Feasibility study of a SiPM-fiber detector for non-invasive measurement of arterial input function for preclinical and clinical positron emission tomography.

Pharmacokinetic positron emission tomography (PET) studies rely on the measurement of the arterial input function (AIF), which represents the time-activity curve of the radiotracer concentration in the blood plasma. Traditionally, obtaining the AIF requires invasive procedures, such as arterial catheterization, which can be challenging, time-consuming, and associated with potential risks. Therefore, the development of non-invasive techniques for AIF measurement is highly desirable. This study presents a detector for the non-invasive measurement of the AIF in PET studies. The detector is based on the combination of scintillation fibers and silicon photomultipliers (SiPMs) which leads to a very compact and rugged device. The feasibility of the detector was assessed through Monte Carlo simulations conducted on mouse tail and human wrist anatomies studying relevant parameters such as energy spectrum, detector efficiency and minimum detectable activity (MDA). The simulations involved the use of 18F and 68Ga isotopes, which exhibit significantly different positron ranges. In addition, several prototypes were built in order to study the different components of the detector including the scintillation fiber, the coating of the fiber, the SiPMs, and the operating configuration. Finally, the simulations were compared with experimental measurements conducted using a tube filled with both 18F and 68Ga to validate the obtained results. The MDA achieved for both anatomies (approximately 1000 kBq/mL for mice and 1 kBq/mL for humans) falls below the peak radiotracer concentrations typically found in PET studies, affirming the feasibility of conducting non-invasive AIF measurements with the fiber detector. The sensitivity for measurements with a tube filled with 18F (68Ga) was 1.2 (2.07) cps/(kBq/mL), while for simulations, it was 2.81 (6.23) cps/(kBq/mL). Further studies are needed to validate these results in pharmacokinetic PET studies.

Zinc-Doped Iron Oxide Nanoparticles as a Proton-Activatable Agent for Dose Range Verification in Proton Therapy.

Proton therapy allows the treatment of specific areas and avoids the surrounding tissues. However, this technique has uncertainties in terms of the distal dose fall-off. A promising approach to studying the proton range is the use of nanoparticles as proton-activatable agents that produce detectable signals. For this, we developed an iron oxide nanoparticle doped with Zn (IONP@Zn-cit) with a hydrodynamic size of 10 nm and stability in serum. Cytotoxicity, defined as half of the surveillance, was 100 µg Zn/mL in the U251 cell line. The effect on clonogenic cell death was tested after X-ray irradiation, which suggested a radioprotective effect of these nanoparticles at low concentrations (1-10 µg Zn/mL). To evaluate the production of positron emitters and prompt-gamma signals, IONP@Zn-cit was irradiated with protons, obtaining prompt-gamma signals at the lowest measured concentration (10 mg Zn/mL). Finally, 67Ga-IONP@Zn-cit showed accumulation in the liver and spleen and an accumulation in the tumor tissue of 0.95% ID/g in a mouse model of U251 cells. These results suggest the possibility of using Zn nanoparticles as proton-activatable agents to verify the range by prompt gamma detection and face the challenges of prompt gamma detection in a specific biological situation, opening different avenues to go forward in this field.

Cardiac Insulin Resistance in Subjects With Metabolic Syndrome Traits and Early Subclinical Atherosclerosis.

OBJECTIVE: Experimental evidence suggests that metabolic syndrome (MetS) is associated with changes in cardiac metabolism. Whether this association occurs in humans is unknown. RESEARCH DESIGN AND METHODS: 821 asymptomatic individuals from the Progression of Early Subclinical Atherosclerosis (PESA) study (50.6 [46.9-53.6] years, 83.7% male) underwent two whole-body 18F-fluorodeoxyglucose positron emission tomography-magnetic resonance (18F-FDG PET-MR) 4.8 ± 0.6 years apart. Presence of myocardial 18F-FDG uptake was evaluated qualitatively and quantitatively. No myocardial uptake was grade 0, while positive uptake was classified in grades 1-3 according to target-to-background ratio tertiles. RESULTS: One hundred fifty-six participants (19.0%) showed no myocardial 18F-FDG uptake, and this was significantly associated with higher prevalence of MetS (29.0% vs. 13.9%, P < 0.001), hypertension (29.0% vs. 18.0%, P = 0.002), and diabetes (11.0% vs. 3.2%, P < 0.001), and with higher insulin resistance index (HOMA-IR, 1.64% vs. 1.23%, P < 0.001). Absence of myocardial uptake was associated with higher prevalence of early atherosclerosis (i.e., arterial 18F-FDG uptake, P = 0.004). On follow-up, the associations between myocardial 18F-FDG uptake and risk factors were replicated, and MetS was more frequent in the group without myocardial uptake. The increase in HOMA-IR was associated with a progressive decrease in myocardial uptake (P < 0.001). In 82% of subjects, the categorization according to presence/absence of myocardial 18F-FDG uptake did not change between baseline and follow-up. MetS regression on follow-up was associated with a significant (P < 0.001) increase in myocardial uptake. CONCLUSIONS: Apparently healthy individuals without cardiac 18F-FDG uptake have higher HOMA-IR and higher prevalence of MetS traits, cardiovascular risk factors, and early atherosclerosis. An improvement in cardiometabolic profile is associated with the recovery of myocardial 18F-FDG uptake at follow-up.

Bone marrow activation in response to metabolic syndrome and early atherosclerosis.

AIMS: Experimental studies suggest that increased bone marrow (BM) activity is involved in the association between cardiovascular risk factors and inflammation in atherosclerosis. However, human data to support this association are sparse. The purpose was to study the association between cardiovascular risk factors, BM activation, and subclinical atherosclerosis. METHODS AND RESULTS: Whole body vascular 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI) was performed in 745 apparently healthy individuals [median age 50.5 (46.8-53.6) years, 83.8% men] from the Progression of Early Subclinical Atherosclerosis (PESA) study. Bone marrow activation (defined as BM 18F-FDG uptake above the median maximal standardized uptake value) was assessed in the lumbar vertebrae (L3-L4). Systemic inflammation was indexed from circulating biomarkers. Early atherosclerosis was evaluated by arterial metabolic activity by 18F-FDG uptake in five vascular territories. Late atherosclerosis was evaluated by fully formed plaques on MRI. Subjects with BM activation were more frequently men (87.6 vs. 80.0%, P = 0.005) and more frequently had metabolic syndrome (MetS) (22.2 vs. 6.7%, P < 0.001). Bone marrow activation was significantly associated with all MetS components. Bone marrow activation was also associated with increased haematopoiesis-characterized by significantly elevated leucocyte (mainly neutrophil and monocytes) and erythrocyte counts-and with markers of systemic inflammation including high-sensitivity C-reactive protein, ferritin, fibrinogen, P-selectin, and vascular cell adhesion molecule-1. The associations between BM activation and MetS (and its components) and increased erythropoiesis were maintained in the subgroup of participants with no systemic inflammation. Bone marrow activation was significantly associated with high arterial metabolic activity (18F-FDG uptake). The co-occurrence of BM activation and arterial 18F-FDG uptake was associated with more advanced atherosclerosis (i.e. plaque presence and burden). CONCLUSION: In apparently healthy individuals, BM 18F-FDG uptake is associated with MetS and its components, even in the absence of systemic inflammation, and with elevated counts of circulating leucocytes. Bone marrow activation is associated with early atherosclerosis, characterized by high arterial metabolic activity. Bone marrow activation appears to be an early phenomenon in atherosclerosis development.[Progression of Early Subclinical Atherosclerosis (PESA); NCT01410318].

In vivo production of fluorine-18 in a chicken egg tumor model of breast cancer for proton therapy range verification.

Range verification of clinical protontherapy systems via positron-emission tomography (PET) is not a mature technology, suffering from two major issues: insufficient signal from low-energy protons in the Bragg peak area and biological washout of PET emitters. The use of contrast agents including 18O, 68Zn or 63Cu, isotopes with a high cross section for low-energy protons in nuclear reactions producing PET emitters, has been proposed to enhance the PET signal in the last millimeters of the proton path. However, it remains a challenge to achieve sufficient concentrations of these isotopes in the target volume. Here we investigate the possibilities of 18O-enriched water (18-W), a potential contrast agent that could be incorporated in large proportions in live tissues by replacing regular water. We hypothesize that 18-W could also mitigate the problem of biological washout, as PET (18F) isotopes created inside live cells would remain trapped in the form of fluoride anions (F-), allowing its signal to be detected even hours after irradiation. To test our hypothesis, we designed an experiment with two main goals: first, prove that 18-W can incorporate enough 18O into a living organism to produce a detectable signal from 18F after proton irradiation, and second, determine the amount of activity that remains trapped inside the cells. The experiment was performed on a chicken embryo chorioallantoic membrane tumor model of head and neck cancer. Seven eggs with visible tumors were infused with 18-W and irradiated with 8-MeV protons (range in water: 0.74 mm), equivalent to clinical protons at the end of particle range. The activity produced after irradiation was detected and quantified in a small-animal PET-CT scanner, and further studied by placing ex-vivo tumours in a gamma radiation detector. In the acquired images, specific activity of 18F (originating from 18-W) could be detected in the tumour area of the alive chicken embryo up to 9 h after irradiation, which confirms that low-energy protons can indeed produce a detectable PET signal if a suitable contrast agent is employed. Moreover, dynamic PET studies in two of the eggs evidenced a minimal effect of biological washout, with 68% retained specific 18F activity at 8 h after irradiation. Furthermore, ex-vivo analysis of 4 irradiated tumours showed that up to 3% of oxygen atoms in the targets were replaced by 18O from infused 18-W, and evidenced an entrapment of 59% for specific activity of 18F after washing, supporting our hypothesis that F- ions remain trapped within the cells. An infusion of 18-W can incorporate 18O in animal tissues by replacing regular water inside cells, producing a PET signal when irradiated with low-energy protons that could be used for range verification in protontherapy. 18F produced inside cells remains entrapped and suffers from minimal biological washout, allowing for a sharper localization with longer PET acquisitions. Further studies must evaluate the feasibility of this technique in dosimetric conditions closer to clinical practice, in order to define potential protocols for its use in patients.

Analysis of 18F-Sodium Fluoride Positron Emission Tomography Signal Sources in Atherosclerotic Minipigs Shows Specific Binding of 18F-Sodium Fluoride to Plaque Calcifications.

Objective: 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) imaging is thought to visualize active atherosclerotic plaque calcification. This is supported by the binding of 18F-NaF to plaque calcification ex vivo, but no prior studies have examined binding of 18F-NaF to human-like plaque in vivo. Our aim was to validate the specificity of 18F-NaF PET for plaque calcifications in atherosclerotic minipigs. Approach and Results: Gain-of-function PCSK9D374Y (proprotein convertase/subtilisin kexin type 9) transgenic Yucatan minipigs (n=4) were fed high-fat diet for 2.5 years to develop atherosclerosis and then subjected to 18F-NaF PET/computed tomography imaging. The heart, aorta, and iliac arteries were immediately re-scanned ex vivo after surgical extraction. Lesions from the abdominal aorta, iliac arteries, and coronary arteries were cryo-sectioned for autoradiography. Histological plaque characteristics, PET/computed tomography signal, and autoradiography were linked through regression and co-localization analysis. Arterial 18F-NaF PET signal had intensities comparable to clinical scans and colocalized moderately with calcification detected by computed tomography. Histological analysis showed calcification spanning from microcalcifications near lipid pools and necrotic core to more homogenous macrocalcifications. Comparison with arteries from autopsy cases confirmed the resemblance in localization and appearance with early human plaque calcification. Regression analysis in the abdominal aorta showed correlations with calcified plaque but could not rule out contributions from noncalcified plaque. This was resolved by autoradiography, which showed specific accumulation in plaque calcifications in all examined arteries. In the context of porcine abdominal aorta, 18F-NaF PET imaging was, however, less accurate than computed tomography for detecting small calcifications. Conclusions: 18F-NaF accumulates specifically in calcifications of atherosclerotic plaques in vivo.

Radiochromic film dosimetry for protons up to 10 MeV with EBT2, EBT3 and unlaminated EBT3 films.

Passive dosimetry with radiochromic films is widely used in proton radiotherapy, both in clinical and scientific environments, thanks to its simplicity, high spatial resolution and dose-rate independence. However, film under-response for low-energy protons, the so-called linear-energy transfer (LET) quenching, must be accounted and corrected for. We perform a meta-analysis on existing film under-response data with EBT, EBT2 and EBT3 GAFchromic™ films and provide a common framework to integrate it, based on the calculation of dose-averaged LET in the active layer of the films. We also report on direct measurements with the 10 MeV proton beam at the Center for Microanalysis of Materials (CMAM) for EBT2, EBT3 and unlaminated EBT3 films, focusing on the 20-80 keVµm-1LET range, where previous data was scarce. Measured film relative efficiency (RE) values are in agreement with previously reported data from the literature. A model on film RE constructed with combined literature and own experimental values in the 5-80 keVµm-1LET range is presented, supporting the hypothesis of a linear decrease of RE with LET, with no remarkable differences between the three types of films analyzed.

Effects of Colchicine on Atherosclerotic Plaque Stabilization: a Multimodality Imaging Study in an Animal Model.

Colchicine demonstrated clinical benefits in the treatment of stable coronary artery disease. Our aim was to evaluate the effects of colchicine on atherosclerotic plaque stabilization. Atherosclerosis was induced in the abdominal aorta of 20 rabbits with high-cholesterol diet and balloon endothelial denudation. Rabbits were randomized to receive either colchicine or placebo. All animals underwent MRI, 18F-FDG PET/CT, optical coherence tomography (OCT), and histology. Similar progression of atherosclerotic burden was observed in the two groups as relative increase of normalized wall index (NWI). Maximum 18F-FDG standardized uptake value (meanSUVmax) decreased after colchicine treatment, while it increased in the placebo group with a trend toward significance. Animals with higher levels of cholesterol showed significant differences in favor to colchicine group, both as NWI at the end of the protocol and as relative increase in meanSUVmax. Colchicine may stabilize atherosclerotic plaque by reducing inflammatory activity and plaque burden, without altering macrophage infiltration or plaque typology.

Explicit measurement of multi-tracer arterial input function for PET imaging using blood sampling spectroscopy.

BACKGROUND: Conventional PET imaging has usually been limited to a single tracer per scan. We propose a new technique for multi-tracer PET imaging that uses dynamic imaging and multi-tracer compartment modeling including an explicitly derived arterial input function (AIF) for each tracer using blood sampling spectroscopy. For that purpose, at least one of the co-injected tracers must be based on a non-pure positron emitter. METHODS: The proposed technique was validated in vivo by performing cardiac PET/CT studies on three healthy pigs injected with 18FDG (viability) and 68Ga-DOTA (myocardial blood flow and extracellular volume fraction) during the same acquisition. Blood samples were collected during the PET scan, and separated AIF for each tracer was obtained by spectroscopic analysis. A multi-tracer compartment model was applied to the myocardium in order to obtain the distribution of each tracer at the end of the PET scan. Relative activities of both tracers and tracer uptake were obtained and compared with the values obtained by ex vivo analysis of excised myocardial tissue segments. RESULTS: A high correlation was obtained between multi-tracer PET results, and those obtained from ex vivo analysis (18FDG relative activity: r = 0.95, p < 0.0001; SUV: r = 0.98, p < 0.0001). CONCLUSIONS: The proposed technique allows performing PET scans with two tracers during the same acquisition obtaining separate information for each tracer.

Simultaneous emission and attenuation reconstruction in time-of-flight PET using a reference object.

BACKGROUND: Simultaneous reconstruction of emission and attenuation images in time-of-flight (TOF) positron emission tomography (PET) does not provide a unique solution. In this study, we propose to solve this limitation by including additional information given by a reference object with known attenuation placed outside the patient. Different configurations of the reference object were studied including geometry, material composition, and activity, and an optimal configuration was defined. In addition, this configuration was tested for different timing resolutions and noise levels. RESULTS: The proposed strategy was tested in 2D simulations obtained by forward projection of available PET/CT data and noise was included using Monte Carlo techniques. Obtained results suggest that the optimal configuration corresponds to a water cylinder inserted in the patient table and filled with activity. In that case, mean differences between reconstructed and true images were below 10%. However, better results can be obtained by increasing the activity of the reference object. CONCLUSION: This study shows promising results that might allow to obtain an accurate attenuation map from pure TOF-PET data without prior knowledge obtained from CT, MRI, or transmission scans.

Biological and Mechanical Synergies to Deal With Proton Therapy Pitfalls: Minibeams, FLASH, Arcs, and Gantryless Rooms.

Proton therapy has advantages and pitfalls comparing with photon therapy in radiation therapy. Among the limitations of protons in clinical practice we can selectively mention: uncertainties in range, lateral penumbra, deposition of higher LET outside the target, entrance dose, dose in the beam path, dose constraints in critical organs close to the target volume, organ movements and cost. In this review, we combine proposals under study to mitigate those pitfalls by using individually or in combination: (a) biological approaches of beam management in time (very high dose rate "FLASH" irradiations in the order of 100 Gy/s) and (b) modulation in space (a combination of mini-beams of millimetric extent), together with mechanical approaches such as (c) rotational techniques (optimized in partial arcs) and, in an effort to reduce cost, (d) gantry-less delivery systems. In some cases, these proposals are synergic (e.g., FLASH and minibeams), in others they are hardly compatible (mini-beam and rotation). Fixed lines have been used in pioneer centers, or for specific indications (ophthalmic, radiosurgery,…), they logically evolved to isocentric gantries. The present proposals to produce fixed lines are somewhat controversial. Rotational techniques, minibeams and FLASH in proton therapy are making their way, with an increasing degree of complexity in these three approaches, but with a high interest in the basic science and clinical communities. All of them must be proven in clinical applications.

Quantitative assessment of myocardial blood flow and extracellular volume fraction using 68Ga-DOTA-PET: A feasibility and validation study in large animals.

BACKGROUND: Here we evaluated the feasibility of PET with Gallium-68 (68Ga)-labeled DOTA for non-invasive assessment of myocardial blood flow (MBF) and extracellular volume fraction (ECV) in a pig model of myocardial infarction. We also aimed to validate MBF measurements using microspheres as a gold standard in healthy pigs. METHODS: 8 healthy pigs underwent three sequential 68Ga-DOTA-PET/CT scans at rest and during pharmacological stress with simultaneous injection of fluorescent microspheres to validate MBF measurements. Myocardial infarction was induced in 5 additional pigs, which underwent 68Ga-DOTA-PET/CT examinations 7-days after reperfusion. Dynamic PET images were reconstructed and fitted to obtain MBF and ECV parametric maps. RESULTS: MBF assessed with 68Ga-DOTA-PET showed good correlation (y = 0.96x + 0.11, r = 0.91) with that measured with microspheres. MBF values obtained with 68Ga-DOTA-PET in the infarcted area (LAD, left anterior descendant) were significantly reduced in comparison to remote ones LCX (left circumflex artery, P < 0.0001) and RCA (right coronary artery, P < 0.0001). ECV increased in the infarcted area (P < 0.0001). CONCLUSION: 68Ga-DOTA-PET allowed non-invasive assessment of MBF and ECV in pigs with myocardial infarction and under rest-stress conditions. This technique could provide wide access to quantitative measurement of both MBF and ECV with PET imaging.

Optimization of purification techniques for lumen-loaded magnetoliposomes.

Liposomes encapsulating magnetic nanoparticles (MNPs), known as magnetoliposomes (MLs), have become a hot topic in biomedical research for applications in remote-triggered drug delivery and diagnostic imaging. One of the most crucial steps in the preparation of MLs is the purification of non-encapsulated MNPs, as a non-efficient purification can lead to misleading results. Purification is challenging especially when MNPs are loaded in the liposome lumen due to the small size differences between the MLs and the non-encapsulated MNPs. This work presents a comparison of three well known purification techniques, namely size exclusion chromatography, centrifugation and salt-induced aggregation, using five commercial MNPs with different configurations. The optimal purification techniques for two MNPs were studied further in the synthesis of MLs. In conclusion, we show that an efficient MLs purification requires the performance of a detailed study to select a valid method that is strongly dependent upon MNPs choices.

Development of a blood sample detector for multi-tracer positron emission tomography using gamma spectroscopy.

BACKGROUND: Multi-tracer positron emission tomography (PET) imaging can be accomplished by applying multi-tracer compartment modeling. Recently, a method has been proposed in which the arterial input functions (AIFs) of the multi-tracer PET scan are explicitly derived. For that purpose, a gamma spectroscopic analysis is performed on blood samples manually withdrawn from the patient when at least one of the co-injected tracers is based on a non-pure positron emitter. Alternatively, these blood samples required for the spectroscopic analysis may be obtained and analyzed on site by an automated detection device, thus minimizing analysis time and radiation exposure of the operating personnel. In this work, a new automated blood sample detector based on silicon photomultipliers (SiPMs) for single- and multi-tracer PET imaging is presented, characterized, and tested in vitro and in vivo. RESULTS: The detector presented in this work stores and analyzes on-the-fly single and coincidence detected events. A sensitivity of 22.6 cps/(kBq/mL) and 1.7 cps/(kBq/mL) was obtained for single and coincidence events respectively. An energy resolution of 35% full-width-half-maximum (FWHM) at 511 keV and a minimum detectable activity of 0.30 ± 0.08 kBq/mL in single mode were obtained. The in vivo AIFs obtained with the detector show an excellent Pearson's correlation (r = 0.996, p < 0.0001) with the ones obtained from well counter analysis of discrete blood samples. Moreover, in vitro experiments demonstrate the capability of the detector to apply the gamma spectroscopic analysis on a mixture of 68Ga and 18F and separate the individual signal emitted from each one. CONCLUSIONS: Characterization and in vivo evaluation under realistic experimental conditions showed that the detector proposed in this work offers excellent sensibility and stability. The device also showed to successfully separate individual signals emitted from a mixture of radioisotopes. Therefore, the blood sample detector presented in this study allows fully automatic AIFs measurements during single- and multi-tracer PET studies.

Vascular Inflammation in Subclinical Atherosclerosis Detected by Hybrid PET/MRI.

BACKGROUND: Atherosclerosis is a chronic inflammatory disease, but data on arterial inflammation at early stages is limited. OBJECTIVES: The purpose of this study was to characterize vascular inflammation by hybrid 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/magnetic resonance imaging (PET/MRI). METHODS: Carotid, aortic, and ilio-femoral 18F-FDG PET/MRI was performed in 755 individuals (age 40 to 54 years; 83.7% men) with known plaques detected by 2-/3-dimensional vascular ultrasound and/or coronary calcification in the PESA (Progression of Early Subclinical Atherosclerosis) study. The authors evaluated the presence, distribution, and number of arterial inflammatory foci (increased 18F-FDG uptake) and plaques with or without inflammation (coincident 18F-FDG uptake). RESULTS: Arterial inflammation was present in 48.2% of individuals (24.4% femorals, 19.3% aorta, 15.8% carotids, and 9.3% iliacs) and plaques in 90.1% (73.9% femorals, 55.8% iliacs, and 53.1% carotids). 18F-FDG arterial uptakes and plaques significantly increased with cardiovascular risk factors (p < 0.01). Coincident 18F-FDG uptakes were present in 287 of 2,605 (11%) plaques, and most uptakes were detected in plaque-free arterial segments (459 of 746; 61.5%). Plaque burden, defined by plaque presence, number, and volume, was significantly higher in individuals with arterial inflammation than in those without (p < 0.01). The number of plaques and 18F-FDG uptakes showed a positive albeit weak correlation (r = 0.25; p < 0.001). CONCLUSIONS: Arterial inflammation is highly prevalent in middle-aged individuals with known subclinical atherosclerosis. Large-scale multiterritorial PET/MRI allows characterization of atherosclerosis-related arterial inflammation and demonstrates 18F-FDG uptake in plaque-free arterial segments and, less frequently, within plaques. These findings suggest an arterial inflammatory state at early stages of atherosclerosis. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318).

Assessment of regional pulmonary blood flow using 68Ga-DOTA PET.

BACKGROUND: In vivo determination of regional pulmonary blood flow (PBF) is a valuable tool for the evaluation of many lung diseases. In this study, the use of 68Ga-DOTA PET for the in vivo quantitative determination of regional PBF is proposed. This methodology was implemented and tested in healthy pigs and validated using fluorescent microspheres. The study was performed on young large white pigs (n = 4). To assess the reproducibility and consistency of the method, three PET scans were obtained for each animal. Each radiotracer injection was performed simultaneously to the injection of fluorescent microspheres. PBF images were generated applying a two-compartment exchange model over the dynamic PET images. PET and microspheres values were compared by regression analysis and Bland-Altman plot. RESULTS: The capability of the proposed technique to produce 3D regional PBF images was demonstrated. The correlation evaluation between 68Ga-DOTA PET and microspheres showed a good and significant correlation (r = 0.74, P < 0.001). CONCLUSIONS: Assessment of PBF with the proposed technique allows combining the high quantitative accuracy of PET imaging with the use of 68Ga/68Ge generators. Thus, 68Ga-DOTA PET emerges as a potential inexpensive method for measuring PBF in clinical settings with an extended use.

Cardiovascular imaging: what have we learned from animal models?

Cardiovascular imaging has become an indispensable tool for patient diagnosis and follow up. Probably the wide clinical applications of imaging are due to the possibility of a detailed and high quality description and quantification of cardiovascular system structure and function. Also phenomena that involve complex physiological mechanisms and biochemical pathways, such as inflammation and ischemia, can be visualized in a non-destructive way. The widespread use and evolution of imaging would not have been possible without animal studies. Animal models have allowed for instance, (i) the technical development of different imaging tools, (ii) to test hypothesis generated from human studies and finally, (iii) to evaluate the translational relevance assessment of in vitro and ex-vivo results. In this review, we will critically describe the contribution of animal models to the use of biomedical imaging in cardiovascular medicine. We will discuss the characteristics of the most frequent models used in/for imaging studies. We will cover the major findings of animal studies focused in the cardiovascular use of the repeatedly used imaging techniques in clinical practice and experimental studies. We will also describe the physiological findings and/or learning processes for imaging applications coming from models of the most common cardiovascular diseases. In these diseases, imaging research using animals has allowed the study of aspects such as: ventricular size, shape, global function, and wall thickening, local myocardial function, myocardial perfusion, metabolism and energetic assessment, infarct quantification, vascular lesion characterization, myocardial fiber structure, and myocardial calcium uptake. Finally we will discuss the limitations and future of imaging research with animal models.

In Vivo ¹8F-FDG-PET Imaging in Mouse Atherosclerosis.

Positron emission tomography (PET) is an important technique in cardiovascular research. Vascular inflammation detected by fluorodeoxyglucose (FDG)-PET has been shown to predict cardiovascular (CV) events independent of traditional risk factors and is also highly associated with overall burden of atherosclerosis. The use of PET imaging in mouse models of atherosclerosis is challenged by the reduced size of the scanned organs. However, the last generation of dedicated PET scanners has an improved spatial resolution (<1 mm) and increased sensitivity allowing those studies to be performed. Here, we describe a procedure to perform FDG-PET experiments in atherosclerosis mouse models, the required equipment for animal handling and imaging, and the tools and procedures for image analysis and validation of the results.

Magnetic Resonance Imaging of the Atherosclerotic Mouse Aorta.

Plaque development has been extensively studied using magnetic resonance imaging (MRI) in animal models of rapidly progressing atherosclerosis, such as apolipoprotein E-knockout (apoE-KO) mice. Preclinical MRI plays a significant role in the study of experimental atherosclerosis. Currently, MRI is capable of detecting luminal narrowing, plaque size, and morphology with high accuracy and reproducibility, providing reliable measurements of plaque burden. Therefore, MRI offers a noninvasive approach to serially monitor the progression of the disease. Compared with other imaging modalities, MRI appears to have the greatest potential for plaque characterization, through the use of multiple contrast weightings (e.g., T1, T2, and proton density). Here, we illustrate a standard procedure to image the aorta of atherosclerotic mice using noninvasive MRI.