Human Brain Positron Emission Tomography Research Articles

Pridopidine Does Not Significantly Prolong the QTc Interval at the Clinically Relevant Therapeutic Dose.

Pridopidine is a highly selective sigma-1 receptor (S1R) agonist in development for the treatment of Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Pridopidine's activation of S1R enhances cellular processes that are crucial for neuronal function and survival but are impaired in neurodegenerative diseases. Human brain positron emission tomography (PET) imaging studies show that at the therapeutic dose of 45mg twice daily (bid), pridopidine selectively and robustly occupies the S1R. We conducted concentration-QTc (C-QTc) analyses to assess pridopidine's effect on the QT interval and investigated its cardiac safety profile. C-QTc analysis was conducted using data from PRIDE-HD, a phase 2, placebo-controlled trial evaluating four pridopidine doses (45, 67.5, 90, 112.5mg bid) or placebo over 52weeks in HD patients. Triplicate electrocardiograms (ECGs) with simultaneous plasma drug concentrations were determined in 402 patients with HD. The effect of pridopidine on the Fridericia-corrected QT interval (QTcF) was evaluated. Cardiac-related adverse events (AEs) were analyzed from PRIDE-HD alone and from pooled safety data of three double-blind, placebo-controlled trials with pridopidine in HD (HART, MermaiHD, and PRIDE-HD). A concentration-dependent effect of pridopidine on the change from baseline in the Fridericia-corrected QT interval (ΔQTcF) was observed, with a slope of 0.012ms (ms) per ng/mL (90% confidence interval (CI), 0.0109-0.0127). At the therapeutic dose of 45mg bid, the predicted placebo-corrected ΔQTcF (ΔΔQTcF) was 6.6ms (upper bound 90% CI, 8.0ms), which is below the level of concern and not clinically relevant. Analysis of pooled safety data from three HD trials demonstrates that at 45mg bid, pridopidine cardiac-related AE frequencies are similar to those with placebo. No patients reached a QTcF of 500ms and no patients experienced torsade de pointes (TdP) at any pridopidine dose. At the 45mg bid therapeutic dose, pridopidine demonstrates a favorable cardiac safety profile, with an effect on the QTc interval that is below the level of concern and not clinically relevant. PRIDE-HD (TV7820-CNS-20002) trial registration: ClinicalTrials.gov identifier, NCT02006472, EudraCT 2013-001888-23; HART (ACR16C009) trial registration: ClinicalTrials.gov identifier, NCT00724048; MermaiHD (ACR16C008) trial registration: ClinicalTrials.gov identifier, NCT00665223, EudraCT No. 2007-004988-22.

A conformal TOF-DOI Prism-PET prototype scanner for high-resolution quantitative neuroimaging.

Positron emission tomography (PET) has had a transformative impact on oncological and neurological applications. However, still much of PET's potential remains untapped with limitations primarily driven by low spatial resolution, which severely hampers accurate quantitative PET imaging via the partial volume effect (PVE). We present experimental results of a practical and cost-effective ultra-high resolution brain-dedicated PET scanner, using our depth-encoding Prism-PET detectors arranged along a compact and conformal gantry, showing substantial reduction in PVE and accurate radiotracer uptake quantification in small regions. The decagon-shaped prototype scanner has a long diameter of 38.5cm, a short diameter of 29.1 cm, and an axial field-of-view (FOV) of 25.5mm with a single ring of 40 Prism-PET detector modules. Each module comprises a 16 × 16 array of 1.5 × 1.5 × 20-mm3 lutetium yttrium oxyorthosillicate (LYSO) scintillator crystals coupled 4-to-1 to an 8 × 8 array of silicon photomultiplier (SiPM) pixels on one end and to a prismatoid light guide array on the opposite end. The scanner's performance was evaluated by measuring depth-of-interaction (DOI) resolution, energy resolution, timing resolution, spatial resolution, sensitivity, and image quality of ultra-micro Derenzo and three-dimensional (3D) Hoffman brainphantoms. The full width at half maximum (FWHM) DOI, energy, and timing resolutions of the scanner are 2.85 mm, 12.6%, and 271 ps, respectively. Not considering artifacts due to mechanical misalignment of detector blocks, the intrinsic spatial resolution is 0.89-mm FWHM. Point source images reconstructed with 3D filtered back-projection (FBP) show an average spatial resolution of 1.53-mm FWHM across the entire FOV. The peak absolute sensitivity is 1.2% for an energy window of 400-650 keV. The ultra-micro Derenzo phantom study demonstrates the highest reported spatial resolution performance for a human brain PET scanner with perfect reconstruction of 1.00-mm diameter hot-rods. Reconstructed images of customized Hoffman brain phantoms prove that Prism-PET enables accurate radiotracer uptake quantification in small brain regions (2-3 mm). Prism-PET will substantially strengthen the utility of quantitative PET in neurology for early diagnosis of neurodegenerative diseases, and in neuro-oncology for improved management of both primary and metastatic brain tumors.

Alzheimer’s Disease-Related Genes Identified by Linking Spatial Patterns of Pathology and Gene Expression

BackgroundAlzheimer’s Disease (AD) is an age-related neurodegenerative disease with a poorly understood etiology, shown to be partly genetic. Glucose hypometabolism, extracellular Amyloid-beta (Aβ) deposition, and intracellular Tau deposition are cardinal features of AD and display characteristic spatial patterns in the brain. We hypothesize that regional differences in underlying gene expression confer either resistance or susceptibility to AD pathogenic processes and are associated with these spatial patterns. Data-driven methods for the identification of genes involved in AD pathogenesis complement hypothesis-driven approaches that reflect current theories about the disease. Here we present a data driven method for the identification of genes involved in AD pathogenesis based on comparing spatial patterns of normal gene expression to Positron Emission Tomography (PET) images of glucose hypometabolism, Aβ deposition, and Tau deposition.MethodsWe performed correlations between the cerebral cortex microarray samples from the six cognitively normal (CN) post-mortem Allen Human Brain Atlas (AHBA) specimens and PET FDG-18, AV-45, and AV-1451 tracer images from AD and CN participants in the Alzheimer’s Disease and Neuroimaging Initiative (ADNI) database. Correlation coefficients for each gene by each ADNI subject were then entered into a partial least squares discriminant analysis (PLS-DA) to determine sets that best classified the AD and CN groups. Pathway analysis via BioPlanet 2019 was then used to infer the function of implicated genes.ResultsWe identified distinct sets of genes strongly associated with each PET modality. Pathway analyses implicated novel genes involved in mitochondrial function, and Notch signaling, as well as genes previously associated with AD.ConclusionUsing an unbiased approach, we derived sets of genes with expression patterns spatially associated with FDG hypometabolism, Aβ deposition, and Tau deposition in AD. This methodology may complement population-based approaches for identifying the genetic underpinnings of AD.

Brain-Dedicated Emission Tomography Systems: A Perspective on Requirements for Clinical Research and Clinical Needs in Brain Imaging

Research applications of human brain positron emission tomography (PET) imaging have been in place for over 40 years. The unique combination of quantitative PET instrumentation and reconstruction, novel radiotracers, and kinetic modeling has led to the development and application of a huge number of imaging paradigms. These have been applied to the understanding of normal function and pathophysiology, the development of drugs for neuropsychiatric disorders, and the study of drug interactions with the brain. I have had been fortunate to be part of this great endeavor throughout my research career, using brain-dedicated PET scanners, such as the HRRT [item [1] in the Appendix]. Over time, these systems have offered important advantages over whole-body systems. However, due to the limited clinical market for brain PET imaging, scanner manufacturers have focused exclusively on large field-of-view systems for the past two decades [item [2] in the Appendix]. The goal of this perspective is to share a viewpoint on the utility of brain-dedicated PET systems for human research, particularly in the context of novel radiotracers with dynamic studies using kinetic modeling.

Development of a dual-ended readout detector with segmented crystal bars made using a subsurface laser engraving technique

Depth of interaction (DOI) information is indispensable to improving the sensitivity and spatial resolution of positron emission tomography (PET) systems, especially for small field-of-view PET such as small animal PET and human brain PET. We have already developed a series of X’tal cube detectors for isotropic spatial resolution and we obtained the best isotropic resolution of 0.77 mm for detectors with six-sided readout. However, it is still challenging to apply the detector for PET systems due to the high cost of six-sided readout electronics and carrying out segmentation of a monolithic cubic scintillator in three dimensions using the subsurface laser engraving (SSLE) technique. In this work, we propose a more practical X’tal cube with a two-sided readout detector, which is made of crystal bars segmented in the height direction only by using the SSLE technique. We developed two types of prototype detectors with a 3 mm cubic segment and a 1.5 mm cubic segment by using 3 × 3 × 20 mm3 and 1.5 × 1.5 × 20 mm3 crystal bars segmented into 7 and 13 DOI segments, respectively, using the SSLE technique. First, the performance of the detector, composed of one crystal bar with different DOI segments and two thorough silicon via (TSV) multi-pixel photon counters (MPPCs) as readout at both ends of the crystal bar, were evaluated in order to demonstrate the capability of the segmented crystal bars as a DOI detector. Then, performance evaluation was carried out for a 4 × 4 crystal array of 3 × 3 × 20 mm3 with 7 DOI segments and an 8 × 8 crystal array of 1.5 × 1.5 × 20 mm3 with 13 DOI segments. Each readout included a 4 × 4 channel of the 3 × 3 mm2 active area of the TSV MPPCs. The three-dimensional position maps of the detectors were obtained by the Anger-type calculation. All the segments in the 4 × 4 array were identified very clearly when there was air between the crystal bars, as each crystal bar was coupled to one channel of the MPPCs; however, it was necessary to optimize optical conditions between crystal bars for the 8 × 8 array because of light sharing between crystal bars coupled to one channel of the MPPCs. The optimization was performed for the 8 × 8 array by inserting reflectors fully or partially between the crystal bars and the best crystal identification performance was obtained with the partial reflectors between the crystal bars. The mean energy resolutions at the 511 keV photo peak for the 4 × 4 array with air between the crystal bars and for the 8 × 8 array with partial reflectors between the crystal bars were 10.1% ± 0.3% and 10.8% ± 0.8%, respectively. Timing resolutions of 783 ± 36 ps and 1.14 ± 0.22 ns were obtained for the detectors composed of the 4 × 4 array and the 8 × 8 array with partial reflectors, respectively. These values correspond to single photon timing resolutions. Practical X’tal cubes with 3 mm and 1.5 mm DOI resolutions and two-sided readout were developed.

Synthesis and evaluation of 18F-labeled 5-HT2A receptor agonists as PET ligands

IntroductionThe serotonin 2A receptor (5-HT2AR) is the most abundant excitatory 5-HT receptor in the human brain and implicated in various brain disorders such as schizophrenia, depression, and Alzheimer's disease. Positron emission tomography (PET) can be used to image specific proteins and processes in the human brain and several 5-HT2AR PET antagonist radioligands are available. In contrast to an antagonist radioligand, an agonist radioligand should be able to image the population of functional receptors, i.e., those capable of inducing neuroreceptor signaling. Recently, we successfully developed and validated the first 5-HT2AR agonist PET tracer, [11C]Cimbi-36, for neuroimaging in humans and herein disclose some of our efforts to develop an 18F-labeled 5-HT2AR agonist PET-ligand. Methods and resultsThree fluorine containing derivatives of Cimbi-36 were synthesized and found to be potent 5-HT2A agonists. 18F-labeling of the appropriate precursors was performed using [18F]FETos, typically yielding 0.2–2.0GBq and specific activities of 40–120GBq/μmol. PET studies in Danish landrace pigs revealed that [18F]1 displayed brain uptake in 5-HT2AR rich regions. However, high uptake in bone was also observed. No blocking effect was detected during a competition experiment with a 5-HT2AR selective antagonist. [18F]2 and [18F]3 showed very low brain uptake. ConclusionNone of the investigated 18F-labeled Cimbi-36 derivatives [18F]1, [18F]2 and [18F]3 show suitable tracer characteristics for in vivo PET neuroimaging of the 5-HT2AR. Although for [18F]1 there was reasonable brain uptake, we suggest that a large proportion radioactivity in the brain was due to radiometabolites, which would explain why it could not be displaced by a 5-HT2AR antagonist.

Spatial resolution limits for the isotropic-3D PET detector X’tal cube

Positron emission tomography (PET) has become a popular imaging method in metabolism, neuroscience, and molecular imaging. For dedicated human brain and small animal PET scanners, high spatial resolution is needed to visualize small objects. To improve the spatial resolution, we are developing the X’tal cube, which is our new PET detector to achieve isotropic 3D positioning detectability. We have shown that the X’tal cube can achieve 1mm3 uniform crystal identification performance with the Anger-type calculation even at the block edges. We plan to develop the X’tal cube with even smaller 3D grids for sub-millimeter crystal identification. In this work, we investigate spatial resolution of a PET scanner based on the X’tal cube using Monte Carlo simulations for predicting resolution performance in smaller 3D grids. For spatial resolution evaluation, a point source emitting 511keV photons was simulated by GATE for all physical processes involved in emission and interaction of positrons. We simulated two types of animal PET scanners. The first PET scanner had a detector ring 14.6cm in diameter composed of 18 detectors. The second PET scanner had a detector ring 7.8cm in diameter composed of 12 detectors. After the GATE simulations, we converted the interacting 3D position information to digitalized positions for realistic segmented crystals. We simulated several X’tal cubes with cubic crystals from (0.5mm)3 to (2mm)3 in size. Also, for evaluating the effect of DOI resolution, we simulated several X’tal cubes with crystal thickness from (0.5mm)3 to (9mm)3. We showed that sub-millimeter spatial resolution was possible using cubic crystals smaller than (1.0mm)3 even with the assumed physical processes. Also, the weighted average spatial resolutions of both PET scanners with (0.5mm)3 cubic crystals were 0.53mm (14.6cm ring diameter) and 0.48mm (7.8cm ring diameter). For the 7.8cm ring diameter, spatial resolution with 0.5×0.5×1.0mm3 crystals was improved 39% relative to the (1mm)3 cubic crystals. On the other hand, spatial resolution with (0.5mm)3 cubic crystals was improved 47% relative to the (1mm)3 cubic crystals. The X’tal cube promises better spatial resolution for the 3D crystal block with isotropic resolution.

Preliminary study on potential of the jPET-D4 human brain scanner for small animal imaging

One trend in positron emission tomography (PET) instrumentation over the last decade has been the development of scanners dedicated to small animals such as rats and mice. Thicker crystals, which are necessary to obtain higher sensitivity, result in degraded spatial resolution in the peripheral field-of-view (FOV) owing to the parallax error. On the other hand, we are developing the jPET-D4, which is a dedicated human brain PET scanner that has a capability for depth-of-interaction (DOI) measurement. Although its crystal width is about twice that of commercially available small animal PET scanners, we expect the jPET-D4 to have a potential for small animal imaging by making full use of the DOI information. In this article, we investigate the jPET-D4's potential for small animal imaging by comparing it with the microPET Focus220, a state-of-the-art PET scanner dedicated to small animals. The jPET-D4 uses four-layered GSO crystals measuring 2.9 mm x 2.9 mm x 7.5 mm, whereas the microPET Focus220 uses a single layer of LSO crystals measuring 1.5 mm x 1.5 mm x 10.0 mm. First, the absolute sensitivity, counting rate performance and spatial resolution of both scanners were measured. Next a small hot-rod phantom was used to compare their imaging performance. Finally, a rat model with breast tumors was imaged using the jPET-D4. Thanks to the thicker crystals and the longer axial FOV, the jPET-D4 had more than four times higher sensitivity than the microPET Focus220. The noise equivalent counting-rate performance of the jPETD4 reached 1,024 kcps for a rat-size phantom, whereas that of the microPET Focus220 reached only 165 kcps. At the center of the FOV, the resolution was 1.7 mm for the microPET Focus220, whereas it was 3.2 mm for the jPET-D4. On the other hand, the difference of resolution became smaller at the off-center position because the radial resolution degraded faster for the microPET Focus220. The results of phantom imaging showed that the jPET-D4 was comparable to the microPET Focus220 at the off-center position even as the microPET Focus220 outperformed the jPET-D4 except for the peripheral FOV. The jPET-D4 human brain PET scanner, which was designed to achieve not only high resolution but also high sensitivity by measuring DOI information, was proven to have a potential for small animal imaging.

Masked-Volume-Wise PCA and "reference Logan" illustrate similar regional differences in kinetic behavior in human brain PET study using [11C]-PIB

BackgroundKinetic modeling using reference Logan is commonly used to analyze data obtained from dynamic Positron Emission Tomography (PET) studies on patients with Alzheimer's disease (AD) and healthy volunteers (HVs) using amyloid imaging agent N-methyl [11C]2-(4'-methylaminophenyl)-6-hydroxy-benzothiazole, [11C]-PIB. The aim of the present study was to explore whether results obtained using the newly introduced method, Masked Volume Wise Principal Component Analysis, MVW-PCA, were similar to the results obtained using reference Logan.MethodsMVW-PCA and reference Logan were performed on dynamic PET images obtained from four Alzheimer's disease (AD) patients on two occasions (baseline and follow-up) and on four healthy volunteers (HVs). Regions of interest (ROIs) of similar sizes were positioned in different parts of the brain in both AD patients and HVs where the difference between AD patients and HVs is largest. Signal-to-noise ratio (SNR) and discrimination power (DP) were calculated for images generated by the different methods and the results were compared both qualitatively and quantitatively.ResultsMVW-PCA generated images that illustrated similar regional binding patterns compared to reference Logan images and with slightly higher quality, enhanced contrast, improved SNR and DP, without being based on modeling assumptions. MVW-PCA also generated additional MVW-PC images by using the whole dataset, which illustrated regions with different and uncorrelated kinetic behaviors of the administered tracer. This additional information might improve the understanding of kinetic behavior of the administered tracer.ConclusionMVW-PCA is a potential multivariate method that without modeling assumptions generates high quality images, which illustrated similar regional changes compared to modeling methods such as reference Logan. In addition, MVW-PCA could be used as a new technique, applicable not only on dynamic human brain studies but also on dynamic cardiac studies when using PET.

Image derived input functions for dynamic High Resolution Research Tomograph PET brain studies

The High Resolution Research Tomograph (HRRT) is a dedicated human brain positron emission tomography (PET) scanner. The aim of the present study was to validate the use of image derived input functions (IDIF) as an alternative for arterial sampling for HRRT human brain studies. To this end, IDIFs were extracted from 3D ordinary Poisson ordered subsets expectation maximization (OP-OSEM) and reconstruction based partial volume corrected (PVC) OP-OSEM images. IDIFs, either derived directly from regions of interest or further calibrated using manual samples taken during scans, were evaluated for dynamic [ 11C]flumazenil data ( n = 6). Results obtained with IDIFs were compared with those obtained using blood sampler input functions (BSIF). These comparisons included areas under the curve (AUC) for peak (0–3.3 min) and tail (3.3–55.0 min). In addition, slope, intercept and Pearson's correlation coefficient of tracer kinetic analysis results based on IDIF and BSIF were calculated for each subject. Good peak AUC ratios (0.83 ± 0.21) between IDIF and BSIF were found for calibrated IDIFs extracted from OP-OSEM images. This combination of IDIFs and images also provided good slope values (1.07 ± 0.11). Improved resolution, as obtained with PVC OP-OSEM, changed AUC ratios to 1.14 ± 0.35 and, for tracer kinetic analysis, slopes changed to 0.95 ± 0.13. For all reconstructions, non-calibrated IDIFs gave poorer results (> 61 ± 34% higher slopes) compared with calibrated IDIFs. The results of this study indicate that the use of IDIFs, extracted from OP-OSEM or PVC OP-OSEM images, is feasible for dynamic HRRT data, thereby obviating the need for online arterial sampling.

Gap Filling Strategies for 3-D-FBP Reconstructions of High-Resolution Research Tomograph Scans

The High-Resolution Research Tomograph (HRRT) is a dedicated human brain positron emission tomography scanner. Currently available iterative reconstruction algorithms show bias due to nonnegativity constraints. Consequently, implementation of 3-D filtered backprojection (3-D-FBP) is of interest. To apply 3-D-FBP all missing data including those due to gaps between detector heads need to be estimated. The aim of this study was to evaluate various gap filling strategies for 3-D-FBP reconstructions of HRRT data, such as linear and bilinear interpolation or constraint Fourier space gap filling (confosp). Furthermore, missing planes were estimated using segment 0 image data only (noniterative) or by using reconstructed images based on all previous segments (iterative method). Use of bilinear interpolation showed worst correspondence between reconstructed and true activity concentration, especially for small structures. Moreover, phantom data indicated that use of linear interpolation resulted in artifacts in planes located near the edge of the field-of-view. Use of confosp did not show these artifacts. Iterative estimations of the missing planes for |segments| 0 improved image quality at the cost of more computation time. Therefore, use of confosp for filling sinogram gaps with both iterative and noniterative estimation of missing planes are recommended for quantitative 3-D-FBP of HRRT studies.

Comparison of 3D-OP-OSEM and 3D-FBP reconstruction algorithms for High-Resolution Research Tomograph studies: effects of randoms estimation methods

The High-Resolution Research Tomograph (HRRT) is a dedicated human brain positron emission tomography (PET) scanner. Recently, a 3D filtered backprojection (3D-FBP) reconstruction method has been implemented to reduce bias in short duration frames, currently observed in 3D ordinary Poisson OSEM (3D-OP-OSEM) reconstructions. Further improvements might be expected using a new method of variance reduction on randoms (VRR) based on coincidence histograms instead of using the delayed window technique (DW) to estimate randoms. The goal of this study was to evaluate VRR in combination with 3D-OP-OSEM and 3D-FBP reconstruction techniques. To this end, several phantom studies and a human brain study were performed. For most phantom studies, 3D-OP-OSEM showed higher accuracy of observed activity concentrations with VRR than with DW. However, both positive and negative deviations in reconstructed activity concentrations and large biases of grey to white matter contrast ratio (up to 88%) were still observed as a function of scan statistics. Moreover 3D-OP-OSEM+VRR also showed bias up to 64% in clinical data, i.e. in some pharmacokinetic parameters as compared with those obtained with 3D-FBP+VRR. In the case of 3D-FBP, VRR showed similar results as DW for both phantom and clinical data, except that VRR showed a better standard deviation of 6–10%. Therefore, VRR should be used to correct for randoms in HRRT PET studies.

Temporal and spatial blood information estimation using Bayesian ICA in dynamic cerebral positron emission tomography

Positron emission tomography (PET) is a nuclear medicine technique that provides tomographic images of the distribution of positron-emitting radiopharmaceuticals. We have previously proposed a method for estimating an input blood curve based on a standard independent component analysis using a specially designed cost function and a preprocessing scheme. While the input blood curve was successfully extracted, the voxels with a negative sign remained in the estimated blood volume image. They should be positive because of its physiological meaning. In this study, ensemble learning introduces a nonnegative constraint to correctly estimate temporal and spatial blood information from dynamic cerebral PET images. The rectified Gaussian distribution and exponential distribution were adopted as nonnegative priors on the elements of the time curves and the source images, respectively. The proposed method (extraction of the plasma time-activity curve using ensemble learning, EPEL) was applied to human brain PET studies with three kinds of radiopharmaceuticals for investigating its validity. The results implied that the EPEL-estimated blood curve was similar to the measured curve, and that the estimated blood volume correlated well with that measured clinically. We concluded that EPEL is a valid method for estimating the blood curve and the blood volume image in a noninvasive way.

A new application of pre-normalized principal component analysis for improvement of image quality and clinical diagnosis in human brain PET studies—Clinical brain studies using [ 11C]-GR205171, [ 11C]- l-deuterium-deprenyl, [ 11C]-5-Hydroxy- l-Tryptophan, [ 11C]- l-DOPA and Pittsburgh Compound-B

Principal component analysis (PCA) is one of the most applied multivariate image analysis tool on dynamic Positron Emission Tomography (PET). Independent of used reconstruction methodologies, PET images contain correlation in-between pixels, correlations in-between frame and errors caused by the reconstruction algorithm including different corrections, which can affect the performance of the PCA. In this study, we have investigated a new approach of application of PCA on pre-normalized, dynamic human PET images. A range of different tracers have been used for this purpose to explore the performance of the new method as a way to improve detection and visualization of significant changes in tracer kinetics and to enhance the discrimination between pathological and healthy regions in the brain. We compare the new results with the results obtained using other methods. Images generated using the new approach contain more detailed anatomical information with higher quality, precision and visualization, compared with images generated using other methods.

Monitoring Drug‐Induced Neurodegeneration by Imaging of Peripheral Benzodiazepine Receptors

Several drugs of abuse are known to produce an array of deleterious effects, including alterations in neuronal circuitry and, ultimately, neuronal degeneration. For instance, methamphetamine was shown to induce substantial nigrostriatal dopaminergic terminal damage, including an increase in glial fibrillary acidic protein, a marker for astrocyte proliferation. Nevertheless, there was almost no attempt to define neurodegeneration by measuring the abundance of reactive microglia. In fact, some investigators fail to differentiate between astrocytes and microglia and claim glial fibrillary acidic protein to be a marker for gliosis. To date, there are numerous methods designed to assess brain neuropathologies resulting from a wide arsenal of insults. Regardless of the cause of neuronal damage, reactive glial cells always appear at and around the site of degeneration. These cells are distinguished by the exceptional abundance of peripheral benzodiazepine receptors (PBRs; omicron3 sites), particularly as compared to surrounding neurons. Measuring the binding of specific ligands to these PBRs (for example, [3H]PK 11195) offers a unique indirect marker for reliable impairment estimation in the central nervous system. Moreover, the availability of agents such as [11C]PK 11195 paved the road to in vivo animal and human brain positron emission tomography scanning, demonstrating inflammation-like processes in several diseases. Additionally, the measurement of increased binding of PBR ligands provides a faithful indicator for the behavioral and cognitive deficits accompanying neuronal injury.

The electronics system for the LBNL positron emission mammography (PEM) camera

Describes the electronics for a high-performance positron emission mammography (PEM) camera. It is based on the electronics for a human brain positron emission tomography (PET) camera (the Siemens/CTI HRRT), modified to use a detector module that incorporates a photodiode (PD) array. An application-specified integrated circuit (ASIC) services the photodetector (PD) array, amplifying its signal and identifying the crystal of interaction. Another ASIC services the photomultiplier tube (PMT), measuring its output and providing a timing signal. Field-programmable gate arrays (FPGAs) and lookup RAMs are used to apply crystal-by-crystal correction factors and measure the energy deposit and the interaction depth (based on the PD/PMT ratio). Additional FPGAs provide event multiplexing, derandomization, coincidence detection, and real-time rebinning. Embedded PC/104 microprocessors provide communication, real-time control, and configure the system. Extensive use of FPGAs make the overall design extremely flexible, allowing many different functions (or design modifications) to be realized without hardware changes. Incorporation of extensive onboard diagnostics, implemented in the FPGAs, is required by the very high level of integration and density achieved by this system.

The cloned dopamine D 2 receptor reveals different densities for dopamine receptor antagonist ligands. Implications for human brain positron emission tomography

Since [ 3H]cmonapride ([ 3H]YM-0915-2), a benzamide neuroleptic, consistently detects more dopamine D 2 receptors than [ 3H]spiperone in the same tissue, we tested whether this property was inherent in the cloned dopamine D 2 receptor. We found that the density of dopamine D 2 receptors labelled by [ 3H]cmonapride was 15-fold to 2-fold (mean of 1.8-fold) higher than the density of dopamine D 2 receptors labelled by [ 3H]spiperone in cells expressing cloned dopamine D 2 receptors (either the short form (from rat) or the long form (from human)), matching similar findings in anterior pituitary tissue (rat or pig) or in post-mortem human caudate nucleus tissue. The situation was similar for another benzamide, [ 3H]raclopride, which revealed 1.3-fold to 1.8-fold (mean of 1.5-fold) more binding sites than that for [ 3H]spiperone in cell membranes containing cloned dopamine D 2 receptors. The apparently different dopamine D 2 receptor densities revealed by these two types of 3H-ligands (i.e. [ 3H]spiperone and the [ 3H]benzamides), therefore, arise from an inherent property of the dopamine D 2 receptor protein. These findings for the cloned dopamine D 2 receptor, therefore, partly explain the higher dopamine D 2 receptor density measured in human brain (by positron emission tomography) when using radioactive raclopride compared to results using radioactive methylspiperone. Hence, the apparent density of dopamine D 2 receptors measured by radioactive raclopride may be lower or higher than that revealed by radioactive spiperone or methylspiperone, depending on the magnitude of endogenous dopamine (which inhibits the binding of radioactive raclopride) and the inherent property of dopamine D 2 receptor proteins to exhibit more binding sites (D 2 monomers, possibly) for radioactive benzamides than for radioactive spiperone or methylspiperone (D 2 dimers, possibly).