X-ray dark-field chest radiography: a reader study to evaluate the diagnostic quality of attenuation chest X-rays from a dual-contrast scanning prototype.

OBJECTIVES: To compare the visibility of anatomical structures and overall quality of the attenuation images obtained with a dark-field X-ray radiography prototype with those from a commercial radiography system. METHODS: Each of the 65 patients recruited for this study obtained a thorax radiograph at the prototype and a reference radiograph at the commercial system. Five radiologists independently assessed the visibility of anatomical structures, the level of motion artifacts, and the overall image quality of all attenuation images on a five-point scale, with 5 points being the highest rating. The average scores were compared between the two image types. The differences were evaluated using an area under the curve (AUC) based z-test with a significance level of p ≤ 0.05. To assess the variability among the images, the distributions of the average scores per image were compared between the systems. RESULTS: The overall image quality was rated high for both devices, 4.2 for the prototype and 4.6 for the commercial system. The rating scores varied only slightly between both image types, especially for structures relevant to lung assessment, where the images from the commercial system were graded slightly higher. The differences were statistically significant for all criteria except for the bronchial structures, the cardiophrenic recess, and the carina. CONCLUSIONS: The attenuation images acquired with the prototype were assigned a high diagnostic quality despite a lower resolution and the presence of motion artifacts. Thus, the attenuation-based radiographs from the prototype can be used for diagnosis, eliminating the need for an additional conventional radiograph. KEY POINTS: • Despite a low tube voltage (70 kVp) and comparably long acquisition time, the attenuation images from the dark-field chest radiography system achieved diagnostic quality for lung assessment. • Commercial chest radiographs obtained a mean rating score regarding their diagnostic quality of 4.6 out of 5, and the grating-based images had a slightly lower mean rating score of 4.2 out of 5. • The difference in rating scores for anatomical structures relevant to lung assessment is below 5%.

Qualitative and Quantitative Assessment of Emphysema Using Dark-Field Chest Radiography.

Background Dark-field chest radiography allows for assessment of lung alveolar structure by exploiting wave optical properties of x-rays. Purpose To evaluate the qualitative and quantitative features of dark-field chest radiography in participants with pulmonary emphysema as compared with those in healthy control subjects. Materials and Methods In this prospective study conducted from October 2018 to October 2020, participants aged at least 18 years who underwent clinically indicated chest CT were screened for participation. Inclusion criteria were an ability to consent to the procedure and stand upright without help. Exclusion criteria were pregnancy, serious medical conditions, and any lung condition besides emphysema that was visible on CT images. Participants were examined with a clinical dark-field chest radiography prototype that simultaneously acquired both attenuation-based radiographs and dark-field chest radiographs. Dark-field coefficients were tested for correlation with each participant's CT-based emphysema index using the Spearman correlation test. Dark-field coefficients of adjacent groups in the semiquantitative Fleischner Society emphysema grading system were compared using a Wilcoxon Mann-Whitney U test. The capability of the dark-field coefficient to enable detection of emphysema was evaluated with receiver operating characteristics curve analysis. Results A total of 83 participants (mean age, 65 years ± 12 [standard deviation]; 52 men) were studied. When compared with images from healthy participants, dark-field chest radiographs in participants with emphysema had a lower and inhomogeneous dark-field signal intensity. The locations of focal signal intensity loss on dark-field images corresponded well with emphysematous areas found on CT images. The dark-field coefficient was negatively correlated with the quantitative CT-based emphysema index (r = -0.54, P < .001). Participants with Fleischner Society grades of mild, moderate, confluent, or advanced destructive emphysema exhibited a lower dark-field coefficient than those without emphysema (eg, 1.3 m-1 ± 0.6 for participants with confluent or advanced destructive emphysema vs 2.6 m-1 ± 0.4 for participants without emphysema; P < .001). The area under the receiver operating characteristic curve for detection of mild emphysema was 0.79. Conclusion Pulmonary emphysema leads to reduced signal intensity on dark-field chest radiographs, showing the technique has potential as a diagnostic tool in the assessment of lung diseases. © RSNA, 2022 See also the editorial by Hatabu and Madore in this issue.

X-ray Dark-Field Chest Imaging: Qualitative and Quantitative Results in Healthy Humans.

Background X-ray dark-field radiography takes advantage of the wave properties of x-rays, with a relatively high signal in the lungs due to the many air-tissue interfaces in the alveoli. Purpose To describe the qualitative and quantitative characteristics of x-ray dark-field images in healthy human subjects. Materials and Methods Between October 2018 and January 2020, patients of legal age who underwent chest CT as part of their diagnostic work-up were screened for study participation. Inclusion criteria were a normal chest CT scan, the ability to consent, and the ability to stand upright without help. Exclusion criteria were pregnancy, serious medical conditions, and changes in the lung tissue, such as those due to cancer, pleural effusion, atelectasis, emphysema, infiltrates, ground-glass opacities, or pneumothorax. Images of study participants were obtained by using a clinical x-ray dark-field prototype, recently constructed and commissioned at the authors' institution, to simultaneously acquire both attenuation-based and dark-field thorax radiographs. Each subject's total dark-field signal was correlated with his or her lung volume, and the dark-field coefficient was correlated with age, sex, weight, and height. Results Overall, 40 subjects were included in this study (average age, 62 years ± 13 [standard deviation]; 26 men, 14 women). Normal human lungs have high signal, while the surrounding osseous structures and soft tissue have very low and no signal, respectively. The average dark-field signal was 2.5 m-1 ± 0.4 of examined lung tissue. There was a correlation between the total dark-field signal and the lung volume (r = 0.61, P < .001). No difference was found between men and women (P = .78). Also, age (r = -0.18, P = .26), weight (r = 0.24, P = .13), and height (r = 0.01, P = .96) did not influence dark-field signal. Conclusion This study introduces qualitative and quantitative values for x-ray dark-field imaging in healthy human subjects. The quantitative x-ray dark-field coefficient is independent from demographic subject parameters, emphasizing its potential in diagnostic assessment of the lung. ©RSNA, 2021 See also the editorial by Hatabu and Madore in this issue.

Correction for Mechanical Inaccuracies in a Scanning Talbot-Lau Interferometer.

Grating-based X-ray phase-contrast and in particular dark-field radiography are promising new imaging modalities for medical applications. Currently, the potential advantage of dark-field imaging in early-stage diagnosis of pulmonary diseases in humans is being investigated. These studies make use of a comparatively large scanning interferometer at short acquisition times, which comes at the expense of a significantly reduced mechanical stability as compared to tabletop laboratory setups. Vibrations create random fluctuations of the grating alignment, causing artifacts in the resulting images. Here, we describe a novel maximum likelihood method for estimating this motion, thereby preventing these artifacts. It is tailored to scanning setups and does not require any sample-free areas. Unlike any previously described method, it accounts for motion in between as well as during exposures.

Dark-Field Chest Radiography Outperforms Conventional Chest Radiography for the Diagnosis and Staging of Pulmonary Emphysema.

OBJECTIVES: Dark-field chest radiography (dfCXR) has recently reached clinical trials. Here we compare dfCXR to conventional radiography for the detection and staging of pulmonary emphysema. MATERIALS AND METHODS: Subjects were included after a medically indicated computed tomography (CT) scan, showing either no lung impairments or different stages of emphysema. To establish a ground truth, all CT scans were assessed by 3 radiologists assigning emphysema severity scores based on the Fleischner Society classification scheme.Participants were imaged at a commercial chest radiography device and at a prototype for dfCXR, yielding both attenuation-based and dark-field images. Three radiologists blinded to CT score independently assessed images from both devices for presence and severity of emphysema (no, mild, moderate, severe).Statistical analysis included evaluation of receiver operating characteristic curves and pairwise comparison of adjacent Fleischner groups using an area under the curve (AUC)-based z test with a significance level of 0.05. RESULTS: A total of 88 participants (54 men) with a mean age of 64 ± 12 years were included. Compared with conventional images (AUC = 0.73), readers were better able to identify emphysema with images from the dark-field prototype (AUC = 0.85, P = 0.005). Although ratings of adjacent emphysema severity groups with conventional radiographs differed only for trace and mild emphysema, ratings based on images from the dark-field prototype were different for trace and mild, mild and moderate, and moderate and confluent emphysema. CONCLUSIONS: Dark-field chest radiography is superior to conventional chest radiography for emphysema diagnosis and staging, indicating the technique's potential as a low-dose diagnostic tool for emphysema assessment.

Correction of Motion Artifacts in Dark-Field Radiography of the Human Chest.

Dark-field radiography of the human chest is a promising novel imaging technique with the potential of becoming a valuable tool for the early diagnosis of chronic obstructive pulmonary disease and other diseases of the lung. The large field-of-view needed for clinical purposes could recently be achieved by a scanning system. While this approach overcomes the limited availability of large area grating structures, it also results in a prolonged image acquisition time, leading to concomitant motion artifacts caused by intrathoracic movements (e.g. the heartbeat). Here we report on a motion artifact reduction algorithm for a dark-field X-ray scanning system, and its successful evaluation in a simulated chest phantom and human in vivo chest X-ray dark-field data. By partitioning the acquired data into virtual scans with shortened acquisition time, such motion artifacts may be reduced or even fully avoided. Our results demonstrate that motion artifacts (e.g. induced by cardiac motion or diaphragmatic movements) can effectively be reduced, thus significantly improving the image quality of dark-field chest radiographs.

Dark-field chest X-ray imaging for the assessment of COVID-19-pneumonia.

BACKGROUND: Currently, alternative medical imaging methods for the assessment of pulmonary involvement in patients infected with COVID-19 are sought that combine a higher sensitivity than conventional (attenuation-based) chest radiography with a lower radiation dose than CT imaging. METHODS: Sixty patients with COVID-19-associated lung changes in a CT scan and 40 subjects without pathologic lung changes visible in the CT scan were included (in total, 100, 59 male, mean age 58 ± 14 years). All patients gave written informed consent. We employed a clinical setup for grating-based dark-field chest radiography, obtaining both a dark-field and a conventional attenuation image in one image acquisition. Attenuation images alone, dark-field images alone, and both displayed simultaneously were assessed for the presence of COVID-19-associated lung changes on a scale from 1 to 6 (1 = surely not, 6 = surely) by four blinded radiologists. Statistical analysis was performed by evaluation of the area under the receiver-operator-characteristics curves (AUC) using Obuchowski's method with a 0.05 level of significance. RESULTS: We show that dark-field imaging has a higher sensitivity for COVID-19-pneumonia than attenuation-based imaging and that the combination of both is superior to one imaging modality alone. Furthermore, a quantitative image analysis shows a significant reduction of dark-field signals for COVID-19-patients. CONCLUSIONS: Dark-field imaging complements and improves conventional radiography for the visualisation and detection of COVID-19-pneumonia.

Computed tomography (CT) imaging uses X-rays to obtain images of the inside of the body. It is used to look at lung damage in patients with COVID-19. However, CT imaging exposes the patient to a considerable amount of radiation. As radiation exposure can lead to the development of cancer, exposure should be minimised. Conventional plain X-ray imaging uses lower amounts of radiation but lacks sensitivity. We used dark-field chest X-ray imaging, which also uses low amounts of radiation, to assess the lungs of patients with COVID-19. Radiologists identified pneumonia in patients more easily from dark-field images than from usual plain X-ray images. We anticipate dark-field X-ray imaging will be useful to follow-up patients suspected of having lung damage.

Dark-field chest x-ray imaging: first experience in patients with alpha1-antitrypsin deficiency.

BACKGROUND: Spirometry and conventional chest x-ray have limitations in investigating early emphysema, while computed tomography, the reference imaging method in this context, is not part of routine patient care due to its higher radiation dose. In this work, we investigated a novel low-dose imaging modality, dark-field chest x-ray, for the evaluation of emphysema in patients with alpha1-antitrypsin deficiency. METHODS: By exploiting wave properties of x-rays for contrast formation, dark-field chest x-ray visualises the structural integrity of the alveoli, represented by a high signal over the lungs in the dark-field image. We investigated four patients with alpha1-antitrypsin deficiency with a novel dark-field x-ray prototype and simultaneous conventional chest x-ray. The extent of pulmonary function impairment was assessed by pulmonary function measurement and regional emphysema distribution was compared with CT in one patient. RESULTS: We show that dark-field chest x-ray visualises the extent of pulmonary emphysema displaying severity and regional differences. Areas with low dark-field signal correlate with emphysematous changes detected by computed tomography using a threshold of -950 Hounsfield units. The airway parameters obtained by whole-body plethysmography and single breath diffusing capacity of the lungs for carbon monoxide demonstrated typical changes of advanced emphysema. CONCLUSIONS: Dark-field chest x-ray directly visualised the severity and regional distribution of pulmonary emphysema compared to conventional chest x-ray in patients with alpha1-antitrypsin deficiency. Due to the ultra-low radiation dose in comparison to computed tomography, dark-field chest x-ray could be beneficial for long-term follow-up in these patients.

X-ray dark-field chest imaging for detection and quantification of emphysema in patients with chronic obstructive pulmonary disease: a diagnostic accuracy study.

BACKGROUND: Although advanced medical imaging technologies give detailed diagnostic information, a low-dose, fast, and inexpensive option for early detection of respiratory diseases and follow-ups is still lacking. The novel method of x-ray dark-field chest imaging might fill this gap but has not yet been studied in living humans. Enabling the assessment of microstructural changes in lung parenchyma, this technique presents a more sensitive alternative to conventional chest x-rays, and yet requires only a fraction of the dose applied in CT. We studied the application of this technique to assess pulmonary emphysema in patients with chronic obstructive pulmonary disease (COPD). METHODS: In this diagnostic accuracy study, we designed and built a novel dark-field chest x-ray system (Technical University of Munich, Munich, Germany)-which is also capable of simultaneously acquiring a conventional thorax radiograph (7 s, 0·035 mSv effective dose). Patients who had undergone a medically indicated chest CT were recruited from the department of Radiology and Pneumology of our site (Klinikum rechts der Isar, Technical University of Munich, Munich, Germany). Patients with pulmonary pathologies, or conditions other than COPD, that might influence lung parenchyma were excluded. For patients with different disease stages of pulmonary emphysema, x-ray dark-field images and CT images were acquired and visually assessed by five readers. Pulmonary function tests (spirometry and body plethysmography) were performed for every patient and for a subgroup of patients the measurement of diffusion capacity was performed. Individual patient datasets were statistically evaluated using correlation testing, rank-based analysis of variance, and pair-wise post-hoc comparison. FINDINGS: Between October, 2018 and December, 2019 we enrolled 77 patients. Compared with CT-based parameters (quantitative emphysema ρ=-0·27, p=0·089 and visual emphysema ρ=-0·45, p=0·0028), the dark-field signal (ρ=0·62, p<0·0001) yields a stronger correlation with lung diffusion capacity in the evaluated cohort. Emphysema assessment based on dark-field chest x-ray features yields consistent conclusions with findings from visual CT image interpretation and shows improved diagnostic performance than conventional clinical tests characterising emphysema. Pair-wise comparison of corresponding test parameters between adjacent visual emphysema severity groups (CT-based, reference standard) showed higher effect sizes. The mean effect size over the group comparisons (absent-trace, trace-mild, mild-moderate, and moderate-confluent or advanced destructive visual emphysema grades) for the COPD assessment test score is 0·21, for forced expiratory volume in 1 s (FEV1)/functional vital capacity is 0·25, for FEV1% of predicted is 0·23, for residual volume % of predicted is 0·24, for CT emphysema index is 0·35, for dark-field signal homogeneity within lungs is 0·38, for dark-field signal texture within lungs is 0·38, and for dark-field-based emphysema severity is 0·42. INTERPRETATION: X-ray dark-field chest imaging allows the diagnosis of pulmonary emphysema in patients with COPD because this technique provides relevant information representing the structural condition of lung parenchyma. This technique might offer a low radiation dose alternative to CT in COPD and potentially other lung disorders. FUNDING: European Research Council, Deutsche Forschungsgemeinschaft, Royal Philips, and Karlsruhe Nano Micro Facility.

Dosimetry on first clinical dark-field chest radiography.

PURPOSE: The purpose of this study was to evaluate the dose characteristic for patient examinations at the first clinical X-ray dark-field chest radiography system and to determine whether the effective patient dose is within a clinically acceptable dose range. METHODS: A clinical setup for grating-based dark-field chest radiography was constructed and commissioned, operating at a tube voltage of 70 kVp. Thermoluminescent dosimeter (TLD) measurements were conducted using an anthropomorphic phantom modeling the reference person to obtain a conversion coefficient relating dose area product (DAP) to effective patient dose at the dark-field system. For 92 patients, the DAP values for posterior-anterior measurements were collected at the dark-field system. Using the previously determined conversion coefficient, the effective dose was calculated. RESULTS: A reference person, modeled by an anthropomorphic phantom, receives an effective dose of 35 µSv. For the examined patients, a mean effective dose of 39 µSv was found. CONCLUSIONS: The effective dose at the clinical dark-field radiography system, generating both attenuation and dark-field images, is within the range of reported standard dose values for chest radiography.

Differential inhibition of galanin- and ghrelin-induced food intake by i.c.v. GLP-1(7-36)-amide.

Feeding regulation involves both anorectic and orexigenic neuropeptides mainly located in the hypothalamus. To gain further insight into the interaction between these two groups of regulators inhibition of feeding induced by glucagon-like peptide-1 (GLP-1) was examined during stimulation of food intake by equimolar doses of ghrelin and galanin. The experiments were carried out in freely feeding rats. Intracerebroventricular (i.c.v.) injections were accomplished through stereotaxically implanted cannulae aimed at the lateral cerebral ventricle. Food intake of standard rat chow pellets was subsequently recorded for 2 h. Ghrelin and galanin stimulated food intake significantly with no difference between these two peptides. During ghrelin stimulation GLP-1 inhibited feeding in doses between 0.015 and 1.5 nmol. During galanin stimulation of food intake a ten fold higher dose (0.15 nmol) was required to inhibit food intake. In conclusion equimolar doses of i.c.v. ghrelin and galanin are similarly effective stimuli of food intake when given alone. However in combination with an anorectic neuropeptide such as GLP-1 they have substantially different potencies of feeding stimulation. Such interaction could also be of interest for therapeutic strategies involving both regulating groups of neuropeptides.

Arginine-vasopressin directly promotes a thermogenic and pro-inflammatory adipokine expression profile in brown adipocytes.

Arginine-vasopressin (AVP) - via activation of the hypothalamic-pituitary-adrenal (HPA) axis - may play a role in the regulation of energy homeostasis and related cardiovascular complications. Brown adipose tissue (BAT) - via dissipation of energy in the form of heat - contributes to whole body energy balance. BAT expresses vasopressin receptors. We investigated direct effects of AVP on brown adipose endocrine and metabolic functions. UCP-1 protein expression in differentiated brown adipocytes was induced after acute exposure of adipocytes to AVP. This effect was time-dependent with a maximum increase after 8h. AVP also induced a time- and dose-dependent increase in p38 MAP kinase phosphorylation. Pharmacological inhibition of p38 MAP kinase with SB 202190 abolished the induction of UCP-1 protein expression. Furthermore, while acute AVP treatment enhanced mRNA expression of MCP-1 and IL-6, adiponectin mRNA expression was reduced. Yet, on the level of intracellular glucose uptake, there was no AVP-induced change of adipose insulin-induced glucose uptake. Finally, there was no difference in lipid accumulation between control and AVP-treated cells. Taken together, our data demonstrate direct effects of AVP on thermogenic, inflammatory, and glucoregulatory gene expression in brown adipocytes, thus expanding the hitherto known spectrum of this neuropeptides's biological effects and suggesting a direct adipotropic role as a stress-promoting factor.

Importance of orexigenic counter-regulation for multiple targeted feeding inhibition.

OBJECTIVE: Central feeding regulation involves both anorectic and orexigenic pathways. This study examined whether targeting both systems could enhance feeding inhibition induced by anorectic neuropeptides. RESEARCH METHODS AND PROCEDURES: Experiments were carried out in 24-hour fasted rats. Intracerebroventricular (ICV) injections were accomplished through stereotaxically implanted cannulae aimed at the lateral cerebral ventricle. Food intake of standard rat chow pellets was subsequently recorded for 2 hours. RESULTS: Blockade of orexigenic central opioids and neuropeptide Y (NPY) by ICV naloxone (25 microg) or the NPY receptor antagonist [D-Trp32]NPY (NPY-Ant; 10 micro g) powerfully augmented the feeding suppression induced by ICV glucagon-like peptide 1 (7-36)-amide (GLP-1; 10 microg) or xenin-25 (xenin; 15 microg) in 24-hour fasted rats. Most importantly, in combination with naloxone or NPY-Ant, even a low and ineffective dose of GLP-1 (5 microg) caused a 40% reduction of food intake, which was augmented further when both antagonists were given in combination with GLP-1. The combination of GLP-1 (5 microg) and xenin (10 microg) at individually ineffective doses caused a 46% reduction of food intake, which was abolished at a 10-fold lower dose. This ineffective dose, however, reduced food intake by 72% when administered in combination with naloxone and NPY-Ant. DISCUSSION: Targeting up to four pathways of feeding regulation in the central nervous system by blockade of endogenous feeding stimuli and simultaneous administration of anorectic neuropeptides potentiated reduction of food intake. This raises a promising perspective for treatment of obesity.

Peptides that regulate food intake: glucagon-like peptide 1-(7-36) amide acts at lateral and medial hypothalamic sites to suppress feeding in rats.

Glucagon-like peptide 1-(7-36) amide (GLP-1) potently inhibits rat feeding behavior after central administration. Because third ventricular injection of GLP-1 appeared to be less effective than lateral ventricular injection, we have reexamined this issue. In addition, we attempted to identify brain regions other than the paraventricular nucleus of the hypothalamus that are sensitive toward GLP-1-induced feeding suppression. Finally, we examined the local role of endogenous GLP-1 by specific GLP-1 receptor blockade. After lateral ventricular injection, GLP-1 significantly inhibited food intake of 24-h-fasted rats in a dose-dependent fashion with a minimal effective dose of 1 microg. After third ventricular injection, GLP-1 (1 microg) was similarly effective in suppressing food intake, which extends previous findings. Intracerebral microinjections of GLP-1 significantly suppressed food intake in the lateral (LH), dorsomedial (DMH), and ventromedial hypothalamus (VMH), but not in the medial nucleus of the amygdala. The minimal effective dose of GLP-1 was 0.3 microg at LH sites and 1 microg at DMH or VMH sites. LH microinjections of exendin-(9-39) amide, a GLP-1 receptor antagonist, at 1 or 2.5 microg did not alter feeding behavior in 24-h-fasted rats. In satiated animals, however, a single LH injection of 1 microg exendin-(9-39) amide significantly augmented food intake, but only during the first 20 min (0.6 vs. 0.1 g). With three repeated injections of 2.5 microg exendin-(9-39) amide every 20 min, 1-h food intake was significantly increased by 300%. These data strongly support and extend the concept of GLP-1 as a physiological regulator of food intake in the hypothalamus.