Abstract Background FOOTPRINTS® is a prospective, longitudinal, 3-year study assessing the association between biomarkers of inflammation/lung tissue destruction and chronic obstructive pulmonary disease (COPD) severity and progression in ex-smokers with mild-to-severe COPD. Here, we present baseline characteristics and select biomarkers of study subjects. Methods The methodology of FOOTPRINTS® has been published previously. The study population included ex-smokers with a range of COPD severities (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages 1–3), ex-smokers with COPD and alpha-1-antitrypsin deficiency (A1ATD) and a control group of ex-smokers without airflow limitation (EwAL). At study entry, data were collected for: demographics, disease characteristics, history of comorbidities and COPD exacerbations, symptoms, lung function and volume, exercise capacity, soluble biomarkers, and quantitative and qualitative computed tomography. Baseline data are presented with descriptive statistical comparisons for soluble biomarkers in the individual GOLD and A1ATD groups versus EwAL. Results In total, 463 subjects were enrolled. The per-protocol set comprised 456 subjects, mostly male (64.5%). The mean (standard deviation) age was 60.7 (6.9) years. At baseline, increasing pulmonary symptoms, worse lung function, increased residual volume, reduced diffusing capacity of the lung for carbon monoxide (DLco) and greater prevalence of centrilobular emphysema were observed with increasing disease severity amongst GOLD 1–3 subjects. Subjects with A1ATD (n = 19) had similar lung function parameters to GOLD 2–3 subjects, a high residual volume comparable to GOLD 3 subjects, and similar air trapping to GOLD 2 subjects. Compared with EwAL (n = 61), subjects with A1ATD had worse lung function, increased residual volume, reduced DLco, and a greater prevalence of confluent or advanced destructive emphysema. The soluble inflammatory biomarkers white blood cell count, fibrinogen, high-sensitivity C-reactive protein and plasma surfactant protein were higher in GOLD 1–3 groups than in the EwAL group. Interleukin-6 was expressed less often in EwAL subjects compared with subjects in the GOLD and A1ATD groups. Soluble receptor for advanced glycation end product was lowest in GOLD 3 subjects, indicative of more severe emphysema. Conclusions These findings provide context for upcoming results from FOOTPRINTS®, which aims to establish correlations between biomarkers and disease progression in a representative COPD population. Trial registration number: NCT02719184, study start date 13/04/2016.

BackgroundDynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) allows the assessment of pulmonary perfusion, which may play a key role in the development of muco-obstructive lung disease. One problem with quantifying pulmonary perfusion is the high variability of metrics. Quantifying the extent of abnormalities using unsupervised clustering algorithms in residue function maps leads to intrinsic normalization and could reduce variability.PurposeWe investigated the reproducibility of perfusion defects in percent (QDP) in clinically stable patients with cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD).Methods15 CF (29.3 ± 9.3y, FEV1%predicted = 66.6 ± 15.8%) and 20 COPD (66.5 ± 8.9y, FEV1%predicted = 42.0 ± 13.3%) patients underwent DCE-MRI twice 1 month apart. QDP, pulmonary blood flow (PBF), and pulmonary blood volume (PBV) were computed from residue function maps using an in-house quantification pipeline. A previously validated MRI perfusion score was visually assessed by an expert reader.ResultsOverall, mean QDP, PBF, and PBV did not change within 1 month, except for QDP in COPD (p < 0.05). We observed smaller limits of agreement (± 1.96 SD) related to the median for QDP (CF: ± 38%, COPD: ± 37%) compared to PBF (CF: ± 89%, COPD: ± 55%) and PBV (CF: ± 55%, COPD: ± 51%). QDP correlated moderately with the MRI perfusion score in CF (r = 0.46, p < 0.05) and COPD (r = 0.66, p < 0.001). PBF and PBV correlated poorly with the MRI perfusion score in CF (r =−0.29, p = 0.132 and r =−0.35, p = 0.067, respectively) and moderately in COPD (r =−0.57 and r =−0.57, p < 0.001, respectively).ConclusionIn patients with muco-obstructive lung diseases, QDP was more robust and showed a higher correlation with the MRI perfusion score compared to the traditionally used perfusion metrics PBF and PBV.

Objectives Pulmonary perfusion abnormalities are prevalent in patients with chronic obstructive pulmonary disease (COPD), are potentially reversible, and may be associated with emphysema development. Therefore, we aimed to evaluate the clinical meaningfulness of perfusion defects in percent (QDP) using DCE-MRI. Methods We investigated a subset of baseline DCE-MRIs, paired inspiratory/expiratory CTs, and pulmonary function testing (PFT) of 83 subjects (age = 65.7 ± 9.0 years, patients-at-risk, and all GOLD groups) from one center of the “COSYCONET” COPD cohort. QDP was computed from DCE-MRI using an in-house developed quantification pipeline, including four different approaches: Otsu’s method, k-means clustering, texture analysis, and 80 th percentile threshold. QDP was compared with visual MRI perfusion scoring, CT parametric response mapping (PRM) indices of emphysema (PRM Emph ) and functional small airway disease (PRM fSAD ), and FEV1/FVC from PFT. Results All QDP approaches showed high correlations with the MRI perfusion score ( r = 0.67 to 0.72, p < 0.001), with the highest association based on Otsu’s method ( r = 0.72, p < 0.001). QDP correlated significantly with all PRM indices ( p < 0.001), with the strongest correlations with PRM Emph ( r = 0.70 to 0.75, p < 0.001). QDP was distinctly higher than PRM Emph (mean difference = 35.85 to 40.40) and PRM fSAD (mean difference = 15.12 to 19.68), but in close agreement when combining both PRM indices (mean difference = 1.47 to 6.03) for all QDP approaches. QDP correlated moderately with FEV1/FVC ( r = − 0.54 to − 0.41, p < 0.001). Conclusion QDP is associated with established markers of disease severity and the extent corresponds to the CT-derived combined extent of PRM Emph and PRM fSAD . We propose to use QDP based on Otsu’s method for future clinical studies in COPD. Key Points • QDP quantified from DCE-MRI is associated with visual MRI perfusion score, CT PRM indices, and PFT. • The extent of QDP from DCE-MRI corresponds to the combined extent of PRM Emph and PRM fSAD from CT. • Assessing pulmonary perfusion abnormalities using DCE-MRI with QDP improved the correlations with CT PRM indices and PFT compared to the quantification of pulmonary blood flow and volume.

Background: Segmental LPS challenge is used in studies which examine inflammation induced edema in the lung. Currently, bronchoalveolar lavage (BAL) is used to quantify the LPS-induced amount of inflammation. Objectives: MRI is investigated to quantify regional edema following endobronchial LPS challenge using a scoring system and a quantitative method. Methods: In 23 healthy smokers segments 4 or 5 of the right lung were challenged with LPS and of the left lung with saline as control. BAL was performed prior to challenge and 24h after. Seven days before and prior the BAL 24h post LPS challenge the volunteers underwent a lung MRI scan. Edema was quantified on the TIRM images (score) and T1 maps (volume over threshold [VOT]) before contrast agent (CA) administration. Results: The percentage of neutrophilic cells was higher in LPS challenged segments (58.5%) compared to baseline (0.75%;p<0.0001) and saline treated segments (1.5 %;p<0.0001). Median [min; max] TIRM score and VOT showed a significantly higher amount of edema (3[1;4] and 7.3[0.2;36.6]mL) in LPS challenged segments compared to baseline (0[0;1];p<0.0001 and 0.0[0.0; 1.8]mL;p<0.0001) and saline treated segments (0[0;2];p<0.0001 and 1.1[0.0;10.5]mL;p=0.001). Median CA washout time was not significantly different between the corresponding segments before challenge (1.01[0.9;1.12]h vs 0.97[0.8;1.11]h, p=0.29) and remained stable in the LPS challenged (1.08[0.93;1.18]h;p=0.47) and saline treated segments (0.88[0.68;1.07]h;p=0.21). CA washout time was different in LPS challenged segments compared to saline treated segments (p=0.003) at 24h. Conclusion: Proton lung MRI can detect regional edema after segmental LPS challenge in healthy smokers.

In preclinical research, allergic asthma is investigated in rats sensitised with the antigen ovalbumin (OVA), followed by a challenge with aerosolised OVA to induce an inflammatory reaction of the lower airways. This causes diffuse, nonfocal ventilation defects that lead to heterogeneously distributed signal intensities in hyperpolarised (HP) (3)He MR images, which are difficult to assess directly by diagnostic grading or volumetry. Texture analysis can characterise these changes and does not require segmentation of the lung structures prior to the analysis. The aim of this work was to evaluate a texture analysis approach to quantify changes in lung ventilation in HP (3)He MRI of OVA-challenged rats. OVA-challenged animals were treated with two different compound doses to evaluate the sensitivity of the texture analysis. Four groups were investigated using HP (3)He MRI at 4.7 T: controls, vehicle-treated, and low- and high-dose budesonide-treated rats. In addition, broncho-alveolar lavage was performed and the eosinophil cell count was used as a biological reference marker. First-order texture, geometrical features and features based on second-order statistics using run-length and grey-level co-occurrence matrices were calculated. In addition, wavelet transforms were applied to compute first-order statistics on multiple scales. The texture analysis was able to show significant differences between the control and untreated vehicle groups as well as between the vehicle and treatment groups. This is in agreement with the findings of the eosinophil cell counts, which were used as a marker for the severity of inflammation. However, not all features used in the different texture analysis methods could differentiate between the treatment groups. In conclusion, texture analysis can be used to quantify changes in lung ventilation as measured with HP (3)He MRI after therapeutic intervention with budesonide.

To evaluate whether careful exercise training improves pulmonary perfusion and blood flow in patients with pulmonary hypertension (PH), as assessed by magnetic resonance imaging (MR).

Purpose Magnetic resonance imaging (MRI) allows for quantitative evaluation of pulmonary perfusion and has shown high clinical usefulness for the evaluation and differentiation of different lung pathologies. The reproducibility of quantitative analysis of whole-lung perfusion has not been investigated previously. Our aim was to assess the intraobserver and interobserver repeatability and reproducibility of perfusion MRI to prove the concept that perfusion is suitable for therapy monitoring. Materials and Methods The study was approved by the International Review Board. Fourteen healthy volunteers were examined using a time-resolved FLASH 3-dimensional perfusion sequence (1.5-T MRI, TREAT, GRAPPA 2, coronal orientation, voxel size 3.9×3.9×6.3 mm3). Perfusion was assessed initially and after 24 hours during an inspiratory and an expiratory breath hold. For each examination, 0.05 mmol/kg BW of Gd-DTPA was injected. Perfusion parameters such as pulmonary blood flow (PBF), pulmonary blood volume, and mean transit time were calculated. The evaluation was performed independently by 2 blinded observers. Intraobserver and interobserver differences were determined. Results The intraobserver differences between the initial and follow-up examinations for pulmonary blood volume, mean transit time, and time to peak were not significantly different for observers 1 and 2. PBF showed a significant difference for both observers only on inspiration (P<0.006 for observer 1 and P<0.009 for observer 2). For interobserver evaluation, all parameters, except inspiratory PBF, were significantly different (P<0.0001). Conclusions Intraobserver quantitative perfusion MRI showed reproducible results. However, the evaluation is highly dependent on the observer. Therefore, quantitative analysis of the serial examinations should be performed by the same observer.

Purpose The purpose of this study was to evaluate in vivo the influence of inversion pulse slice selectivity on oxygen-enhanced magnetic resonance imaging (MRI). Materials and methods Thirteen healthy volunteers were studied with a two-dimensional cardiac- and respiratory-gated adiabatic inversion-recovery half-Fourier single-shot turbo spin-echo (HASTE) sequence with either slice-selective or non-slice-selective inversion recovery (IR) pulse at inversion times increasing from 300 to 1400 ms. The signal-to-noise ratio (SNR) at every inversion time (TI), real signal difference (ΔSI), and relative enhancement ratio of lung parenchyma at TI ≥ 800 ms were statistically compared for oxygen-enhanced and non-oxygen-enhanced MR images with slice-selective or non-slice-selective IR pulses. Results The SNRs of acquisitions with slice-selective IR pulses were significantly higher than those of non-sliceselective IR pulses ( P < 0.05). At TI 800 ms, the ΔSI of lung parenchyma on IR-HASTE images with slice-selective inversion pulse type was significantly higher than on that with the non-slice-selective type ( P < 0.05). Relative enhancement ratios of the slice-selective IR pulses were significantly lower than those of non-slice-selective IR pulses at TIs between 800 and 1400 ms ( P < 0.05). Conclusion Slice selectivity of inversion pulse type affects oxygen-enhanced MRI in vivo.

Purpose: Regional T1 changes are viewed as a potential diagnostic biomarker in many pulmonary diseases. However, accurate T1 mapping of the lungs, as needed for instance when performing quantitative oxygen enhanced MRI [1], is hampered by low SNRs and cardio-respiratory motion artifacts, especially in small animals. To address these issues, a segmented 2D-IR sequence with ultrashort echo-time (UTE) and radial kspace sampling [2] was implemented. The protocol was validated in phantoms and applied to in vivo measurements in rats. Simulations were performed to determine the optimal pulse sequence parameters and to verify the method accuracy.

We proposed to assess the feasibility of low mechanical index (MI) contrast enhanced ultrasound (CEUS) in the characterisation of thoracic lesions. Fifty patients were prospectively examined by CEUS and images acquired on a low MI (0.17-0.24) setting following injection of SonoVue. From region-of-interest (ROI) generated signal intensity (SI) time curves, the maximum SI, bolus arrival time (BAT), time to peak intensity (TTP), wash-in slope and mean transit time (MTT) were calculated. Using the Wilcoxon rank test; parameters and threshold values for positive differentiation were determined. In addition, for the parameters that allowed positive differentiation between malignant and benign lesions receiver operator curves (ROC) were obtained. The wash-in slope, TTP and MTT (p = 0.0003, <0.0001, 0.02) allowed positive differentiation. The sensitivity and specificity was 93% and 78%, with 6.87 s(-1) threshold value for the wash-in slope, 78% and 89% with 11.84 s threshold for the TTP and 48% and 89% with 78.6 s threshold for the MTT. CEUS is a useful tool for differentiating malignant and benign thoracic lesions. (E-mail: nagmi.qureshi@papworth.nhs.uk) (C) 2011 World Federation for Ultrasound in Medicine & Biology.

Background: In vitro studies have shown that the 3-Tesla (T) magnetic resonance (MR) characteristics of high- and standard-molar gadolinium-based contrast agents differ. Such differences may indicate that high-molar (1.0 M) agents offer advantages for perfusion-weighted imaging (PWI) at 3T, as has been previously reported at 1.5T. Purpose: To investigate possible intraindividual differences of high- versus low-molar contrast agents on PWI at 3T in patients with intracranial space-occupying lesions. Material and Methods: Six patients with intraaxial and five patients with extraaxial tumors underwent two MR examinations at 3T, separated by at least 48 hours. On each occasion, an exogenous contrast-based, T2*-weighted, gradient-recalled echo-planar imaging (EPI) technique was used to determine the intracranial perfusion characteristics using one of two intravenous contrast agents: either 5 ml of 1.0 M gadobutrol or 10 ml of 0.5 M gadopentetate dimeglumine. The primary PWI outcome measure was region-of-interest maximal signal change (Cmax). Results: The difference in Cmax for gray and white matter (ΔCmax) was significantly higher for gadobutrol compared to gadopentetate dimeglumine (P<0.01). The ratio of Cmax between gray and white matter (rCmax = CmaxGray/CmaxWhite) was also significantly higher (median 24.6%, range 13.7–36.5%) for gadobutrol (P<0.01). The ratio of Cmax between the whole tumor and whole normal side hemisphere was higher in five out of the six intraaxial tumor cases. A significantly higher ratio (ΔCmax/Cmax) in the difference between Cmax of gray and white matter (from hemisphere without brain lesion) compared to Cmax for the hemisphere containing the neoplasm (hemisphere with brain lesion) was demonstrated for gadobutrol in intraaxial tumors (P<0.05). Conclusion: Higher-concentration 1.0 M gadobutrol can offer advantages over standard 0.5 M gadopentetate dimeglumine, particularly with respect to delineation between gray and white matter and for the demarcation of highly vascularized tumor tissue on brain PWI performed at 3T.

Pulmonary perfusion is the blood flow of an organ at the capillary level. It is closely related to the blood supply of the lung and moreover to lung function. It is altered in various diseases of the lung such as pulmonary hypertension or cystic fibrosis, etc. Therefore, perfusion is an important functional parameter in the diagnosis of pulmonary diseases and quantitative values are urgently required to study physiology and pathophysiology of various lung diseases as well as monitor treatment response and identify differences under therapy. Pulmonary perfusion MRI is based on three-dimensional time-resolved contrast-enhanced T1-weighted sequences. The rapid acquisition of perfusion images facilitates the tracking of the first pass of a contrast agent through the lung parenchyma. Based on this information, it is possible to quantify perfusion in the entire lung using the indicator dilution theory. Quantification is challenging due to potential extravasation of the contrast agent during the first pass as well as the non-linear relationship between the concentration of the contrast agent and signal intensity. Some of these challenges can be addressed by a dual bolus technique.

INTRODUCTION:The investigation of pulmonary perfusion by three-dimensional (3D) dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was proposed recently. Subtraction images are generated for clinical evaluation, but temporal information is lost and perfusion defects might therefore be masked in this process. The aim of this study is to demonstrate a simple analysis strategy and classification for 3D-DCE-MRI perfusion datasets in the lung without omitting the temporal information. MATERIALS AND METHODS:Pulmonary perfusion measurements were performed in patients with different lung diseases using a 1.5 T MR-scanner with a time-resolved 3D-GRE pulse sequence. 25 3D-volumes were acquired after iv-injection of 0.1 mmol/kg KG Gadolinium-DTPA. Three parameters were determined for each pixel: (1) peak enhancement S(n,max) normalized to the arterial input function to detect regions of reduced perfusion; (2) time between arterial peak enhancement in the large pulmonary artery and tissue peak enhancement τ to visualize regions with delayed bolus onset; and (3) ratio R=S(n,max)/τ was calculated to visualize impaired perfusion, irrespectively of whether related to reduced or delayed perfusion. RESULTS:A manual selection of peak perfusion images is not required. Five different types of perfusion can be found: (1) normal perfusion; (2) delayed non-reduced perfusion; (3) reduced non-delayed perfusion; (4) reduced and delayed perfusion; and (5) no perfusion. Types II and IV could not be seen in subtraction images since the temporal information is necessary for this purpose. CONCLUSIONS:The analysis strategy in this study allows for a simple and observer-independent visualization and classification of impaired perfusion in dynamic contrast-enhanced pulmonary perfusion MRI by using the temporal information of the datasets.

The purpose of the study was to evaluate the feasibility of suppressing the pulmonary vasculature in lung perfusion MRI using cross-correlation analysis (CCA). Perfusion magnetic resonance imaging (MRI) (3D FLASH, TR/TE/flip angle: 0.8 ms/2.1 ms/40°) of the lungs was performed in seven healthy volunteers at 1.5 Tesla after injection of Gd-DTPA. CCA was performed pixel-wise in lung segmentations using the signal time-course of the main pulmonary artery and left atrium as references. Pixels with high correlation coefficients were considered as arterial or venous and excluded from further analysis. Quantitative perfusion parameters [pulmonary blood flow (PBF) and volume (PBV)] were calculated for manual lung segmentations separately, with the entire left and right lung with all intrapulmonary vessels (IPV) included, excluded manually or excluded using CCA. The application of CCA allowed reliable suppression of hilar and large IPVs. Using vascular suppression by CCA, perfusion parameters were significantly reduced (p ≤ 0.001). The reduction was 8% for PBF and 13% for PBV compared with manual exclusion and 15% for PBF and 25% for PBV when all vessel structures were included. The application of CCA improves the visualisation and quantification of lung perfusion in MRI. Overestimation of perfusion parameters caused by pulmonary vessels is significantly reduced.

Three-dimensional (3D) dynamic contrast-enhanced magnetic resonance imaging (3D DCE-MRI) has been proposed for the assessment of regional perfusion. The aim of this work was the implementation of an algorithm for a 3D parametric visualization of lung perfusion using different cutting planes and volume rendering. Our implementation was based on 3D DCE-MRI data of the lungs of five patients and five healthy volunteers. Using the indicator dilution theory, the regional perfusion parameters, tissue blood flow, blood volume and mean transit time were calculated. Due to the required temporal resolution, the volume elements of dynamic MR data sets show a reduced spatial resolution in the z-direction. Therefore, perfusion parameter volumes were interpolated. Linear interpolation and a combination of linear and nearest-neighbor interpolation were evaluated. Additionally, ray tracing was applied for 3D visualization. The linear interpolation algorithm caused interpolation errors at the lung borders. Using the combined interpolation, visualization of perfusion information in arbitrary cutting planes and in 3D using volume rendering was possible. This facilitated the localization of perfusion deficits compared with the coronal orientated source data. The 3D visualization of perfusion parameters using a combined interpolation algorithm is feasible. Further studies are required to evaluate the additional benefit from the 3D visualization.

A linear relationship between MR signal and contrast-agent concentration (CAC) of the arterial-input function (AIF) is crucial for MR lung-perfusion quantification. The aim was to determine the in-vivo real maximum CAC of the AIF, using cine CT measurements in a porcine model. A dilution series (Gd-DTPA, 0-20 mM) was examined by clinical time-resolved 3D-GRE MRI and by MDCT in cine CT mode. Using the CT setup, data were acquired in five pigs immediately after the injection of 0.05 mmol and 0.07 mmol/kg BW Gd-DTPA. For phantom measurements, mean signal values were determined using a region-of-interest (ROI) analysis and for animal measurements, a ROI was placed in the pulmonary trunk of the cine CT perfusion data sets. The CT phantom measurements were used to calculate the in-vivo maximum CAC corresponding to the HU values obtained in the pulmonary trunk by the cine CT study. Linearity of the AIF of the CT perfusion measurements was verified using the MR phantom measurement results. MR phantom measurements demonstrated linearity for concentrations of 0-4 mM. CT phantom measurements showed linear relation for the entire CAC range. Comparing in-vivo and in-vitro measurements, three of five CA injections at 0.05 mmol/kg and all 0.07 mmol/kg injections exceeded the range of linearity in MRI. The CA dose for quantification of lung perfusion with time-resolved MR studies must be chosen carefully since even with low doses (0.05 mmol/kg) the CAC may exceed the range of linearity in the AIF.