Targeted molecular imaging of angiogenesis in PET and SPECT: a review

Over the past few decades, there have been significant advancements in the imaging techniques of positron emission tomography (PET) and single photon emission tomography (SPECT). These changes have allowed for the targeted imaging of cellular processes and the development of hybrid imaging systems (e.g., SPECT/CT and PET/CT), which provide both functional and structural images of biological systems. One area that has garnered particular attention is angiogenesis as it relates to ischemic heart disease and limb ischemia. Though the aforementioned techniques have benefits and consequences, they enable scientists and clinicians to identify regions that are vulnerable to or have been exposed to ischemic injury via non-invasive means. This literature review highlights the advancements in molecular imaging techniques and specific probes as they pertain to the process of angiogenesis in cardiovascular disease.     

缺血性心肌病的多模态心血管影像学方法进展

近年来,超声(ultrasound, US)、CT冠状动脉造影(CT coronary angiography, CCTA)、血管内超声(intravenous ultrasound,IVUS)、光学相干断层成像(optical coherence tomography, OCT)、多层螺旋CT成像(multi-slice computed tomography, MSCT)、单光子发射计算机断层成像(single-photon emission computed tomography, SPECT)、正电子发射计算机断层成像(positron emission computed tomography, PET)及心脏磁共振(cardiac magnetic resonance, CMR)等多种心血管成像技术能够提供与冠脉病变及心肌形态和功能相关的解剖学、血流动力学、细胞生物学及病理生理学等方面的重要信息,在缺血性心肌病的临床诊疗及预后评估中发挥着日益重要的作用。然而,如何恰当选择的多模态心血管影像技术是临床医师面临的一大难题。因此,本文在归纳总结主要心血管成像技术临床应用进展的基础上,对多模态心血管影像学在缺血性心肌病相关的冠脉解剖与斑块成像、心肌功能、心肌灌注及心肌活性显像中的临床应用价值进行综述。旨在帮助临床医师客观认识各种成像技术的优势与不足,从而制定最优化的选择方案。     

Les examens cardiaques en tomographie par émission de positons

Cardiac positron emission tomography (PET) is yet considered as a reference imaging technique but remains poorly used in clinical practice. At the present time, the advantages of cardiac PET investigations are far to be evident, when compared with conventional tomoscintigraphy (SPECT), except for perfusion imaging in the obese and for viability assessment in case of very severe cardiac dysfunction. However, this situation might quickly move because of an enhanced availability of PET imaging, dramatic technical progresses and promising new tracers. In particular, the last-generation PET-cameras allow reaching spatial resolutions and detection sensitivities, which are now spectacularly higher than those from conventional SPECT imaging. In addition, the list mode recording allows the subsequent images reconstruction to be synchronized to cardiac cycle but also to respiratory cycle; and the quantifications of myocardial perfusion flow and of coronary flow reserve are now available in clinical routine. Furthermore, new tracers labelled with fluorine-18 are under development, especially for perfusion investigations, and kinetics properties of these new tracers are dramatically enhanced when compared with current perfusion SPECT tracers.     

Nuclear cardiac imaging for the assessment of myocardial viability

An important aspect of the diagnostic and prognostic work-up of patients with ischaemic cardiomyopathy is the assessment of myocardial viability. Patients with left ventricular dysfunction who have viable myocardium are the patients at highest risk because of the potential for ischaemia but at the same time benefit most from revascularisation. It is important to identify viable myocardium in these patients, and radionuclide myocardial scintigraphy is an excellent tool for this. Single-photon emission computed tomography perfusion scintigraphy (SPECT), whether using ²⁰¹thallium, ^99mTc-sestamibi, or ^99mTc- tetrofosmin, in stress and/or rest protocols, has consistently been shown to be an effective modality for identifying myocardial viability and guiding appropriate management.Metabolic and perfusion imaging with positron emission tomography radiotracers frequently adds additional information and is a powerful tool for predicting which patients will have an improved outcome from revascularisation. New techniques in the nuclear cardiology field, such as attenuation corrected SPECT, dual isotope simultaneous acquisition (DISA) SPECT and gated FDG PET are promising and will further improve the detection of myocardial viability. Also the combination of multislice computed tomography scanners with PET opens possibilities of adding coronary calcium scoring and noninvasive coronary angiography to myocardial perfusion imaging and quantification.     

A realistic utilization of nanotechnology in molecular imaging and targeted radiotherapy of solid tumors

Precise dose delivery to malignant tissue in radiotherapy is of paramount importance for treatment efficacy while minimizing morbidity of surrounding normal tissues. Current conventional imaging techniques, such as magnetic resonance imaging (MRI) and computerized tomography (CT), are used to define the three-dimensional shape and volume of the tumor for radiation therapy. In many cases, these radiographic imaging (RI) techniques are ambiguous or provide limited information with regard to tumor margins and histopathology. Molecular imaging (MI) modalities, such as positron emission tomography (PET) and single photon-emission computed-tomography (SPECT) that can characterize tumor tissue, are rapidly becoming routine in radiation therapy. However, their inherent low spatial resolution impedes tumor delineation for the purposes of radiation treatment planning. This review will focus on applications of nanotechnology to synergize imaging modalities in order to accurately highlight, as well as subsequently target, tumor cells. Furthermore, using such nano-agents for imaging, simultaneous coupling of novel therapeutics including radiosensitizers can be delivered specifically to the tumor to maximize tumor cell killing while sparing normal tissue.     

Anesthesia and other considerations for in vivo imaging of small animals

The use of small animal imaging is increasing in biomedical research thanks to its ability to localize altered biochemical and physiological processes in the living animal and to follow these processes longitudinally and noninvasively. In contrast to human studies, however, imaging of small animals generally requires anesthesia, and anesthetic agents can have unintended effects on animal physiology that may confound the results of the imaging studies. In addition, repeated anesthesia, animal preparation for imaging, exposure to ionizing radiation, and the administration of contrast agents may affect the processes under study. We discuss this interplay of factors for small animal imaging in the context of four common imaging modalities for small animals: positron emission tomography (PET) and single photon emission computed tomography (SPECT), computed tomography (CT), magnetic resonance imaging (MRI), and optical imaging. We discuss animal preparation for imaging, including choice of animal strain and gender, the role of fasting and diet, and the circadian cycle. We review common anesthesias used in small animal imaging, such as pentobarbital, ketamine/xylazine, and isoflurane, and describe techniques for monitoring the respiration and circulation of anesthetized animals that are being imaged as well as developments for imaging conscious animals. We present current imaging literature exemplifying how anesthesia and animal handling can influence the biodistribution of PET tracers. Finally, we discuss how longitudinal imaging studies may affect animals due to repeated injections of radioactivity or other substrates and the general effect of stress on the animals. In conclusion, there are many animal handling issues to consider when designing an imaging experiment. Reproducible experimental conditions require clear, consistent reporting, in the study design and throughout the experiment, of the animal strain and gender, fasting, anesthesia, and how often individual animals were imaged.     

Real time non-invasive imaging of receptor-ligand interactions in vivo

Non-invasive longitudinal detection and evaluation of gene expression in living animals can provide investigators with an understanding of the ontogeny of a gene's biological function(s). Currently, mouse model systems are used to optimize magnetic resonance imaging (MRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT), and optical imaging modalities to detect gene expression and protein function. These molecular imaging strategies are being developed to assess tumor growth and the tumor microenvironment. In addition, pre-labeling of progenitor cells can provide invaluable information about the developmental lineage of stem cells both in organogenesis and tumorigenesis. The feasibility of this approach has been extensively tested by targeting of endogenous tumor cell receptors with labeled ligand (or ligand analog) reporters and targeting enzymes with labeled substrate (or substrate analog). We will primarily discuss MRI, PET, and SPECT imaging of cell surface receptors and the feasibility of non-invasive imaging of gene expression using the tumor microenvironment (e.g., hypoxia) as a conditional regulator of gene expression.     

Imaging neurodegeneration in Parkinson's disease

Neuroimaging techniques have evolved over the past several years giving us unprecedented information about the degenerative process in Parkinson's disease (PD) and other movement disorders. Functional imaging approaches such as positron emission tomography (PET) and single photon emission computerised tomography (SPECT) have been successfully employed to detect dopaminergic dysfunction in PD, even while at a preclinical stage, and to demonstrate the effects of therapies on function of intact dopaminergic neurons within the affected striatum. PET and SPECT can also monitor PD progression as reflected by changes in brain levodopa and glucose metabolism and dopamine transporter binding. Structural imaging approaches include magnetic resonance imaging (MRI) and transcranial sonography (TCS). Recent advances in voxel-based morphometry and diffusion-weighted MRI have provided exciting potential applications for the differential diagnosis of parkinsonian syndromes. Substantia nigra hyperechogenicity, detected with TCS, may provide a marker of susceptibility to PD, probably reflecting disturbances of iron metabolism, but does not appear to correlate well with disease severity or change with disease progression. In the future novel radiotracers may help us assess the involvement of non-dopaminergic brain pathways in the pathology of both motor and non-motor complications in PD.     

Diagnostic imaging tests and microbial infections

Despite significant advances in the understanding of its pathogenesis, infection remains a major cause of patient morbidity and mortality. While the presence of infection may be suggested by signs and symptoms, imaging tests are often used to localize or confirm its presence. There are two principal imaging test types: morphological and functional. Morphological tests include radiographs, computed tomography (CT), magnetic resonance imaging, and sonongraphy. These procedures detect anatomic, or structural, alterations produced by microbial invasion and host response. Functional imaging tests reflect the physiological changes that are part of this process. Prototypical functional tests are radionuclide procedures such as bone, gallium, labelled leukocyte and fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging. In-line functional/morphological tomographic imaging systems, PET/CT and single photon emission tomography (SPECT)/CT, have revolutionized diagnostic imaging. These devices consist of a functional imaging device (PET or SPECT) joined together with a CT scanner. The patient undergoes both tests sequentially without leaving the examination table. Images from each study can be viewed separately and as fused images, providing precisely localized anatomic and functional information. It must be noted, however, that none of the current morphological or functional tests, either alone or in combination, are specific for infection and the goal of finding such an imaging test remains elusive.     

Development and application of a multimodal contrast agent for SPECT/CT hybrid imaging

Hybrid or multimodality imaging is often applied in order to take advantage of the unique and complementary strengths of individual imaging modalities. This hybrid noninvasive imaging approach can provide critical information about anatomical structure in combination with physiological function or targeted molecular signals. While recent advances in software image fusion techniques and hybrid imaging systems have enabled efficient multimodal imaging, accessing the full potential of this technique requires development of a new toolbox of multimodal contrast agents that enhance the imaging process. Toward that goal, we report the development of a hybrid probe for both single photon emission computed tomography (SPECT) and X-ray computed tomography (CT) imaging that facilitates high-sensitivity SPECT and high spatial resolution CT imaging. In this work, we report the synthesis and evaluation of a novel intravascular, multimodal dendrimer-based contrast agent for use in preclinical SPECT/CT hybrid imaging systems. This multimodal agent offers a long intravascular residence time (t(1/2) = 43 min) and sufficient contrast-to-noise for effective serial intravascular and blood pool imaging with both SPECT and CT. The colocalization of the dendritic nuclear and X-ray contrasts offers the potential to facilitate image analysis and quantification by enabling correction for SPECT attenuation and partial volume errors at specified times with the higher resolution anatomic information provided by the circulating CT contrast. This may allow absolute quantification of intramyocardial blood volume and blood flow and may enable the ability to visualize active molecular targeting following clearance from the blood.     

Imagerie hybride (TEMP/TDM,TEP/TDM) et cancer différencié de la thyroïde

Differentiated thyroid cancer (DTC) is generally associated with a good prognosis. Local recurrences, mainly lymph-node involvement, account for 15–20% of cases and are surgically treated. Distant metastases, mostly in lungs and more rarely in bones, are present in 5% of patients. When iodine uptake is sufficient (in approximately 60% of patients), distant metastases can be destroyed by iterative activities of iodine 131. Serum thyroglobulin (Tg), which can be assessed either on hormonal treatment or on TSH stimulation is considered as the tumour marker in DTC. Functional (iodine 131 scintigraphy, FDG PET, bone scintigraphy) or anatomical (neck ultrasound, thoracic CT, bone MRI) imaging methods can be performed when Tg increases in order to show residual/recurrent disease. In recent years, new hybrid equipments integrating both a gamma camera and CT scan (SPECT/CT) have been commercialized while positron emission tomography cameras associated with CT (PET/CT) have been installed on the whole French territory. These equipments, which allow us to directly correlate functional and anatomical images, greatly improve the interpretation of planar scintigraphy or that of PET alone. Hybrid imaging enables us to precisely localize scintigraphic foci and most often, to immediately verify whether they correspond to tumour lesions. The aim of this article is to review the role of SPECT/CT and PET/CT in the management of patients with DTC in 2010.     

La perfusion pulmonaire en morphoTEMP dans le diagnostic de l’embolie pulmonaire : comparaison à la scintigraphie pulmonaire planaire de ventilation/perfusion

The aim of this study is to assess a new tool for the diagnosis of acute pulmonary embolism (PE): single-photon emission computed tomography lung perfusion imaging associated with unenhanced computed tomography (SPECT/CT) compared to planar ventilation-perfusion (VQ) lung scintigraphy.MethodsOne hundred and three patients with suspected acute PE underwent VQ scintigraphy (two scans were uninterpretable) followed by perfusion SPECT/CT. The two types of images were analysed separately: (1) according to the modified PIOPED scintigraphic criteria for VQ lung scan and (2) with regard to SPECT/CT mismatches suggestive acute PE (segmental perfusion defects detected on SPECT images not matched with CT abnormalities).ResultsOn average, the number of segmental perfusion defects per patient was higher with SPECT/CT than with planar scintigraphy (4.3 ± 3.6 versus 2.8 ± 2.6; p < 0.001). A mismatch was found with SPECT-CT in 0% (0/18) of normal scintigraphy, and 8% (3/39) for low, 32% (8/25) for intermediate and 74% (14/19) for high probabilities of PE at scintigraphy. The presence of a SPECT/CT mismatch was also associated with higher pretest probability of acute PE (p = 0.001), even for the 25 patients in the intermediate-probability subgroup (p = 0.02). Finally, a SPECT/CT match was found in 29 patients that was not suggestive of acute PE due to the presence, in areas with perfusion defects on SPECT images, of the following CT abnormalities: hypodensity and/or emphysema (71%), condensation or atelectasis (38%), pleural disease (7%), extrapulmonary structure (14%) and/or bronchial obstruction (7%).ConclusionIn patients with suspected acute PE, the results obtained with pulmonary SPECT/CT images are consistent with those obtained with VQ scintigraphy and the pretest probability of PE. Further studies comparing SPECT/CT imaging with angiographic techniques are now required to evaluate more specifically the diagnostic value of this new tool.     

La TEP et la TEMP pour l’étude des épilepsies

Positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging are very useful for the management of patients with medically refractory partial epilepsy. Presurgical evaluation of patients with medically refractory partial epilepsy often included PET imaging using FDG. The use of SPECT in these patients adds some more information and gives the clinicians the possibility of having ictal imaging. Furthermore, PET and SPECT imaging are performed to better understand the pathophysiology of epilepsy.     

Imaging regional PAO2 and gas exchange

Several methods allow regional gas exchange to be inferred from imaging of regional ventilation and perfusion (V/Q) ratios. Each method measures slightly different aspects of gas exchange and has inherent advantages and drawbacks that are reviewed. Single photon emission computed tomography can provide regional measure of ventilation and perfusion from which regional V/Q ratios can be derived. PET methods using inhaled or intravenously administered nitrogen-13 provide imaging of both regional blood flow, shunt, and ventilation. Electric impedance tomography has recently been refined to allow simultaneous measurements of both regional ventilation and blood flow. MRI methods utilizing hyperpolarized helium-3 or xenon-129 are currently being refined and have been used to estimate local PaO(2) in both humans and animals. Microsphere methods are included in this review as they provide measurements of regional ventilation and perfusion in animals. One of their advantages is their greater spatial resolution than most imaging methods and the ability to use them as gold standards against which new imaging methods can be tested. In general, the reviewed methods differ in characteristics such as spatial resolution, possibility of repeated measurements, radiation exposure, availability, expensiveness, and their current stage of development.     

单光子发射计算机断层扫描肺灌注显像(SPECT/CT)在肺恶性肿瘤放疗中 的应用进展

放射性肺损伤是肺恶性肿瘤放疗后常见的并发症,其限制肺恶性肿瘤的放疗剂量并影响总体疗效及患者生存质量。本文复习放射性肺损伤发生机制及影响因素,分析剂量体积直方图、肺功能测定、TGF-β1等临床常用放射性肺损伤评估指标的利弊。参考近年文献,总结了单光子发射计算机断层扫描肺灌注显像(SPECT/CT)在肺恶性肿瘤放疗中的应用,从其原理、区域肺功能的显像、对放疗的评估与指导应用几方面阐述。认为SPECT/CT能实时反映区域肺功能、肺功能改变以及其解剖定位,可在放疗中起监测作用,对准确评估肺功能、预测放疗后肺损伤,优化放疗计划有重要价值。SPECT/CT肺灌注显像还需要多中心、大样本、长时间随访资料进一步深入研究。     

18F-2-deoxy-2-fluoro-D-glucose positron emission tomography, computed tomography, and magnetic resonance imaging for the detection of experimental colorectal liver metastases

During the treatment of colorectal liver metastases, evaluation of treatment efficacy is of the utmost importance for decision making. The aim of the present study was to explore the ability of preclinical imaging modalities to detect experimental liver metastases. Nine male Wag/Rij rats underwent a laparotomy with intraportal injection of CC531 tumor cells. On days 7, 10, and 14 after tumor induction, sequential positron emission tomography (PET), computed tomography (CT), and magnetic resonance imaging (MRI) scans were acquired of each rat. At each time point, three rats were euthanized and the metastases in the liver were documented histologically. Topographically, the liver was divided into eight segments and the image findings were compared on a segment-by-segment basis with the histopathologic findings. Sixty-four liver segments were analyzed, 20 of which contained tumor deposits. The overall sensitivity of PET, CT, and MRI was 30%, 25%, and 20%, respectively. For the detection of tumors with a histologic diameter exceeding 1 mm (n = 8), the sensitivity of PET, CT, and MRI was 63%, 38%, and 38%, respectively. The overall specificity of PET, CT, and MRI was 98%, 100%, and 93%, respectively. This study showed encouraging detectability and sensitivity for preclinical imaging of small liver tumors and provides valuable information on the imaging techniques for designing future protocols.     

Imaging of angiogenesis: from microscope to clinic

Advances in imaging are transforming our understanding of angiogenesis and the evaluation of drugs that stimulate or inhibit angiogenesis in preclinical models and human disease. Vascular imaging makes it possible to quantify the number and spacing of blood vessels, measure blood flow and vascular permeability, and analyze cellular and molecular abnormalities in blood vessel walls. Microscopic methods ranging from fluorescence, confocal and multiphoton microscopy to electron microscopic imaging are particularly useful for elucidating structural and functional abnormalities of angiogenic blood vessels. Magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), ultrasonography and optical imaging provide noninvasive, functionally relevant images of angiogenesis in animals and humans. An ongoing dilemma is, however, that microscopic methods provide their highest resolution on preserved tissue specimens, whereas clinical methods give images of living tissues deep within the body but at much lower resolution and specificity and generally cannot resolve vessels of the microcirculation. Future challenges include developing new imaging methods that can bridge this resolution gap and specifically identify angiogenic vessels. Another goal is to determine which microscopic techniques are the best benchmarks for interpreting clinical images. The importance of angiogenesis in cancer, chronic inflammatory diseases, age-related macular degeneration and reversal of ischemic heart and limb disease provides incentive for meeting these challenges.     

Coronary computed tomography angiography and [15O]H2O positron emission tomography perfusion imaging for the assessment of coronary artery disease

Determining the anatomic severity and extent of coronary artery disease (CAD) by means of coronary computed tomography angiography (CCTA) and its effect on perfusion using myocardial perfusion imaging (MPI) form the pillars of the non-invasive imaging assessment of CAD. This review will 1) focus on CCTA and [¹⁵O]H₂O positron emission tomography MPI as stand-alone imaging modalities and their combined use for detecting CAD, 2) highlight some of the lessons learned from the PACIFIC trial (Comparison of Coronary CT Angiography, SPECT, PET, and Hybrid Imaging for Diagnosis of Ischemic Heart Disease Determined by Fractional Flow Reserve (FFR) (NCT01521468)), and 3) discuss the use of [¹⁵O]H₂O PET MPI in the clinical work-up of patients with a chronic coronary total occlusion (CTO).

     

TEMP/TDM et TEP/TDM en cardiologie : quel avenir ?

Over the recent years, clinical cardiology has witnessed a rapid evolution of multi-slice computed tomography (CT), starting with 4-slice CT developing into the current state of the heart 64-slice CT technology. This technology permits non-invasive visualization of the coronaries with high precision. CT coronary angiography will likely play an important role in the diagnosis of coronary artery disease. Because not all coronary stenoses detected by CT angiography are flow limiting, the stress myocardial perfusion imaging data complement the CT information. The integration of nuclear imaging (SPECT or PET) and CT data provides a potential opportunity to delineate the anatomic extent and the physiologic severity of coronary artery disease. The objective of this article is to provide a critical view of the relative strengths and weaknesses of myocardial perfusion imaging and CT coronary angiography, which we hope will help elucidate the potential role of these modalities in the diagnosis and management algorithms of patients with known or suspected coronary artery disease.     

Regional lung perfusion estimated by electrical impedance tomography in a piglet model of lung collapse

The assessment of the regional match between alveolar ventilation and perfusion in critically ill patients requires simultaneous measurements of both parameters. Ideally, assessment of lung perfusion should be performed in real-time with an imaging technology that provides, through fast acquisition of sequential images, information about the regional dynamics or regional kinetics of an appropriate tracer. We present a novel electrical impedance tomography (EIT)-based method that quantitatively estimates regional lung perfusion based on first-pass kinetics of a bolus of hypertonic saline contrast. Pulmonary blood flow was measured in six piglets during control and unilateral or bilateral lung collapse conditions. The first-pass kinetics method showed good agreement with the estimates obtained by single-photon-emission computerized tomography (SPECT). The mean difference (SPECT minus EIT) between fractional blood flow to lung areas suffering atelectasis was -0.6%, with a SD of 2.9%. This method outperformed the estimates of lung perfusion based on impedance pulsatility. In conclusion, we describe a novel method based on EIT for estimating regional lung perfusion at the bedside. In both healthy and injured lung conditions, the distribution of pulmonary blood flow as assessed by EIT agreed well with the one obtained by SPECT. The method proposed in this study has the potential to contribute to a better understanding of the behavior of regional perfusion under different lung and therapeutic conditions.