PET Techniques Research Articles

Multimodality Image Post-processing in Detection of Extratemporal MRI-Negative Cortical Dysplasia.

Purpose: To determine the diagnostic value of individual image post-processing techniques in a series of patients who underwent extratemporal operations for histologically proven, MRI-negative focal cortical dysplasia (FCD).Methods: The morphometric analysis program (MAP), PET/MRI co-registration and statistical parametric mapping (SPM) analysis of PET (SPM-PET) techniques were analyzed in 33 consecutive patients. The epileptogenic zone (EZ) assumed by MAP, PET/MRI, and SPM-PET was compared with the location of the FCD lesions determined by stereoelectroencephalography (SEEG) and histopathological study. The detection rate of each modality was statistically compared.Results: Three lesions were simultaneously detected by the three post-processing methods, while two lesions were only MAP positive, and 8 were only PET/MRI positive. The detection rate of MAP, PET/MRI, SPM-PET and the combination of the three modalities was 24.2, 90.9, 57.6, and 97.0%, respectively. Taking the pathological subtype into account, no type I lesions were detected by MAP, and PET/MRI was the most sensitive method for detecting FCD types II and IIA. During a mean follow-up period of 22.94 months, seizure freedom was attained in 26/33 patients (78.8%) after focal corticectomy.Conclusions: MAP, PET/MRI, and SPM-PET provide complementary information for FCD detection, intracranial electrode design, and lesion resection. PET/MRI was particularly useful, with the highest detection rate of extratemporal MRI-negative FCD.

Abass Alavi: A giant in Nuclear Medicine turns 80 and is still going strong!

Abass Alavi: A giant in Nuclear Medicine turns 80 and is still going strong!

Assessing the repeatability of absolute CMRO2, OEF and haemodynamic measurements from calibrated fMRI

As energy metabolism in the brain is largely oxidative, the measurement of cerebral metabolic rate of oxygen consumption (CMRO2) is a desirable biomarker for quantifying brain activity and tissue viability. Currently, PET techniques based on oxygen isotopes are the gold standard for obtaining whole brain CMRO2 maps. Among MRI techniques that have been developed as an alternative are dual calibrated fMRI (dcFMRI) methods, which exploit simultaneous measurements of BOLD and ASL signals during a hypercapnic-hyperoxic experiment to modulate brain blood flow and oxygenation.In this study we quantified the repeatability of a dcFMRI approach developed in our lab, evaluating its limits and informing its application in studies aimed at characterising the metabolic state of human brain tissue over time. Our analysis focussed on the estimates of oxygen extraction fraction (OEF), cerebral blood flow (CBF), CBF-related cerebrovascular reactivity (CVR) and CMRO2 based on a forward model that describes analytically the acquired dual echo GRE signal.Indices of within- and between-session repeatability are calculated from two different datasets both at a bulk grey matter and at a voxel-wise resolution and finally compared with similar indices obtained from previous MRI and PET measurements. Within- and between-session values of intra-subject coefficient of variation (CVintra) calculated from bulk grey matter estimates 6.7 ± 6.6% (mean ± std.) and 10.5 ± 9.7% for OEF, 6.9 ± 6% and 5.5 ± 4.7% for CBF, 12 ± 9.7% and 12.3 ± 10% for CMRO2. Coefficient of variation (CV) and intraclass correlation coefficient (ICC) maps showed the spatial distribution of the repeatability metrics, informing on the feasibility limits of the method.In conclusion, results show an overall consistency of the estimated physiological parameters with literature reports and a satisfactory level of repeatability considering the higher spatial sensitivity compared to other MRI methods, with varied performance depending on the specific parameter under analysis, on the spatial resolution considered and on the study design.

Decorated Superparamagnetic Iron Oxide Nanoparticles with Monoclonal Antibody and Diethylene-Triamine-Pentaacetic Acid Labeled with Thechnetium-99m and Galium-68 for Breast Cancer Imaging.

In this study we developed and tested an iron oxide nanoparticle conjugated with DTPA and Trastuzumab, which can efficiently be radiolabeled with 99m-Tc and Ga-68, generating a nanoradiopharmaceutical agent to be used for SPECT and PET imaging. The production of iron oxide nanoparticle conjugated with DTPA and Trastuzumab was made using phosphorylethanolamine (PEA) surface modification. Both radiolabeling process was made by the direct radiolabeling of the nanoparticles. The in vivo assay was done in female Balb/c nude mice xenografted with breast cancer. Also a planar imaging using the radiolabeled nanoparticle was performed. No thrombus and immune response leading to unwanted interaction and incorporation of nanoparticles by endothelium and organs, except filtration by the kidneys, was observed. In fact, more than 80% of 99mTc-DTPA-TZMB@Fe3O4 nanoparticles seems to be cleared by the renal pathway but the implanted tumor whose seems to increase the expression of HER2 receptors enhancing the uptake by all other organs. However, even in this unfavorable situation the tumor bioconcentrated much larger amounts of the nano-agent than normal tissues giving clear enough contrast for breast cancer imaging for diagnostics purpose by both SPECT and PET technique. Graphical Abstract ᅟ.

Randomized Controlled Trials for Diagnostic Imaging: Conceptual and Pratical Problems

We raise a problem of applicability of RCTs to validate nuclear diagnostic imaging tests. In spite of the wide application of PET and other similar techniques that use radiopharmaceuticals for diagnostic purposes, RCT-based evidence on their validity is sparse. We claim that this is due to a general conceptual problem that we call Prevalence of Treatment, which arises in connection with designing RCTs for testing any diagnostic procedure in the present context of medical research, and is particularly apparent in this case. We also identify three practical reasons why RCTs do not qualify as the best option for PET validation, which have to do with specific characteristics of nuclear diagnostic imaging, and of radiopharmaceuticals. The paper is meant to contribute both to the philosophical discussion on the EBM hierarchy of evidence, and on the specific debate on radiopharmaceuticals in nuclear medicine.

Three‐Dimensional Imaging of High Performance Liquid Chromatography Processes Using a Mini Positron Emission Tomograph

AbstractPositron emission tomography (PET) is a widely used technique for following radiotracer distribution, molecule specific binding or biochemical processes in living animals or in human body. Small animal PET cameras with high spatial resolution and high sensitivity are also useful, beyond their original pre‐clinical application, in the following of surface chemical and the physicochemical processes.The purpose of this study was the introduction of the three‐dimensional real‐time PET based visualization method in separation processes. The separated tracer compounds can be followed and displayed in three dimension along chromatography column using the PET technique. We studied the separation of 11C‐labeled methanol and 11C‐labeled methyl iodide using reversed‐phase high performance liquid chromatography (HPLC) on semi‐preparative and analytical columns in order to determine the detection limits of our PET camera (MiniPET). The PET imaging is suitable for analyzing the column efficiency and the underlying processes in the liquid chromatography.Synthesis, separation and quality control of PET radiopharmaceuticals are performed in radiochemistry labs (in PET Centers) with the help of the liquid chromatography, therefore equipment, infrastructure and other lab conditions are usually available for researchers and for private companies to study chromatographic separation processes and to develop columns.

Imaging behavioural complications of Parkinson's disease.

In addition to motor symptoms, behavioural complications are commonly found in patients with Parkinson's disease (PD). Behavioural complications, including depression, anxiety, apathy, impulse control disorder and psychosis, together have a large impact on PD patient's quality of life. Many neuroimaging studies using PET, SPECT and MRI techniques have been conducted to study the underlying neural mechanisms of PD pathogenesis and pathophysiology in relation to its behavioural complications. This review will survey these PET, SPECT and MRI studies to describe the current understanding of the neuro-chemical, functional and structural changes associated with behavioural complications in PD patients.

Verbal fluency in research conducted with PET technique under conditions of extended cognitive activation with the use of 18F-fluorodeoxyglucose (FDG) tracer.

Functional neuroimaging of the brain is a widely used method to study cognitive functions. The aim of this study was to compare the activity of the brain during performance of the tasks of phonemic and semantic fluency with the paced-overt technique in terms of prolonged activation of the brain. The study included 17 patients aged 20-40 years who were treated in the past for Hodgkin'slymphoma, now in remission. Due to the type of task, the subjectswere divided into two groups. Nine people performed the phonemic fluency task, and eight semantic. Due to the disease, all subjects were subject to neuropsychological diagnosis. The diagnosis of any cognitive impairment was an exclusion criterion. Neuroimaging was performed using PET technique with 18F-fluorodeoxyglucose (FDG) tracer. Performance of a verbal fluency test, regardless of the version of the task, was associated with greater activity of the left hemisphere of the brain. The most involved areas compared with other areas of key importance for the performance of verbal fluency tasks were frontal lobes. An increased activity of parietal structures was also shown. The study did not reveal differences in brain activity depending on the type of task. Performing the test in both phonemic and semantic form for a long time, in terms of increased cognitive control resulting from the test procedure, could result in significant advantage of prefrontal lobe activityin both types of tasks and made it impossible to observe the processes specific to each of them.

Advances in neuro-oncology imaging.

Despite the fact that MRI has evolved to become the standard method for diagnosis and monitoring of patients with brain tumours, conventional MRI sequences have two key limitations: the inability to show the full extent of the tumour and the inability to differentiate neoplastic tissue from nonspecific, treatment-related changes after surgery, radiotherapy, chemotherapy or immunotherapy. In the past decade, PET involving the use of radiolabelled amino acids has developed into an important diagnostic tool to overcome some of the shortcomings of conventional MRI. The Response Assessment in Neuro-Oncology working group - an international effort to develop new standardized response criteria for clinical trials in brain tumours - has recommended the additional use of amino acid PET imaging for brain tumour management. Concurrently, a number of advanced MRI techniques such as magnetic resonance spectroscopic imaging and perfusion weighted imaging are under clinical evaluation to target the same diagnostic problems. This Review summarizes the clinical role of amino acid PET in relation to advanced MRI techniques for differential diagnosis of brain tumours; delineation of tumour extent for treatment planning and biopsy guidance; post-treatment differentiation between tumour progression or recurrence versus treatment-related changes; and monitoring response to therapy. An outlook for future developments in PET and MRI techniques is also presented.

Application of gamma imaging techniques for the characterisation of position sensitive gamma detectors

A device to characterize position-sensitive germanium detectors has been implemented at GSI. The main component of this so called scanning table is a gamma camera that is capable of producing online 2D images of the scanned detector by means of a PET technique. To calibrate the gamma camera Compton imaging is employed. The 2D data can be processed further offline to obtain depth information. Of main interest is the response of the scanned detector in terms of the digitized pulse shapes from the preamplifier. This is an important input for pulse-shape analysis algorithms as they are in use for gamma tracking arrays in gamma spectroscopy. To validate the scanning table, a comparison of its results with a second scanning table implemented at the IPHC Strasbourg is envisaged. For this purpose a pixelated germanium detector has been scanned.

Radiolabeled peptides: current and new perspectives.

Radiolabeled peptides have been the subject of research for over 20 years and during that time possibility/variety of peptide receptor imaging and later targeted radiotherapy increased significantly. The targeted receptors belong to the large family of G-protein-coupled receptors or tyrosine kinases receptors partially connected with them. They both regulate large signaling networks, control multiple cell functions and are implicated in many diseases including cancers. The essential feature of peptides used in nuclear medicine involves their ability to binding with high affinity and specify to their receptors overexpressed on tumor cells. Currently most important peptide radiotracers are somatostatin, GLP-1, bombesin, gastrin/cholecystokinin-2, neurokinin type 1, CXCR4, EGF, VEGF and integrins. These tracers are mainly based on nuclides which are radiometals or on 18F and may be used in both SPECT or PET techniques as well as for hybrid imaging. Using of chelators suitable for peptide labeling with diagnostic and therapeutic radionuclids enables the theranostic approach. In this review we will provide a brief overview over currently available radiopharmaceuticals based on different groups of peptides.

DoPET: an in-treatment monitoring system for proton therapy at 62 MeV

Proton beam radiotherapy is highly effective in treating cancer thanks to its conformal dose deposition. This superior capability in dose deposition has led to a massive growth of the treated patients around the world, raising the need of treatment monitoring systems. An in-treatment PET system, DoPET, was constructed and tested at CATANA beam-line, LNS-INFN in Catania, where 62 MeV protons are used to treat ocular melanoma. The PET technique profits from the beta+ emitters generated by the proton beam in the irradiated body, mainly 15-O and 11-C. The current DoPET prototype consists of two planar 15 cm × 15 cm LYSO-based detector heads. With respect to the previous versions, the system was enlarged and the DAQ up-graded during the years so now also anthropomorphic phantoms, can be fitted within the field of view of the system. To demonstrate the capability of DoPET to detect changes in the delivered treatment plan with respect to the planned one, various treatment plans were used delivering a standard 15 Gy fraction to an anthropomorphic phantom. Data were acquired during and after the treatment delivery up to 10 minutes. When the in-treatment phase was long enough (more than 1 minute), the corresponding activated volume was visible just after the treatment delivery, even if in presence of a noisy background. The after-treatment data, acquired for about 9 minutes, were segmented finding that few minutes are enough to be able to detect changes. These experiments will be presented together with the studies performed with PMMA phantoms where the DoPET response was characterized in terms of different dose rates and in presence of range shifters: the system response is linear up to 16.9 Gy/min and has the ability to see a 1 millimeter range shifter.

Hand exposure of workers in 18F-FDG production centre

18F-FDG is the most popular radiopharmaceutical used, among others, in oncological diagnostics by PET technique. The production of 18F-FDG is a multistep process that begins by obtaining the radioisotope 18F, and subsequently labelling the radiopharmaceutical, as well as quality control of the resulting compound. In each of these stages, the employee has contact with ionizing radiation. The production of 18F requires the use of a cyclotron device. Currently in Poland, there are 9 centres equipped with a cyclotron for the production of positron-emitting radioisotopes.The monitoring of the occupational exposure to ionizing radiation in these centres is performed by measuring the effective and equivalent dose. Neither of these forms fully reflects the exposure of the worker, which is largely associated with handling procedures. The 18F radiopharmaceutical preparation process runs automatically, which partially reduces the level of staff exposure, but the quality control step of the pharmaceutical requires handling procedures with a vial containing an activity of a radiopharmaceutical ranging from 4 GBq to 10 GBq.In the work presented, measurements were performed of hand exposure, in units the equivalent dose (Hp(0.07)), of the staff who are involved in the procedures of 18F-FDG production in one of the national production centres. The high-sensitivity thermoluminescent detectors (MCP) were used to measure the doses.The measurements were performed for three groups of workers: operators of the cyclotron, those who produce the 18F-FDG, and quality control staff. Detectors were placed on the fingertips of the left and right hand, as well as in a standard ring dosemeter location.The results indicate that the largest exposure happens among the group of workers involved in the radiopharmaceutical’s quality control. The doses recorded by the MCP detectors placed on the fingertips during one working day reach a value up to 2 mSv, which may result in exceeding the annual dose limit (500 mSv).

Imaging Pulmonary Inflammation.

Lung inflammatory diseases contribute significantly to the socioeconomic burden of disease. Yet very few new, effective therapies for respiratory disease have been approved for use. A major contributing factor is the lack of biomarkers that can accurately quantify the lung inflammatory burden and can be used to understand the contribution of lung inflammation to loss in lung function. Molecular imaging approaches can detect and quantify the recruitment and activation of specific immune cells in lung inflammation. We review the clinical techniques used to image lung inflammation, provide an overview of clinical and emerging PET techniques for quantifying lung inflammation, and discuss potential clinical applications.

Radiopharmaceuticals for somatostatin receptor imaging.

The aim of this review is to summarize the developments and briefly characterize the somatostatin analogs which are currently used for somatostatin receptor imaging in clinical routine or in early phase clinical trials. Somatostatin (sst) receptor targeting with radiolabeled peptides has become an integral part in nuclear oncology during the last 20 years. This integration process has been initiated in Europe with the introduction to the market of 111In-DTPA-DPhe1-octreotide [111In-pentetreotide]. Introducing 99mTc in somatostatin receptor targeting radiopeptides resulted in much better image quality, higher sensitivity of tumor detection and lower mean effective dose for the examined patient. The next generation are 68Ga labeled somatostatin analogs. Due to the spatial resolution of PET technique and increasing number of PET scanners, the PET or PET/CT technique became very important in somatostatin receptor imaging. Until up to a couple of years ago the analogs of somatostatin were constructed aiming at their agonistic behavior, expecting that their internalization with the receptor acti-vated by the radiolabeled ligand and its retention within the tumor cell are crucial for efficient imaging and therapy. Recently it has been shown that the antagonists recognize more binding sites at the tumor cell membrane and hence offer an improved diagnostic efficacy, especially when the density of sst receptors is low. This approach may in future improve diagnostic value of somatostatin receptor imaging techniques. The developments in tracer design are followed by the improvements in imaging techniques. The new SPECT scanners offer resolution close to that of PET, which might open a new era for 99mTc and other SPECT radiotracers.

Novel MRI and PET markers of neuroinflammation in multiple sclerosis.

Gadolinium-enhancement depicts blood-brain barrier disruption associated with new inflammatory MRI lesions in multiple sclerosis (MS) and is widely used for diagnosis and therapeutic monitoring. However, earlier and more specific markers of inflammation are urgently needed. Susceptibility-weighted images demonstrate the importance of the central vein in the formation of MS lesions. Perfusion weighted imaging techniques can show focal and diffuse low-grade inflammatory changes not visible on conventional MRI. Leptomeningeal enhancement could be part of the aetiology of subpial cortical MS lesions. Ultrasmall superparamagnetic particles of iron oxide can identify neuroinflammatory changes in addition to gadolinium enhancement and as such identify different types and phases of MS lesions. 18kD-translocator protein PET tracers identify activated microglia and an increase in TSPO uptake in both MS lesions and normal appearing brain tissue is related to disease severity and progression. A range of novel tracers for microglia activation is under development as well as radioligands that can label therapeutic drugs. Novel MRI and PET techniques improve in-vivo visualization and quantification of the pleomorphic aspects of neuroinflammation, providing us with a unique insight in its pathogenesis, clinical relevance, and therapy responsiveness in MS.

Dual PET and Near-Infrared Fluorescence Imaging Probes as Tools for Imaging in Oncology.

The purpose of this article is to summarize advances in PET fluorescence resolution, agent design, and preclinical imaging that make a growing case for clinical PET fluorescence imaging. Existing SPECT, PET, fluorescence, and MRI contrast imaging techniques are already deeply integrated into the management of cancer, from initial diagnosis to the observation and management of metastases. Combined positron-emitting fluorescent contrast agents can convey new or substantial benefits that improve on these proven clinical contrast agents.

Imaging of bacteria with radiolabeled ubiquicidin by SPECT and PET techniques

The ability to differentiate infection from sterile inflammation and monitor antimicrobial therapy against multidrug-resistant pathogens through imaging of bacteria with radiolabeled ubiquicidin (UBI 29-41) is a truly unique feature of the single photon emission computed tomography and positron emission tomography techniques, considering that conventional computed tomography; magnetic resonance imaging and ultrasound are not able to detect microorganisms. In this article, a systematic review of the reported diagnostic accuracy of 99mTc-UBI scintigraphy in detection of infections, as well as a review of the recent 68Ga-UBI studies for bacteria-targeted imaging, is presented. The results of 15 clinical studies (622 patients) carried out from 2004 to 2015 using 99mTc-UBI indicate a pooled sensitivity and specificity as high as 95.5 and 92.5 %, respectively, with an overall accuracy of 94.4 % (95 % confidence interval of 91.6–97.2 %). Preclinical studies reveal the same ability of 68Ga-UBI to identify bacteria by PET images. The reviewed studies demonstrated that radiolabeled UBI is a useful tracer for the accurate diagnosis of infections.

In-beam PET data characterization with the large area DoPET prototype

Range verification with in-beam PET techniques is a powerful tool for monitoring the correctness of dose delivery in particle therapy. Among the major limitations of in-beam PET systems are the limited detectors size due to the constrained space in which they can be placed to allow the irradiation, and the necessity of a high read-out modularization, due to high activity rates during the irradiation. In this work we present the data acquired at the CNAO (Centro Nazionale di Adroterapia Oncologica) treatment center in Pavia, Italy, with the new DoPET system, specifically designed to operate in in-beam conditions. The new prototype consists of two planar 15cm × 15cm LYSO-based detectors, read out by 9 PMT detector modules each. In particular, we test the capability of our system to determine particle range in various irradiation conditions. Several plastic phantoms were irradiated at the CNAO treatment centre with protons and carbon ions of various energies. The used dose in treatment plans is 2 Gy and the monitoring feedback is produced in a few minutes after the end of the treatment.

Non-invasive techniques for studying macrophages in joint inflammation

Folate-based radiotracers have been used in patients with cancer and inflammatory diseases to visualize folate receptor expressing cells using PET or SPECT techniques. Activated macrophages express folate receptor beta (FR-β) and this allows specific imaging of these cells in-vivo. From previous work using SPECT imaging to visualize folate receptor expressing macrophages in both animal models and in patients with OA we know that macrophages are present in OA affected joints. However, it remains unclear what role these macrophages play in the different stages of OA and whether their role can be influenced by specific targeting. In Wistar rats osteoarthritis was induced using a low dose of intra-articular papain injections in one knee joint combined with exposure to a moderate exercise protocol. After six weeks and twelve an in vivo folate SPECT/CT scan and micro-CT analyses were performed. Macrophages from human peripheral blood monocytes were cultured (7 days) in the presence of GM-CSF (M1 proinflammatory phenotype) or M-CSF (M2 anti-inflammatory phenotype). Subsequently the macrophages were treated with LPS, cytokines (IL-4, IL-10, IFN-y) or a corticoid steroid (triamcinolone acetonide, 1µg/ml). Folate receptor beta (FRβ) as well as other macrophage marker expressions were measured using FACS. Intra-articular injections with triamcinolone strongly enhanced FRβ+ macrophage activation and fully prevented osteophyte formation. There were no beneficial effects of the corticoid steroid against cartilage degradation or subchondral bone sclerosis. In in-vitro cultures triamcinolone strongly induced the monocyte-macrophages differentiation towards CD163+ and FRβ+ cells, specifically in GM-CSF stimulated (M1) cultures. Addition of triamcinolone to M-CSF stimulated (M2) monocytes showed enhanced IL10 expression on mRNA level. In conclusion triamcinolone enhanced FRβ expression in monocytes that were induced to macrophage differentiation. The triamcinolone injections stimulate synovial macrophage activation and triggers the macrophages towards a more anti-inflammatory subtype. Figure 1 Macrophage activation determined after injection of 111In-DTPA-folate using SPECT/CT in Papain induced osteoarthritis (OA) combined with moderate exercise. Representative sagittal SPECT/CT images of knee joints from representative animals per experimental ...