PET (positron emission tomography) scans are still in the experimental phase, as one of the newest breast cancer diagnostic techniques. It is becoming the new standard in neurology, oncology and cardiology. PET, like other nuclear medicine diagnostic and treatment techniques, involves the use of radiation. Because of the negative impact of radioactivity to our bodies the radiation doses in PET should be small. The existing computing algorithms for calculating PET images can be divided into two broad categories: analytical and iterative methods. In the analytical approach the relation between the picture and its projections is expressed by a set of integral equations which are then solved analytically. The Fourier backprojection (FBP) algorithm is a numerical approximation of this analytical solution. Iterative approaches use deterministic (ART = Algebraic Reconstructed Technique) or stochastic (EM = Expectation Maximization) algorithms. My proposed kernel density estimation (KDE) algorithm also falls also into the category of iterative methods. However, in this approach each coincidence event is considered individually. The estimate location of the annihilation event that caused each coincidence event is based on the previously assigned location of events processed earlier. To accomplish this, we construct a probability distribution along each coincidence line. This is generated from previous annihilation points by density estimation. It is shown that this density estimation approach to PET can reconstruct an image of an existing tumor using significantly less data than the standard CT algorithms, such as FBP. Therefore, it might be very promising technique allowing reduced radiation dose for patients, while retaining or improving image quality. / October 2007

PET (positron emission tomography) scans are still in the experimental phase, as one of the newest breast cancer diagnostic techniques. It is becoming the new standard in neurology, oncology and cardiology. PET, like other nuclear medicine diagnostic and treatment techniques, involves the use of radiation. Because of the negative impact of radioactivity to our bodies the radiation doses in PET should be small. The existing computing algorithms for calculating PET images can be divided into two broad categories: analytical and iterative methods. In the analytical approach the relation between the picture and its projections is expressed by a set of integral equations which are then solved analytically. The Fourier backprojection (FBP) algorithm is a numerical approximation of this analytical solution. Iterative approaches use deterministic (ART = Algebraic Reconstructed Technique) or stochastic (EM = Expectation Maximization) algorithms. My proposed kernel density estimation (KDE) algorithm also falls also into the category of iterative methods. However, in this approach each coincidence event is considered individually. The estimate location of the annihilation event that caused each coincidence event is based on the previously assigned location of events processed earlier. To accomplish this, we construct a probability distribution along each coincidence line. This is generated from previous annihilation points by density estimation. It is shown that this density estimation approach to PET can reconstruct an image of an existing tumor using significantly less data than the standard CT algorithms, such as FBP. Therefore, it might be very promising technique allowing reduced radiation dose for patients, while retaining or improving image quality.

PET (positron emission tomography) scans are still in the experimental phase, as one of the newest breast cancer diagnostic techniques. It is becoming the new standard in neurology, oncology and cardiology. PET, like other nuclear medicine diagnostic and treatment techniques, involves the use of radiation. Because of the negative impact of radioactivity to our bodies the radiation doses in PET should be small. The existing computing algorithms for calculating PET images can be divided into two broad categories: analytical and iterative methods. In the analytical approach the relation between the picture and its projections is expressed by a set of integral equations which are then solved analytically. The Fourier backprojection (FBP) algorithm is a numerical approximation of this analytical solution. Iterative approaches use deterministic (ART = Algebraic Reconstructed Technique) or stochastic (EM = Expectation Maximization) algorithms. My proposed kernel density estimation (KDE) algorithm also falls also into the category of iterative methods. However, in this approach each coincidence event is considered individually. The estimate location of the annihilation event that caused each coincidence event is based on the previously assigned location of events processed earlier. To accomplish this, we construct a probability distribution along each coincidence line. This is generated from previous annihilation points by density estimation. It is shown that this density estimation approach to PET can reconstruct an image of an existing tumor using significantly less data than the standard CT algorithms, such as FBP. Therefore, it might be very promising technique allowing reduced radiation dose for patients, while retaining or improving image quality.

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Background: Lewy body dementia (LBD), consisting of Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB), is known to make up more than 15% of dementia cases at autopsy, however the clinical prevalence rate is reported to be much lower at around 5-6%. Difficulties with diagnosis and/or lack of specific treatments may contribute to this difference. This study investigated the diagnosis and management pathways of LBD and whether inflammation could play a role in the pathophysiology and hence provide a route for future diagnostic and treatment pathways. Methods: Clinical diagnostic rates of LBD in clinics across several NHS trusts in East Anglia were reviewed, followed by an in-depth notes review of patients identified with LBD together with age and gender matched controls. A literature review of the current evidence for inflammation in LBD, preceded a case control study to investigate further. Nineteen DLB patients together with 16 age and gender matched healthy controls underwent [11C]PK11195 PET imaging, and the same cohorts, plus an additional 10 matched control subjects underwent peripheral cytokine analysis. Results: The clinical prevalence rate of LBD was low compared to the known pathology rates, with delays identified in the diagnosis of DLB compared to other dementia subtypes. Delays were also seen between the onset of dementia symptoms and the clinical diagnosis of dementia in Parkinson's disease (PD). The literature review identified studies providing evidence of inflammation in PD but few studies had been carried out in DLB. PET imaging revealed microglial activation negatively correlated with disease severity in DLB, suggesting inflammation occurs early in the disease. DLB patients also showed evidence of differences in cytokine levels compared to healthy controls. Conclusion: The study showed evidence of inflammatory changes in DLB, providing a potential target for treatment and/or biomarkers, that could assist in increasing clinical diagnostic rates.

Introduction The 80kD glycoprotein transferrin (TF) and its related receptor (TFR1) play a major role in the recruitment by cancer cells of factors for their multiplication, adhesion, invasion and metastatic potential. Though primarily designed to bind iron and then be internalised into cells with its receptor, TF can also bind most transition metals such as Co, Cr, Mn, Zr, Ni, Cu, V, In & Ga. Under certain conditions TF binds Ti (IV) even more tightly than it does Fe and that this occurs at the N-lobe (as distinct from C) of apoTF. Further, under physiological conditions the species Fe(C)Ti(N)-TF may provide the route for Ti entry into cells via TFR1 (1). Thus, the radiometal PET reporter isotope 45Ti with an ‘intermediate’ (~hrs) half-life suited to tracking cell-focused biological mechanisms is an attractive option for elucidating cellular mechanisms involving TF binding and internalisation, at least in (preclinical) animal models. 45Ti (T½ = 3.08 hr; + branching ratio = 85 %; mean β+ energy = 439keV, no significant dose-conferring non-511keV γ-emissions) was produced using the reaction 45Sc(p,n)45Ti by irradiating (monoisotopic) scandium discs with an energy-degraded proton beam produced by an 18MeV isochronous medical cyclotron. Separation and purification was achieved with an hydroxylamine hydrochloride functionalised resin. Comparative microPET imaging was performed in an immunodeficient mouse model, measuring biodistributions of the radiolabels 45Ti-oxalate and 45Ti-human-TF (45Ti-h-TF), out to 6hr post-injection. Materials and Methods High purity 15mm diameter scandium disc foils (99.5%, Goodfellow, UK) each thickness 0.100 ± 0.005 mm (55 mg) were loaded into an in-house constructed solid-targetry system mounted on a 300mm external beam line utilising helium-gas and chilled water to cool the target body (2). The proton beam was degraded to 11.7 MeV using a graphite disc integrated into the graphite collimator. This energy abolishes the competing ‘contaminant’ reactions 45Sc(p,n+p)44Sc and 45Sc(p,2n)44Ti. Beam current was measured using the well documented 65Cu(p,n)65Zn reaction. Calculations showed that the chosen energy is close to the optimal primary energy (~12 MeV) for maximising the (thin-target) yield from a 0.100 mm thick target. For separation of Ti from the Sc target two methods were examined; (i) ion exchange column separation using 2000 mg AG 50W-X8 resin conditioned with 10mL 9M HCl. Disc is dissolved in 1 mL of 9M HCl, which at completion of reaction is pipetted into column. Successive 1 mL volumes of 9M HCl are added, and subsequent elutions collected. (ii) Following Gagnon et al., (3) a method employing hydroxylamine hydro-chloride functionalised resin (’hydroxamate method’) was applied, similar to its use in our hands for purification and separation of 89Zr (2) following its original description for 89Zr by Holland et al., (4). Disc dissolved in 2mL 6M HCl, then diluted to 2M. Elute through column to waste fraction 1 (w1 – see FIG. 1). Then elute 6 mL of 2M HCl through column to w2, followed by 6 mL of traceSELECT H2O to w3. Finally, elute Ti into successive 1 mL product fractions (p1, 2 etc.) using 5 mL of 1M oxalic acid. This procedure takes approximate 1 hr. 45Ti in elution vials was measured using γ-spectroscopy. Sc in the same vials was determined later using ICP-MS. Results A typical production run using a beam current of 40 μA for 60min on a 0.100mm-thick disc produced an activity of 1.83 GBq. Radionuclidic analysis of an irradiated disc using calibrated cryo-HPGe γ-spectroscopy revealed T½ = 2.97–3.19 hr (95% CI) for 45Ti, and with contaminant 44Sc < 0.19 %, with no other isotopes detected. Despite systematic adjustments to column conditions satisfactory chemical separation was not achieved using the ion exchange column method (i), despite previous reports of its success (5). Typical results of separation using the successful hydroxamate method (ii) are shown on the FIGURE 1. It is seen that significant portion of 45Ti is lost in the initial washing steps leading to waste collection. N = 4 replicate experiments showed a variation (SD) of 10 % of the mean in each elu-tion fraction. Subsequent ICP-MS of the same elutions for (cold) Sc showed approximately 80 % by mass appeared in w1 and 20 % in w2, with negligible total mass (total fraction ~1/6000) of Sc in product (p1–4) vials. However, the FIG. 1 shows that a total of only 30% of the original activity of 45Ti (corrected to EOB) is available in the product vials, with the vial of highest specific activity (p1) containing 14 %. However, using a stack of 2×0.100mm thick Sc discs as a target yields isotope of adequate specific activity with-out need for concentration, for subsequent labelling and small-animal imaging purposes. In a ‘proof-of-principle’ experiment, two groups of healthy Balb/c-nu/nu female adult mice were administered with 45Ti radiotracers. The first group (N = 3) received approximately 20 MBq IP of 45Ti-oxalate buffered to pH = 7.0, and under-went microPET/CT imaging (Super Argus PET, Sedecal, Spain) out to 6hr post-injection, plus biodistribution analysis of radioactivity by dis-section at sacrifice (6hr). The second group (N = 3) received approximately 20 MBq IP of 45Ti-h-TF and were also studied to 6hr post-injection, followed by radioactive analysis after dissection at sacrifice. Organ and tissue biodistributions of the two groups at 6hr were similar but with 45Ti-oxalate showing slightly greater affinity for bone. Biodistribution by dissection results broadly confirmed the findings from PET images. However, TLC results suggested that similarity of radiolabel biodistributions of the two groups may be due to contamination of the TF radiolabel with non-conjugated Ti at time of injection. An alternative explanation is dechelation in vivo of 45Ti from 45Ti-h-TF. Conclusion Despite significant loss of 45Ti to the waste fractions of the separation process (total 53 %, corrected to EOB), 45Ti of acceptable specific activity and high radionuclidic purity has been produced from the reaction 45Sc(p,n)45Ti, with separation and purification of the product by hydroxamate column chemistry, confirming an earlier report. Though microPET in vivo imaging using 45Ti-based radiolabels was shown to be feasible, the similarity in the results for the label 45Ti-h-TF compared with ‘raw’ 45Ti-oxalate suggests further investigations. These may include a direct comparison of in vivo 45Ti-h-TF small-animal imaging plus post-dissection biodistribution with the same procedures using 89Zr labelled h-apotransferrin (6).

In this work, a major effort has been made to establish an Internet accessible system for medical imaging simulation as a convenient service under the cloud computing environment. First, an Internet accessible, medical imaging education platform has been developed. It includes teaching and dynamic assessment tracking system for five commonly used imaging modalities. The system is integrated by the open source MySQL database software that manages updating materials and also tracks students’ learning engagements, which allow the reliability and appropriateness of the on-line teaching material and assessment methods to be optimized. The evaluation results have shown increased learning gains promisingly. Second, a prototype simulation service platform has been established. It is based on a job-oriented work flow to provide different kinds of service to users to perform medical imaging simulation. These simulations not only include the straightforward CT data reconstruction based on Radon transform, but also the sophisticated PET imaging simulation based on GATE as well. The QGATE’s client-server configuration can manage the GATE system to queue and monitor the submitted simulation scripts and return simulation results. The system is suitable for classroom training and easy to use for students or new users to the field of nuclear medicine imaging simulation. Finally, based on the developed simulation platform, a simulation study on PET imaging has been carried out. Event-based dynamic justification method has been tested based on the phantoms generated by NCAT associated with different breathing signals. The results show its potential capability of motion correction for PET data acquisition.

Positron Emission Tomography (PET) plays an essential role in the management of patients with cancer. It is used to detect and characterise malignancy as well as monitor response to therapy. PET is a quantitative imaging tool, producing images that quantify the uptake of a radiotracer that has been administered to the patient. The most common measure of uptake derived from the image is known as a Standardised Uptake Value (SUV). Data acquired on the scanner is processed to produce images that are reported by clinicians. This task is known as image reconstruction and uses computational algorithms to process the scan data. The last decade has seen substantial development of these algorithms, which have become commercially available: modelling of the scanner spatial resolution (resolution modelling) and time of flight (TOF). The Biograph mCT was the first scanner from Siemens Healthcare to feature these two algorithms and the scanner at Central Manchester University Hospitals was the first Biograph mCT to go live in the UK. This PhD project, sponsored by Siemens Healthcare, aims to evaluate the effect of these algorithms on SUV in routine oncology imaging through a combination of phantom and patient studies. Resolution modelling improved visualisation of small objects and resulted in significant increases of uptake measurements. This may pose a challenge to clinicians when interpreting established uptake metrics that are used as an indication of disease status. Resolution modelling reduced the variability of SUV. This improved precision is particularly beneficial when assessing SUV changes during therapy monitoring. TOF was shown to reduce image noise with a conservation of FDG uptake measurements, relative to non-TOF algorithms. As a result of this work, TOF has been used routinely since mid-2014 at the CMUH department. This has facilitated a reduction of patient and staff radiation dose and an increase of 100 scans performed each year in the department.

Poly(ADP-ribose)polymerase-1 and -2 (PARP1/2) are nuclear proteins involved in DNA repair. Tumors with defects in homologous recombination, including BRCA1- and BRCA2-deficient cancers, have been shown to be sensitive to PARP inhibition. The Weissleder group has synthesized fluorescent and radioactive derivatives of the PARP1/2 inhibitor AZD2281. We hypothesized that fluorescent and radioactive AZD2281-based imaging agents would quantify PARP1/2 expression in vitro and in vivo. To test this hypothesis, a panel of pancreatic ductal adenocarcinoma and ovarian carcinoma cell lines were characterized by immunocytochemistry for PARP1/2 expression. AZD2281-derived fluorescence signal correlated with anti-PARP antibody fluorescence signal strength in vitro. Four cell lines representing a range of PARP1/2 expression levels were then xenografted into Nu/Nu mice. Mice bearing four tumor types each were imaged with AZD2281-derived imaging agents, sacrificed, and their tumors excised for stand-alone imaging and Western blot. AZD2281-derived signal correlated with tumor PARP1/2 expression determined by Western blot, indicating that PARP1/2 expression level is a determinant of fluorescent signal strength and SUVs of AZD2281-derived agents in vivo. These data indicate that AZD2281-derived agents are useful tools for quantifying intracellular PARP1/2 both in vitro and in vivo, which could one day enable prospective identification of tumors likely to respond to PARP inhibitors.

Cardiovascular complications represent the leading cause of death in chronic kidney disease (CKD) patients. Significant renal mass reduction induced by 5/6 subtotal nephrectomy (Nx) animal model leads to a chain of events that culminates in hypertension and CKD. The renin angiotensin (Ang) system (RAS) is known to be dysregulated, specifically Ang type 1 receptor (AT1R) plays a major role in development and progression of the disease. However, conflicting results have been reported on intrarenal AT1R levels, and the impact of antihypertensive drugs on RAS signaling is divergent. We hypothesize that PET imaging will be able to quantify kidney AT1R expression reliably in healthy and disease states. The broad objectives of this research project were: (i) to develop a positron emission tomography (PET) probe capable of detecting changes in the AT1R binding in the kidney; (ii) to elucidate the nature/temporal role of renal AT1R in Nx rat model of CKD; and (iii) to explore the predictive value of non-invasive PET imaging of AT1R to guide the use of antihypertensive therapy in preventing the progression of the disease. The novel selective AT1R PET radioligand [18F]FPyKYNE-losartan was successfully used with PET in detecting renal AT1Rs at early and late stages of the CKD. The PET results correlated well with in vitro [125I]-[Sar1, Ile8]Ang II autoradiography. Over the time-course of the study (10-20 weeks), the Nx rats exhibited renal impairment, proteinuria and sustained hypertension. Echocardiography indicated the development of cardiac hypertrophy most likely secondary to the hyperdynamic circulation. These abnormalities were associated with increasing plasma and kidney levels of Ang II, and compensatory downregulation of renal AT1Rs. ACEI enalapril attenuated renal impairment, hypertension and prevented progression of cardiac hypertrophy in Nx rats. This was successfully accomplished through reduction of systemic and kidney Ang II, and consequent normalization of renal AT1R as measured by PET (and autoradiography). The non-dihydropyridine CCB diltiazem also reduced blood pressure but did not normalize renal AT1R expression. Diltiazem induced elevation in Ang II levels in plasma, kidney and heart, associated with exacerbation of renal and cardiac dysfunction, and no change in AT1R renal expression. This outcome adds value to the use of [18F]FPyKYNE-losartan PET for determination of receptor abnormalities with progression of the disease and monitoring of therapy.