Tumor-Targeted Interleukin 2 Boosts the Anticancer Activity of FAP-Directed Radioligand Therapeutics.

We studied the antitumor efficacy of a combination of 177Lu-labeled radioligand therapeutics targeting the fibroblast activation protein (FAP) (OncoFAP and BiOncoFAP) with the antibody-cytokine fusion protein L19-interleukin 2 (L19-IL2) providing targeted delivery of interleukin 2 to tumors. Methods: The biodistribution of 177Lu-OncoFAP and 177Lu-BiOncoFAP at different molar amounts (3 vs. 250 nmol/kg) of injected ligand was studied via SPECT/CT in mice bearing subcutaneous HT-1080.hFAP tumors, and self-absorbed tumor and organ doses were calculated. The in vivo anticancer effect of 5 MBq of the radiolabeled preparations was evaluated as monotherapy or in combination with L19-IL2 in subcutaneously implanted HT-1080.hFAP and SK-RC-52.hFAP tumors. Tumor samples from animals treated with 177Lu-BiOncoFAP, L19-IL2, or both were analyzed by mass spectrometry-based proteomics to identify therapeutic signatures on cellular and stromal markers of cancer and on immunomodulatory targets. Results: 177Lu-BiOncoFAP led to a significantly higher self-absorbed dose in FAP-positive tumors (0.293 ± 0.123 Gy/MBq) than did 177Lu-OncoFAP (0.157 ± 0.047 Gy/MBq, P = 0.01) and demonstrated favorable tumor-to-organ ratios at high molar amounts of injected ligand. Administration of L19-IL2 or 177Lu-BiOncoFAP as single agents led to cancer cures in only a limited number of treated animals. In 177Lu-BiOncoFAP-plus-L19-IL2 combination therapy, complete remissions were observed in all injected mice (7/7 complete remissions for the HT-1080.hFAP model, and 4/4 complete remissions for the SK-RC-52.hFAP model), suggesting therapeutic synergy. Proteomic studies revealed a mechanism of action based on the activation of natural killer cells, with a significant enhancement of the expression of granzymes and perforin 1 in the tumor microenvironment after combination treatment. Conclusion: The combination of OncoFAP-based radioligand therapeutics with concurrent targeting of interleukin 2 shows synergistic anticancer effects in the treatment of FAP-positive tumors. This experimental finding should be corroborated by future clinical studies.

Dispersion-corrected extracorporeal arterial input functions in PET studies of mice: a comparison to intracorporeal microprobe measurements.

BACKGROUND: Kinetic modelling of dynamic PET typically requires knowledge of the arterial radiotracer concentration (arterial input function, AIF). Its accurate determination is very difficult in mice. AIF measurements in an extracorporeal shunt can be performed; however, this introduces catheter dispersion. We propose a framework for extracorporeal dispersion correction and validated it by comparison to invasively determined intracorporeal AIFs using implanted microprobes. RESULTS: The response of an extracorporeal radiation detector to radioactivity boxcar functions, characterised by a convolution-based dispersion model, gave best fits using double-gamma variate and single-gamma variate kernels compared to mono-exponential kernels for the investigated range of flow rates. Parametric deconvolution with the optimal kernels was performed on 9 mice that were injected with a bolus of 39 ± 25 MBq [18F]F-PSMA-1007 after application of an extracorporeal circulation for three different flow rates in order to correct for dispersion. Comparison with synchronous implantation of microprobes for invasive aortic AIF recordings showed favourable correspondence, with no significant difference in terms of area-under-curve after 300 s and 5000 s. One-tissue and two-tissue compartment model simulations were performed to investigate differences in kinetic parameters between intra- and extracorporeally measured AIFs. Results of the modelling study revealed kinetic parameters close to the chosen simulated values in all compartment models. CONCLUSION: The high correspondence of simultaneously intra- and extracorporeally determined AIFs and resulting model parameters establishes a feasible framework for extracorporeal dispersion correction. This should allow more precise and accurate kinetic modelling in small animal experiments.

Voxel-Based Analysis of the Relation of 3'-Deoxy-3'-[18F]fluorothymidine ([18F]FLT) PET and Diffusion-Weighted (DW) MR Signals in Subcutaneous Tumor Xenografts Does Not Reveal a Direct Spatial Relation of These Two Parameters.

PURPOSE: Multimodal molecular imaging allows a direct coregistration of different images, facilitating analysis of the spatial relation of various imaging parameters. Here, we further explored the relation of proliferation, as measured by [18F]FLT PET, and water diffusion, as an indicator of cellular density and cell death, as measured by diffusion-weighted (DW) MRI, in preclinical tumor models. We expected these parameters to be negatively related, as highly proliferative tissue should have a higher density of cells, hampering free water diffusion. PROCEDURES: Nude mice subcutaneously inoculated with either lung cancer cells (n = 11 A549 tumors, n = 20 H1975 tumors) or colorectal cancer cells (n = 13 Colo205 tumors) were imaged with [18F]FLT PET and DW-MRI using a multimodal bed, which was transferred from one instrument to the other within the same imaging session. Fiducial markers allowed coregistration of the images. An automatic post-processing was developed in MATLAB handling the spatial registration of DW-MRI (measured as apparent diffusion coefficient, ADC) and [18F]FLT image data and subsequent voxel-wise analysis of regions of interest (ROIs) in the tumor. RESULTS: Analyses were conducted on a total of 76 datasets, comprising a median of 2890 data points (ranging from 81 to 13,597). Scatterplots showing [18F]FLT vs. ADC values displayed various grades of relations (Pearson correlation coefficient (PCC) varied from - 0.58 to 0.49, median: -0.07). When relating PCC to tumor volume (median: 46 mm3, range: 3 mm3 to 584 mm3), lung tumors tended to have a more pronounced negative spatial relation of [18F]FLT and ADC with increasing tumor size. However, due to the low number of large tumors (> ~ 200 mm3), this conclusion has to be treated with caution. CONCLUSIONS: A spatial relation of water diffusion, as measured by DW-MRI, and cellular proliferation, as measured by [18F]FLT PET, cannot be detected in the experimental datasets investigated in this study.

Comparison of two elastic motion correction approaches for whole-body PET/CT: motion deblurring vs gate-to-gate motion correction.

BACKGROUND: Respiratory motion in PET/CT leads to well-known image degrading effects commonly compensated using elastic motion correction approaches. Gate-to-gate motion correction techniques are promising tools for improving clinical PET data but suffer from relatively long reconstruction times. In this study, the performance of a fast elastic motion compensation approach based on motion deblurring (DEB-MC) was evaluated on patient and phantom data and compared to an EM-based fully 3D gate-to-gate motion correction method (G2G-MC) which was considered the gold standard. METHODS: Twenty-eight patients were included in this study with suspected or confirmed malignancies in the thorax or abdomen. All patients underwent whole-body [18F]FDG PET/CT examinations applying hardware-based respiratory gating. In addition, a dynamic anthropomorphic thorax phantom was studied with PET/CT simulating tumour motion under controlled but realistic conditions. PET signal recovery values were calculated from phantom scans by comparing lesion activities after motion correction to static ground truth data. Differences in standardized uptake values (SUV) and metabolic volume (MV) between both reconstruction methods as well as between motion-corrected (MC) and non motion-corrected (NOMC) results were statistically analyzed using a Wilcoxon signed-rank test. RESULTS: Phantom data analysis showed high lesion recovery values of 91% (2 cm motion) and 98% (1 cm) for G2G-MC and 83% (2 cm) and 90% (1 cm) for DEB-MC. The statistical analysis of patient data found significant differences between NOMC and MC reconstructions for SUV max, SUV mean, MV, and contrast-to-noise ratio (CNR) for both reconstruction algorithms. Furthermore, both methods showed similar increases of 11-12% in SUV max and SUV mean after MC. The statistical analysis of the MC/NOMC ratio found no significant differences between the methods. CONCLUSION: Both motion correction techniques deliver comparable improvements of SUV max, SUV mean, and CNR after MC on clinical and phantom data. The fast elastic motion compensation technique DEB-MC may thereby be a valuable alternative to state-of-the art motion correction techniques.

Toward precise arterial input functions derived from DCE-MRI through a novel extracorporeal circulation approach in mice.

PURPOSE: Dynamic contrast-enhanced MRI can be used in pharmacokinetic models to quantify functional parameters such as perfusion and permeability. However, precise quantification in preclinical models is challenged by the difficulties to dynamically measure the true arterial blood contrast agent concentration. We propose a novel approach toward a precise and experimentally feasible method to derive the arterial input function from DCE-MRI in mice. METHODS: Arterial blood was surgically shunted from the femoral artery to the tail vein and led through an extracorporeal circulation that resided on the head of brain tumor-bearing mice inside the FOV of a 9.4T MRI scanner. Dynamic 3D-FLASH scanning was performed after injection of gadobutrol with an effective resolution of 0.175 × 0.175 × 1 mm and a temporal resolution of 4 seconds. Pharmacokinetic modeling was performed using the extended Tofts and two-compartment exchange model. RESULTS: Arterial input functions measured inside the extracorporeal circulation showed little noise, small interindividual variance, and typical curve shapes. Ex vivo and mass spectrometry validation measurements documented the influence of shunt flow velocity and hematocrit on estimation of contrast agent concentrations. Modeling of tumors and muscles allowed fitting of the recorded dynamic concentrations, resulting in quantitative plausible parameters. CONCLUSION: The extracorporeal circulation allows deriving the contrast agent dynamics in arterial blood with high robustness and at acceptable experimental effort from DCE-MRI, previously not achievable in mice. It sets the basis for quantitative precise pharmacokinetic modeling in small animals to enhance the translatability of preclinical DCE-MRI measurements to patients.

Respiratory Motion Detection and Correction for MR Using the Pilot Tone: Applications for MR and Simultaneous PET/MR Examinations.

OBJECTIVES: The aim of this study was to develop a method for tracking respiratory motion throughout full MR or PET/MR studies that requires only minimal additional hardware and no modifications to the sequences. MATERIALS AND METHODS: Patient motion that is caused by respiration affects the quality of the signal of the individual radiofrequency receive coil elements. This effect can be detected as a modulation of a monofrequent signal that is emitted by a small portable transmitter placed inside the bore (Pilot Tone). The frequency is selected such that it is located outside of the frequency band of the actual MR readout experiment but well within the bandwidth of the radiofrequency receiver, that is, the oversampling area. Temporal variations of the detected signal indicate motion. After extraction of the signal from the raw data, principal component analysis was used to identify respiratory motion. The approach and potential applications during MR and PET/MR examinations that rely on a continuous respiratory signal were validated with an anthropomorphic, PET/MR-compatible motion phantom as well as in a volunteer study. RESULTS: Respiratory motion detection and correction were presented for MR and PET data in phantom and volunteer studies. The Pilot Tone successfully recovered the ground-truth respiratory signal provided by the phantom. CONCLUSIONS: The presented method provides reliable respiratory motion tracking during arbitrary imaging sequences throughout a full PET/MR study. All results can directly be transferred to MR-only applications as well.

Dynamic Cell Imaging in PET With Optimal Transport Regularization.

We propose a novel dynamic image reconstruction method from PET listmode data that could be particularly suited to tracking single or small numbers of cells. In contrast to conventional PET reconstruction our method combines the information from all detected events not only to reconstruct the dynamic evolution of the radionuclide distribution, but also to improve the reconstruction at each single time point by enforcing temporal consistency. This is achieved via optimal transport regularization where in principle, among all possible temporally evolving radionuclide distributions consistent with the PET measurement, the one is chosen with least kinetic motion energy. The reconstruction is found by convex optimization so that there is no dependence on the initialization of the method. We study its behaviour on simulated data of a human PET system and demonstrate its robustness even in settings with very low radioactivity. In contrast to previously reported cell tracking algorithms, our technique is oblivious to the number of tracked cells. Without any additional complexity one or multiple cells can be reconstructed, and the model automatically determines the number of particles. For instance, four radiolabelled cells moving at a velocity of 3.1 mm/s and a PET recorded count rate of 1.1 cps (for each cell) could be simultaneously tracked with a tracking accuracy of 5.3 mm inside a simulated human body.

Cardiorespiratory motion-tracking via self-refocused rosette navigators.

PURPOSE: To develop a flexible method for tracking respiratory and cardiac motions throughout MR and PET-MR body examinations that requires no additional hardware and minimal sequence modification. METHODS: The incorporation of a contrast-neutral rosette navigator module following the RF excitation allows for robust cardiorespiratory motion tracking with minimal impact on the host sequence. Spatial encoding gradients are applied to the FID signal and the desired motion signals are extracted with a blind source separation technique. This approach is validated with an anthropomorphic, PET-MR-compatible motion phantom as well as in 13 human subjects. RESULTS: Both respiratory and cardiac motions were reliably extracted from the proposed rosette navigator in phantom and patient studies. In the phantom study, the MR-derived motion signals were additionally validated against the ground truth measurement of diaphragm displacement and left ventricle model triggering pulse. CONCLUSION: The proposed method yields accurate respiratory and cardiac motion-state tracking, requiring only a short (1.76 ms) additional navigator module, which is self-refocusing and imposes minimal constraints on sequence design.

Data-driven gating in PET: Influence of respiratory signal noise on motion resolution.

PURPOSE: Data-driven gating (DDG) approaches for positron emission tomography (PET) are interesting alternatives to conventional hardware-based gating methods. In DDG, the measured PET data themselves are utilized to calculate a respiratory signal, that is, subsequently used for gating purposes. The success of gating is then highly dependent on the statistical quality of the PET data. In this study, we investigate how this quality determines signal noise and thus motion resolution in clinical PET scans using a center-of-mass-based (COM) DDG approach, specifically with regard to motion management of target structures in future radiotherapy planning applications. METHODS: PET list mode datasets acquired in one bed position of 19 different radiotherapy patients undergoing pretreatment [18 F]FDG PET/CT or [18 F]FDG PET/MRI were included into this retrospective study. All scans were performed over a region with organs (myocardium, kidneys) or tumor lesions of high tracer uptake and under free breathing. Aside from the original list mode data, datasets with progressively decreasing PET statistics were generated. From these, COM DDG signals were derived for subsequent amplitude-based gating of the original list mode file. The apparent respiratory shift d from end-expiration to end-inspiration was determined from the gated images and expressed as a function of signal-to-noise ratio SNR of the determined gating signals. This relation was tested against additional 25 [18 F]FDG PET/MRI list mode datasets where high-precision MR navigator-like respiratory signals were available as reference signal for respiratory gating of PET data, and data from a dedicated thorax phantom scan. RESULTS: All original 19 high-quality list mode datasets demonstrated the same behavior in terms of motion resolution when reducing the amount of list mode events for DDG signal generation. Ratios and directions of respiratory shifts between end-respiratory gates and the respective nongated image were constant over all statistic levels. Motion resolution d/dmax could be modeled as d/dmax=1-e-1.52(SNR-1)0.52, with dmax as the actual respiratory shift. Determining dmax from d and SNR in the 25 test datasets and the phantom scan demonstrated no significant differences to the MR navigator-derived shift values and the predefined shift, respectively. CONCLUSIONS: The SNR can serve as a general metric to assess the success of COM-based DDG, even in different scanners and patients. The derived formula for motion resolution can be used to estimate the actual motion extent reasonably well in cases of limited PET raw data statistics. This may be of interest for individualized radiotherapy treatment planning procedures of target structures subjected to respiratory motion.

Thymidine Metabolism as a Confounding Factor for 3'-Deoxy-3'-18F-Fluorothymidine Uptake After Therapy in a Colorectal Cancer Model.

Noninvasive monitoring of tumor therapy response helps in developing personalized treatment strategies. Here, we performed sequential PET and diffusion-weighted MRI to evaluate changes induced by a FOLFOX-like combination chemotherapy in colorectal cancer xenografts, to identify the cellular and molecular determinants of these imaging biomarkers. Methods: Tumor-bearing CD1 nude mice, engrafted with FOLFOX-sensitive Colo205 colorectal cancer xenografts, were treated with FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) weekly. On days 1, 2, 6, 9, and 13 of therapy, tumors were assessed by in vivo imaging and ex vivo analyses. In addition, HCT116 xenografts, which did not respond to the FOLFOX treatment, were imaged on day 1 of therapy. Results: In Colo205 xenografts, FOLFOX induced a profound increase in uptake of the proliferation PET tracer 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) accompanied by increases in markers for proliferation (Ki-67, thymidine kinase 1) and for activated DNA damage response (γH2AX), whereas the effect on cell death was minimal. Because tracer uptake was unaltered in the HCT116 model, these changes appear to be specific for tumor response. Conclusion: We demonstrated that 18F-FLT PET can noninvasively monitor cancer treatment-induced molecular alterations, including thymidine metabolism and DNA damage response. The cellular or imaging changes may not, however, be directly related to therapy response as assessed by volumetric measurements.

Anthropomorphic thorax phantom for cardio-respiratory motion simulation in tomographic imaging.

Patient motion during medical imaging using techniques such as computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), or single emission computed tomography (SPECT) is well known to degrade images, leading to blurring effects or severe artifacts. Motion correction methods try to overcome these degrading effects. However, they need to be validated under realistic conditions. In this work, a sophisticated anthropomorphic thorax phantom is presented that combines several aspects of a simulator for cardio-respiratory motion. The phantom allows us to simulate various types of cardio-respiratory motions inside a human-like thorax, including features such as inflatable lungs, beating left ventricular myocardium, respiration-induced motion of the left ventricle, moving lung lesions, and moving coronary artery plaques. The phantom is constructed to be MR-compatible. This means that we can not only perform studies in PET, SPECT and CT, but also inside an MRI system. The technical features of the anthropomorphic thorax phantom Wilhelm are presented with regard to simulating motion effects in hybrid emission tomography and radiotherapy. This is supplemented by a study on the detectability of small coronary plaque lesions in PET/CT under the influence of cardio-respiratory motion, and a study on the accuracy of left ventricular blood volumes.

PET attenuation correction for flexible MRI surface coils in hybrid PET/MRI using a 3D depth camera.

PET attenuation correction for flexible MRI radio frequency surface coils in hybrid PET/MRI is still a challenging task, as position and shape of these coils conform to large inter-patient variabilities. The purpose of this feasibility study is to develop a novel method for the incorporation of attenuation information about flexible surface coils in PET reconstruction using the Microsoft Kinect V2 depth camera. The depth information is used to determine a dense point cloud of the coil's surface representing the shape of the coil. From a CT template-acquired once in advance-surface information of the coil is extracted likewise and converted into a point cloud. The two point clouds are then registered using a combination of an iterative-closest-point (ICP) method and a partially rigid registration step. Using the transformation derived through the point clouds, the CT template is warped and thereby adapted to the PET/MRI scan setup. The transformed CT template is converted into an attenuation map from Hounsfield units into linear attenuation coefficients. The resulting fitted attenuation map is then integrated into the MRI-based patient-specific DIXON-based attenuation map of the actual PET/MRI scan. A reconstruction of phantom PET data acquired with the coil present in the field-of-view (FoV), but without the corresponding coil attenuation map, shows large artifacts in regions close to the coil. The overall count loss is determined to be around 13% compared to a PET scan without the coil present in the FoV. A reconstruction using the new µ-map resulted in strongly reduced artifacts as well as increased overall PET intensities with a remaining relative difference of about 1% to a PET scan without the coil in the FoV.

Partial volume correction for improved PET quantification in 18F-NaF imaging of atherosclerotic plaques.

BACKGROUND: Accurate quantification of plaque imaging using 18F-NaF PET requires partial volume correction (PVC). METHODS: PVC of PET data was implemented by the use of a local projection (LP) method. LP-based PVC was evaluated with an image quality (NEMA) and with a thorax phantom with "plaque-type" lesions of 18-36 mL. The validated PVC method was then applied to a cohort of 17 patients, each with at least one plaque in the carotid or ascending aortic arteries. In total, 51 calcified (HU > 110) and 16 non-calcified plaque lesions (HU < 110) were analyzed. The lesion-to-background ratio (LBR) and the relative change of LBR (ΔLBR) were measured on PET. RESULTS: Following PVC, LBR of the spheres (NEMA phantom) was within 10% of the original values. LBR of the thoracic lesions increased by 155% to 440% when the LP-PVC method was applied to the PET images. In patients, PVC increased the LBR in both calcified [mean = 78% (-8% to 227%)] and non-calcified plaques [mean = 41%, (-9%-104%)]. CONCLUSIONS: PVC helps to improve LBR of plaque-type lesions in both phantom studies and clinical patients. Better results were obtained when the PVC method was applied to images reconstructed with point spread function modeling.

Impact of presynaptic sympathetic imbalance in long-QT syndrome by positron emission tomography.

OBJECTIVE: We investigated the impact of cardiac presynaptic norepinephrine recycling in patients with long-QT syndrome (LQTS) using positron emission tomography (PET) with 11C-meta-hydroxyephedrine ([11C]mHED-PET). METHODS: [11C]mHED-PET was performed in 25 patients with LQTS (LQT1: n=14; LQT2: n=11) and 20 healthy controls and correlated with clinical parameters. [11C]mHED-PET images were analysed for global and regional retention indices (RI) and washout rates (WO) reflecting dynamic parameters of the tracer activity. RESULTS: Global and regional RI values were similar between patients with LQTS and controls. Although the global WO rates were similar between these groups, regional WO rates were on average higher in the lateral left ventricle (LV) wall in patients with LQTS (dose, mean ±SD; 0.08±0.14 vs 0.00%±0.09% min-1; p=0.033). In addition, patients with LQTS with a longer QTc interval showed a higher global WO rate. Clinical symptoms correlated with higher global WO rates. In the presence of normal global WO rates, asymptomatic LQTS patients showed higher global RI values. CONCLUSION: The increased regional WO rate of [11C]mHED in the lateral LV suggests an imbalance of presynaptic catecholamine reuptake and release, resulting in a higher synaptic catecholamine concentration, in particular in LQT1 patients. This might enhance ß-adrenoceptor signalling and thereby aggravate inherited ion channel dysfunction and may facilitate occurrence of ventricular tachyarrhythmias. Detection of regional differences in LV sympathetic nervous function may modify disease expression and potentially serve as a non-invasive risk marker in congenital LQTS. TRIAL REGISTRATION NUMBER: 2006-002767-41;Results.

Data-Driven Methods for the Determination of Anterior-Posterior Motion in PET.

Physiological motion combined with elongated scanning times in PET leads to image degradation and quantification errors. Correction approaches usually require 1-D signals that can be obtained with hardware-based or data-driven methods. Most of the latter are optimized or limited to capture internal motion along the superior-inferior (S-I) direction. In this work we present methods for also extracting anterior-posterior (A-P) motion from PET data and propose a set of novel weighting mechanisms that can be used to emphasize certain lines-of-response (LORs) for an increased sensitivity and better signal-to-noise ratio (SNR). The proper functioning of the methods was verified in a phantom experiment. Further, their application to clinical [18F]-FDG-PET data of 72 patients revealed that using the weighting mechanisms leads to signals with significantly higher spectral respiratory weights, i.e. signals with higher quality. Information about multi-dimensional motion is contained in PET data and can be derived with data-driven methods. Motion models or correction techniques such as respiratory gating might benefit from the proposed methods as they allow to describe the three-dimensional movements of PET-positive structures more precisely.

Sex differences in absolute myocardial perfusion. Non-invasive H2(15)O-PET in young healthy adults.

AIM: To investigate sex differences in myocardial perfusion especially in healthy individuals since former studies are rare and findings are controversial. Participants, methods: 26 subjects were enrolled: 16 healthy women (age: 34 ±7 years) were compared with 10 healthy men (age: 34 ± 3 years; p = ns). Myocardial blood flow (MBF) and coronary vascular resistance (CVR) were quantified at rest, during adenosine infusion and cold-pressor-testing, using positron emission tomography and radioactive-labelled water (H2(15)O-PET). RESULTS: Women showed higher MBF than men at rest (1.10 ± 0.18 vs. 0.85 ± 0.20 ml/min/ml; p = 0.003) and cold-stress (1.39 ± 0.38 vs. 1.06 ± 0.28 ml/min/ml; p = 0.026). Corrected for rate-pressure-product, baseline findings maintained significance (1.41 ± 0.33 vs. 1.16 ± 0.19 ml/min/ml; p = 0.024). CVR was lower in women at baseline (81 ± 14 vs. 107 ± 22 mmHg*ml(-1)*min*ml; p = 0.006) and during cold-pressor-testing (71 ± 17 vs. 91 ± 20 mmHg*ml(-1)*min*ml; p = 0.013). Under adenosine neither maximal MBF (4.06 ± 1.0 vs. 3.91 ± 0.88 ml/min/ml; p = ns) nor coronary flow reserve (3.07 ± 1.12 vs. 3.44 ± 0.92; p = ns) nor CVR (24 ± 8 vs. 24 ± 6 mmHg*ml(-1)*min*ml; p = ns) showed sex-related differences. CONCLUSION: Women show higher myocardial perfusion and lower coronary vascular resistance than men in physiologic states. Maximum perfusion and vasodilation under adenosine are not sex-specific.

Impact of Data-driven Respiratory Gating in Clinical PET.

Purpose To study the feasibility and impact of respiratory gating in positron emission tomographic (PET) imaging in a clinical trial comparing conventional hardware-based gating with a data-driven approach and to describe the distribution of determined parameters. Materials and Methods This prospective study was approved by the ethics committee of the University Hospital of Münster (AZ 2014-217-f-N). Seventy-four patients suspected of having abdominal or thoracic fluorine 18 fluorodeoxyglucose (FDG)-positive lesions underwent clinical whole-body FDG PET/computed tomographic (CT) examinations. Respiratory gating was performed by using a pressure-sensitive belt system (belt gating [BG]) and an automatic data-driven approach (data-driven gating [DDG]). PET images were analyzed for lesion uptake, metabolic volumes, respiratory shifts of lesions, and diagnostic image quality. Results Forty-eight patients had at least one lesion in the field of view, resulting in a total of 164 lesions analyzed (range of number of lesions per patient, one to 13). Both gating methods revealed respiratory shifts of lesions (4.4 mm ± 3.1 for BG vs 4.8 mm ± 3.6 for DDG, P = .76). Increase in uptake of the lesions compared with nongated values did not differ significantly between both methods (maximum standardized uptake value [SUVmax], +7% ± 13 for BG vs +8% ± 16 for DDG, P = .76). Similarly, gating significantly decreased metabolic lesion volumes with both methods (-6% ± 26 for BG vs -7% ± 21 for DDG, P = .44) compared with nongated reconstructions. Blinded reading revealed significant improvements in diagnostic image quality when using gating, without significant differences between the methods (DDG was judged to be inferior to BG in 22 cases, equal in 12 cases, and superior in 15 cases; P = .32). Conclusion Respiratory gating increases diagnostic image quality and uptake values and decreases metabolic volumes compared with nongated acquisitions. Data-driven approaches are clinically applicable alternatives to belt-based methods and might help establishing routine respiratory gating in clinical PET/CT. (©) RSNA, 2016 Online supplemental material is available for this article.

Imaging Reveals the Connection Between Spontaneous Coronary Plaque Ruptures, Atherothrombosis, and Myocardial Infarctions in HypoE/SRBI-/- Mice.

UNLABELLED: The hyperlipidemic mouse model HypoE/SRBI(-/-) has been shown to develop occlusive coronary atherosclerosis followed by myocardial infarctions and premature deaths in response to high-fat, high-cholesterol diet (HFC). However, the causal connection between myocardial infarctions and atherosclerotic plaque rupture events in the coronary arteries has not been investigated so far. The objective of this study was to assess whether diet-induced coronary plaque ruptures trigger atherothrombotic occlusions, resulting in myocardial infarctions in HFC-fed HypoE/SRBI(-/-) mice. METHODS: HypoE/SRBI(-/-) mice were characterized with respect to the individual dynamics of myocardial infarctions and features of infarct-related coronary atherosclerosis by serial noninvasive molecular and functional imaging, histopathology, and a pharmaceutical intervention. Detailed histologic analysis of whole mouse hearts was performed when spontaneously occurring acute myocardial infarctions were diagnosed by imaging. RESULTS: Using the imaging-triggered approach, we discovered thrombi in 32 (10.8%) of all 296 atherosclerotic coronary plaques in 14 HFC-fed HypoE/SRBI(-/-) mice. These thrombi typically were found in arteries presenting with inflammatory plaque phenotypes. Acetylsalicylic acid treatment did not attenuate the development of atherosclerotic coronary plaques but profoundly reduced the incidence of premature deaths, the number of thrombi (7 in 249 plaques), and also the degree of inflammation in the culprit lesions. CONCLUSION: HFC-induced ruptures of coronary plaques trigger atherothrombosis, vessel occlusions, myocardial infarctions, and sudden death in these mice. Thus, the HypoE/SRBI(-/-) mouse model mimics major features of human coronary heart disease and might therefore be a valuable model for the investigation of molecular and cellular parameters driving plaque rupture-related events and the development of new interventional approaches.

6-hydroxydopamine-induced Parkinson's disease-like degeneration generates acute microgliosis and astrogliosis in the nigrostriatal system but no bioluminescence imaging-detectable alteration in adult neurogenesis.

Parkinson's disease is a slowly progressing neurodegenerative disorder caused by loss of dopaminergic neurons in the substantia nigra (SN), leading to severe impairment in motor and non-motor functions. Endogenous subventricular zone (SVZ) neural stem cells constantly give birth to new cells that might serve as a possible source for regeneration in the adult brain. However, neurodegeneration is accompanied by neuroinflammation and dopamine depletion, potentially compromising regeneration. We therefore employed in vivo imaging methods to study striatal deafferentation (N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-[(123) I]iodophenyl)nortropane single photon emission computed tomography, DaTscan(™) ) and neuroinflammation in the SN and striatum (N,N-diethyl-2-(2-(4-(2-[(18) F]fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide positron emission tomography, [(18) F]DPA-714 PET) in the intranigral 6-hydroxydopamine Parkinson's disease mouse model. Additionally, we transduced cells in the SVZ with a lentivirus encoding firefly luciferase and followed migration of progenitor cells in the SVZ-olfactory bulb axis via bioluminescence imaging under disease and control conditions. We found that activation of microglia in the SN is an acute process accompanying the degeneration of dopaminergic cell bodies in the SN. Dopaminergic deafferentation of the striatum does not influence the generation of doublecortin-positive neuroblasts in the SVZ, but generates chronic astrogliosis in the nigrostriatal system.