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S R Cherry

Publications and source records attributed to S R Cherry.

At least 19 recordsLinked to original sources
PubMed2004

Performance measurements of a depth-encoding PET detector module based on position-sensitive avalanche photodiode read-out.

We are developing a high-resolution, high-efficiency positron emission tomography (PET) detector module with depth of interaction (DOI) capability based on a lutetium oxyorthosilicate (LSO) scintillator array coupled at both ends to position-sensitive avalanche photodiodes (PSAPDs). In this paper we present the DOI resolution, energy resolution and timing resolution results for complete detector modules. The detector module consists of a 7 x 7 matrix of LSO scintillator crystals (1 x 1 x 20 mm3 in dimension) coupled to 8 x 8 mm2 PSAPDs at both ends. Flood histograms were acquired and used to generate crystal look-up tables. The DOI resolution was measured for individual crystals within the array by using the ratio of the signal amplitudes from the two PSAPDs on an event-by-event basis. A measure of the total scintillation light produced was obtained by summing the signal amplitudes from the two PSAPDs. This summed signal was used to measure the energy resolution. The DOI resolution was measured to be 3-4 mm FWHM irrespective of the position of the crystal within the array, or the interaction location along the length of the crystal. The total light signal and energy resolution was almost independent of the depth of interaction. The measured energy resolution averaged 14% FWHM. The coincidence timing resolution measured using a pair of identical detector modules was 4.5 ns FWHM. These results are consistent with the design goals and the performance required of a compact, high-resolution and high-efficiency PET detector module for small animal and breast imaging applications.

Equipment Design↗
PubMed2004

Lutetium oxyorthosilicate block detector readout by avalanche photodiode arrays for high resolution animal PET.

Avalanche photodiodes (APDs) have proven to be useful as light detectors for high resolution positron emission tomography (PET). Their compactness makes these devices excellent candidates for replacing bulky photomultiplier tubes (PMTs) in PET systems where space limitations are an issue. The readout of densely packed, 10 x 10 lutetium oxyorthosilicate (LSO) block detectors (crystal size 2.0 x 2.0 x 12 mm3) with custom-built monolithic 3 x 3 APD arrays was investigated. The APDs had a 5 x 5 mm2 active surface and were arranged on a 6.25 mm pitch. The dead space on the edges of the array was 1.25 mm. The APDs were operated at a bias voltage of approximately 380 V for a gain of 100 and a dark current of 10 nA per APD. The standard deviation in gain between the APDs in the array ranged from 1.8 to 6.5% as the gain was varied from 50 to 108. A fast, low-noise, multi-channel charge sensitive preamplifier application-specific integrated circuit (ASIC) was developed for the APD readout. The amplifier had a rise time of 8 ns, a noise floor of 515 e- rms and a 9 e- pF(-1) noise slope. An acquired flood image showed that all 100 crystals from the block detector could be resolved. Timing measurements with single-channel LSO-APD detectors, as well as with the array, against a plastic scintillator and PMT assembly showed a time resolution of 1.2 ns and 2.5 ns, respectively. The energy resolution measured with a single 4.0 x 4.0 x 10 mm3 LSO crystal, wrapped in four-layer polytetrafluoroethylene (PTFE) tape and coupled with optical grease on a single APD of the array, yielded 15% (full width at half maximum, FWHM) at 511 keV. Stability tests over 9 months of operation showed that the APD arrays do not degrade appreciably. These results demonstrate the ability to decode densely packed LSO scintillation blocks with compact APD arrays. The good timing and energy resolution makes these detectors suitable for high resolution PET.

Equipment Design↗
PubMed2003

An improved analytical detector response function model for multilayer small-diameter PET scanners.

The optimization of spatial resolution is a critical consideration in the design of small-diameter positron emission tomography (PET) scanners for animal imaging, and is often addressed with Monte Carlo simulations. As a faster and simpler solution, we have developed a new analytical model of the PET detector response function, and implemented the model for a small single-slice, multilayer PET scanner. The accuracy of the model has been assessed by comparison with both Monte Carlo simulations and experimental measurements published in the literature. Results from the analytical model agreed well with the Monte Carlo method, being noise free and two to three orders of magnitude faster. The only major discrepancy was a slight underestimation of the width of the point spread function by the analytical method as inter-crystal scatter is neglected. We observed good agreement between the predictions of the model and experimental measurements. For two large-diameter scanners additional discrepancies were seen due to photon acollinearity, which is not considered in the model. We have shown that the simple and fast analytical detector response function model can provide accurate estimates of spatial resolution for small-diameter PET scanners, and could be a useful tool for several applications, complementing or cross-validating other simulation methods.

Algorithms↗
PubMed2002

Effects of image resolution on autoradiographic measurements of posterior cingulate activity in PDAPP mice: implications for functional brain imaging studies of transgenic mouse models of Alzheimer's Disease.

Fluorodeoxyglucosepositron emission tomography (PET) studies find that persons with Alzheimer's disease have preferential reductions in posterior cingulate activity. Using fluorodeoxyglucose autoradiography, we found that transgenic mice overexpressing a mutant form of the human amyloid precursor protein have preferentially reduced activity in the same region, providing a potential brain imaging indicator of Alzheimer's disease in these animals. In this study, we considered the feasibility of using in vivo imaging techniques, such as PET, to detect this reduction despite their limitations in spatial resolution. Autoradiographic measurements of posterior cingulate activity were remeasured in the previously studied PDAPP transgenic and littermate control mice after the images were filtered to lower spatial resolutions. We continued to detect significantly lower cingulate activity in the transgenic mice when the images were blurred to 0.50 mm, failed to detect significantly abnormal activity when the images were blurred to 0.75 mm, and, indeed, found significantly higher activity when the images were blurred to 1.0 mm. Reversal in direction of the abnormality appears attributable to a previously observed truncation in the corpus callosum in PDAPP mice. With the possible exception of future in vivo imaging techniques that have a spatial resolution greater than or equal to 0.50 mm and high sensitivity, noninvasive functional brain imaging techniques like PET may not be suitable for detecting declines in regional activity in PDAPP mice. It remains possible that these imaging techniques will prove useful in transgenic mouse lines that do not exhibit the same morphological abnormalities in neighboring white matter regions.

Alzheimer Disease↗
PubMed2001

Evaluation of a stereotactic frame for repositioning of the rat brain in serial positron emission tomography imaging studies.

For serial imaging studies of the rat brain with positron emission tomography (PET), reproducible positioning of the head can facilitate spatial alignment of images and quantitative analysis. To achieve this aim, we constructed a plastic head frame and tested the positioning reproducibility on a high-resolution small-animal PET scanner, microPET. Two sets of ear bars, with tapers of either 18 degrees (sharp) or 45 degrees (blunt), were evaluated for their relative precision in securing the animal to the frame. For sequential positioning of an animal, average distances from the mean position of 0.51 mm (SD 0.41 mm) and 0.91 mm (SD 0.48 mm) were measured with the sharp and blunt ear bars, respectively. These results show that a rat brain can be reproducibly positioned using the frame, with a variation of position less than the spatial resolution of modern animal PET scanners. Brain regions of interest defined on one scan and copied across subsequent scans of a frame-repositioned animal resulted in an average coefficient of variation of 5.4% (SD 2.7%) using the sharp ear bars and 6.8% (SD 2.5%) using the blunt ear bars. This methodology has the potential to improve quantitative assessment for serial PET studies.

Animals↗
PubMed2001

Combining anatomy and function: the path to true image fusion.

Modern imaging technologies visualize different aspects of disease in a non-invasive way. Considerable progress has been made in the fusion of images from different imaging modalities using software approaches. One goal of fusion software is to align anatomical and functional images and allow improved spatial localization of abnormalities. The resulting correlation of the anatomical and functional images may clarify the nature of the abnormality and help diagnose or stage the underlying disease. Whereas successful image fusion software has been developed for the brain, only limited success has been achieved for image alignment in other parts of the body. The development and current status of alternative approaches are presented. Dual-modality imaging is described with devices where two modalities are combined and mounted in a single gantry. The use of existing scanner technology ensures that no compromises are made in the clinical efficacy of either the anatomical or functional imaging modality. A combined positron emission tomography (PET) and computed tomography (CT) scanner has been developed and is undergoing clinical evaluation. Combining PET with MR is technologically more challenging because of the strong magnetic fields restricting the use of certain electronic components. An overview of the current status and future prospects of dual-modality imaging devices is presented.

Diagnostic Imaging↗
PubMed2001

Complementary emerging techniques: high-resolution PET and MRI.

Noninvasive imaging technologies provide a unique window on the anatomy, physiology and function of living organisms. Imaging systems and methods have been developed for the study of small animal model systems that offer exciting new possibilities in neuroscience. Advances in magnetic resonance microscopy and positron emission tomography, and their applications in brain imaging, have provided many benefits to neurobiology, ranging from detailed in vivo neuroanatomy to the measurement of specific molecular targets.

Animals↗
PubMed2001

A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival.

The role of DNA methylation and of the maintenance DNA methyltransferase Dnmt1 in the epigenetic regulation of developmental stage- and cell lineage-specific gene expression in vivo is uncertain. This is addressed here through the generation of mice in which Dnmt1 was inactivated by Cre/loxP-mediated deletion at sequential stages of T cell development. Deletion of Dnmt1 in early double-negative thymocytes led to impaired survival of TCRalphabeta(+) cells and the generation of atypical CD8(+)TCRgammadelta(+) cells. Deletion of Dnmt1 in double-positive thymocytes impaired activation-induced proliferation but differentially enhanced cytokine mRNA expression by naive peripheral T cells. We conclude that Dnmt1 and DNA methylation are required for the proper expression of certain genes that define fate and determine function in T cells.

Animals↗
PubMed2001

Detector development for microPET II: a 1 microl resolution PET scanner for small animal imaging.

We are currently developing a small animal positron emission tomography (PET) scanner with a design goal of 1 microlitre (1 mm3) image resolution. The detectors consist of a 12 x 12 array of 1 x 1 x 10 mm lutetium oxyorthosilicate (LSO) scintillator crystals coupled to a 64-channel photomultiplier tube (PMT) via 5 cm long optical fibre bundles. The optical fibre connection allows a high detector packing fraction despite the dead space surrounding the active region of the PMT. Optical fibre bundles made from different types of glass were tested for light transmission, and also their effects on crystal identification and energy resolution, and compared to direct coupling of the LSO arrays to the PMTs. We also investigated the effects of extramural absorber (EMA) in the fibre bundles. Based on these results, fibre bundles manufactured from F2 glass were selected. We built three pairs of prototype detectors (directly coupled LSO array, fibre bundle without EMA and fibre bundle with EMA) and measured flood histograms, energy resolution, intrinsic spatial resolution and timing resolution. The results demonstrated an intrinsic spatial resolution (FWHM) of 1.12 mm (directly coupled), 1.23 mm (fibre bundle without EMA coupling) and 1.27 mm (fibre bundle with EMA coupling) using an approximately 500 microm diameter Na-22 point source. Using a 330 microm outer diameter steel needle line source filled with F-18, spatial resolution for the detector with the EMA optical fibre bundle improved to 1.05 mm. The respective timing and energy FWHM values were 1.96 ns, 21% (directly coupled), 2.20 ns, 23% (fibre bundle without EMA) and 2.99 ns, 30% (fibre bundle with EMA). The peak-to-valley ratio in the flood histograms was better with EMA (5:1) compared to the optical fibre bundle without EMA (2.5:1), due to the decreased optical cross-talk. In comparison to the detectors used in our current generation microPET scanner, these detectors substantially improve on the spatial resolution, preserve the timing resolution and provide adequate energy resolution for a modern high-resolution animal PET tomograph.

Animals↗
PubMed2001

Performance evaluation of the microPET P4: a PET system dedicated to animal imaging.

The microPET Primate 4-ring system (P4) is an animal PET tomograph with a 7.8 cm axial extent, a 19 cm diameter transaxial field of view (FOV) and a 22 cm animal port. The system is composed of 168 detector modules, each with an 8 x 8 array of 2.2 x 2.2 x 10 mm3 lutetium oxyorthosilicate crystals, arranged as 32 crystal rings 26 cm in diameter. The detector crystals are coupled to a Hamamatsu R5900-C8 PS-PMT via a 10 cm long optical fibre bundle. The detectors have a timing resolution of 3.2 ns, an average energy resolution of 26%, and an average intrinsic spatial resolution of 1.75 mm. The system operates in 3D mode without inter-plane septa, acquiring data in list mode. The reconstructed image spatial resolution ranges from 1.8 mm at the centre to 3 mm at 4 cm radial offset. The tomograph has a peak system sensitivity of 2.25% at the centre of the FOV with a 250-750 keV energy window. The noise equivalent count rate peaks at 100-290 kcps for representative object sizes. Images from two phantoms and three different types of laboratory animal demonstrate the advantage of the P4 system over the original prototype microPET. including its threefold improvement in sensitivity and a large axial FOV sufficient to image an entire mouse in a single bed position.

Animals↗
PubMed2001

Use of positron emission tomography in animal research.

Among the several imaging technologies applied to in vivo studies of research animals, positron emission tomography (PET) is a nuclear imaging technique that permits the spatial and temporal distribution of compounds labeled with a positron-emitting radionuclide to be determined noninvasively. It can be viewed as an in vivo analog of classic autoradiographic methods. Many different positron-labeled compounds have been synthesized as tracers that target a range of specific markers or pathways. These tracers permit the measurement of quantities of biological interest ranging from glucose metabolism to gene expression. PET has been extensively used in imaging studies of larger research animals such as dogs and nonhuman primates. Now, using newly developed high-resolution dedicated animal PET scanners, these types of studies can be performed in small laboratory animals such as mice and rats. The entire whole-body biodistribution kinetics can be determined in a single imaging study in a single animal. This technique should enable statistically significant biodistribution data to be obtained from a handful of animals, compared with the tens or hundreds of animals that might be required for a similar study by autoradiography. PET also enables repeat studies in a single subject, facilitating longitudinal study designs and permitting each animal to serve as its own control in experiments designed to evaluate the effects of a particular interventional strategy. This paper provides a basic overview of the methodology of PET imaging, a discussion of the advantages and drawbacks of PET as a tool in animal research, a description of the latest generation of dedicated animal PET scanners, and a review of a few of the many applications of PET in animal research to date.

Anatomy, Cross-Sectional↗
PubMed2001

Fundamentals of positron emission tomography and applications in preclinical drug development.

Positron emission tomography (PET) is a nuclear imaging technique that can dynamically image trace amounts of positron-labeled radiopharmaceuticals in vivo. Tracer concentrations can be determined quantitatively, and by application of appropriate tracer kinetic models, the rates of a wide range of different biological processes can be measured noninvasively in humans. PET has been used as a research tool for more than 25 years and has also found clinical applications, particularly in oncology, neurological disorders, and cardiovascular disease. Recently, there has been tremendous interest in applying PET technology to in vivo small-animal imaging. Significant improvements in the imaging technology now permit a wide range of PET studies in mice and rats, using compact, relatively low-cost, dedicated small-animal PET scanners. This article reviews the fundamental basis of PET imaging and discusses the development of small-animal PET scanners and their possible application in preclinical drug development.

Animals↗
PubMed2000

PET imaging of transgene expression.

A vital step in transgenic animal study and gene therapy is the ability to assay the extent of transgene expression. Unfortunately, classic methods of assaying transgene expression require biopsies or death of the subject. We are developing techniques to noninvasively and repetitively determine the location, duration, and magnitude of transgene expression in living animals. This will allow investigators and clinicians to assay the effectiveness of their particular experimental and therapeutic paradigms. Of radionuclide (single photon emission computed tomography, positron emission tomography [PET]), optical (green fluorescent protein, luciferase), and magnetic (magnetic resonance imaging) approaches, only the radionuclide approach has sufficient sensitivity and quantitation to measure the expression of genes in vivo. We describe the instrumentation involved in high resolution PET scanning. We also describe the principles of PET reporter gene/reporter probe in vivo imaging, the development of two in vivo reporter gene imaging systems, and the validation of our ability to noninvasively, quantitatively, and repetitively image gene expression in murine viral gene transfer and transgenic models. We compare the two reporter gene systems and discuss their utility for the study of transgenic animals and gene therapies. Finally, we mention alternative approaches to image gene expression by using radiolabeled antibody fragments to image specific proteins and radiolabeled oligonucleotides to image RNA messages directly.

Animals↗
PubMed2000

V(D)J recombination is not activated by demethylation of the kappa locus.

V(D)J recombination is thought to be regulated by changes in the accessibility of target sites, such as modulation of methylation. To test whether demethylation of the kappa locus can activate recombination, we generated two recombinationally active B cell lines in which the gene for maintenance of genomic DNA methylation, Dnmt1, was flanked with loxP sites. Transduction with a retrovirus expressing both the cre recombinase and green fluorescent protein allowed us to purify recombinationally active cells devoid of methylation. Loss of methylation of the kappa locus was not sufficient to activate recombination, although transcription was activated in one line. It appears that demethylation of the kappa locus is not the rate-limiting step for altering accessibility and thus regulated demethylation does not generate specificity of recombination.

Animals↗
PubMed2000

Dynamic changes in cerebral glucose metabolism in conscious infant monkeys during the first year of life as measured by positron emission tomography.

Recently, advances in spatial resolution have provided the opportunity to utilize positron emission tomography (PET) to examine local cerebral metabolic rates for glucose (lCMR(glc)) in large animals noninvasively, thereby allowing repeated lCMR(glc) measurements in the same animal. Previous studies have attempted to describe the ontogeny of cerebral glucose metabolism in anesthetized nonhuman primates using [18F]fluorodeoxyglucose (FDG) and PET. However, the use of sedation during the tracer uptake period may influence lCMR(glc). This study was conducted to describe lCMR(glc) in conscious infant vervet monkeys (Cercopithecus aethiops sabaeus) during the first year of life utilizing FDG-PET. Cross-sectional studies (n=23) displayed lowest and highest lCMR(glc) in all structures at the 2-3 and 8-9 month age groups, respectively. The metabolic pattern suggested an increase in lCMR(glc) values between 2 and 8 months of age with decreased metabolism observed at 10-12 months of age in all regions. Peak lCMR(glc) values at 8 months were an average of 84+/-24% higher than values seen at the youngest age examined quantitatively (2-3 months). The regions of greatest and smallest increases in lCMR(glc) at 8 months were the cerebellar hemispheres (90%) and the thalamus (39%), respectively. Longitudinal analysis in 4 animals supported this developmental pattern, demonstrating the ability to detect changes in cerebral glucose metabolism within animals and the potential for FDG-PET in nonhuman primate models of brain maturation. By determining the normative profile of lCMR(glc) during development in monkeys, future application of FDG-PET will provide the opportunity to longitudinally assess the effects of environmental or pharmacological intervention on the immature brain.

Aging↗
PubMed2000

Seeing is believing: non-invasive, quantitative and repetitive imaging of reporter gene expression in living animals, using positron emission tomography.

The ability to monitor reporter gene expression in living animals and in patients will permit longitudinal examinations both of somatically transferred DNA in experimental animals and patients and of transgenic constructs expressed in experimental animals. If investigators can non-invasively monitor the organ and tissue specificity, the magnitude and the duration of gene expression from somatically transferred DNA and from transgenes, conceptually new experimental paradigms will be possible. If clinicians can non-invasively monitor the location, extent and duration of somatically transferred genes, they will be better able to determine the correlations between expression of therapeutic genes and clinical outcomes. We have developed two reporter gene systems for in vivo reporter gene imaging in which the protein products of the reporter genes sequester positron-emitting reporter probes. The "PET reporter gene" dependent sequestration of the "PET reporter probes" is subsequently measured in living animals by Positron Emission Tomography (PET). We describe here the principles of PET reporter gene/PET reporter probe in vivo imaging, the development of two imaging systems, and the validation of their ability to non-invasively, quantitatively and repetitively image reporter gene expression in murine viral gene transfer and transgenic models.

Animals↗
PubMed2000

Deficits in striatal dopamine D(2) receptors and energy metabolism detected by in vivo microPET imaging in a rat model of Huntington's disease.

Functional imaging by repeated noninvasive scans of specific (18)F tracer distribution using a high-resolution small-animal PET scanner, the microPET, assessed the time course of alterations in energy utilization and dopamine receptors in rats with unilateral striatal quinolinic acid lesions. Energy utilization ipsilateral to the lesion, determined using scans of 2-deoxy-2-[(18)F]fluoro-d-glucose uptake, was compromised severely 1 week after intrastriatal excitotoxin injections. When the same rats were imaged 5 and 7 weeks postlesion, decrements in energy metabolism were even more prominent. In contrast, lesion-induced effects on dopamine D(2) receptor binding were more progressive, with an initial upregulation of [3-(2'-(18)F]fluoroethyl)spiperone binding apparent 1 week postlesion followed by a decline 5 and 7 weeks thereafter. Additional experiments revealed that marked upregulation of dopamine D(2) receptors consequent to quinolinic acid injections could be detected as early as 3 days after the initial insult. Postmortem markers of striatal GABAergic neurons were assessed in the same rats 7 weeks after the lesion: expression of glutamic acid decarboxylase and dopamine D(1) receptor mRNA, as well as [(3)H]SCH-23,390 and [(3)H]spiperone binding to dopamine D(1) and D(2) receptors, respectively, detected prominent decrements consequent to the lesion. In contrast, by 7 weeks postlesion [(3)H]WIN-35,428 binding to dopamine transport sites within the striatum appeared to be enhanced proximal to the quinolinic acid injection sites. The results demonstrate that functional imaging using the microPET is a useful technique to explore not only the progressive neurodegeneration that occurs in response to excitotoxic insults, but also to examine more closely the intricacies of neurotransmitter activity in a small animal model of HD.

Animals↗