Application of positron emission tomography to neuroimaging in sports sciences

To investigate exercise-induced regional metabolic and perfusion changes in the human brain, various methods are available, such as positron emission tomography (PET), functional magnetic resonance imaging (fMRI), near-infrared spectroscopy (NIRS) and electroencephalography (EEG). In this paper, details of methods of metabolic measurement using PET, [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) and [¹⁵O]radio-labelled water ([¹⁵O]H₂O) will be explained.Functional neuroimaging in the field of neuroscience was started in the 1970s using an autoradiography technique on experimental animals. The first human functional neuroimaging exercise study was conducted in 1987 using a rough measurement system known as ¹³³Xe inhalation. Although the data was useful, more detailed and exact functional neuroimaging, especially with respect to spatial resolution, was achieved by positron emission tomography. Early studies measured the cerebral blood flow changes during exercise. Recently, PET was made more applicable to exercise physiology and psychology by the use of the tracer [¹⁸F]FDG. This technique allowed subjects to be scanned after an exercise task is completed but still obtain data from the exercise itself, which is similar to autoradiography studies.In this report, methodological information is provided with respect to the recommended protocol design, the selection of the scanning mode, how to evaluate the cerebral glucose metabolism and how to interpret the regional brain activity using voxel-by-voxel analysis and regions of interest techniques (ROI).Considering the important role of exercise in health promotion, further efforts in this line of research should be encouraged in order to better understand health behavior. Although the number of research papers is still limited, recent work has indicated that the [¹⁸F]FDG-PET technique is a useful tool to understand brain activity during exercise.     

Non-invasive Imaging and Analysis of Cerebral Ischemia in Living Rats Using Positron Emission Tomography with 18F-FDG

Stroke is the third leading cause of death among Americans 65 years of age or older¹. The quality of life for patients who suffer from a stroke fails to return to normal in a large majority of patients², which is mainly due to current lack of clinical treatment for acute stroke. This necessitates understanding the physiological effects of cerebral ischemia on brain tissue over time and is a major area of active research. Towards this end, experimental progress has been made using rats as a preclinical model for stroke, particularly, using non-invasive methods such as ¹⁸F-fluorodeoxyglucose (FDG) coupled with Positron Emission Tomography (PET) imaging^3,10,17. Here we present a strategy for inducing cerebral ischemia in rats by middle cerebral artery occlusion (MCAO) that mimics focal cerebral ischemia in humans, and imaging its effects over 24 hr using FDG-PET coupled with X-ray computed tomography (CT) with an Albira PET-CT instrument. A VOI template atlas was subsequently fused to the cerebral rat data to enable a unbiased analysis of the brain and its sub-regions⁴. In addition, a method for 3D visualization of the FDG-PET-CT time course is presented. In summary, we present a detailed protocol for initiating, quantifying, and visualizing an induced ischemic stroke event in a living Sprague-Dawley rat in three dimensions using FDG-PET.     

A study of non-invasive Patlak quantification for whole-body dynamic FDG-PET studies of mice

Physiological changes in dynamic PET images can be quantitatively estimated by kinetic modeling technique. The process of PET quantification usually requires an input function in the form of a plasma-time activity curve (PTAC), which is generally obtained by invasive arterial blood sampling. However, invasive arterial blood sampling poses many challenges especially for small animal studies, due to the subjects' limited blood volume and small blood vessels. A simple non-invasive quantification method based on Patlak graphical analysis (PGA) has been recently proposed to use a reference region to derive the relative influx rate for a target region without invasive blood sampling, and evaluated by using the simulation data of human brain FDG-PET studies. In this study, the non-invasive Patlak (nPGA) method was extended to whole-body dynamic small animal FDG-PET studies. The performance of nPGA was systematically investigated by using experimental mouse studies and computer simulations. The mouse studies showed high linearity of relative influx rates between the nPGA and PGA for most pairs of reference and target regions, when an appropriate underlying kinetic model was used. The simulation results demonstrated that the accuracy of the nPGA method was comparable to that of the PGA method, with a higher reliability for most pairs of reference and target regions. The results proved that the nPGA method could provide a non-invasive and indirect way for quantifying the FDG kinetics of tumor in small animal studies.     

Review article: FDG-PET in inflammatory diseases

Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) has for the past several years demonstrated its high value in oncology. The physiopathology of FDG explains its increasingly frequent use for inflammatory diseases such as vasculitis (giant cell arteritis or Takayasu's arteritis) as well as for granulomatous diseases (sarcoidosis, tuberculosis). The value of FDG-PET lies in its usefulness for the diagnosis of systemic diseases which includes a whole body analysis as well as a therapeutic evaluation. This review article will attempt to identify and illustrate the main features of this functional imaging.     

A Statistical Parametric Mapping Toolbox Used for Voxel-Wise Analysis of FDG-PET Images of Rat Brain

Purpose

PET (positron emission tomography) imaging researches of functional metabolism using fluorodeoxyglucose (¹⁸F-FDG) of animal brain are important in neuroscience studies. FDG-PET imaging studies are often performed on groups of rats, so it is desirable to establish an objective voxel-based statistical methodology for group data analysis.

Material and Methods

This study establishes a statistical parametric mapping (SPM) toolbox (plug-ins) named spmratIHEP for voxel-wise analysis of FDG-PET images of rat brain, in which an FDG-PET template and an intracranial mask image of rat brain in Paxinos & Watson space were constructed, and the default settings were modified according to features of rat brain. Compared to previous studies, our constructed rat brain template comprises not only the cerebrum and cerebellum, but also the whole olfactory bulb which made the later cognitive studies much more exhaustive. And with an intracranial mask image in the template space, the brain tissues of individuals could be extracted automatically. Moreover, an atlas space is used for anatomically labeling the functional findings in the Paxinos & Watson space. In order to standardize the template image with the atlas accurately, a synthetic FDG-PET image with six main anatomy structures is constructed from the atlas, which performs as a target image in the co-registration.

Results

The spatial normalization procedure is evaluated, by which the individual rat brain images could be standardized into the Paxinos & Watson space successfully and the intracranial tissues could also be extracted accurately. The practical usability of this toolbox is evaluated using FDG-PET functional images from rats with left side middle cerebral artery occlusion (MCAO) in comparison to normal control rats. And the two-sample t-test statistical result is almost related to the left side MCA.

Conclusion

We established a toolbox of SPM8 named spmratIHEP for voxel-wise analysis of FDG-PET images of rat brain.     

La tomographie par émission de positons (TEP) hors oncologie : l’exploration du cerveau

Positron emission tomography (PET) allows evaluation of the central nervous system function. Imaging of regional cerebral blood flow and metabolism, and of several neurotransmission systems may be obtained using PET. PET quantification is accurate and has good test–retest reliability. For research purposes, PET has been used to study brain physiology, to explore neurological and psychiatric diseases patophysiology and for the new drugs research and development. FDG is the only PET radioligand with clinical application. Following criteria of evidence-based medicine, the clinical indications of FDG-PET are: evaluation of treated gliomas, presurgical study of partial refractory epilepsy and diagnosis of Alzheimer's disease when it is impossible to differentiate clinically from frontotemporal dementia.     

Brain PET imaging optimization with time of flight and point spread function modelling

PurposeTo assess the influence of reconstruction algorithms and parameters on the PET image quality of brain phantoms in order to optimize reconstruction for clinical PET brain studies in a new generation PET/CT.MethodsThe 3D Hoffman phantom that simulates ¹⁸F-fluorodeoxyglucose (FDG) distribution was imaged in a Siemens Biograph mCT TrueV PET/CT with Time of Flight (TOF) and Point Spread Function (PSF) modelling. Contrast-to-Noise Ratio (CNR), contrast and noise were studied for different reconstruction models: OSEM, OSEM + TOF, OSEM + PSF and OSEM + PSF + TOF.The 2D multi-compartment Hoffman phantom was filled to simulate 4 different tracers' spatial distribution: FDG, ¹¹C-flumazenil (FMZ), ¹¹C-Methionine (MET) and 6-¹⁸F-fluoro-l-dopa (FDOPA). The best algorithm for each tracer was selected by visual inspection. The maximization of CNR determined the optimal parameters for each reconstruction.ResultsIn the 3D Hoffman phantom, both noise and contrast increased with increasing number of iterations and decreased with increasing FWHM. OSEM + PSF + TOF reconstruction was generally superior to other reconstruction models. Visual analysis of the 2D Hoffman brain phantom suggested that OSEM + PSF + TOF is the optimum algorithm for tracers with focal uptake, such as MET or FDOPA, and OSEM + TOF for tracers with diffuse cortical uptake (i.e. FDG and FMZ). Optimization of CNR demonstrated that OSEM + TOF reconstruction must be performed with 2 iterations and a filter FWHM of 3 mm, and OSEM + PSF + TOF reconstruction with 4 iterations and 1 mm FWHM filter.ConclusionsOptimization of reconstruction algorithm and parameters has been performed to take particular advantage of the last generation PET scanner, recommending specific settings for different brain PET radiotracers.     

Influence de la rhTSH sur la fixation du 18 FDG dans une population de 42 patients avec cancer différencié de la thyroïde suspect de récidive

PurposeThe role of positron emission tomography with 18 fluoro-deoxy-glucose (FDG-PET) in case of differentiated thyroid carcinoma recurrence is established. However, the influence of TSH levels on 18 FDG is still discussed. Our study aims at comparing respective performances of FDG-PET performed at low TSH levels and under rhTSH stimulation, when a recurrence of a thyroid carcinoma is suspected.Material and methodsForty-two patients have been included, in a prospective way; each of them has been explored by FDG-PET at low (PET1) and high TSH levels with Thyrogen^® (PET2). The number of hypermetabolic foci, the intensity of uptake, both visual and with Standardized Uptake Values (SUV) have been compared.ResultsPET1: 82 foci were detected, including 75 true positive (TP) and seven false positive (FP). Sensitivity by lesion is 85.23 and 58.6% on a patient basis. Twelve pathological sites, not visualized (false negative) in PET1, were seen under stimulation. PET2: 89 foci were detected, including 87 TP and two FP; two tumoral sites visualized with PET1 are not detected. Sensitivity by lesion is 97.75 and 75.9% on a patient basis. SUV are significantly higher under stimulation. In three patients, therapeutic strategy has been modified, based on PET2 data.ConclusionStimulation by rhTSH improves FDG-PET performances. Therefore, it is justified to resort to it in case of recurrence of differentiated thyroid carcinoma, when the usual workup is negative.     

The Role of F-Fluorodeoxyglucose (FDG) Positron Emission Tomography–Computed Tomography (PET/CT) in the Screening of Cervical Cancer: A Literature Review

F-fluorodeoxyglucose (FDG) positron emission tomography–computed tomography (PET/CT) has of late gained prominence in the investigation of cervical cancer since it gives a better clarity on imaging modalities for the status of the lymph node and distant metastasis. The current review is an appraisal of the recent updates on the role of FDG-PET/CT in the screening of cervical cancer as evidenced by publications till date. 985 studies were obtained in the initial search on cervical cancer and publications selected based on inclusion and exclusion criteria. In the final selection, 14 were selected and coded as the most appropriate for the present review. Valuable studies on (FDG) PET/CT have been identified. These studies point to the fact that recent advanced protocols like PET/CT supported by therapeutic innovations ensure better cancer care and survival chances in cervical cancer patients.     

Application clinique des nouveaux traceurs TEP en oncologie. La vision d’un médecin nucléaire en Espagne

PET is an excellent and sensitive molecular imaging technique using positron-emitting radioisotopes coupled to specific ligands. Many biological targets of great interest can be imaged with these radiolabelled ligands. ¹⁸F-FDG is the most widely tracer PET used, but is not a oncospecific tracer and many malignancies are poorly imaged by FDG-PET. In the last years, the investigation and development of novel ligands will be an alternative to the limitations of FDG in clinical oncology. This review describes the current status of non-FDG PET tracers that have a potential clinical effect in the management of patients affected by cancer.     

Multimodal Discrimination of Alzheimer’s Disease Based on Regional Cortical Atrophy and Hypometabolism

Structural MR image (MRI) and ¹⁸F-Fluorodeoxyglucose-positron emission tomography (FDG-PET) have been widely employed in diagnosis of both Alzheimer’s disease (AD) and mild cognitive impairment (MCI) pathology, which has led to the development of methods to distinguish AD and MCI from normal controls (NC). Synaptic dysfunction leads to a reduction in the rate of metabolism of glucose in the brain and is thought to represent AD progression. FDG-PET has the unique ability to estimate glucose metabolism, providing information on the distribution of hypometabolism. In addition, patients with AD exhibit significant neuronal loss in cerebral regions, and previous AD research has shown that structural MRI can be used to sensitively measure cortical atrophy. In this paper, we introduced a new method to discriminate AD from NC based on complementary information obtained by FDG and MRI. For accurate classification, surface-based features were employed and 12 predefined regions were selected from previous studies based on both MRI and FDG-PET. Partial least square linear discriminant analysis was employed for making diagnoses. We obtained 93.6% classification accuracy, 90.1% sensitivity, and 96.5% specificity in discriminating AD from NC. The classification scheme had an accuracy of 76.5% and sensitivity and specificity of 46.5% and 89.6%, respectively, for discriminating MCI from AD. Our method exhibited a superior classification performance compared with single modal approaches and yielded parallel accuracy to previous multimodal classification studies using MRI and FDG-PET.     

Metabolism of [14C]fluorodeoxyglucose by rat brain in vivo

Rats were intravenously injected with 10μCi of [U-¹⁴C]deoxyglucose (DG) or [U-¹⁴C]fluorodeoxyglucose (FDG) and sacrificed by microwave irradiation 4, 45 and 240 min later. Fluorodeoxyglucose phosphate (FDGP) accumulated at a significantly greater rate than did deoxyglucose phosphate (DGP) in brain. Loss of the phosphorylated compounds from brain between 45 and 240 min after administration was similar. The per cent of radioactivity in non-phosphorylated compounds was lower with FDG as tracer at all times after injection. The probable basis for the difference in rate of phosphorylation of the two compounds is a difference in the kinetic properties of rat brain hexokinase with FDG and DG as substrates.The principal use of these isotopes is for studies of regional glucose utilization in brain. In the rat, our data indicate that FDG has two advantages over DG for such studies. Since FDGP accumulates in brain at about 150% the rate of DGP, the amounts (and costs) of isotope can be reduced by up to one third with FDG as tracer. The more rapid decrease in background of non-phosphorylated FDG potentially allows the study of shorter periods of time in autoradiographic work. These considerations apply to both qualitative and quantitative studies of glucose utilization by rat brain. For quantitative work, however, the constants necessary to convert rates of FDG phosphorylation to rates of glucose phosphorylation by rat brain have yet to be determined.     

Application of metabolic PET imaging in radiation oncology

Positron emission tomography (PET) is a noninvasive imaging technique that provides functional or metabolic assessment of normal tissue or disease conditions and is playing an increasing role in cancer radiotherapy planning. (18)F-Fluorodeoxyglucose PET imaging (FDG-PET) is widely used in the clinic for tumor imaging due to increased glucose metabolism in most types of tumors; its role in radiotherapy management of various cancers is reviewed. In addition, other metabolic PET imaging agents at various stages of preclinical and clinical development are reviewed. These agents include radiolabeled amino acids such as methionine for detecting increased protein synthesis, radiolabeled choline for detecting increased membrane lipid synthesis, and radiolabeled acetate for detecting increased cytoplasmic lipid synthesis. The amino acid analogs choline and acetate are often more specific to tumor cells than FDG, so they may play an important role in differentiating cancers from benign conditions and in the diagnosis of cancers with either low FDG uptake or high background FDG uptake. PET imaging with FDG and other metabolic PET imaging agents is playing an increasing role in complementary radiotherapy planning.     

Métabolomique et imagerie TEP-FDG des cancers du sein

Cancer metabolism is an essential aspect of tumorogenesis, as cancer cells have increased energy requirements in comparison to normal cells. Metabolomic techniques can provide quantitative data for a large number of small molecules in tissues and enable the analysis of multiple intricate metabolic pathways. Positron emission tomography (PET) using ¹⁸F-Fluorodeoxyglucose (FDG) enables in vivo analysis of glycolysis and is widely used in oncology. High tumor FDG uptake is a prognostic factor in breast cancer and has been associated with tumor aggressively. Seventy breast cancer samples obtained from untreated patients who had underwent FDG-PET imagery were analyzed through an untargeted metabolomic approach using liquid chromatography-mass spectroscopy (LC-MS) to study possible correlations between metabolomic data and FDG uptake. Tumors were split into two groups depending on avidity for FDG as measured with PET. The Compound Discoverer 4.0 software enabled identification of 854 metabolites. PLSDA based models predicted FDG uptake with an accuracy ranging from 0,73 to 0,77. Selected metabolites varied depending on the use of scaling or log transformation. Metabolites correlated with tumor FDG uptake were, among others, glutathione, amino-acids such as glutamate, proline or tyrosine, L-acetyl-carnitine, metabolites from the kynurenine pathway such as L-kynurenine or formyl-kynurenine and polyamines such as N1,N12-diacetylspermine or N1-acetylspermine. These metabolites have been previously shown to reflect cancer aggressivity. The correlation between the glycolytic pathway activation and tumor FDG uptake could not be directly assessed but indirect signs showed a higher glycolytic activity in tumours presenting a higher FDG uptake. Studying new metabolites identified through this process could enable a better understanding of tumor metabolism and identification of new biomarkers.     

Automated Movement Correction for Dynamic PET/CT Images: Evaluation with Phantom and Patient Data

Head movement during a dynamic brain PET/CT imaging results in mismatch between CT and dynamic PET images. It can cause artifacts in CT-based attenuation corrected PET images, thus affecting both the qualitative and quantitative aspects of the dynamic PET images and the derived parametric images. In this study, we developed an automated retrospective image-based movement correction (MC) procedure. The MC method first registered the CT image to each dynamic PET frames, then re-reconstructed the PET frames with CT-based attenuation correction, and finally re-aligned all the PET frames to the same position. We evaluated the MC method''s performance on the Hoffman phantom and dynamic FDDNP and FDG PET/CT images of patients with neurodegenerative disease or with poor compliance. Dynamic FDDNP PET/CT images (65 min) were obtained from 12 patients and dynamic FDG PET/CT images (60 min) were obtained from 6 patients. Logan analysis with cerebellum as the reference region was used to generate regional distribution volume ratio (DVR) for FDDNP scan before and after MC. For FDG studies, the image derived input function was used to generate parametric image of FDG uptake constant (K_i) before and after MC. Phantom study showed high accuracy of registration between PET and CT and improved PET images after MC. In patient study, head movement was observed in all subjects, especially in late PET frames with an average displacement of 6.92 mm. The z-direction translation (average maximum = 5.32 mm) and x-axis rotation (average maximum = 5.19 degrees) occurred most frequently. Image artifacts were significantly diminished after MC. There were significant differences (P<0.05) in the FDDNP DVR and FDG Ki values in the parietal and temporal regions after MC. In conclusion, MC applied to dynamic brain FDDNP and FDG PET/CT scans could improve the qualitative and quantitative aspects of images of both tracers.     

Corrélations des profils TEP au 18F-FDG,IRM et clinico-biologiques des encéphalites dysimmunitaires

IntroductionDysimmune encephalitis (DE) are rare and serious diseases. Their diagnosis is based on a set of arguments, in absence of gold standard. The discovery of anti-neuronal antibodies, although specific, is inconstant. FDG PET has a high sensitivity in this indication. Accordingly, its place is increasing in the diagnosis and monitoring of DE. We looked for associations between different patterns found in ¹⁸FDG PET in ED, and different data from the medical file, including biology, MRI, and EEG.Material and methodsWe collected retrospectively the medical records data of 30 patients of the Marseille La Timone hospital, having had a diagnosis of DE, and benefited from both a ¹⁸FDG cerebral PET/CT and a lumbar puncture in a time lapse of maximum of 15 days, from January 2010 to September 2015.ResultsThe statistical analysis showed significant associations between brain hypermetabolism and intrathecal synthesis. The second interesting finding concerned brain hypometabolism, which was significantly associated with more serious conditions, both paraclinically, with MRI more often pathological, and antibodies identified in CSF more frequently, and clinically. It also proved that the patterns of cerebral ¹⁸FDG PET, although pathological, most often varied widely, and no specific pattern was found.DiscussionFuture research will determine if there are associations between cerebral ¹⁸FDG PET findings, and prognostic factors, particularly in terms of therapeutic response in the DE.     

TEP-FDG et pathologies infectieuses

Interests of ¹⁸F-fluorodeoxyglucose positron emission tomography-computed tomography (¹⁸F-FDG PET/CT) have been demonstrated since many years. FDG physiopathology explains its use for infectious diseases, especially in infective endocarditis, cardiac electronic device infection, and in vascular graft infection, as well as in fever of unknown origin. FDG PET is very interesting to make the diagnostic and for the extension of these infectious diseases, thanks to the whole body acquisition. This synthesis article identifies and illustrates principal indications in this field of this imagery modality.     

Intranasal Cabergoline: Pharmacokinetic and Pharmacodynamic Studies

Aims of this investigation were to prepare and characterize cabergoline intranasal microemulsion formulations, determine brain drug delivery through biodistribution using technetium-99m (^99mTc) as a tracer, and assess its performance pharmacodynamically in weight control. Cabergoline microemulsions of different compositions were prepared by water titration method and characterized for globule size and zeta potential. Microemulsion with maximum drug solubilization and stability was considered optimal and taken for further studies with or without addition of mucoadhesive agent. Pharmacokinetics of optimized ^99mTc-labeled cabergoline formulations and ^99mTc-labeled drug solution were studied by estimating radioactivity in brain and blood of albino rats post intranasal, intravenous, and oral administrations. To confirm localization of drug in brain following intranasal, intravenous, and oral administrations, gamma scintigraphy imaging was also performed. To assess weight control performance of formulations, body weight, white adipose tissue mass, serum lipids, leptin, and prolactin were determined before and after 40 days of intranasal administrations of these formulations to Wistar rats. Microemulsions were found to be stable both physically and chemically when stored at various stress conditions. Brain/blood uptake ratios, drug targeting efficiency, and direct drug transport were found to be highest for drug mucoadhesive microemulsion followed by drug microemulsion and drug solution post-intranasal administration compared to intravenous drug microemulsion. Significant (p < 0.05) reduction in assessed pharmacodynamic parameters was observed after intranasal administration of mucoadhesive microemulsion against control group. The results of the studies conclusively demonstrate that intranasal microemulsion formulations developed in this investigation are stable and can deliver cabergoline selectively and in higher amounts to the brain compared to both drug administrations as a solution intranasally or microemulsion intravenously. The results also demonstrate reduction in weight, adipose tissue mass, serum lipids, and serum prolactin after intranasal administration of drug microemulsion. Hence, long-term studies in at least two more animal models followed by extensive clinical evaluation can safely result into a product for clinical use.     

Glucose Metabolic Trapping in Mouse Arteries: Nonradioactive Assay of Atherosclerotic Plaque Inflammation Applicable to Drug Discovery

Background

¹⁸F-Fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging of atherosclerosis in the clinic is based on preferential accumulation of radioactive glucose analog in atherosclerotic plaques. FDG-PET is challenging in mouse models due to limited resolution and high cost. We aimed to quantify accumulation of nonradioactive glucose metabolite, FDG-6-phosphate, in the mouse atherosclerotic plaques as a simple alternative to PET imaging.

Methodology/Principal Findings

Nonradioactive FDG was injected 30 minutes before euthanasia. Arteries were dissected, and lipids were extracted. The arteries were re-extracted with 50% acetonitrile-50% methanol-0.1% formic acid. A daughter ion of FDG-6-phosphate was quantified using liquid chromatography and mass spectrometry (LC/MS/MS). Thus, both traditional (cholesterol) and novel (FDG-6-phosphate) markers were assayed in the same tissue. FDG-6-phosphate was accumulated in atherosclerotic lesions associated with carotid ligation of the Western diet fed ApoE knockout mice (5.9 times increase compare to unligated carotids, p<0.001). Treatment with the liver X receptor agonist T0901317 significantly (2.1 times, p<0.01) reduced FDG-6-phosphate accumulation 2 weeks after surgery. Anti-atherosclerotic effects were independently confirmed by reduction in lesion size, macrophage number, cholesterol ester accumulation, and macrophage proteolytic activity.

Conclusions/Significance

Mass spectrometry of FDG-6-phosphate in experimental atherosclerosis is consistent with plaque inflammation and provides potential translational link to the clinical studies utilizing FDG-PET imaging.