William A. Hallett

Lactate: A Preferred Fuel for Human Brain Metabolism in Vivo

Recent in vitro studies suggest that lactate, rather than glucose, may be the preferred fuel for neuronal metabolism. The authors examined the effect of lactate on global brain glucose uptake in euglycemic human subjects using 18fluorodeoxyglucose (FDG) positron emission tomography (PET). Eight healthy men, aged 40 to 54 years, underwent a 60-minute FDG-PET scan on two occasions in random order. On one occasion, 6.72% sodium lactate was infused at a rate of 50 μmol · kg−1 · min−1 for 20 minutes and then reduced to 30 μmol · kg−1 · min−1; 1.4% sodium bicarbonate was infused as a control on the other occasion. Plasma glucose levels were not different between the two groups (5.3 ± 0.23 and 5.3 ± 0.24 mmol/L, P = 0.55). Plasma lactate was significantly elevated by lactate infusion (4.08 ± 0.35 vs. 0.63 ± 0.22 mmol/L, P < 0.0005. The whole-brain rate of glucose uptake was significantly reduced by approximately 17% during lactate infusion (0.195 ± 0.022 vs. 0.234 ± 0.020 μmol · g−1 · min−1, P = 0.001). The authors conclude that, in vivo in humans, circulating lactate is used by the brain at euglycemia, with sparing of glucose.

Design and development of an MR-compatible PET scanner for imaging small animals

An MR compatible PET system has been designed and is currently under construction. It will consist of four concentric rings of LSO crystals, each coupled to one of eight multi-channel photomultiplier tubes via 3.5 m optical fibres. The photomultiplier tubes may be located outside the main magnetic field of the MR scanner. A highly reproducible method has been established to optimise the amount of scintillation light that reaches the PM tubes, as this factor will heavily influence the scanner performance. Two small sections of the scanner, each containing 4 by 4 crystal arrays, demonstrated good flood position histograms with all sixteen channels clearly identifiable. The light loss through a fibre of length of 3.25 m was approximately 70%. The spatial resolution of the two arrays in coincidence was measured at 1.6 mm (FWHM). The temporal resolution of one array in coincidence with a single LSO crystal was measured to be 10.9 ns. A technique for improving sampling at the centre of the field of view within the scanner has also been investigated, whereby the concentric rings are offset with respect to one another. An offset of one quarter of the crystal width between layers results in significantly improved sampling. These results indicate that the scanner will be capable of carrying out the studies for which it has been designed.

A Multi-Center Randomized Proof-of-Concept Clinical Trial Applying [18F]FDG-PET for Evaluation of Metabolic Therapy with Rosiglitazone XR in Mild to Moderate Alzheimer's Disease

Here we report the first multi-center clinical trial in Alzheimers disease (AD) using fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) measures of brain glucose metabolism as the primary outcome. We contrasted effects of 12 months treatment with the PPARγ agonist Rosiglitazone XR versus placebo in 80 mild to moderate AD patients. Secondary objectives included testing for reduction in the progression of brain atrophy and improvement in cognition. Active treatment was associated with a sustained but not statistically significant trend from the first month for higher mean values in Kiindex and CMRgluindex, novel quantitative indices related to the combined forward rate constant for [18F]FDG uptake and to the rate of cerebral glucose utilization, respectively. However, neither these nor another analytical approach recently validated using data from the Alzheimers Disease Neuroimaging Initiative indicated that active treatment decreased the progression of decline in brain glucose metabolism. Rates of brain atrophy were similar between active and placebo groups and measures of cognition also did not suggest clear group differences. Our study demonstrates the feasibility of using [18F]FDG-PET as part of a multi-center therapeutics trial. It suggests that Rosiglitazone is associated with an early increase in whole brain glucose metabolism, but not with any biological or clinical evidence for slowing progression over a 1 year follow up in the symptomatic stages of AD.

18F-ICMT-11, a Caspase-3–Specific PET Tracer for Apoptosis: Biodistribution and Radiation Dosimetry

Effective anticancer therapy induces tumor cell death through apoptosis. Noninvasive monitoring of apoptosis during therapy may provide predictive outcome information and help tailor treatment. A caspase-3–specific imaging radiotracer, 18F-(S)-1-((1-(2-fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)-5-(2(2,4-difluorophenoxymethyl)-pyrrolidine-1-sulfonyl)isatin (18F-ICMT-11), has been developed for use in PET studies. We report the safety, biodistribution, and internal radiation dosimetry profiles of 18F-ICMT-11 in 8 healthy human volunteers. Methods: 18F-ICMT-11 was intravenously administered as a bolus injection (mean ± SD, 159 ± 2.75 MBq; range, 154–161 MBq) to 8 healthy volunteers (4 men, 4 women). Whole-body (vertex to mid thigh) PET/CT scans were acquired at 6 time points, up to 4 h after tracer injection. Serial whole blood, plasma, and urine samples were collected for radioactivity measurement and radiotracer stability. In vivo 18F activities were determined from quantitative analysis of the images, and time–activity curves were generated. The total numbers of disintegrations in each organ normalized to injected activity (residence times) were calculated as the area under the curve of the time–activity curve, normalized to injected activities and standard values of organ volumes. Dosimetry calculations were then performed using OLINDA/EXM 1.1. Results: Injection of 18F-ICMT-11 was well tolerated in all subjects, with no serious tracer-related adverse events reported. The mean effective dose averaged over both men and women was estimated to be 0.025 ± 0.004 mSv/MBq (men, 0.022 ± 0.004 mSv/MBq; women, 0.027 ± 0.004 mSv/MBq). The 5 organs receiving the highest absorbed dose (mGy/MBq), averaged over both men and women, were the gallbladder wall (0.59 ± 0.44), small intestine (0.12 ± 0.05), upper large intestinal wall (0.08 ± 0.07), urinary bladder wall (0.08 ± 0.02), and liver (0.07 ± 0.01). Elimination was both renal and via the hepatobiliary system. Conclusion: 18F-ICMT-11 is a safe PET tracer with a dosimetry profile comparable to other common 18F PET tracers. These data support the further development of 18F-ICMT-11 for clinical imaging of apoptosis.

Radiation dose estimates for carbon-11-labelled PET tracers

INTRODUCTION Carbon-11-labelled positron emission tomography (PET) tracers commonly used in biomedical research expose subjects to ionising radiation. Dosimetry is the measurement of radiation dose, but also commonly refers to the estimation of health risk associated with ionising radiation. This review describes radiation dosimetry of carbon-11-labelled molecules in the context of current PET research and the most widely used regulatory guidelines. METHODS A MEDLINE literature search returned 42 articles; 32 of these were based on human PET data dealing with radiation dosimetry of carbon-11 molecules. Radiation burden expressed as effective dose and maximum absorbed organ dose was compared between tracers. RESULTS All but one of the carbon-11-labelled PET tracers have an effective dose under 9 μSv/MBq, with a mean of 5.9 μSv/MBq. Data show that serial PET scans in a single subject are feasible for the majority of radiotracers. CONCLUSION Although differing in approach, the two most widely used regulatory frameworks (those in the USA and the EU) do not differ substantially with regard to the maximum allowable injected activity per PET study. The predictive validity of animal dosimetry models is critically discussed in relation to human dosimetry. Finally, empirical PET data are related to human dose estimates based on homogenous distribution, generic models and maximum cumulated activities. Despite the contribution of these models to general risk estimation, human dosimetry studies are recommended where continued use of a new PET tracer is foreseen.

Performance Evaluation of an MRI-Compatible Pre-Clinical PET System Using Long Optical Fibers

We have designed and constructed an MR-compatible PET system for fully simultaneous PET/MR studies of small animals. The scanner uses long optical fibers to distance the magnetic field sensitive PET PMTs from the high magnetic field at the center of an MR scanner. It is a single slice system with an inner diameter of 7 cm. A full evaluation of the performance of the PET system and the results of an MR compatibility assessment in a Philips Achieva whole body 3 T MRI scanner are presented. The reconstructed resolution of the PET scanner is 1.5 mm at the center falling to 2.5 mm at the edge of the field of view; the system sensitivity is 0.95%; the count rate is linear up to an activity of 6 MBq (~4 kcps) and the scatter fraction is 42% which can be reduced to 26% using MR-compatible gamma shields. Simultaneous PET/MR images of phantoms and a mouse have been acquired. The system is highly MR compatible, as demonstrated here, showing no degradation in performance of either the MR or PET system in the presence of the other modality. The system will be used to demonstrate novel pre-clinical applications of simultaneous PET/MR.

Accurate attenuation correction in PET using short transmission scans and consistency information

The authors show how the consistency conditions of the Radon transform can be used to aid attenuation correction in positron emission tomography (PET) using short transmission scans. The technique is expected to be useful in situations where limited time is available for transmission imaging (e.g., whole-body PET). The proposed method uses 2-min transmission scans that are reconstructed and then segmented into regions of uniform attenuation. Consistency information is used to determine the thresholds for segmentation of the transmission image and the attenuation coefficients. In particular, a downhill simplex algorithm is used to find the parameters that are most consistent with the measured emission data. One potential advantage of the proposed technique over conventional segmentation methods (which work purely on the transmission data) is that the emission data are used to drive the segmentation process. Therefore, the technique should produce the attenuation image that is most appropriate for attenuation correction. The algorithm is tested using simulated data and compared with an adaptive thresholding technique using clinical PET data. The results show that the method produces reconstructed images with similar accuracy and noise levels to those obtained using a 10 min transmission scan. The results also show that the proposed technique has some advantages over the adaptive thresholding technique when imaging the abdomen. The authors conclude that the proposed technique may provide a viable means of producing quantitatively accurate whole-body PET images in a clinically feasible time.

Accurate markerless respiratory tracking for gated whole body PET using the Microsoft Kinect

The motion due to respiration is responsible for greatly reducing image quality of whole body positron emission tomography, PET. A simple method to produce a respiratory signal to enable gating of PET listmode data using the Microsoft Kinect, a consumer grade 3D scanner, is presented. Phantom data produced by a sinusoidally oscillating phantom being tracked by an existing commercially available respiratory monitoring system and a Kinect based contactless tracking system shows that the Kinect system outperforms the Varian RPM tracking by producing higher resolution traces. When testing the Kinect using human subjects, the collected surface trace is sensitive enough to detect the patients heart rate. This has potential for improving motion correction of whole body imaging by including extra surface information provided by the Kinect, in addition to the basic respiratory signal.

The design and initial calibration of an optical tracking system using the Microsoft Kinect

Robust motion correction in medical imaging requires accurate and reliable motion tracking. Current systems use devices such as the Polaris Vicra position sensor to monitor the position and orientation of a tracking tool which is fixed to the subject. Although in principle these methods offer high positional accuracy this is lost if the tool slips. Markerless motion tracking aims to track the object directly without the use of markers or a tracking tool. To date these methods have either been unsuccessful or too expensive to have been widely implemented. The Microsoft Kinect is a low cost RGB+D (colour plus depth) video camera. We have used the Kinect to perform motion tracking of a head phantom using a CT of the head as a high resolution template. We present initial results that show the Kinect can track rigid body motion to within &#60;2 mm of that measured by a Polaris system. We use the PointCloudLibrary open project [1] algorithm implementations to register the CT template to the Kinect frames.

Biodistribution and Radiation Dosimetry of Deuterium-Substituted 18F-Fluoromethyl-[1, 2-2H4]Choline in Healthy Volunteers

11C-choline and 18F-fluoromethylcholine (18F-FCH) have been used in patients to study tumor metabolic activity in vivo; however, both radiotracers are readily oxidized to respective betaine analogs, with metabolites detectable in plasma soon after injection of the radiotracer. A more metabolically stable FCH analog, 18F-fluoromethyl-[1,2-2H4]choline (18F-D4-FCH), based on the deuterium isotope effect, has been developed. We report the safety, biodistribution, and internal radiation dosimetry profiles of 18F-D4-FCH in 8 healthy human volunteers. Methods: 18F-D4-FCH was intravenously administered as a bolus injection (mean ± SD, 161 ± 2.17 MBq; range, 156–163 MBq) to 8 healthy volunteers (4 men, 4 women). Whole-body (vertex to mid thigh) PET/CT scans were acquired at 6 time points, up to 4 h after tracer injection. Serial whole-blood, plasma, and urine samples were collected for radioactivity measurement and plasma radiotracer metabolites. Tissue 18F radioactivities were determined from quantitative analysis of the images, and time–activity curves were generated. The total numbers of disintegrations in each organ normalized to injected activity (residence times) were calculated as the area under the curve of the time–activity curve normalized to injected activities and standard organ volumes. Dosimetry calculations were performed using OLINDA/EXM 1.1. Results: The injection of 18F-D4-FCH was well tolerated in all subjects, with no radiotracer-related serious adverse event reported. The mean effective dose averaged over both men and women (±SD) was estimated to be 0.025 ± 0.004 (men, 0.022 ± 0.002; women, 0.027 ± 0.002) mSv/MBq. The 5 organs receiving the highest absorbed dose (mGy/MBq) were the kidneys (0.106 ± 0.03), liver (0.094 ± 0.03), pancreas (0.066 ± 0.01), urinary bladder wall (0.047 ± 0.02), and adrenals (0.046 ± 0.01). Elimination was through the renal and hepatic systems. Conclusion: 18F-D4-FCH is a safe PET radiotracer with a dosimetry profile comparable to other common 18F PET tracers. These data support the further development of 18F-D4-FCH for clinical imaging of choline metabolism.