and cross-section, revealed by X-ray energy dispersive spectroscopy (EDX), enabled water to wet these fibres completely (i.e., zero contact angle) and remained active for up to 12 months after immersing in water. PCL and PCL-PSi fibres with uniaxial orientation were constructed into water-filled phantoms. MR measurement revealed that water molecules diffuse anisotropically in the PCL-PSi phantom. Co-electrospun hollow PCL-PSi microfibres have desirable hydrophilic properties for the construction of a new generation of tissue-mimicking dMRI phantoms.