Cerebrovascular disease encompasses a range of pathologies that affect different components of the cerebral vasculature and brain parenchyma. Large artery atherosclerosis, acute cerebral ischaemia, and intracerebral small vessel disease all demonstrate altered metabolic processes that are key to their pathogenesis. Positron Emission Tomography (PET) can detect and quantify metabolic processes that are relevant to each facet of cerebrovascular disease. The review article published in the November 2017 issue of Nature Reviews Neurology describes how PET-based imaging of metabolic processes at the neurovascular interface has contributed to our understanding of cerebrovascular disease.
Evans, N. R. et al. PET imaging of the neurovascular interface in cerebrovascular disease. Nat Rev Neurol 13, 676–688 (2017). doi:10.1038/nrneurol.2017.129
PET imaging employs various radioligands to detect physiological processes in vivo. The article written by Nicholas R. Evans, University of Cambridge, Cambridge, UK and his colleagues summaries the radioisotopes of PET ligands used for the following list of cellular or physiological targets of vascular biology, actute ischaemic stroke and small vessel disease:
- Increased metabolic rate (inflammation): 18F-FDG
2. Macrophages: 68Ga-DOTATATE (targeting somatostatin receptor type 2)
3. Microcalcification: 18F-NaF (hydroapatite)
4. Hypoxia: 18F-FMISO (targeting selective reduction in hypoxia)
5. Macrophages and microglia: 11C-PK11195, 11C-PBR28, 18F-DPA-714, 11C-vinpocetine, 18F-GE-180 (all targeting TSPO)
6. Neurons: 11C-FMZ (GABA-A receptor)
7. Amyloid: 11C-PiB (analogue of thioflavin T)
8. Neurons: 18F-FNDP (epoxide hydrolase enzyme)
9. Expressed on neurons, astrocytes, microglia and endothelial cells: 18F-NS14490 (α7 nicotonic acetylcholine receptor)
10. Apoptosis: 18F-labeled isatins (caspase 3, caspase 7)
The review article considers sensitivity, specificity, technical considerations and also clinical implications for each radiotracersThe nanoScan PET/MRI3T is an ideal combination of modalities for research of cerebrovascular diseases: structural imaging provided by MRI is co-registered and combined with the PET ability to detect and quantify these pathophysiological processes in vivo. Information obtained from PET studies has helped to shape the understanding of key concepts in cerebrovascular medicine, including vulnerable atherosclerotic plaque, salvageable ischaemic penumbra, neuroinflammation and selective neuronal loss after ischaemic insult. New PET ligands continue to be developed that have superior specificity or that target new processes of interest.
Nanomedicine and Personalized Treatments
Nanomedicine is simply the medical application of nanotechnologies. The idea is the involvement the use of nanoparticles to improve the behaviour of drug substances. The goal is to achieve improvement over conventional chemotherapies. Customized treatments will be required to overcome the issues raised by clinical patient and disease heterogeneity. As one might expect, the same drug will accumulate in tumors at varying concentrations in patients with different cancers. But this also happens in patients with the same kind of cancer. It has to be ensured that drug nanocarriers are really accumulating in the specific tissues to better treat patients. This brings in the necessity of a treatment prediction tool to select the patients most likely to accumulate high amounts of the nanomedicine of interest and hence benefit from nanomedicinal treatment.
Positron Emission Tomography (PET) is such a noninvasive quantitative imaging tool with excellent sensitivity and spatial/temporal resolution required at the whole-body level. Radiolabeling of liposomal nanomedicines with single-photon emission computed tomography (SPECT) radionuclides has been successfully used to study their biodistribution in preclinical and clinical studies, but SPECT imaging suffers from lower sensitivity and temporal/spatial resolution than PET. However, an ideal PET radiolabeling method viable for both preclinical and clinical imaging wasn’t explored before. Rafael T. M. de Rosales, Alberto Gabizon and colleagues at King’s College London and the Shaare Zedek Medical Center sought to address this challenge.
Edmonds, S. et al. Exploiting the Metal-Chelating Properties of the Drug Cargo for In Vivo Positron Emission Tomography Imaging of Liposomal Nanomedicines. ACS Nano (2016). doi:10.1021/acsnano.6b05935
The following Mediso systems were used to conduct the animal imaging studies: nanoScan PET/CT and NanoSPECT/CT Silver upgrade. Both systems are equipped with the MultiCell animal handling and monitoring system , thus enabling a combined PET-CT/SPECT-CT imaging strategy. Interestingly both PET and SPECT were performed in the same animals (by moving the same bed from scanner from scanner, while the animals were anesthetized in fixed position) that allowed to image the tumour cells with SPECT and the nanomedicine with PET.
Liposomal Drug PET Radiolabeling Method Development
The researchers introduced a simple and efficient PET radiolabeling method exploiting the metal-chelating properties of certain drugs (e.g., bisphosphonates such as alendronate and anthracyclines such as doxorubicin) and widely used ionophores radiolabeled with long half-life metallic PET isotopes, such as 89Zr, 52Mn and 64Cu. The labels — and thus the liposomal drugs — could then be tracked using positron emission tomography (PET) to see where they go within the body. The article discusses in details the feasibility and effectiveness of their method, as well as its advantages and limitations, and show its utility for detecting and quantifying the biodistribution of a liposomal nanomedicine containing an aminobisphosphonate in vivo.
In a model of metastatic breast cancer, the researchers demonstrated that their technique allows quantification of the biodistribution of a radiolabeled stealth liposomal nanomedicine. Alendronate (ALD), an aminobisphosphonate, was selected as the radionuclide-binding drug of choice to develop this method for two reasons: (i) known ability to act as metal chelator to form inert coordination complexes with zirconium, copper, and manganese; and (ii) demonstrated anticancer activity and γ−δ T-cell immunotherapy sensitizing properties. The used liposomal formulation is referred to as PLA in the article.
Monitoring Liposomal Nanomedicine Distribution
The biodistribution of the radiolabeled liposomes was monitored using PET imaging with 89Zr-PLA in a metastatic mammary carcinoma mouse model established in immunocompromised NSG mice. This cancer model is also traceable by SPECT imaging/fluorescence due to a dual-modality reporter gene, the human sodium iodide symporter (hNIS-tagRFP), that allows sensitive detection of viable cancer tissues (primary tumor and metastases) using SPECT imaging with 99mTc-pertechnetate and fluorescence during dissection and histological studies. The imaging protocol was as follows: first, mice were injected with 89Zr-PLA (4.6 ± 0.4 MBq) at t = 0 followed by nanoScan PET-CT imaging (liposome biodistribution). The same mice were then injected with 99mTc-pertechnetate (30 MBq) and imaged by SPECT-CT. The SPECT injection was repeated at t = 24 h, 72 h, and 168 h. It was confirmed by separate phantom studies that the presence of 99mTc was not affecting the quality/quantification of the PET study. CT images revealed a significant increase in tumor volume during the imaging study. Using the tumor volumes from SPECT and CT, the researchers calculated the percentage of necrotic tumor tissue over time, by subtracting the hNIS-positive volume (SPECT) to the total tumor volume (CT). A PET-CT study was also performed using 64Cu-PLA in an ovarian cancer model (SKOV-3/SCID-Beige) over 48 h to test the versatility and capability of the radiolabeling method.
The common MultiCell animal handling and monitoring system (developed by Mediso) on both imaging systems gave the possibility to easily co-register the PET-CT/SPECT-CT and PET/SPECT studies as the animals were moved in co-registered position between the systems.
MIP video (3D, rotating along z-axis) showing co-registration of PET (red signal, 89Zr-PLA) and SPECT (green signal, 99mTcO4-, hNIS positive viable tumour tissue) of representative tumor from the mutimodal PET/SPECT study in the 3E.Δ.NT/NSG model. Both signals/radiotracers accumulate predominantly at the rim of the tumour and areas of low colocalization as well as high co-localization (yellow) are evident.
Imaging with PET in mouse models of breast and ovarian cancer showed the drugs accumulated in tumors and metastatic tissues in varying concentrations and at levels well above those in normal tissues, the researchers report. In one mouse strain, the nanomedicines unexpectedly showed up in uteruses, a result that wouldn’t have been detected without conducting the imaging study, according to the researchers.
The results establish that preformed liposomal nanomedicines, including some currently in clinical use, can be efficiently labeled with PET radiometals and tracked in vivo by exploiting the metal affinity and high concentration of the encapsulated drugs. Importantly, the technique allows radiolabeling of preformed liposomal nanomedicines, without modification of their components and without affecting their physicochemical properties.
The versatility, efficiency, simplicity, and GMP compatibility of this method may enable submicrodosing imaging studies of liposomal nanomedicines containing chelating drugs in humans and may have clinical impact by facilitating the introduction of image-guided therapeutic strategies in current and future nanomedicine clinical studies. The ultimate goal is to use non-invasive imaging data to predict how much drug will be delivered to cancer tissues in specific patients, and whether the nanomedicine is reaching all the patient’s tumors in therapeutic concentrations.
Many thanks for Rafael T. M. de Rosales, the last author of the original article.
In the first published article from MSKCC (Carney, B. et al. Non-invasive PET Imaging of PARP1 Expression in Glioblastoma Models. Mol Imaging Biol 1–7 (2015)), using the nanoScan PET/MRI (1T) small animal imaging system, in vivo whole body PET/MRI imaging of [18F]PARPi in orthotopic brain tumor-bearing mice is referenced.
[18F]PARPi is a selective PARP1 imaging agent that can be used to visualize glioblastoma in xenograft and orthotopic mouse models with high precision and good signal/noise ratios offering new opportunities to non-invasively image tumor growth and monitor interventions.
Figure 6 in the article shows coronal views of contrast-enhanced MRI, [18F]PARPi PET images, and fused PET/MRI of orthotopic U251 MG tumor-bearing mice. In the top row the mouse receivied only [18F]PARPi, in the bottom row the mouse receivied [18F]PARPi after a 500-fold excess of olaparib.
The animals were injected with 200 µCi of [18F]-PARPi and a 20 minutes static PET scan was acquired 2 hours post injection. 200 µL of diluted gadopentate dimegumine in saline solution was administered intravenously one minute prior to MRI acquisition. Tumor regions were identified on anatomic images acquired using a post-contrast T-weighted spin-echo (SE) acquisition. The co-localization of [18F]PARPi and tumor in PET/MRI studies was confirmed by ex vivo autoradiography. In PET/MRI fusion images, accumulation in the tumor was co-aligned with the orthotopic tumor on MRI. In mice receiving an injection of olaparib ahead of the radiotracer, the [18F]PARPi tumor uptake was negligible.
It's important to note that no further or manual co-registration was required at all as the PET/MRI studies performed on the nanoSCan PET/MRI are co-registered by nature due to the common gantry and automated acquisition system. The very same images are displayed in the viewer when the dual-modality study is loaded from the DICOM server after reconstruction. This gives scientists confidence when evaluating multi-modal data; changing animal physiology and data obtained at different times won't distort the findings.
Coast to Coast
We were thrilled this year to announce that Mediso USA reached a major milestone with the establishment of its tenth preclinical nanoScan imaging system in North America. We are looking back this holiday season with so much appreciation for all of you in making this possible.
It was a great honor to have our first site in North America designated as a Center of Excellence for Preclinical Imaging. Many thanks to the Center for Quantitative Cancer Imaging team at the Huntsman Cancer Institute (HCI), part of the University of Utah Health Care system in Salt Lake City. We look forward to continuing our partnership into the New Year.
State of the Art
With its nanoScan PET/MRI(3T) installations dotting the globe, Mediso accepts only the best in imaging performance. As such, the nanoScan PET/MRI(3T) system features a 3T translational MR field strength combined with exceptional PET performance in a compact cryogen-free and low fringe field design, guarantying low running costs and an easy-to-use workflow.
Up and Coming
Our team is also looking forward to a major advance on our horizon. We are proud to say that 2016 will feature our first MultiScan LFER 150 PET/CT installation in the U.S. The large bore in-vivo imaging system is tuned for translational research, capable of whole-body NHP imaging. Time to plan those F220 replacements!
SfN's 45th annual meeting is the premier venue for neuroscientists to present emerging science, learn from experts, forge collaborations with peers, explore new tools and technologies, and advance careers. Neuroscience 2015 will take place October 17-21 at McCormick Place in Chicago.
Please visit us at Booth #343 where we look forward to showing you the nanoScan PET/MRI(3T), the ultimate translational imaging tool for neuroscience. You can navigate the whole floor plan at My Neuroscience Marketplace.
We're looking forward to seeing you in Chicago!
ISMRM 2015 was a nice experience, our first time as an exhibitor - introduced the nanoScan PET/MRI 3T. Compact and charming as all nanoScan product - sharing the Nucline acquisition framework, MultiCell animal handling system with other nanoScan systems. We're leaving Toronto, ON to Baltimore, MD for the SNMMI 2015 Annual Conference: http://www.medisousa.com/events/mediso-usa-at-snmmi-2015-annual-meeting.
See you at our Booth #135!
The submission deadline is May 29, 2015.
The objective of these programs is to make available to institutions expensive, commercially available research systems that cost at least $50,000 (SIG Program) or at least $600,000 (HEI Program). The maximum award is $600,000 for the SIG program and $2,000,000 for the HEI Program.
The instruments can only be justified on a shared-use basis and that are needed for NIH-supported projects in basic, translational or clinical areas of biomedical/behavioral research (description from nih.gov). The SIG Program provides funds to purchase or upgrade a single item of expensive, specialized, commercially available instrument or an integrated instrumentation system to be used for research purposes only. To promote cost effectiveness, to encourage optimal sharing among individual investigators, research groups and departments, and to foster a collaborative multidisciplinary environment, the instrument should be integrated in a centralized core facility, whenever possible.
We, Mediso USA provide support to submit a successful instrumentation grant and we are committed to supporting you throughout the grant process. Please contact us for more details.
- Shared Instrumentation Grant (SIG) Program (S10): http://grants.nih.gov/grants/guide/pa-files/PAR-15-088.html
- High-End Instrumentation (HEI) Grant Program (S10): http://grants.nih.gov/grants/guide/pa-files/PAR-15-118.html
The annual meeting of the Society for Neuroscience is ongoing with the exhibition starting tomorrow. on Sunday. We're looking forward to seeing you in Washington DC.
Please visit us at booth #711 where we look forward to showing you what’s new in the world of preclinical and translational molecular imaging.
Related to Neuroscience, especially Imaging: The list of recommended publications page was expanded again before the event: 'Positron Emission Tomography in CNS Drug Discovery and Drug Monitoring' from Piel at al published in the August 2014 issue of the Journal of Medicinal Chemistry. The article summarizes how PET can be be a valuable tool in CNS drug research and also features our nanoScan PET/MRI.
Right now, we especially offer two of our products to the interest of the Neuroscience 2014 participants for neurology research: the nanoScan PET/MRI and the MultiScan LFER 150 PET/CT.
We hope to see you on the exhibition floor.
This post summarizes the results on a research of a new Zr89 PET tracer for cell labeling. The open access article was published last month in the European Journal of Nuclear Medicine and Molecular Imaging journal:
Charoenphun, P. et al. [89Zr]Oxinate4 for long-term in vivo cell tracking by positron emission tomography. EJNMMI (2014)
The preclinical PET/CT images were acquired on a nanoScan PET/CT in vivo small animal imaging system at King’s College London.
Increasing sensitivity of cell tracking by changing labeling and detection from SPECT to PET
Cell tracking by gamma imaging with radionuclides has been performed clinically for over 30 years and is used for tracking autologous leukocytes to detect sites of infection/inflammation. The standard radiolabelling methodology has been non-specific assimilation of lipophilic, metastable complexes of indium-111 (with oxine) or technetium-99m (with HMPAO). Regenerative medicine and immune cell-based therapies are creating new roles for clinical tracking of these cells. Conventional cell radiolabelling methods have been applied for some of these cell types, but for clinical use new applications will require detection of small lesions and small numbers of cells beyond the sensitivity of traditional gamma camera imaging with In-111 or Tc-99m (e.g. coronary artery disease, diabetes, neurovascular inflammation and thrombus), creating a need for positron-emitting radiolabels to exploit the better sensitivity, quantification and resolution of clinical PET.
So far the search for positron emitting (PET) radiolabels for cells has met with limited success. The near-ubiquitous presence of glucose transporters allows labelling with [18F]-FDG but labelling efficiencies are highly variable, the radiolabel is prone to rapid efflux, and the short half-life (110 min) of F-18 allows only brief tracking. Copper-64 offers a longer (12 h) half-life and efficient cell labelling using lipophilic tracers but rapid efflux of label from cells is a persistent problem and a still longer half-life would be preferred. A “PET analogue” of In-111 oxine, capable of cell tracking over 7 days or more, would be highly desirable but is not yet available.
Zr-89 Oxine: a PET cell radiolabelling agent for long term in vivo cell tracking
This paper describes the first synthesis of Zr-89 oxine, and comparison with In-111 oxine for labelling several cell lines, human leukocytes and tracking of the cancer cell line GFP-5T33 cells in mice. The new lipophilic, metastable complex of Zr-89 can radiolabel a range of cells, independently of specific phenotypes, providing a long-sought solution to the unmet need for a long half-life positron-emitting radiolabel to replace In-111 for cell migration imaging. In addition to the expected advantages (enhanced sensitivity, resolution and quantification) of cell tracking with PET rather than scintigraphy or SPECT, Zr-89 shows less efflux from cells in vitro and in vivo than In-111. GFP-5T33 is a syngeneic murine multiple myeloma model originating from the C57Bl/KaLwRij strain, engineered to express green fluorescent protein (GFP). It was chosen for this work because the fate of the cells after i.v. inoculation is known from the literature. Intravenously injected cells migrate exclusively to the liver, spleen and bone marrow. Furthermore as the radiolabelled cells were GFP positive it was possible to validate the non-invasive images by using flow sorting of the GFP positive cells and negative cells. After flow sorting the authors were able to show that after 7 days in vivo the Zr-89 Oxine cells remained viable for the duration of the study, and that ~95% of radioactivity was present in viable GFP+ cells. The excellent in vivo survival and retention of radioactivity by the cells at 7 days, coupled with the demonstrated ability to acquire useful PET images up to 14 days, significantly extend the typical period over which cells can be tracked by radionuclide imaging with directly labelled cells.
The use of PET Zr-89 oxine for cell tracking could have a dramatic impact in the investigation of infection, inflammation and cell-based therapies in humans.
Gnad, T. et al. Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors. Nature advance online publication, (2014) Published online 15 October 2014
It’s rare when an Nature article is directly relied on in vivo imaging experiment. The ‘Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors’ article was published online in Nature on 15 October 2014. Dr. Peter Brust, Professor at Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig participated in the design and data analysis of the PET/MRI studies published in article. In his very recent talk at the EANM 2014 Mediso Preclinical User Workshop he gave the insight for the audience that molecular biology and conventional laboratory test results were actually crowned by the results of the in vivo imaging experiments performed with our nanoScan PET/MRI.
Brown adipose tissue (BAT) is specialized in energy expenditure, making it a potential target for anti-obesity therapies. However current BAT therapies based on cold exposure or B-adrenergic agonists are clinically not feasible, therefore alternative strategies has to be explored for developing new therapy possibilities. The researchers showed that adenosine activates human and murine brown adipocytes at low nanomolar concentrations. and induces browning of WAT. In the light of the world-wide obesity pandemic, activators of BAT may be potential drug targets for anti-obesity therapies and as shown here, adenosine is a previously unappreciated activator of BAT.
Adenosine role in BAT activating
Adenosine is released in BAT during stimulation of sympathetic nerves as well as from brown adipocytes. Pharmacological blockade or genetic loss of A receptors in mice caused a decrease in BAT-dependent thermogenesis, whereas treatment with A2A agonists significantly increases energy expenditure. Moreover, pharmacological stimulation of A2A receptors or injection of lentiviral vectors expressing the A receptor into white fat induced brown-like cells—so-called beige adipocytes. Importantly, mice fed a high-fat diet and treated with an A agonist are leaner with improved glucose tolerance.
The detailed analysis required a suitable animal model that mimics the response of human BAT to adenosine. The in vivo imaging results validated the original hypothesis that adenosine receptors' agonist ligands really activate the activities of brown adipose tissue.
The PET/MRI studies of BAT activation were performed on nanoScan PET/MRI (Mediso Medical Imaging Systems, Hungary) using male anaesthetized C57BL/6 WTmice. Subcutaneous injection of vehicle, noradrenaline or PSB-0777 (the A2A agonist) (both 1 mg per kg body weight) was performed one minute before intraperitoneal injection of 14.7+/-0.4 MBq of [18F]FDG. The activity in the interscapular BAT region at 75 min post injection was expressed as mean standardized uptake value.
Stimulation with noradrenaline or AAA agonist caused a significantly higher uptake of [18F]FDG compared to vehicle treatment into murine BAT as measured with positron emission tomography/magnetic resonance imaging.
Taken together, the results demonstrated that adenosine–A2A signalling plays an unexpected physiological role in sympathetic BAT activation and protects mice from high-fat diet-induced obesity. Those findings reveal new possibilities for developing novel obesity therapies. The featured Mediso nanoScan fully integrated PET/MRI system is completely mature, reliable system and installed at fifteen sites currently, including Kayvan R. Keshari, PhD lab at Memorial Sloan Kettering Cancer Center in New York City, NY.
October 18-22, Gothenburg, Sweden
Visit Mediso at booth #171 - our booth is conveniently located next to the biggest cafeteria on the exhibition floor!
The Mediso Preclinical User Workshop will be held on Monday from 1pm to 3pm. More details at the EANM 2014 Event Page.
The European Association of Nuclear Medicine (EANM) is the umbrella organisation of nuclear medicine in Europe and represents the sector towards the European Institutions. The EANM 2014 Annual Meeting will be held in Lyon, France this year in October.
WMIS released a call for Late Breaking Abstracts between June 30- July 9, 2014 for the World Molecular Imaging Congress 2014 in Seoul, Korea. The organizers will accept submissions for both oral and poster presentations. To submit your abstract, please visit http://wmis2014.abstractcentral.com/ on or after June 30.
Make sure that you include a Persuasive Data file if you would like your abstract to be considered for an oral presentation. Persuasive data should include figure captions that explain the results of the figure without requiring the reviewer to re-read the main text. Without a Persuasive Data file it is very likely that your submission won't be accepted for oral presentation.
WMIC 2014 Program Emphases are:
- • Chemistry and Imaging Probes: CT, Multimodal, MRI, Nuclear Imaging, Optical Imaging, Photo-Acoustic Imaging, Ultrasound
- • First-in-Human & Clinical Studies: Cardiology, Infectious Disease, Inflammation/Immunology, Metabolic Disease, Neurology, Oncology
- • Preclinical Cell & Tissue Level Studies: Cardiology, Cells, Infectious Disease, Inflammation/Immunology, Neurology, Oncology, Reporter Genes / Signal, Transduction & Epigenetics
- • Preclinical in vivo Studies: Cardiology, Infectious Disease, Inflammation/Immunology, Metabolic Disease, Neurology, Oncology, Reporter Genes / Signal, Transduction & Epigenetics
- • Technology and Software Developments: CT, Clinical PET/SPECT, Hybrid Multimodality, MRI, Optical Imaging, Preclinical PET/SPECT, Photo-Acoustic Imaging, Systems Biology, Ultrasound
In the field of highly sophisticated pre-clinical imaging systems we all know that it’s important to publish articles, technical validations and independent peer reviewed performance evaluation papers on instrumentation. Eventually these performance evaluation, characterization or comparison articles make their way into review articles.
The "review article" is one of the most useful tools available for individuals who need to research a certain topic in the rapidly expanding body of scientific literature. According to Huth  a "well-conceived review written after careful and critical assessment of the literature is a valuable document” and it spares time for researchers to keep abreast of all published information. A review article should provide a critical appraisal of the subject.
It is extremely difficult to compare the performance of two imaging systems from different vendors if there is no standardized methodology that is independent of the camera design. Such a methodology should be applicable to a wide range of camera models and geometries. Fortunately for the Primary Investigators there is a NEMA standard publication for performance measurements of small animal positron emission tomographs (NEMA Standards Publication NU 4-2008 ) since 2008.
I myself have an engineering background and I’m always astonished how creatively sales people can distort the reality (i.e. numbers) in their marketing materials. I started an excel sheet back in 2007 by filling out numerous specifications for every small animal PET systems, either commercial or academic, when we started the design of our nanoScan small animal PET system at Mediso. Currently it lists about 40 pre-clinical systems including variants (while most of them are now obsolete or discontinued, such as the the Siemens Inveon). As part of my position I closely follow the published performance evaluation and review articles.
Balancing a system design is very delicate question – sensitivity and resolution do not walk hand in hand and it’s easy to get lost in the quagmire of different parameters: ultimately the detector design, the basic parameters and image characteristics together define the image quality. Also the image quality of a certain measurement series does not say anything about reproducibility, long term imaging performance, usability and feature sets.
Review of Review Article
My particular problem with instrumentation review articles is that they usually have a limited/selected subset of parameters which subconsciously (or consciously as I will give the benefit of doubt here) can lead to distortion of the reality. My apologies to the authors of the article by Kuntner & Stout, but this latest review article for preclinical PET imaging and may serve as example . It is a really good article and lists various factors affecting the quantification accuracy of small PET systems. It’s a recommended article to read!
In the first table it shows the characteristics of preclinical PET scanners (visit to the link to view the original table)
The article was published on 28 February 2014, and was originally received on 27 November 2013. It references the Mediso’s microPET system based on an article from JNM 2011 . However the performance evaluation of our next generation nanoScan PET was published online on August 29, 2013 in JNM . Fortunately Spinks and his colleagues published a new paper on the quantitative performance of Albira PET with its largest axial FOV variant in February 2014 , so the Albira’s characteristics won’t be distorted – their ‘flagship’ variant is also listed. Lack of access to projection data by the researchers, the standard NEMA procedure could not be used for some of their measurements (e.g. sensitivity, scatter fraction, noise-equivalent counts).
Updated comparison table
So let’s include the updated characteristics in our new table and have a closer look on the parameters.
My problems with the original Table 1 in :
- The ‘ring diameter’ was listed in the comparison table, which is quite non-relevant unless you want disassemble the system. It’s much more useful to list the bore diameter and the transaxial FOV. The bore diameter shows how wide object you can stick into the system, while the transaxial FOV shows that actually where you will collect data from!
- The resolution values listed are not comparable– some of them were listed according to the NEMA NU-4 2008 standard performed with SSRB+FBP (e.g. Inveon), and some of them with iterative reconstruction methods like OSEM (e.g. Genisys4). The pre-clinical PET NEMA standard allows only the usage of the filtered back projection reconstruction method to measure the resolution. More importantly the results have to show the values in all directions: in the transverse slice in radial and tangential directions and additionally the axial resolution shall be measured across transverse slices at 5, 10, 15 and 25 mm radial distances from the center. Example from :
Currently based on the published literature the nanoScan PET subsystem from Mediso delivers the best resolution values for the NEMA NU-4 2008 measurements – even without using the sophisticated 3D Tera-Tomo Reconstruction engine. Based on the original article the reader may derive the false conclusion that the Genisys4 PET delivers the best resolution – while it’s hardly the situation. The FBP recon values had not been published for Genisys4 so far.
- The 2D FBP recon provides comparable information on the detector design, but not the system performance! The advanced 3D iterative reconstruction methods allow to incorporate lot of corrections and they provide better spatial resolution, image characteristics – if used properly. Let’s call these resolution values performed by ‘advanced’ reconstruction methods ‘claimed by manufacturer’ values.
- Please always pay attention to the energy window setting when comparing sensitivity values!
This is general remark for almost all review articles on preclinical PET systems with the exception of JNM article from Goertzen et al .
If I’d be interested in the acquisition of a capital equipment, which will be used for at least 10 years, I wanted to see not the peak sensitivity value of the system. This sensitivity is valid usually only in one position – in the radial and transaxial center of the field-of-view. In reality the standard imaged objects are mice, rats and other species, and not point- or line sources. The NEMA standard does contain a method of sensitivity measurement and evaluation for mouse and rat applications which encompass the central 7 cm and 15 cm axial extent. The problem is in practice that these parameters are not listed in the articles for most of the systems – while it’s a really useful value.
In the literature sensitivity values for mouse-sized region are listed only for 3 small animal PET systems: Albira, Inveon and nanoScan. For rat-sized object you can find value only for the Mediso’s system.
The Truth Lies in the Details.
- Edward J. Huth, How to Write and Publish Papers in the Medical Sciences (Williams & Wilkins, 1990).
- National Electrical Manufacturers Association. NEMA Standard Publication NU 4-2008: Performance Measurements of Small Animal Positron Emission Tomographs. Rosslyn, VA: National Electrical Manufacturers Association; 2008
- Claudia Kuntner and David B. Stout, “Quantitative Preclinical PET Imaging: Opportunities and Challenges,” Biomedical Physics 2 (2014): 12, doi:10.3389/fphy.2014.00012. http://journal.frontiersin.org/Journal/10.3389/fphy.2014.00012/full
- Istvan Szanda et al., “National Electrical Manufacturers Association NU-4 Performance Evaluation of the PET Component of the NanoPET/CT Preclinical PET/CT Scanner,” Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine 52, no. 11 (November 2011): 1741–47, doi:10.2967/jnumed.111.088260. http://jnm.snmjournals.org/content/52/11/1741.long
- Kálmán Nagy et al., “Performance Evaluation of the Small-Animal nanoScan PET/MRI System,” Journal of Nuclear Medicine, October 1, 2013, jnumed.112.119065, doi:10.2967/jnumed.112.119065. http://jnm.snmjournals.org/content/early/2013/08/26/jnumed.112.119065
- T. J. Spinks et al., “Quantitative PET and SPECT Performance Characteristics of the Albira Trimodal Pre-Clinical Tomograph,” Physics in Medicine and Biology 59, no. 3 (February 7, 2014): 715, doi:10.1088/0031-9155/59/3/715. http://iopscience.iop.org/0031-9155/59/3/715
- Qinan Bao et al., “Performance Evaluation of the Inveon Dedicated PET Preclinical Tomograph Based on the NEMA NU-4 Standards,” Journal of Nuclear Medicine 50, no. 3 (2009): 401–8. http://jnm.snmjournals.org/content/50/3/401.short
- Andrew L. Goertzen et al., “NEMA NU 4-2008 Comparison of Preclinical PET Imaging Systems,” Journal of Nuclear Medicine 53, no. 8 (2012): 1300–1309. http://jnm.snmjournals.org/content/53/8/1300.short
- Stephen Adler, Jurgen Seidel, and Peter Choyke, “NEMA and Non-NEMA Performance Evaluation of the Bioscan BioPET/CT Pre-Clinical Small Animal Scanner,” Society of Nuclear Medicine Annual Meeting Abstracts 53, no. Supplement 1 (May 1, 2012): 2402. http://jnumedmtg.snmjournals.org/cgi/content/meeting_abstract/53/1_MeetingAbstracts/2402
- Ken Herrmann et al., “Evaluation of the Genisys4, a Bench-Top Preclinical PET Scanner,” Journal of Nuclear Medicine, July 1, 2013, doi:10.2967/jnumed.112.114926. http://jnm.snmjournals.org/content/early/2013/04/29/jnumed.112.114926
- F. Sánchez et al., “Small Animal PET Scanner Based on Monolithic LYSO Crystals: Performance Evaluation,” Medical Physics 39, no. 2 (2012): 643, doi:10.1118/1.3673771. http://link.aip.org/link/MPHYA6/v39/i2/p643/s1&Agg=doi
Development of dual-modality, aluminium hydroxide stabilised magnetic nanoparticles probes is published in the Biomaterials 2014 July issue. The main author of the article titled ‘Aluminium hydroxide stabilised MnFe2O4 and Fe3O4 nanoparticles as dual-modality contrasts agent for MRI and PET imaging’  is Dr. Xianjin Cui, member of Philip Blower’s group at King's College London, Division of Imaging Sciences and Biomedical Engineering. The article is a collaboration between researchers from King’s College London (UK), Nottingham University (UK), Aston University (UK), CROmed Ltd. (Hungary). This is an open access article. Download the Article in PDF, Appendix A in Word.
Superparamagnetic nanoparticles (NPs) have been intensively investigated due to their potential applications in biosensors, targeted drug develivery, MRI and localised hyperthermia induction. The problem with these nanoparticles is that they tend to aggregate to minimize the surface energy. Bio-applications require colloidal stability and dispersibility in water and biological environments. There are several methods described in the literature to obtain stable colloids of magnetic nanoparticles. A simple approach is presented in the article to stabilise magnetic nanoparticles by coating them with an Al(OH)3 layer via a hydrolysis process for conjugation. The use of an inorganic shell material introduces stability, functionality (nanoparticle recognised by the macrophage-monocytic system) and water-solubility. The materials, general characterisation, synthesis and radiolabelling are described in the article.
in vivo PET/MR imaging
What is interesting for our blog is that for in vivo PET/MR imaging of the agents on mice were performed on the integrated nanoScan preclinical PET/MRI imaging system installed at the Nanobiotechnology & In Vivo Imaging Center, Semmelweis University in Budapest, Hungary.
The total injected F-18 activity was 0.95 MBq (25.7 microCi). PET scanning was started immediately after injection and continued for 120 min. Acquisition took place in 1–5 coincidence mode with 5 ns coincidence window, 400–600 keV energy window. MR scanning was performed immediately after PET. A 3D expectation maximisation (3D EM) PET reconstruction algorithm (Mediso Tera-Tomo™) was applied to produce PET images including corrections for attenuation and scatter, dead time, decay and randoms. After 8 iterations the reconstruction stopped resulting in images with 0.1 mm voxel size and time frames of 8 × 15 min. The images of the two modalities were fused automatically.
The PET/MRI fused image is presented in the Appendix A. of the article. The injected activity was only 0.95 MBq (25.7 microCi) and the PET images show only 15 minutes of acquisition!
In vivo PET/MRI images of a normal young C57BL/6 mouse using 18F radiolabelled 3: (a) whole body PET image showing distribution of 18F 30 minutes post injection (maximum intensity projection, mice in prone position); (b) PET/MRI fused image (coronal section, 0-15 minutes); (c) PET/MRI fused image (coronal section, 105-120 minutes); (d) MR image prior to the injection of NPs, and (e) MR image post the injection of NPs, showing a darkening contrast at lung and live area. Due to the unstable Al(OH)3 shell, 18F-fluoride radioactivity was released from magnetic NPs 3 within 15 minutes and localised in bone.
The reconstruction features the TeraTomo algorithm's latest version which will be available for all our sites this autumn. In our opinion it is hard to get better bone images nowadays with PET for such a low injected activity than it’s featured in this article. Funnily enough noone intended to make bone images as this is a proof that the radiolabel went off from the nanoparticles and trapped in bones of the mouse. Remember, this is not a F-18 flouride bone scan! The ‘grainy’ PET image isn't the result of any regularization issue – this represents the real uneven flour uptake in the bones. You can notice the anatomical features of the knee joint – the patella, condyles of femur can be distinguished as well!
Read more about the integrated, automated small animal whole-body PET/MRI system.
 Cui, X. et al. Aluminium hydroxide stabilised MnFe2O4 and Fe3O4 nanoparticles as dual-modality contrasts agent for MRI and PET imaging. Biomaterials doi:10.1016/j.biomaterials.2014.04.004
This year the SNMMI Annual Meeting will take place in St. Louis, MO, from June 7-11, 2014.
We all know that Washington University in St. Louis has a special place in the history of nuclear medicine. The first “in hospital” cyclotron in the United States was run by physicist Michel Ter-Pogossian in 1965. Positron emission tomography (PET) was developed at the Mallinckrodt Institute of Radiology in the early 1970s, and the first human PET study was acquired in April 1974. Mike Phelps and Ed Hoffman of Washinton University built the system with the group at EG&G ORTEC, included James Kelly Milam, Charles W. Williams, Terry D. Douglass and Ronald Nutt. PET III was composed of 48 NaI(Tl) detectors was a hexagonal array with excellent sampling by a combination linear movement of detectors and a 60-degree rotation of the gantry. The system had its own computer for controlling the motion of the detectors, gantry and bed, as well as performing image reconstruction.
Today the Institute is the world's only medical facility equipped with three dedicated cyclotrons for the production of radiopharmaceuticals used in PET studies.
Also I’ve got some personal connection with WashU – I serviced one of the first NanoSPECT/CT systems in the US at the University in the Spring 2007. During this time I was responsible for the NanoSPECT/CT development at Mediso and the system was even new for the service engineers. Needless to say I’m looking forward again to visit St. Louis! I haven’t been back in the town since then.
Related to the SNMMI Annual Meeting we will have some ad in the JNM Digital Newsline. The mouse image was taken at Charité University Medicine Berlin, Berlin, Germany on their nanoScan PET/MRI.
If you participate at the congress, please stop by Booth 1421 on the SNMMI Exhibition Floor. We have quite a few highlights to make a visit worth your while. The following systems will be demonstrated: nanoScan SPECT/MRI, PET/MRI from the preclinical line and CardioDESK, AnyScan S from the human product line. Stop by our booth at this important event for a good discussion or a friendly chat. We will also hand over invitations for our Sunday evening reception at the booth. You also get a quick product training so that you have a fast time to value.
VivoQuant™ platform for image viewing and analysis 1.23 was released last week by inviCRO.
The VivoQuant™ application is bundled with our nanoScan small animal in vivo imaging systems and software updates are provided for customers with Mediso USA service contracts. As an Imaging Service contract holder, our users not only have access to service and support, but receive the additional capabilities such us upgrading their InVivoScope or VivoQuant software to the new releases.
VivoQuant 1.23 introduces new and improved features, including:
- New Whole Body Atlas Segmentation Tool,
- Deformable Registration Tool,
- Modeling Operator with GLM and Tracer-kinetic Based Modeling,
- Expanded VivoScript Capabilities with New Example Scripts,
- Upgraded 3D ROI Tool with Enhanced Functionality,
- Improved 3D Image Rendering,
- Integration of the Registration / Reorientation Tool with the 3D ROI Tool,
- Improved MR/CT/PET/SPECT Atlas-based Brain Segmentation Plugin - (Sub-region Volume, Signal, fMRI).
To upgrade your VivoQuant version, please go to Tools|Update Check in the software menu or download directly from the VivoQuant website.
Six white CD-1 mice are scurrying through the litter in their cage, climbing the metal bars, nibbling away at the pellets they are being fed, and snuggling with each other. What they don't yet know is they're about to participate in a pivotal study. One that will save lives - those of mice and, one day, of men. As part of his dissertation, Mathias Kranz, Ph.D. student at the HZDR Research Site Leipzig, is currently investigating the degree of radioactivity that builds up within the bodies of mice whenever radioactive probes - called radiotracers - are used, and identifying in which organs specifically it accumulates. Eventually, these data will be extrapolated to the human magnitude. Radiotracers are chemical compounds that include a radioactive element of some sort, which can help scientists observe metabolic processes in living organisms.
Specifically, in the case of the Leipzig project, we're talking about the two radiotracers [18F]fluspidine and [18F]flubatine - both of them molecules containing the radionuclide 18F (fluorine). They're supposed to ultimately find their way into the diagnostics of cancers and neurodegenerative diseases like Alzheimer's. Key is their ability to imitate properties of various endogenous structures.
Before a radioactive probe is ready for use in the hospital setting, its efficacy and safety must first be documented in living organisms.
Once injected into the human body, they bind with high affinity to certain targets - in the case of the "PET sugar" [18F]FDG, which is also used at the Leipzig site, highly metabolically active tissues like tumors. The emitted radiation from the radioactive molecules can be captured and subsequently analyzed using positron emission tomography (PET). However, before a radioactive tracer can be introduced into the hospital setting, its efficacy and safety to the living organism must first be confirmed. This is a prerequisite imposed by the German Federal Office for Radiation Protection (BfS) and the Federal Institute for Drugs and Medical Devices (BfarM). This multistep procedure starts with work on mice and occasionally pigs and ultimately leads to research conducted on healthy human subjects. Here, the HZDR scientists are receiving support from their colleagues at the Clinic for Nuclear Medicine at Leipzig University Hospital.
Leipzig as reference site
As of spring 2013, when operations by experienced colleagues at the HZDR main site Dresden first commenced, Germany's first-ever commercial full-body PET/MRI for small animals opened in Leipzig - one of only a few worldwide. The HZDR is the reference site for Hungarian manufacturer Mediso (Budapest) - which brings with it a number of obvious benefits: "There are still a handful of delayed-onset childhood illnesses but whenever we do report any problem, help typically arrives within a matter of hours," Mathias Kranz explains. The 27-year-old fellow, who holds a master's in engineering, studied biomedical technology at Ilmenau University of Technology, and has been working at the HZDR Institute of Radiopharmaceutical Cancer Research for about a year now. He is thrilled with the new device: "Not only does it allow us to obtain information about metabolic processes that are happening inside the body, it also yields high-resolution three-dimensional images that document the exact location and distribution of soft tissues." especially when it comes to brain imaging, MR devices yield far better results than conventional PET and computer tomography (CT) combinations.
The mice remain safe
"Without these methods, we would need to dissect the animal subjects, remove individual organs, and then measure them in order to determine the degree of radioactivity that has accumulated in the body following injection of the radiotracer. What's interesting is not only the current dose rate but also how it changes over the course of minutes and hours, which helps determine the organ dose. Thanks to PET/MRI, we're able to conduct even long-term studies using the same exact mouse," Mathias Kranz explains. In the case of other methods, one laboratory animal has to be sacrificed each time a single measurement is obtained.
During examination, the mice are lying on a heated animal bed, their breathing monitored with the help of a pressure sensor. The radioactively labeled substance is injected into the tail vein. The mice are fully anesthetized and won't remember anything afterwards. On a screen, Mathias Kranz is now examining a black and grey image showing the inside of the mouse's body. Red, yellow, and blue spots are lighting up in certain body regions. "Red means these are sites where there is a high degree of radioactivity, in other words that a lot of our substance was deposited in these places," the young scientist explains. At first glance, the liver, kidneys, and bladder are easily recognized - organs, which are actively involved in the substance's elimination from the body.
After the experiments are done, Mathias Kranz calculates the expected effective human dose. This serves as a risk-assessment at the time of introducing the probes into the clinical setting. Based on their results, the researchers have filed for approval of a study with the BfS for use of their newly developed radiotracers (+)-[18F]flubatine and (S)-(-)-[18F]fluspidine in humans. The scientists are working closely with their colleagues at Leipzig University Hospital, Department of Nuclear Medicine, on these projects. The projected start date is early 2014.
Hyperpolarized 13C imaging approach increases the MR signal more than 20,000 times for studying real-time metabolism of disease. Metabolic MRI with hyperpolarized agents shows promise by helping support the differentiation of benign and malignant lesions, separating aggressive from slow-growth tumors and facilitating non-invasive treatments.
The Need for Speed
Molecular Imaging describes techniques that directly or indirectly visualize, characterize, and measure the distribution of molecular or cellular processes at the molecular and cellular levels in humans and other living systems.
The most suitable modalities for small-animal in vivo imaging applications are based on nuclear medicine techniques (essentially, positron emission tomography [PET] and single photon emission computed tomography [SPECT]), optical imaging (OI), computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance spectroscopy imaging (MRSI), and ultrasound.
Conventional magnetic resonance imaging (MRI) relies on magnetic resonance (MR) signal from proton nuclei of water within the body. The MR signal is encoded with magnetic field gradients for 2D and 3D imaging with no fundamental barriers to spatial resolution as long as sufficient MR signal is available.MRI provides excellent contrast and spatial resolution without radiation exposure - however one limitation of MRI in particular is low sensitivity, especially when compared to PET or SPECT.
Hyperpolarization may address this problem by polarizing spins of a nucleus by several orders of magnitude that seen at thermodynamic equilibrium. However this technique practically doesn't work in water, because spins return back to their equilibrium state, i.e. very low polarization, within seconds. 3He, 13C, 15N, 129Xe and other nuclear spins can be hyperpolarized to the order of near unity resulting in signal enhancement by 4-6 orders of magnitude. Moreover, the decay of their hyperpolarized spin state can be as long as several hours - making useful chemical compounds as hyperpolarized contrast agents. These agents are prepared by physical and/or chemical manipulations followed by administration of these contrast agents in living organisms and their MRI or MRSI imaging.
Hyperpolarized (HP) 129Xe and 3He have been achieved by optical pumping, with potential for low-radiation imaging of the lungs. For nuclei found in endogenous molecules (in particular carbon and nitrogen), the dynamic nuclear polarization (DNP) technique has emerged as a way to polarize small-molecule metabolites. Briefly, 13C-labeled molecules, doped with small quantities of a stable radical, are cooled to approximately 1 K in a magnetic field; microwave irradiation transfers polarization from the fully polarized electron spins on the radical to the 13C nuclei. The sample is then rapidly dissolved using a hot pressurized solution, which can be injected into an animal (or human) in a separate imaging magnet.
Opening the fourth dimension by Chemical Shift Imaging
This approach increases the MR signal more than 20,000 times, thus increasing the biological sensitivity of hyperpolarized MR imaging. Hyperpolarized contrast agents are similar to radioactive tracers in that their signal- generating capability decays exponentially with time - similar to SPECT and PET tracers. The dramatic signal enhancements obtained allow not only the detection of the introduced metabolic agent, but also its metabolic products in real-time. This enabled by magnetic resonance spectroscopic imaging (MRSI) offering the fourth dimension of chemical shift reporting on composition of tissue, i.e. imaging of protons of metabolites in tumors, cardiac tissue and brain, in addition to three spatial dimensions. Its biggest application so far has been in imaging the glucose consumption in tumors — glucose and lactate for the localization of benign and malignant prostate cancer. this concept has a lot of potential for other kinds of metabolic applications, too, most notably diabetes imaging.
Despite signal boost by several orders of magnitude, hyperpolarized MRI relies on signal from relatively dilute spins of administered hyperpolarized contrast agents. For example, hyperpolarized 13C-lactate concentration in vivo is on the order of a few mM, which is several orders of magnitude lower than proton concentration of tissue water. As a result, SPECT and PET are inherently significantly more sensitive (by orders of magnitude) imaging modalities when accounting for contrast agent quantity. When comparing hyperpolarized MRI to PET imaging, it should also be noted that the vast majority of hyperpolarized contrast agents have significantly shorter lifetime on the order, of 0.5-5 minutes in vivo. This double-edged sword limits the use of hyperpolarized contrast agents from the perspective of metabolic pathways penetration, contrast agent in vivo delivery, pharmaceutical preparation and imaging site distribution. On the other hand, it offers an opportunity to perform a repeat scan within minutes after initial hyperpolarized scan, because there is no background signal from the first initially administered dose.
Bringing it into one system
PET/MR imaging is just a phenomenal tool — it combines two very strong technologies. This field however opens even more new opportunities by potentially combining the power of molecular imaging of hyperpolarized MRI and high sensitivity PET. While the main advantage of hyperpolarized MRI is the large sensitivity boost enabled by increased nuclear spin polarization, this increase is not endowed by the magnetic field of the MRI scanner. As a result, it is possible to perform MRI of hyperpolarized contrast agents in very low magnetic fields. The nanoScan PET/MRI is equipped with a permanent 1T magnet which is seamlessly integrated and automated into the equipment. Our advantage is the inherently low cost maintenance, because the need for a high-field cryogenic magnet is eliminated and also no other site preparation and supportive maintenance, like water cooling is required. The combination of low cost and sub-second scan speed is a clear advantage.
The hyperpolarized MRI is and emerging and quickly developing field, however its importance can assessed by the increasing number of published articles and presentations on conferences. Recently a review article was published on 13C hyperpolarized magnetic resonance using dynamic nuclear polarization in Chemical Society Reviews written by Kayvan R. Keshari and David M. Wilson.
- Keshari, Kayvan R., and David M. Wilson. "Chemistry and Biochemistry of 13C Hyperpolarized Magnetic Resonance Using Dynamic Nuclear Polarization." Chemical Society Reviews 43, no. 5 (February 10, 2014): 1627–59. doi:10.1039/C3CS60124B.
- Gallagher, Ferdia A., Sarah E. Bohndiek, Mikko I. Kettunen, David Y. Lewis, Dmitry Soloviev, and Kevin M. Brindle. "Hyperpolarized 13C MRI and PET: In Vivo Tumor Biochemistry." Journal of Nuclear Medicine 52, no. 9 (September 1, 2011): 1333–36. doi:10.2967/jnumed.110.085258.
- Chekmenev, Eduard Y. MRI "Hyperpolarization and Molecular Imaging" mi Gateway, Newsletter of the SNMMI CMIIT, Vol. 7, Issue 3, 2013-3
The suggested reading list was actually used to prepare this post. This was an introductory post in the realm of HP MRI imaging - hope you enjoyed it.