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1.  FIAU: From reporter gene imaging to imaging of bacterial proliferation 
The radioiodinated thymidine analogue, FIAU, is a tracer that has been developed for reporter gene, for cells that were transfected with herpes simplex virus thymidine kinase, HSV-TK. FIAU is also a specific substrate of bacterial TK due to the homology between viral and bacterial TK. In this issue of AJNMMI (http://www.ajnmmi.us), Pullamb-hatla et al. reported that the accumulation of 125I-FIAU in pulmonary infectious foci correlated with the bacterial burden in the lungs. 125I-FIAU could be used to monitor the efficacy of anti-microbial therapy in mice. Potentially 124I-FIAU PET could be used to discriminate microbial from sterile inflammation in patients with prosthetic implants.
PMCID: PMC3477741  PMID: 23133817
Infection; inflammation; reporter gene imaging; positron emission tomography (PET)
2.  Synthesis and evaluation of 68Ga-labeled DOTA-2-deoxy-D-glucosamine as a potential radiotracer in μPET imaging 
The purposes of this study were to develop an efficient method of labeling D-glucosamine hydrochloride with gallium 68 (68Ga) and investigate the imaging properties of the resulting radiotracer in a human tumor xenograft model using micro-positron emission tomography (μPET). The precursor compound 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-2-deoxy-D-glucosamine (DOTA-DG) was synthesized from D-glucosamine hydrochloride and 2-(4-isothiocyanatobenzyl)-DOTA. Radiolabeling of DOTA-DG with 68Ga was achieved in 10 minutes using microwave heating. The labeling efficiency a nd radiochemical purity after purification of 68Ga-DOTA-DG were ~85% and greater than 98%, respectively. In A431 cells, the percentages of 68Ga-DOTA-DG and 18F-FDG uptakes after 60 min incubation were 15.7% and 16.2%, respectively. In vivo, the mean ± standard deviation of 68Ga-DOTADG uptake values in A431 tumors were 2.38±0.30, 0.75±0.13, and 0.39±0.04 percent of the injected dose per gram of tissue at 10, 30, and 60 minutes after intravenous injection, respectively. μPET imaging of A431-bearing mice clearly delineated tumors at 60 minutes after injection of 68Ga-DOTA-DG at a dose of 3.7 MBq. 68Ga-DOTA-DG displayed significantly higher tumor-to-heart, tumor-to-brain, and tumor-to-muscle ratios than 18F-FDG did. Further studies are needed to identify the mechanism of tumor uptake of this new glucosamine-based PET imaging tracer.
PMCID: PMC3484416  PMID: 23145365
Gallium 68; 2-deoxy-D-glucose; μPET imaging; microwave heating-assisted synthesis
3.  Ready for prime time? Dual tracer PET and SPECT imaging 
Dual isotope single photon emission computed tomography (SPECT) and dual tracer positron emission tomography (PET) imaging have great potential in clinical and molecular applications in the pediatric as well as the adult populations in many areas of brain, cardiac, and oncologic imaging as it allows the exploration of different physiological and molecular functions (e.g., perfusion, neurotransmission, metabolism, apoptosis, angiogenesis) under the same physiological and physical conditions. This is crucial when the physiological functions studied depend on each other (e.g., perfusion and metabolism) hence requiring simultaneous assessment under identical conditions, and can reduce greatly the quantitation errors associated with physical factors that can change between acquisitions (e.g., human subject or animal motion, change in the attenuation map as a function of time) as is detailed in this editorial. The clinical potential of simultaneous dual isotope SPECT, dual tracer PET and dual SPECT/PET imaging are explored and summarized. In this issue of AJNMMI (http://www.ajnmmi.us), Chapman et al. explore the feasibility of simultaneous and sequential SPECT/PET imaging and conclude that down-scatter and crosstalk from 511 keV photons preclude obtaining useful SPECT information in the presence of PET radiotracers. They report on an alternative strategy that consists of performing sequential SPECT and PET studies in hybrid microPET/SPECT/CT scanners, now widely available for molecular imaging. They validate their approach in a phantom consisting of a 96-well plate with variable 99mTc and 18F concentrations and illustrate the utility of such approaches in two sequential SPECT-PET/CT studies that include 99mTc-MAA/18F-NaF and 99mTc-Pentetate/18F-NaF. These approaches will need to be proven reproducible, accurate and robust to variations in the experimental conditions before they can be accepted by the molecular imaging community and be implemented in routine molecular microPET and microSPECT explorations. Although currently not accepted as standard procedures in the molecular imaging community, such approaches have the potential to open the way to new SPECT/PET explorations that allow studying molecular mechanisms and pathways in the living animal under similar physiological conditions. Although still premature for the clinical setting, these approaches can be extended to clinical research once proven accurate and precise in vivo in small and large animal models.
PMCID: PMC3484417  PMID: 23145358
Dualisotope; dual tracer; positron emission tomography (PET); single photon emission tomography (SPECT); quantitative imaging
4.  18F-Deoxyglucose (FDG) kinetics evaluated by a non-compartment model based on a linear regression function using a computer based simulation: correlation with the parameters of the two-tissue compartment model 
Parametric imaging with a linear regression function of the tracer activity curve fit is a non-compartmental method, which can be used for the evaluation of dynamic PET (dPET) studies. However, the dependency of the slope of the regression function fit on the 18F-Deoxyglucose (FDG) 2-tissue compartment parameters (vb, k1-k4) is not known yet. This study is focused on the impact of the 2-tissue compartment parameters on the slope of the curve. A data base of 1760 dynamic PET FDG studies with the corresponding 2-tissue compartment model parameter solutions were available and used to calculate synthetic time-activity data based on the 2-tissue compartment model. The input curve was calculated from the median values of the input curves of the 1760 dynamic data sets. Then, sequentially each of the five parameters (vb, k1-k4) of the 2-tissue compartment model was varied from 0.1 to 0.9 and tracer activity curves were calculated (60000 curves/parameter). A linear regression function was fitted to these curves. The comparison of the slope values of the regression function with the corresponding compartment data revealed a primary dependency on k3, which is associated with the intracellular phosphorylation of FDG. The squared correlation coefficient was high with r2=0.9716, which refers to 97 % explained variance of the data. k2 and vb had only a minor impact, while k1 and k4 had no impact on the slope values. The results demonstrate, that k3 has a major impact on the slope values calculated by the linear regression function.
PMCID: PMC3484418  PMID: 23145361
FDG; non-compartment model; parametric imaging
5.  Dual tracer imaging of SPECT and PET probes in living mice using a sequential protocol 
Over the past 20 years, multimodal imaging strategies have motivated the fusion of Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) scans with an X-ray computed tomography (CT) image to provide anatomical information, as well as a framework with which molecular and functional images may be co-registered. Recently, pre-clinical nuclear imaging technology has evolved to capture multiple SPECT or multiple PET tracers to further enhance the information content gathered within an imaging experiment. However, the use of SPECT and PET probes together, in the same animal, has remained a challenge. Here we describe a straightforward method using an integrated trimodal imaging system and a sequential dosing/acquisition protocol to achieve dual tracer imaging with 99mTc and 18F isotopes, along with anatomical CT, on an individual specimen. Dosing and imaging is completed so that minimal animal manipulations are required, full trimodal fusion is conserved, and tracer crosstalk including down-scatter of the PET tracer in SPECT mode is avoided. This technique will enhance the ability of preclinical researchers to detect multiple disease targets and perform functional, molecular, and anatomical imaging on individual specimens to increase the information content gathered within longitudinal in vivo studies.
PMCID: PMC3484419  PMID: 23145357
Dual tracer imaging; trimodal imaging; Positron Emission Tomography (PET); Single Photon Emission Computed Tomography (SPECT); X-ray Computed Tomography (CT); nuclear imaging
6.  Radiolabelled probes for imaging of atherosclerotic plaques 
Cardiovascular disease is the leading cause of death worldwide. Unstable atherosclerotic plaques are prone to rupture followed by thrombus formation, vessel stenosis, and occlusion and frequently lead to acute myocardial infarction and brain infarction. As such, unstable plaques represent an important diagnostic target in clinical settings and the specific diagnosis of unstable plaques would enable preventive treatments for cardiovascular disease. To date, various imaging methods such as computed tomography (CT), magnetic resonance imaging (MRI), ultrasound (US), and intravascular ultrasound (IVUS) have been widely used clinically. Although these methods have advantages in terms of spatial resolution and the ability to make detailed identification of morphological alterations such as calcifications and vessel stenosis, these techniques require skill or expertise to discriminate plaque instability, which is essential for early diagnosis and treatment and can present difficulties for quantitative estimation. On the other hand, nuclear imaging techniques such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) can noninvasively collect quantitative information on the expression levels of functional molecules and metabolic activities in vivo and thus provide functional diagnoses of unstable plaques with high sensitivity. Specifically, unstable plaques are characterized by an abundance of invasive inflammatory cells (macrophages), increased oxidative stress that increases oxidized LDL and its receptor expressed on cells in the lesions, increased occurrence of apoptosis of macrophages and other cells involved in disease progression, increased protease expression and activity, and finally thrombus formation triggered by plaque rupture, which is the most important mechanism leading to the onset of infarctions and ischemic sudden death. Therefore, these characteristics can all be targets for molecular imaging by PET and SPECT. In this paper, we review the present state and future of radiolabelled probes that have been developed for detecting atherosclerotic unstable plaques with nuclear imaging techniques.
PMCID: PMC3484420  PMID: 23145360
Molecular imaging; atherosclerosis; plaque; positron emission tomography; single photon emission computed tomography; 2-[18F]Fluoro-2-deoxy-D-glucose; lectin-like oxidized low density lipoprotein receptor-1; apoptosis; matrix metalloproteinase; thrombus
7.  Non-invasive imaging of PI3K/Akt/mTOR signalling in cancer 
Platinum based drugs are widely used to treat various types of cancers by inducing DNA damage mediated cytotoxicity. However, acquirement of chemoresistance towards platinum based drugs is a common phenomenon and a major hurdle in combating the relapse of the disease. Oncogenesis and chemoresistance are multifactorial maladies which often involve deregulation of one of the prime cell survival pathways, the PI3K/Akt/mTOR signalling cascade. The genetic alterations related to this pathway are often responsible for initiation and/or maintenance of carcinogenesis. Molecular components of this pathway are long being recognized as major targets for therapeutic intervention and are now also have emerged as potential tools for diagnosis of cancer. To develop novel therapeutics against the key molecules of PI3K pathway, stringent validation is required using both in-vitro and in-vivo models. Repetitive and non-invasive molecular imaging techniques, a relatively recent field in biomedical imaging hold great promises for monitoring such diagnosis and therapy. In this review, we first introduced the PI3K/Akt/mTOR pathway and its role in acquirement of chemoresistance in various cancers. Further we described how non-invasive molecular imaging approaches are sought to use this PI3K signalling axis for the therapeutics and diagnosis. A theranostic approach using various imaging modalities should be the future of PI3K signalling based drug development venture.
PMCID: PMC3484421  PMID: 23145359
PI3K signalling; platinum based chemoresistance; repetitive and non-invasive molecular imaging techniques; PET imaging; bioluminescence imaging; Akt sensor; fluorescence imaging
9.  18F-DOPA PET with and without MRI fusion, a receiver operator characteristics comparison 
This study is a retrospective analysis of the diagnostic accuracy of FDOPA PET with MRI fusion to FDOPA PET without MRI fusion. Clinical FDOPA PET scans obtained between 2000 and 2008 at the University of Wisconsin Hospital and Clinics were assessed using measures derived from regions of interest (ROI) generated with fused MRI (fused group) and again with ROIs derived solely from PET data (non-fused groups). The ROIs were used to calculate ratios (Striatum/Occipital cortex, Striatum/Cerebellum) pertinent to Parkinson’s disease (PD) pathology. The clinical records were assessed for demographic data, follow-up length, and diagnosis. Receiver Operator Characteristics with area under the curve (AUC) measures were calculated and compared using confidence intervals and hypothesis testing. 27 patients had FDOPA PET with median clinical follow-up of 4 years. Of these, 17 patients had FDOPA PET with a fusible MR image. Seven of the 27 had a non-PD movement disorder. AUCs for the ratio measures ranged from 0.97-1.0 (fused), 0.73-0.83 (non-fused), and 0.63-0.82 (matched non-fused). The fused images had improved accuracy compared to the matched non-fused and all non-fused groups for the striatum to occipital group (p=0.04, p=0.03), while the striatum to cerebellum ratio had improvement over the non-fused all group (p=0.041). MR fusion to FDOPA PET improves the accuracy of at least some measures (Striatum/Occiput, Striatum/Cerebellum) in the diagnosis of PD.
PMCID: PMC3484423  PMID: 23145363
18F-Fluorodopa; positron emission tomography; image fusion; receiver operator characteristics; Parkinson’s
10.  PET/MR in oncology: an introduction with focus on MR and future perspectives for hybrid imaging 
After more than 20 years of research, a fully integrated PET/MR scanner was launched in 2010 enabling simultaneous acquisition of PET and MR imaging. Currently, no clinical indication for combined PET/MR has been established, however the expectations are high. In this paper we will discuss some of the challenges inherent in this new technology, but focus on potential applications for simultaneous PET/MR in the field of oncology. Methods and tracers for use with the PET technology will be familiar to most readers of this journal; thus this paper aims to provide a short and basic introduction to a number of different MRI techniques, such as DWI-MR (diffusion weighted imaging MR), DCE-MR (dynamic contrast enhanced MR), MRS (MR spectroscopy) and MR for attenuation correction of PET. All MR techniques presented in this paper have shown promising results in the treatment of patients with solid tumors and could be applied together with PET increasing the amount of information about the tissues of interest. The potential clinical benefit of applying PET/MR in staging, radiotherapy planning and treatment evaluation in oncology, as well as the research perspectives for the use of PET/MR in the development of new tracers and drugs will be discussed.
PMCID: PMC3484424  PMID: 23145362
PET/MR; oncology; diagnosis; staging; therapy evaluation; radiotherapy planning; molecular imaging
11.  Efficient multicistronic co-expression of hNIS and hTPO in prostate cancer cells for nonthyroidal tumor radioiodine therapy 
Radioiodine therapy has proven to be a safe and effective approach in the treatment of differentiated thyroid cancer. Similar treatment strategies have been exploited in nonthyroidal malignancies by transfecting hNIS gene into tumor cells or xenografts. However, rapid radioiodine efflux is often observed after radioiodine uptake, limiting the overall antitumor effects. In this study, we aimed at constructing multicistronic co-expression of hNIS and hTPO genes in tumor cells to enhance the radioiodine uptake and prolong the radioiodine retention. Driven by the cytomegalovirus promoter, hNIS and hTPO were simultaneously inserted into the expression cassette of adenoviral vector. An Ad5 viral vector (Ad-CMV-hTPO-T2A-hNIS) was assembled as a gene therapy vehicle by Gateway technology and 2A method. The co-expression of hNIS and hTPO genes was confirmed by a double-label immunofluorescence assay. The radioiodine (125I) uptake and efflux effects induced by co-expression of hNIS and hTPO genes were determined in transfected and non-transfected PC-3 cells. Significantly higher uptake (6.58 ± 0.56 fold, at 1 h post-incubation) and prolonged retention (5.47 ± 0.36 fold, at 1 h of cell efflux) of radioiodine (125I) were observed in hNIS and hTPO co-expressed PC-3 cells as compared to non-transfected PC-3 cells. We concluded that the new virus vector displayed favorable radioiodine uptake and retention properties in hNIS-hTPO transfected PC-3 cells. Our study will provide valuable information on improving the efficacy of hNIS-hTPO co-mediated radioiodine gene therapy.
PMCID: PMC3484425  PMID: 23145364
Gene therapy; prostate cance; hNIS; hTPO; gateway cloning system
12.  Molecular imaging probe development: a chemistry perspective 
Molecular imaging is an attractive modality that has been widely employed in many aspects of biomedical research; especially those aimed at the early detection of diseases such as cancer, inflammation and neurodegenerative disorders. The field emerged in response to a new research paradigm in healthcare that seeks to integrate detection capabilities for the prediction and prevention of diseases. This approach made a distinct impact in biomedical research as it enabled researchers to leverage the capabilities of molecular imaging probes to visualize a targeted molecular event non-invasively, repeatedly and continuously in a living system. In addition, since such probes are inherently compact, robust, and amenable to high-throughput production, these probes could potentially facilitate screening of preclinical drug discovery, therapeutic assessment and validation of disease biomarkers. They could also be useful in drug discovery and safety evaluations. In this review, major trends in the chemical synthesis and development of positron emission tomography (PET), optical and magnetic resonance imaging (MRI) probes are discussed.
PMCID: PMC3430472  PMID: 22943038
Positron emission tomography; radiochemistry; MRI; optical probes; molecular imaging
13.  Altered sympathetic nervous system signaling in the diabetic heart: emerging targets for molecular imaging 
Diabetes is commonly associated with increased risk of cardiovascular morbidity and mortality. Perturbations in sympathetic nervous system (SNS) signaling have been linked to the progression of diabetic heart disease. Glucose, insulin, and free fatty acids contribute to elevated sympathetic nervous activity and norepinephrine release. Reduced left ventricular compliance and impaired cardiac function lead to further SNS activation. Chronic elevation of cardiac norepinephrine culminates in altered expression of pre- and post-synaptic sympathetic signaling elements, changes in calcium regulatory proteins, and abnormal contraction-excitation coupling. Clinically, these factors manifest as altered resting heart rate, depressed heart rate variability, and impaired cardiac autonomic reflex, which may contribute to elevated cardiovascular risk. Development of molecular imaging probes enable a comprehensive evaluation of cardiac SNS signaling at the neuron, postsynaptic receptor, and intracellular second messenger sites of signal transduction, providing mechanistic insights into cardiac pathology. This review will examine the evidence for abnormal SNS signaling in the diabetic heart and establish the physiological consequences of these changes, drawing from basic biological research in isolated heart and rodent models of diabetes, as well as from clinical reports. Particular attention will be paid to the use of molecular imaging approaches to non-invasively characterize and evaluate sympathetic signal transduction in diabetes, including pre-synaptic norepinephrine reuptake assessment using 11C-meta-hydroxyephedrine (11C-HED) with PET or 123I-metaiodobenzylguanidine (123I-MIBG) with SPECT, and postsynaptic β-adrenoceptor density measurements using CGP12177 derivatives. Finally, the review will attempt to define the future role of these non-invasive nuclear imaging techniques in diabetes research and clinical care.
PMCID: PMC3477737  PMID: 23133819
Sympathetic neuronal imaging; SNS signaling; norepinephrine; β-adrenoceptor; norepinephrine reuptake transporter
14.  Molecular imaging probe development: a chemistry perspective 
Molecular imaging is an attractive modality that has been widely employed in many aspects of biomedical research; especially those aimed at the early detection of diseases such as cancer, inflammation and neurodegenerative disorders. The field emerged in response to a new research paradigm in healthcare that seeks to integrate detection capabilities for the prediction and prevention of diseases. This approach made a distinct impact in biomedical research as it enabled researchers to leverage the capabilities of molecular imaging probes to visualize a targeted molecular event non-invasively, repeatedly and continuously in a living system. In addition, since such probes are inherently compact, robust, and amenable to high-throughput production, these probes could potentially facilitate screening of preclinical drug discovery, therapeutic assessment and validation of disease biomarkers. They could also be useful in drug discovery and safety evaluations. In this review, major trends in the chemical synthesis and development of positron emission tomography (PET), optical and magnetic resonance imaging (MRI) probes are discussed.
PMCID: PMC3430472  PMID: 22943038
Positron emission tomography; radiochemistry; MRI; optical probes; molecular imaging
15.  Interim analyses in diagnostic versus treatment studies: differences and similarities 
The purpose of this paper was to contrast interim analyses in (randomized controlled) treatment studies with interim analyses in paired diagnostic studies of accuracy with respect to planning and conduct. The term ‘treatment study’ refers to a (randomized) clinical trial that aims to demonstrate the superiority or noninferiority of one treatment compared with another, and the term ‘diagnostic study’ to a clinical study that compares two diagnostic procedures, using a third diagnostic procedure as the gold standard. Though interim analyses in treatment studies and paired diagnostic studies show similarities in a priori planning of timing, decision rules, and the consequences of the analyses, they differ with respect to (1) the need for sample size adjustments, (2) the possibility of early decisions without early stopping, and (3) the impact of keeping results secret. These differences are due, respectively, to certain characteristics of paired diagnostic studies: the dependence of the sample size on the agreement rate between the modalities, multiple aims of diagnostic accuracy studies, and the advantages of early unblinding of results at the individual level. We exemplified our points by using a recent investigation at our institution on the detection of bone metastases from prostate cancer in patients with histologically confirmed prostate cancer in which 99mTc-MDP whole body bone scintigraphy was compared to positron emission tomography/computed tomography with 18F-fluorocholine as tracer, using magnetic resonance imaging as a reference.
PMCID: PMC3477734  PMID: 23133821
Study design; diagnostic imaging; PET/CT; efficacy studies; accuracy studies; sample size
16.  The role of PET/CT in decreasing inter-observer variability in treatment planning and evaluation of response for cervical cancer 
We have previously introduced anatomic biologic contouring (ABC) with PET/CT, using a distinct “halo” to unify contouring methods in treatment planning for lung and head and neck cancers. The objective of this study is to assess the utility of PET/CT in planning and treatment response for cervical cancer. Forty-two patients with stages II-IIIB cervix cancer were planned for irradiation using PET/CT. A CT-based Gross Tumor Volume (GTV-CT) was delineated by two independent observers while the PET remained obscured. The Planning Target Volume (PTV) was obtained by adding a 1.5 cm margin around the GTV. The same volumes were recontoured using PET/CT data and termed GTV-ABC and PTV-ABC, respectively. The values of GTV-CT and GTV-ABC and the absolute differences between the two observers were analyzed. Additionally, 23 of these patients had PET/CT performed 3 months after treatment. The anatomic biologic value (ABV) was calculated using the product of maximum diameter and mean SUV of the cervical tumor. The pre- and post-treatment ABVs were compared. A “halo” was observed around areas of maximal SUV uptake. The mean halo SUV was 1.91 ± 0.56 (SD). The mean halo thickness was 2.12 ± 0.5 (SD) mm. Inter-observer GTV variability decreased from a mean volume difference of 55.36 cm3 in CT-based planning to 12.29 cm3 in PET/CT-based planning with a respective decrease in standard deviation (SD) from 55.78 to 10.24 (p <0.001). Comparison of mean pre-treatment and post-treatment ABV’s revealed a decrease of ABV from 48.2 to 7.8 (p<0.001). PET/CT is a valuable tool in radiation therapy planning and evaluation of treatment response for cervical cancer. A clearly visualized “halo” was successfully implemented in GTV contouring in cervical cancer, resulting in decreased inter-observer variability in planning. PET/CT has the ability to quantify treatment response using anatomic biologic value.
PMCID: PMC3477735  PMID: 23133818
Cervical cancer; positron emission tomography; PET/CT; treatment planning; inter-observer variability
17.  False-positive uptake on radioiodine whole-body scintigraphy: physiologic and pathologic variants unrelated to thyroid cancer 
Radioiodine whole-body scintigraphy (WBS), which takes advantage of the high avidity of radioiodine in the functioning thyroid tissues, has been used for detection of differentiated thyroid cancer. Radioiodine is a sensitive marker for detection of thyroid cancer; however, radioiodine uptake is not specific for thyroid tissue. It can also be seen in healthy tissue, including thymus, breast, liver, and gastrointestinal tract, or in benign diseases, such as cysts and inflammation, or in a variety of benign and malignant non-thyroidal tumors, which could be mistaken for thyroid cancer. In order to accurately interpret radioiodine scintigraphy results, one must be familiar with the normal physiologic distribution of the tracer and frequently encountered physiologic and pathologic variants of radioiodine uptake. This article will provide a systematic overview of potential false-positive uptake of radioiodine in the whole body and illustrate how such unexpected findings can be appropriately evaluated.
PMCID: PMC3477738  PMID: 23133823
Differentiated thyroid cancer; radioiodine; I-131; I-123; whole-body scintigraphy; false-positive; physiologic uptake; pathologic uptake
18.  Current neuroimaging techniques in Alzheimer's disease and applications in animal models 
With Alzheimer’s disease (AD) quickly becoming the most costly disease to society, and with no disease-modifying treatment currently, prevention and early detection have become key points in AD research. Important features within this research focus on understanding disease pathology, as well as finding biomarkers that can act as early indicators and trackers of disease progression or potential treatment. With the advances in neuroimaging technology and the development of new imaging techniques, the search for cheap, noninvasive, sensitive biomarkers becomes more accessible. Modern neuroimaging techniques are able to cover most aspects of disease pathology, including visualization of senile plaques and neurofibrillary tangles, cortical atrophy, neuronal loss, vascular damage, and changes in brain biochemistry. These methods can provide complementary information, resulting in an overall picture of AD. Additionally, applying neuroimaging to animal models of AD could bring about greater understanding in disease etiology and experimental treatments whilst remaining in vivo. In this review, we present the current neuroimaging techniques used in AD research in both their human and animal applications, and discuss how this fits in to the overall goal of understanding AD.
PMCID: PMC3477739  PMID: 23133824
Alzheimer’s disease; animal models; ASL; biomarkers; MRI; MRS; neuroimaging; PET
19.  [125I]FIAU imaging in a preclinical model of lung infection: quantification of bacterial load 
2'-Fluoro-2'-deoxy-1β-D-arabinofuranosyl-5-[125I]iodouracil ([125I]FIAU), a substrate for the thymidine kinase (TK) present in most bacteria, has been used as an imaging agent for single photon emission computed tomography (SPECT) in an experimental model of lung infection. Using SPECT-CT we show that [125I]FIAU is specific for bacterial infection rather than sterile inflammation. We report [125I]FIAU lung uptake values of 1.26 ± 0.20 percent injected dose per gram (%ID/g) in normal controls, 1.69 ± 0.32 %ID/g in lung inflammation and up to 7.14 ± 1.09 %ID/g in lung infection in ex vivo biodistribution studies at 24 h after intranasal administration of bacteria. Images of [125I]FIAU signal within lung can be used to estimate the number of bacteria present, with a limit of detection of 109 colony forming units per mL on the X-SPECT scanner. [125I]FIAU-Based bacterial imaging may be useful in preclinical models to facilitate the development of new antibiotics, particularly in cases where a corresponding human trial is planned.
PMCID: PMC3477740  PMID: 23133816
Inflammation; thymidine kinase; nucleoside; SPECT; PET; molecular imaging
20.  Impact of expectation-maximization reconstruction iterations on the diagnosis of temporal lobe epilepsy with PET 
There is a well known tradeoff between image noise and image sharpness that is dependent on the number of iterations performed in ordered subset expectation maximization (OSEM) reconstruction of PET data. We aim to evaluate the impact of this tradeoff on the sensitivity and specificity of 18F-FDG PET for the diagnosis of temporal lobe epilepsy. A retrospective blinded reader study was performed on two OSEM reconstructions, using either 2 or 5 iterations, of 32 18F-FDG PET studies acquired at our institution for the diagnosis of temporal lobe epilepsy. The sensitivity and specificity of each reconstruction for identifying patients who were ultimately determined to be surgical candidates was assessed using an ROC analysis. The sensitivity of each reconstruction for identifying patients who showed clinical improvement following surgery was also assessed. Our results showed no significant difference between the two reconstructions studied for either the sensitivity and specificity of 18F-FDG PET for predicting surgical candidacy, or its sensitivity for predicting positive surgical outcomes. This implies that the number of iterations performed during OSEM reconstruction will have little impact on a reader based interpretation of 18F-FDG PET scans acquired for the diagnosis of temporal lobe epilepsy, and can be determined by physician and institutional preference.
PMCID: PMC3477742  PMID: 23133820
18F-FDG PET; temporal lobe epilepsy; OSEM reconstruction; ROC analysis
21.  Bioluminescence imaging of therapy response does not correlate with FDG-PET response in a mouse model of Burkitt lymphoma 
Since the development and evaluation of novel anti-cancer therapies require molecular insight in the disease state, both FDG-PET and BLI imaging were evaluated in a Burkitt B-cell lymphoma xenograft model treated with cyclophosphamide or temsirolimus. Daudi xenograft mice were treated with either cyclophosphamide or temsirolimus and imaged with BLI and FDG-PET on d0 (before treatment), d2, d4, d7, d9 and d14 following the start of therapy. Besides tumor volume changes, therapy response was assessed with immunohistochemical analysis (apoptosis). BLI revealed a flare following both therapeutics that was significantly higher when compared to control tumors. FDG-PET decreased immediatelly, long before the tumor reduced in size. Late after therapy, BLI signal intensities decreased significantly compared to baseline subsequent to tumor size reduction while apoptosis was immediately induced following both treatment regimen. Unlike FDG, BLI was not able to reflect reduced levels of viable cells and was not able to predict tumor size response and apoptosis response.
PMCID: PMC3477743  PMID: 23133822
Bioluminescence imaging; therapy response; FDG-PET
22.  Cerenkov imaging - a new modality for molecular imaging 
Cerenkov luminescence imaging (CLI) is an emerging hybrid modality that utilizes the light emission from many commonly used medical isotopes. Cerenkov radiation (CR) is produced when charged particles travel through a dielectric medium faster than the speed of light in that medium. First described in detail nearly 100 years ago, CR has only recently applied for biomedical imaging purposes. The modality is of considerable interest as it enables the use of widespread luminescence imaging equipment to visualize clinical diagnostic (all PET radioisotopes) and many therapeutic radionuclides. The amount of light detected in CLI applications is significantly lower than other that in other optical imaging techniques such as bioluminescence and fluorescence. However, significant advantages include the use of approved radiotracers and lack of an incident light source, resulting in high signal to background ratios. As well, multiple subjects may be imaged concurrently (up to 5 in common bioluminescent equipment), conferring both cost and time benefits. This review summarizes the field of Cerenkov luminescence imaging to date. Applications of CLI discussed include intraoperative radionuclide-guided surgery, monitoring of therapeutic efficacy, tomographic optical imaging capabilities, and the ability to perform multiplexed imaging using fluorophores excited by the Cerenkov radiation. While technical challenges still exist, Cerenkov imaging has materialized as an important molecular imaging modality.
PMCID: PMC3477724  PMID: 23133811
Cerenkov radiation; PET; optical imaging; fluorescence
23.  In vitro autoradiography of carcinoembryonic antigen in tissue from patients with colorectal cancer using multifunctional antibody TF2 and 67/68Ga-labeled haptens by pretargeting 
The carcinoembryonic antigen (CEA) was visualized in vitro in tissue from patients with colorectal cancer with trivalent bispecific antibody TF2 and two hapten molecules, [67/68Ga]Ga-IMP461 and [67/68Ga]Ga-IMP485 by means of pretargeting. Colorectal cancer tissue samples obtained from surgery at Uppsala University Hospital, were frozen fresh and cryosectioned. The two hapten molecules comprising 1,4,7-triazacyclononanetriacetic acid chelate moiety (NOTA) were labeled with 67Ga or 68Ga. The autoradiography was conducted by incubating the tissue samples with the bispecific antibody TF2, followed by washing and incubation with one of the radiolabeled hapten molecules. After washing, drying and exposure to phosphor imager plates, the autoradiograms were analyzed and compared to standard histochemistry (hematoxylin-eosin). Pronounced binding was found in the tissue from colorectal cancer using the bispecific antibody TF2 and either of the haptens [67/68Ga]Ga-IMP461 and [67/68Ga]Ga-IMP485. Distinct binding was also detected in the epithelium of most samples of neighboring tissue, taken at a minimum of 10 cm from the site of the tumor. It is concluded that pretargeting CEA with the bispecific antibody TF2 followed by the addition of 67/68Ga-labeled hapten is extremely sensitive for visualizing this marker for colorectal cancer. This methodology is therefore a very specific complement to other histochemical techniques in the diagnosis of biopsies or in samples taken from surgery. Use of the pretargeting technique in vivo may also be an advance in diagnosing patients with colorectal cancer, either using 67Ga and SPECT or 68Ga and PET.
PMCID: PMC3477725  PMID: 23133809
Autoradiography; carcinoembryonic antigen; CEA; colorectal cancer; Ga-67; Ga-68; pretargeting
24.  Synthesis and characterization of intrinsically radiolabeled quantum dots for bimodal detection 
A novel approach was developed to synthesize radioactive quantum dots (r-QDs) thereby enabling both optical and radionuclide signals to be detected from the same intrinsic bimodal probe. This proof-of-concept is exemplified by the incorporation of the radionuclide 109Cadmium into the core/shell of the nanoparticle. Green and near infrared (NIR) emission intrinsic r-QDs were synthesized and characterized. Zwitterionic and Poly-polyethlene glycol (PEGylated) ligands were synthesized and used to coat r-QDs. Zwitterionic NIR r-QDs (quantum yield = 11%) and PEGylated NIR r-QDs (quantum yield = 14%) with an average size of 13.8 nm and 16.8 nm were obtained respectively. The biodistribution of NIR zwitterionic and PEGylated r-QDs in nude mice was investigated and zwitterionic r-QDs showed longer blood circulation (t1/2 = 21.4±1.1 hrs) than their PEGylated counterparts (t1/2 = 6.4±0.5 min). Both zwitterionic and PEGylated r-QDs exhibited progressive accumulation in the liver and spleen, but the magnitude of the accumulation (%ID/g) was about 3-6 fold higher with the PEGylated r-QDs at all the time points. The results demonstrated the feasibility of r-QDs synthesis in quantitative yield and retention of fluorescence following incorporation of radioactivity into the core/shell of the nanoparticle. The gamma signal from the same fluorescent elemental material enabled quantitative and robust pharmacokinetic measurements and how these changed depended on the type of coating ligands used. This strategy for intrinsically radio-labeling the QDs is currently being implemented in our laboratory for the incorporation of other radiometals.
PMCID: PMC3477726  PMID: 23133807
Quantum dots; intrinsically radio-labeled; biodistribution; molecular imaging; bimodal detection
25.  Efficacy of 99mTc-EDDA/HYNIC-TOC SPECT/CT scintigraphy in Graves’ ophthalmopathy 
The aim of this study was to investigate the predictive role of the orbital somatostatin receptor scintigraphy with 99mTc-EDDA/HYNIC-TOC (99mTc-TOC) to detect clinical stage of Graves’ ophthalmopathy and the response to corticosteroid therapy. The subjects of the experiment were 46 patients with Graves’ ophthalmopathy (GO) and four volunteers without eye disease or GO as the normal group (NG). Single photon emission computed tomography (SPECT), computed tomography (CT) and the left and right lateral position planar imaging of the heads of the all subjects were obtained 4 h after the intravenous injection of 555 MBq of 99mTc-TOC. The 99mTc-TOC SPECT/CT was repeated 3 months later. 35 (35/46) patients were received corticosteroid therapy (prednisolone, 10 mg po tid ) for 3 months, however, the other 11 patients as control groups did not receive any treatment. The treatment effect was evaluated both by the orbital 99mTc-TOC uptake and NOSPECS. A significant decrease in the O/OC ratio was observed in 22 GO patients between pre- and post-treatment (1.64 ± 0.13 vs. 1.21 ± 0.09, P < 0.05). There were neither significant difference of the O/OC ratio in 13 GO patients between pre- and post-treatment periods, nor significant difference in the 9 (9/11) patients before and after three months. Orbital 99mTc-TOC scintigraphy is a feasible technique to estimate the Graves’ ophthalmopathy activity and predict the response to subsequent corticosteroid therapy in GO patients. The technique could be a useful tool for physicians not familiar with CAS determination.
PMCID: PMC3477727  PMID: 23133815
Graves’ ophthalmopathy; single photon emission computed tomography (SPECT); somatostatin receptor; 99mTc-TOC

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