Steven R. Meikle

Small animal SPECT and its place in the matrix of molecular imaging technologies

Molecular imaging refers to the use of non-invasive imaging techniques to detect signals that originate from molecules, often in the form of an injected tracer, and observe their interaction with a specific cellular target in vivo. Differences in the underlying physical principles of these measurement techniques determine the sensitivity, specificity and length of possible observation of the signal, characteristics that have to be traded off according to the biological question under study. Here, we describe the specific characteristics of single photon emission computed tomography (SPECT) relative to other molecular imaging technologies. SPECT is based on the tracer principle and external radiation detection. It is capable of measuring the biodistribution of minute (<10(-10) molar) concentrations of radio-labelled biomolecules in vivo with sub-millimetre resolution and quantifying the molecular kinetic processes in which they participate. Like some other imaging techniques, SPECT was originally developed for human use and was subsequently adapted for imaging small laboratory animals at high spatial resolution for basic and translational research. Its unique capabilities include (i) the ability to image endogenous ligands such as peptides and antibodies due to the relative ease of labelling these molecules with technetium or iodine, (ii) the ability to measure relatively slow kinetic processes (compared with positron emission tomography, for example) due to the long half-life of the commonly used isotopes and (iii) the ability to probe two or more molecular pathways simultaneously by detecting isotopes with different emission energies. In this paper, we review the technology developments and design tradeoffs that led to the current state-of-the-art in SPECT small animal scanning and describe the position SPECT occupies within the matrix of molecular imaging technologies.

A convolution-subtraction scatter correction method for 3D PET

3D acquisition and reconstruction in positron emission tomography (PET) produce data with improved signal-to-noise ratios compared with conventional 2D slice-oriented methods. However, the sensitivity increase is accompanied by an increase in the number of scattered photons and random coincidences detected. This paper presents a scatter correction technique for 3D PET data where an estimate of the scattered photon distribution is subtracted from the data before reconstruction. The scatter distribution is estimated by iteratively convolving the photopeak projections with a mono-exponential kernel. The method accounts for the 3D acquisition geometry and nature of scatter by performing the scatter estimation on 2D projections. The assumptions of the method have been investigated by measuring the variation in the scatter fraction and the scatter function at different positions in a cylinder. Both parameters were found to vary by up to 50% from the centre to the edge of a large water-filled cylinder. Despite this, in a uniform cylinder containing water with different concentrations of radioactivity, scatter was reduced from 25% in a non-radioactive region to less than 5% using the convolution-subtraction method. In addition, the relative concentration of a cylinder containing an increased concentration, which was underestimated by almost 50% without scatter correction, was within 5% of the true concentration after correction.

Correction for head movements in positron emission tomography using an optical motion tracking system

Methods capable of correcting for head motion in all six degrees of freedom have been proposed for positron emission tomography (PET) brain imaging but not yet demonstrated in human studies. These methods rely on the accurate measurement of head motion in relation to the reconstruction coordinate frame. We present methodology for the direct calibration of an optical motion-tracking system to the reconstruction coordinate frame using paired coordinate measurements obtained simultaneously from a PET scanner and tracking system. We also describe the implementation of motion correction, based on the multiple acquisition frame method originally described by Picard and Thompson (1997), using data provided by the motion tracking system. Effective compensation for multiple six-degree-of-freedom movements is demonstrated in dynamic PET scans of the Hoffman brain phantom and a normal volunteer. We conclude that reduced distortion and improved quantitative accuracy can be achieved with this method in PET brain studies degraded by head movements.

Does fluorine-18 fluorodeoxyglucose metabolic imaging of tumours benefit oncology?

Fluoro-deoxyglucose (FDG) is a metabolic marker, which follows the same route into cells as that of glucose, and it can be radiolabelled wich fluorine-18,18F-FDG making it suitable for imaging with positron emission tomography (PET). The fact that rapidly proliferating cells such as tumour cells accumulate18F-FDG more avidly than those with a normal turnover rate has given rise to its potential in oncology. The rationale and previous published uses of18F-FDG in oncology are reviewed, together with the various analysis techniques and associated methodological difficulties.

Two-dimensional myocardial strain imaging detects changes in left ventricular systolic function immediately after anthracycline chemotherapy

AIMS The efficacy of anthracyclines is undermined by potential life-threatening cardiotoxicity. Cardiotoxicity is dependent upon several factors and the timing to its development is variable. Moreover, as adjuvant therapy with trastuzumab often follows, a close monitoring of cardiac function in those treated with anthracyclines is mandatory. Left ventricular ejection fraction (LVEF) by echocardiography is currently used for monitoring cardiotoxicity; however, LVEF has numerous limitations. Two-dimensional strain imaging may provide a more sensitive measure of altered LV systolic function, so the aim of the present study was to compare LVEF and LV systolic strain before and after anthracyclines. METHODS AND RESULTS Fifty-two women with histologically confirmed breast cancer were prospectively studied. Echocardiographic LVEF (by Simpsons method), global and regional peak longitudinal, radial, and circumferential 2D systolic strain were measured 1 week before and 1 week after chemotherapy. Global and regional longitudinal LV systolic strain was significantly reduced after treatment; global longitudinal strain decreased from -17.7 to -16.3% (P < 0.01) with 48% of global measurements reduced by >10%. Global and regional radial LV systolic strain after treatment was also significantly reduced; global radial strain dropped from 40.5 to 34.5% (P < 0.01) with 59% of global measurements reduced by >10%. In contrast, no reduction in LVEF >10% after chemotherapy was observed. CONCLUSION Reduced LV systolic strain immediately after anthracycline treatment may indicate early impairment of myocardial function before detectable change in LVEF.

Simultaneous estimation of physiological parameters and the input function - in vivo PET data

Dynamic imaging with positron emission tomography (PET) is widely used for the in-vivo measurement of the regional cerebral metabolic rate for glucose (rCMRGlc) with [/sup 18/F]fluorodeoxy-D-glucose (FDG), and is used for the clinical evaluation of neurological diseases. However, in addition to the acquisition of dynamic images, continuous arterial blood sampling is the conventional method of obtaining the tracer time-activity curve in blood (or plasma) for the numerical estimation of rCMRGlc in mg glucose/100 g tissue/min. The insertion of arterial lines and the subsequent collection and processing of multiple blood samples are impractical for clinical PET studies because it is invasive, it has the remote (but real) potential for producing limb ischemia, and it exposes personnel to additional radiation and the risks associated with handling blood. Based on a method for extracting kinetic parameters from dynamic PET images, we developed a modified version (post-estimation method) to improve the numerical identifiability of the parameter estimates when we deal with data obtained from clinical studies. We applied both methods to dynamic neurological FDG PET studies in three adults. We found that the input function and parameter estimates obtained with our noninvasive methods agreed well with those estimated from the gold-standard method of arterial blood sampling and that rCMRGlc estimates were highly correlated. No significant difference was found between rCMRGlc estimated by our methods and the gold-standard method. We suggest that our proposed noninvasive methods may offer an advance over existing methods.

Accelerated EM reconstruction in total-body PET: potential for improving tumour detectability.

Total-body positron emission tomography (PET) is a useful diagnostic tool for evaluating malignant disease. However, tumour detection is limited by image artefacts due to the lack of attenuation correction and noise. Attenuation correction may be possible using transmission data acquired after or simultaneously with emission data. Despite the elimination of attenuation artefacts, however, tumour detection is still hampered by noise, which is amplified during image reconstruction by filtered backprojection (FBP). We have investigated, as an alternative to FBP, an accelerated expectation maximization (EM) algorithm for its potential to improve tumour detectability in total-body PET. Signal to noise ratio (SNR), calculated for a tumour with respect to the surrounding background, is used as a figure of merit. A software tumour phantom, with conditions typical of those encountered in a total-body PET study using simultaneous acquisition, is used to optimize and compare various reconstruction approaches. Accelerated EM reconstruction followed by two-dimensional filtering is shown to yield significantly higher SNR than FBP for a range of tumour sizes, concentrations and counting statistics (deltaSNR = 6.3 +/- 3.9, p < 0.001). The methods developed are illustrated by examples derived from physical phantom and patient data.

Electrocardiographic measurement of infarct size after thrombolytic therapy.

OBJECTIVES We examined the utility of the 32-point QRS score from the 12-lead electrocardiogram (ECG) for measurement of the ischemic risk region and infarct size in patients receiving thrombolytic therapy. BACKGROUND The QRS score offers a means of evaluating the therapeutic benefit of thrombolytic therapy by comparing final infarct size with the initial extent of ischemic myocardium. METHODS The study included 38 patients (34 men, 4 women; mean [+/-SD] age 54 +/- 10 years) with a first infarction (18 anterior, 20 inferior). The maximal potential QRS score (QRS0) was assigned to all leads with >/= 100-microV ST elevation on the initial ECG. The QRS scores were calculated at 7 and 30 days after infarction. Left ventricular ejection fraction was measured by radionuclide ventriculography at 1 month. Twenty-eight patients had thallium (Tl)-201 and technetium (Tc)-99m pyrophosphate tomographic measurement of the ischemic region and infarct size. RESULTS The QRS0 was 10.3 +/- 3.1 (mean +/- SD) for anterior and 10.4 +/- 3.5 for inferior infarcts. The QRS scores were similar at 7 and 30 days for both anterior (5.6 +/- 3.4 vs. 5.5 +/- 3.4) and inferior infarcts (3.7 +/- 2.6 vs. 2.9 +/- 2.2). The day 7 QRS score and ejection fraction at 1 month were inversely correlated (r = -0.74, p < 0.01). The Tl-201 perfusion defect was 34 +/- 11% of the left ventricle for anterior and 32 +/- 7% for inferior infarcts. Subsequent Tc-99m pyrophosphate infarct size was 15 +/- 9% of the left ventricle for anterior and 17 +/- 9% for inferior infarcts. The QRS0 was correlated with the extent of the Tl-201 perfusion defect (r = 0.79, p < 0.001), and the day 7 QRS score was correlated with Tc-99m pyrophosphate infarct size (r = 0.79, p < 0.005). CONCLUSIONS The 32-point QRS score can provide useful immediate measurements of the ischemic risk region and subsequent infarct size.

Pharmacokinetic assessment of novel anti-cancer drugs using spectral analysis and positron emission tomography: A feasibility study

Purpose: The aim of this study was to investigate the feasibility of evaluating the pharmacokinetics of radiolabeled anti-cancer drugs using spectral analysis, a non-compartmental tracer kinetic modeling technique, and positron emission tomography (PET). Methods: Dynamic PET studies were performed on patients receiving tracer doses of 5-fluorouracil (5-[18F]-FU) and two developmental drugs – [11C]-temozolomide and [11C]-acridine carboxamide. Spectral analysis was then used to (a) determine individual and group average pharmacokinetics, (b) predict tumour handling in response to different drug administration regimens, and (c) produce functional parametric images describing regional pharmacokinetics. Results: Spectral analysis could distinguish tumour kinetics from normal tissue kinetics in an individual [11C]-temozolomide study and demonstrated a markedly greater volume of distribution (VD) in glioma than in normal brain, although there was no appreciable difference in mean residence time. Analysis of pooled acridine carboxamide data (n=22) revealed a relatively large VD (and prolonged retention) in the liver and spleen and a markedly lower VD (and initial uptake) in the brain. Continuous infusion of 5-[18F]-FU was predicted to achieve a concentration in colorectal metastases in liver approximately 10 times that achieved in plasma at 10 h after commencement of the infusion. Conclusions: We conclude that spectral analysis provides important pharmacokinetic information about radiolabeled anti-cancer drugs with relatively few model assumptions.

In vivo imaging of nicotinic receptor upregulation following chronic (-)-nicotine treatment in baboon using SPECT

To quantify changes in neuronal nAChR binding in vivo, quantitative dynamic SPECT studies were performed with 5-[(123)I]-iodo-A-85380 in baboons pre and post chronic treatment with (-)-nicotine or saline control. Infusion of (-)-nicotine at a dose of 2.0 mg/kg/24h for 14 days resulted in plasma (-)-nicotine levels of 27.3 ng/mL. This is equivalent to that found in an average human smoker (20 cigarettes a day). In the baboon brain the regional distribution of 5-[(123)I]-iodo-A-85380 was consistent with the known densities of nAChRs (thalamus > frontal cortex > cerebellum). Changes in nAChR binding were estimated from the volume of distribution (V(d) ) and binding potential (BP) derived from 3-compartment model fits. In the (-)-nicotine treated animal V(d) was significantly increased in the thalamus (52%) and cerebellum (50%) seven days post cessation of (-)-nicotine treatment, suggesting upregulation of nAChRs. The observed 33% increase in the frontal cortex failed to reach significance. A significant increase in BP was seen in the thalamus. In the saline control animal no changes were observed in V(d) or BP under any experimental conditions. In this preliminary study, we have demonstrated for the first time in vivo upregulation of neuronal nAChR binding following chronic (-)-nicotine treatment.