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The integration of magnetic resonance imaging (MRI) and positron emission tomography (PET) is an upcoming hybrid imaging technique. Prototype scanners for pre-clinical and clinical research have been built and tested. However, the potential of the PET part can be better exploited if the arterial input function (AIF) of the administered tracer is known. This work presents a dedicated MR-compatible blood sampling system for precise measurement of the AIF in an MR-PET study. The device basically consists of an LSO/APD-detector assembly which performs a coincidence measurement of the annihilation photons resulting from positron decays. During the measurement, arterial blood is drawn continuously from an artery and lead through the detector unit. Besides successful tests of the MR compatibility and the detector performance, measurements of the AIF of rats have been carried out. The results show that the developed blood sampling system is a practical and reliable tool for measuring the AIF in MR-PET studies.

The purpose of this study was to investigate the potential of 3'-deoxy-3'-[¹⁸F]fluorothymidine ([¹⁸F]FLT) positron emission tomography (PET) to detect early treatment responses in gliomas. Human glioma cells were stably transduced with genes yielding therapeutic activity, sorted for different levels of exogenous gene expression, and implanted subcutaneously into nude mice. Multimodality imaging during prodrug therapy included (a) magnetic resonance imaging, (b) PET with 9-(4-[¹⁸F]fluoro-3-hydroxymethylbutyl)guanine assessing exogenous gene expression, and (c) repeat [¹⁸F]FLT PET assessing antiproliferative therapeutic response. All stably transduced gliomas responded to therapy with significant reduction in tumor volume and [¹⁸F]FLT accumulation within 3 days after initiation of therapy. The change in [¹⁸F]FLT uptake before and after treatment correlated to volumetrically calculated growth rates. Therapeutic efficacy as monitored by [¹⁸F]FLT PET correlated to levels of therapeutic gene expression measured in vivo. Thus, [¹⁸F]FLT PET assesses early antiproliferative effects, making it a promising radiotracer for the development of novel treatments for glioma.

Purpose Compartmental modelling of 3′-deoxy-3′-[18F]-fluorothymidine (18F-FLT) PET-derived kinetics provides a method for noninvasive assessment of the proliferation rate of gliomas. Such analyses, however, require an input function generally derived by serial blood sampling and counting. In the current study, 18F-FLT kinetic parameters obtained from image-derived input functions were compared with those from input functions derived from arterialized blood samples. Methods Based on the analysis of 11 patients with glioma (WHO grade II–IV) a procedure for the automated extraction of an input function from 18F-FLT brain PET data was derived. The time–activity curve of the volume of interest with the maximum difference in 18F-FLT uptake during the first 5 min after injection and the period from 60 to 90 min was corrected for partial-volume effects and in vivo metabolism of 18F-FLT. For each patient a two-compartment kinetic model was applied to the tumour tissue using the image-derived input function. The resulting kinetic rate constants K1 (transport across the blood–brain barrier) and Ki (metabolic rate constant or net influx constant) were compared with those obtained from the same data using the input function derived from blood samples. Additionally, the metabolic rate constant was correlated with the frequency of tumour cells stained with Ki-67, a widely used immunohistochemical marker of cell proliferation. Results The rate constants from kinetic modelling were comparable when the blood sample-derived input functions were replaced by the image-derived functions (K1,img and K1,sample, r = 0.95, p

State-of-the-art data-acquisition systems for positron emission tomography (PET) block detectors use anger logic to determine preliminary 2-D coordinates of the detection location within the block. Typically, a crystal lookup table (CLT) is then used to map from this position to the index of the crystal in which the particle was actually absorbed. Depending on the complexity of the detector design, it is difficult to calculate these CLTs automatically without need for visual inspection and manual readjustment. We propose a novel technique to construct the CLT. The assignment problem is formulated as an optimization problem, where the number of free parameters is initially twice the number of crystals in the block. The core idea is to reduce the dimension of the search space by principal component analysis. The technique was tested successfully for three different block detector designs (Siemens ECAT Exact HR, Siemens microPET Focus 220, and a prototype block detector built of pixelated lutetium oxyorthosilicate crystals with avalanche photodiodes attached). Important virtues of the new algorithm are very fast processing and a high tolerance toward missing peaks, fused peaks, and nonlinear distortions. Furthermore, the algorithm calculates a performance control value that can be used to quickly identify problematic blocks.

Purpose: The aim of this study was to investigate the relationship between the in vivo derived kinetic parameters of 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) and the proliferation rate measured in vitro by Ki-67 staining in patients with newly diagnosed high-grade gliomas. Experimental Design: Thirteen patients with newly diagnosed high-grade gliomas were investigated with 18F-FLT and methyl-11C- l-methionine (11C-MET) positron emission tomography (PET) and T1-, Gd-T1–, and T2-weighted magnetic resonance imaging on consecutive days. Tracer kinetic parameters of 18F-FLT as well as the standardized uptake value and the tumor-to-background (T/B) ratio of 18F-FLT and 11C-MET were determined. Data of kinetic modeling, standardized uptake value, and T/B values derived from 18F-FLT-PET were compared with T/B values derived from 11C-MET-PET and to the in vitro proliferation marker Ki-67. Results: A significant correlation was observed between the metabolic rate constant Ki and the proliferation index as measured by Ki-67 immunostaining [Ki, r = 0.79 (P = 0.004)]. Also, the phosphorylation rate constant k3 correlated with Ki-67 [k3, r = 0.76 (P = 0.006)], whereas the rate constant for transport through the blood brain barrier K1 showed a weaker correlation with Ki-67 [K1, r = 0.62 (P = 0.044)]. No significant correlation between 11C-MET and 18F-FLT uptake ratios and Ki-67 was observed. Conclusions: This study shows that kinetic analysis of 18F-FLT tracer uptake is essential for the in vivo assessment of tumor proliferation in high-grade gliomas, whereas uptake ratios of 11C-MET and 18F-FLT failed to correlate with the in vitro determined proliferation marker. Thus, kinetic analysis of 18F-FLT might provide an accurate method for the assessment of early response to glioma treatment in the future.

SummaryThe aim of the study was to determine the practicability of 18F-FLT in tumours of the head and neck area in terms of visualization, a possible correlation between FLT uptake and proliferation fraction as determined by Ki-67 immunostaining, and if tumoural FLT-uptake has a prognostic meaning, as determined by a correlation to patient survival time. Results were compared to 18F-FDG. Patients, methods: 20 patients with previously untreated lesions of the head and neck area, which were clinically highly suspicious to be malignant, underwent PET scans with 18F-FLT and 18F-FDG, a CT of the head and neck area, and a biopsy. Tumour tracer uptake was determined by standardized uptake value (SUV) normalized to body weight and /non-tumor ratios (T/N). 18F-FDG and 18F-FLT uptake were compared with histopathologic and immunohistochemical results. Results: 19 patients had malignant tumours; one patient had a benign cystadenoma (so called Warthin's tumour) of the parotid gland. One negative lesion turned out to be a malignant T1 stage squamous cell carcinoma in both PET scans, the Warthin's tumour was false positive with 18F-FDG but showed only faint uptake with 18F-FLT, resulting in a sensitivity of 95 % for both tracers. Of all lesions, maximum SUVs of 18F-FLT ranged from 1.53 to 11.70 (mean ± SD 5.81 ± 2.28) those of FDG from 2.63 to 16.50 (mean ± SD 8.91 ± 3.58), p < 0.001. 18F-FLT-T/N ranged from 0.94 to 5.85 (mean ± SD, 3.18 ± 1.21), 18F-FDG-T/N was from 0.92 to 7.50 (mean ± SD, 3.6 ± 1.74), n.s. The mean survival time was 18 months in a maximum follow up time of 36 months. A significant correlation between both PET tracers and survival was detected, but no correlation between the amount of Ki-67 positive cells and FLT. Conclusion: In head and neck cancer in the primary setting 18F-FLT does not provide additional visual information in comparison to 18F-FDG.18F-FLT uptake is inversely correlated with patient survival, as well as 18F-FDG.

Neuroimaging studies in right-handed patients with left hemisphere brain lesions have demonstrated a shift of language activity from left to right inferior frontal gyrus (IFG). This shift may be caused by greater right hemisphere dominance before the injury or by reduced inhibitory activity of the injured left hemisphere. We simulated a brain lesion applying transcranial-magnetic stimulation over left IFG in normal subjects, while simultaneously measuring language activity with positron — emission tomography. Interference with transcranial-magnetic stimulation decreased activity in left and increased it in right IFG in all subjects. We thus demonstrate for the first time that a rightward shift of language activity is caused by the brain lesion and not by greater right-hemisphere dominance, thus supporting the hypothesis of reduced transcallosal inhibition.

The ECAT high-resolution research tomograph (HRRT) is a three-dimensional (3-D)-only dedicated brain positron emission tomograph with LSO and GSO scintillators. In this paper, the system has been looked at as an example of issues that need to be addressed when evaluating LSO-based system following the recent NEMA NU 2-2001 protocols. The LSO scintillators contain the isotope /sup 176/Lu which is radioactive and creates a small amount of single counts and, depending on the low level discriminator threshold for validated singles, also true coincidence events from a cascade of gamma rays following the beta decay of /sup 176/Lu into /sup 176/Hf. The presence of intrinsic random and true coincidence events has an effect on the scatter fraction determination if using the guidelines according to NU 2-2001. We show here that these guidelines have to be changed in order to obtain accurate determination of the scatter fraction. In this paper, we have determined the scatter fraction for different low level discriminator settings. Since the scatter fraction determinations also comprise full count rate studies for the NEMA phantom, we have in addition extracted the sensitivity information for singles, true + scatter, and for the NEC data.

Positron emission tomography (PET) is increasingly used to quantify regional hemodynamic and metabolic changes in different animal models. Most of these (multitracer) studies provided important early data on already functionally altered brain tissue, indicating selective vulnerability by a large variability in the functional blood flow threshold of individual neurons. To fill the gap between experimental studies at early time points and rather late clinical studies at well-defined but singular time points, we repeatedly measured cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), oxygen extraction rate and cerebral metabolic rate of glucose (CMRglc) in three cats before and up to 28 h after decompressive hemicraniectomy on normal brain tissue. Decompressive hemicraniectomy in the cat decreased CBF, and to a lesser extent CMRO2 and CMRglc 2 h after surgical intervention in normal brain tissue that last for at least 1 day. CBF significantly decreased (p

Hemicraniectomy is increasingly used as treatment option in stroke and in head trauma, but little is known on the (patho)physiological regional effects of hemicraniectomy in the normal brain. A standard left-sided craniectomy was performed in three cats. Regional cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2) and cerebral metabolic rate of glucose (CMRglc) were measured from the brain tissue underneath the craniectomy at 2, 20 and 28 h after hemicraniectomy. CBF significantly decreased (P

The microPET R4 scanner is a dedicated positron emission tomograph (PET) for studies of rodents. A number of scanner parameters such as spatial resolution, sensitivity, scatter, and count rate performance were determined in this work, which showed that the microPET R4 is a suitable PET scanner for small animals like mice and rats. In the center of the field of view (FOV) a maximal sensitivity of 43.66 cps/kBq for a centered point source was calculated from a measurement with a germanium-68 line source within an energy widow of 250-750 keV. A spatial resolution of 1.85 mm full-width at half-maximum (FWHM) in the axial direction and 1.66 mm FWHM in the transaxial direction was measured in the center with a 1-mm-diameter sodium-22 point source. Within the inner 20 mm of the FOV the volumetric resolution is better than 15.6 micro l, corresponding to a linear resolution of less than 2.5 mm in all three dimensions. Images of a high-resolution phantom and from mice and rat studies illustrate the good performance of the scanner. A maximal noise equivalent count rate (NECR) was reached at 174 kcps for a mouse phantom and at 93 kcps for a rat phantom (energy window 250-750 keV). Scatter fractions were measured between 0.30 and 0.42 for an energy window of 250-750 keV and phantom diameters similar to mice and rats. A comparison with the microPET P4 model for primates illustrates the gain in sensitivity due to a smaller detector ring diameter but also the changes in NECR.

A phase I/II clinical trial of gene therapy for recurrent glioblastoma has been initiated in which non-invasive monitoring of the critical steps is performed by a combination of standard clinical positron-emission tomography (PET) for metabolic identification/evaluation of malignant lesions with pioneering PET imaging of HSV-1- tk transgene expression. Localization, characterization and trial follow-up of target tumors rely on multitracer PET brain imaging probed with radiolabeled 2-[ 18 F]fluoro-2-deoxy-D-glucose (FDG), methyl-[ 11 C]-L-methionine (MET) and 3´-deoxy-3´-[ 18 F]fluoro-L-thymidine (FLT) while the location, magnitude and duration of therapeutic HSV-1- tk transgene expression is monitored with 2´-fluoro-2´-deoxy-1-β-D-arabinofuranosyl-5-[ 124 I]iod ([ 124 I]-FIAU). In addition, in order to improve the distribution of the vector within the tumor tissue, a stereotactically guided convection-enhanced delivery (CED) protocol was devised in which the transfection of the HSV-1- tk gene into brain tumor cells is mediated by a liposome-DNA complex. Preliminary findings on a first group of five patients demonstrated that FIAU-PET imaging of HSV-1- tk expression in patients with glioblastoma is feasible and that vector-mediated gene expression may predict the therapeutic effect of ganciclovir prodrug activation. In addition, they showed that integration of magnetic resonance (MR) and PET imaging data into a 3D stereotaxic coordinate system results in an efficient non-invasive spatio-temporal monitoring of a brain gene therapy trial. Such a non-invasive imaging provides the means to identify potential critical parameters and to implement dosing/ routing adjustments that will have a critical impact on the development of standardized gene therapy protocols.

For the development of efficient and safe gene therapy protocols for clinical application it is desirable to determine the tissue dose of vector-mediated therapeutic gene expression noninvasively in vivo. The herpes simplex virus type 1 thymidine kinase gene (HSV-1-tk) has been shown to function as a marker gene for the direct noninvasive in vivo localization of thymidine kinase (TK) expression by positron emission tomography (PET). Using bicistronic or multicistronic gene-expressing cassettes with tk as the PET marker gene, the quantitative analysis of tk gene expression may indirectly indicate the distribution and the level of expression of linked and proportionally coexpressed genes. Here, we describe the construction and functional evaluation of HSV-1 amplicon vectors mediating proportional coexpression of HSV-1-tk as PET marker gene and the enhanced green fluorescent protein gene (gfp) as proof of principle and cell culture marker gene and the Escherichia coli cytosine deaminase (cd) as therapeutic gene. Several double-/triple-gene constructs expressing HSV-1-tk, gfp, and E. coli cd were engineered based on gene fusion or the use of an internal ribosome entry site (IRES). Functional analysis in cell culture (green fluorescent protein [GFP] fluorescence and sensitivity to the prodrugs ganciclovir [GCV] and 5-fluorocytosine [5-FC]) and Western blots were carried out after infection of proliferating rat 9L gliosarcoma and human Gli36 glioma cells with helper virus-free packaged HSV-1 amplicon vectors. To study the ability of PET to differentiate various levels of tk expression noninvasively in vivo, retrovirally transduced and selected populations of rat F98 and human Gli36dEGFR glioma cells with defined levels of proportionally coexpressed tk and gfp genes were grown as subcutaneous tumors in nude rats and nude mice, and tk imaging by PET was performed. To study HSV-1 amplicon vector-mediated gene coexpression in vivo, HSV-1 amplicon vectors bearing coexpression constructs were injected (4 x 10(7) to 1 x 10(8) transducing units) into subcutaneously growing Gli36dEGFR gliomas in nude animals, and tk imaging was performed 24 hr later. All vector constructs mediated GFP expression and sensitized 9L and Gli36 cells toward GCV- and 5-FC-mediated cell killing in a drug dose-dependent manner, respectively. The levels of gene expression varied depending on the location of the genes within the constructs indicating the influence of the IRES on the level of expression of the second gene. Moreover, functional proportional coexpression of the PET marker gene HSV-1-tk and the linked therapeutic E. coli cd gene was observed. In selected tumor cell populations, subtle IRES-dependent differences of tk gene expression could be noninvasively distinguished by PET with good correlation between quantitative assays for IRES-dependent attenuated GFP and TK expression in culture and in vivo. After infection of subcutaneously growing gliomas with HSV-1 amplicon vectors, various levels of TK expression were found ranging from 0.011-0.062 percentage injected dose per gram (%ID/g). These values were 4.0- to 5.7-fold lower than positive control tumor cells. TK expression could be imaged by PET in vivo even with the tk gene located at the weak position downstream from the IRES. In conclusion, these HSV-1 amplicon vectors carrying HSV-1-tk as PET marker gene and any linked therapeutic gene will serve an indirect noninvasive assessment of the distribution of therapeutic gene expression by PET. Monitoring the correlation between primary transduction and therapeutic efficiency of a given vector is highly desirable for the development of safe and efficient gene therapy and vector application protocols in clinical applications.

A daily quality check (DQC) plays an important role for clinical medical systems like a Positron Emission Tomograph (PET). To guarantee image quality a constant monitoring of the scanner integrity is essential. On present PET scanners the built-in transmission sources are being used for the measurement of a uniform blank scan and the computation of detector-block efficiencies. These efficiencies can be compared to reference data and deviations indicate changes of the scanner condition. On the High Resolution Research Tomograph (ECAT HRRT) the design of the transmission source makes this method impractical. For that reason we investigated the use of the natural background radioactivity from the new scintillator material LSO as a uniform source. A procedure was developed to measure detector-block sensitivities and energy spectra directly. An initial quality check (QC) scan is the basis for comparison of daily scans, so that PMT gain shifts and specific hardware defects can be detected. In early stage of development of the DQC, the low LSO count rate results in long acquisition times. In the meantime, the listmode based data acquisition was changed so that it was possible to reduce the acquisition time to around 3 hours. With that this routine is now as practical as previous procedures in clinical routine.

The ECAT HRRT (high-resolution research tomograph) is a three-dimensional(3-D)-only dedicated brain positron emission tomograph (PET) with LSO and GSO scintillators. The system is based on eight panels of detectors. The HRRT's imaging performance has previously been tested with phantoms and FDG scans performed in animal and human brains that showed significantly improved spatial resolution, below 2.5 mm for animal studies and below 3 mm for brain studies. The NEC count rate performance has been evaluated based on the NU 2-2001 protocol. The results show a peak NEC approximately 30% higher than the performance of the ECAT HR+, this in spite of a more shallow detector for the HRRT, only 15 mm relative to the 30 mm for the HR+. However, peak NEC as derived from the 70-cm line source phantom is not optimized for the performance of dedicated brain scanner. NEC data derived with a 20-cm diameter, 20-cm long phantoms show a peak NEC more than 60% higher than for the HR+. The reasons for the high performance are due to several factors, the large axial coverage, the short timing window of 6 ns, and the low detector dead time, all factors that imply the use of fast LSO and GSO scintillators.

The [18F]fluorodeoxyglucose (FDG) method to measure glucose metabolism quantitatively in humans is reviewed. The assumptions and the mathematical formulation of the underlying autoradiographic Sokoloff model and its adaptation to positron emission tomography (PET) are described. Various implementations to estimate glucose consumption from measured tissue activity with PET are presented. The dependence on the “lumped constant” and on the accuracy of the input function is discussed. Recommendations for the practical application of different procedures for performing FDG studies are given.

The first and second generation of the Exact and Exact HR family of scanners has been evaluated in terms of noise equivalent count rate (NEC) and count-rate capabilities. The new National Electrical Manufacturers Association standard was used for the evaluation. In spite of improved electronics and improved count-rate capabilities, the peak NEC was found to be fairly constant between the generations. The results are discussed in terms of the different electronic solutions for the two generations and its implications on system dead time and NEC count-rate capability.

Epidural mass lesions may cause ischemia due to progressive intracranial hypertension. In order to investigate the impact of intracranial pressure on accumulation of neuroactive substances, we gradually raised intracranial pressure in five halothane anesthetized cats by inflation of an epidural balloon. We evaluated in the parietal cortex contralateral to the site of balloon inflation, alterations of extracellular glutamate and purine catabolites and of the lactate/pyruvate ratio in relation to changes of intracranial, cerebral perfusion and mean arterial blood pressure. In a complementary experiment, regional cerebral blood flow was assessed by sequential positron emission tomography. In this simplified mass lesion model, extracellular glutamate increased in all cats at a late, critical stage after tentorial herniation, when intracranial pressure had increased to more than 90 mm Hg, cerebral perfusion pressure had decreased below 40-50 mm Hg. Positron emission tomography assessments revealed that the ischemic threshold for glutamate accumulation was in the range of 15-20 mL/100 g/min. Purine catabolites and the lactate/pyruvate ratio increased somewhat earlier than glutamate, but also after reaching the critical, terminal stage. We conclude that in this model of progressive epidural compression, glutamate-mediated excitotoxic processes at sites remote from the initial focal lesion depend on processes such as delayed ischemia in combination with tentorial herniation and systemic hypotension. These processes seem to be initiated by a decrease of cerebral perfusion pressure below a threshold of 40-50 mm Hg.

Measurement of cerebral acetylcholine esterase (AChE) activity is of clinical interest for the differential diagnosis of memory disorders and dementia. We developed and tested a non-invasive method for quantitation of regional cortical AChE activity with carbon-11-labelled N-methyl-4-piperidyl acetate (11C-MP4A) that does not require arterial blood sampling. AChE activity was measured in terms of the rate constant for hydrolysis of 11C-MP4A (k3). The physiological model is based on the very high AChE activity in the basal ganglia, which are used as a reference structure. Non-invasive k3 was compared with k3 determined with a standard technique by fitting kinetic tissue and metabolite-corrected plasma data in nine subjects with and without dementia. Across all regional values, a very high correlation of 0.92 was found, with a tendency towards moderate underestimation of k3 by 5%-14% with the non-invasive technique as compared to the invasive technique. In addition to its advantages with respect to practicability, the new non-invasive technique overcomes problems of the invasive technique that are related to interindividual variation of delay times between cerebral and peripheral tracer arrival and measurement of very small amounts of non-hydrolysed tracer in plasma samples.

Repeat studies in animal models of acute focal ischemia can be compared to incidental studies in the course of ischemic stroke in order to shed light on the development of changes causing ischemic infarcts or recovery of critically perfused tissue. Positron emission tomography (PET) studies of regional cerebral blood flow, cerebral metabolic rate for oxygen, oxygen extraction fraction (OEF), cerebral metabolic rate of glucose and flumazenil (FMZ) binding in the cat middle cerebral artery occlusion (MCAO) model and in patients with acute ischemic hemispheric stroke were reviewed. After permanent MCAO, the development of ‘misery-perfused’ penumbral tissue and its centrifugal conversion into necrosis could be demonstrated, resembling focal pathophysiological changes in patients with ischemic attacks. In the experimental model and in vascular insults in humans, a chance of recovery existed if collateral perfusion developed spontaneously within the first hours. In transient MCAO, reperfusion was only effective in preventing infarction when it was initiated as long as misery perfusion persisted; in these cases tissue was salvaged and large infarcts did not develop. In the other instances when oxygen metabolism broke down, and an increased OEF was no longer seen, reperfusion even at levels above preocclusion had no effect, and large space-occupying infarcts developed. These experimental findings are comparable to the variable outcome after thrombolytic therapy; if reperfusion is achieved within the therapeutic window of tissue viability, large infarcts are prevented and complete or partial recovery can be achieved. In the experimental model of focal ischemia and in human stroke, FMZ can be utilized as a marker of neuronal integrity. If FMZ binding in the cortex is decreased below 4 times the mean value of white matter in the acute stage, permanent infarcts were observed on late CT/MRI; this irreversible damage could not be prevented by thrombolytic therapy. These results demonstrated that PET studies in suitable ischemia models in cats can help to explain various courses and diverging outcomes of acute ischemic stroke. Comparable findings from experimental ischemia and human stroke may affect the selection of appropriate therapeutic strategies.

Background and Purpose —Central benzodiazepine receptor ligands, such as [ 11 C]flumazenil (FMZ), are markers of neuronal integrity and therefore might be useful in the differentiation of functionally and morphologically damaged tissue early in ischemic stroke. We sought to assess the value of a benzodiazepine receptor ligand for the early identification of irreversible ischemic damage to cortical areas that cannot benefit from reperfusion. Methods —Eleven patients (7 male, 4 female, aged 52 to 75 years) with acute, hemispheric ischemic stroke were treated with alteplase (recombinant tissue plasminogen activator; 0.9 mg/kg according to National Institute of Neurological Disorders and Stroke protocol) within 3 hours of onset of symptoms. At the beginning of thrombolysis, cortical cerebral blood flow ([ 15 O]H 2 O) and FMZ binding were assessed by positron emission tomography (PET). Those early PET findings were related to the change in neurological deficit (National Institutes of Health Stroke Scale) and to the extent of cortical damage on MRI or CT 3 weeks after the stroke. Results —Hypoperfusion was observed in all cases, and in 8 patients the values were below critical thresholds estimated at 12 mL/100 g per minute, comprising 1 to 174 cm 3 of cortical tissue. Substantial reperfusion was seen in most of these regions 24 hours after thrombolysis. In 4 cases, distinct areas of decreased FMZ binding were detected. Those patients suffered permanent lesions in cortical areas corresponding to their FMZ defects (112 versus 146, 3 versus 3, 2 versus 1, and 128 versus 136 cm 3 ). In the other patients no morphological defects were detected on MRI or CT, although blood flow was critically decreased in areas ranging in size up to 78 cm 3 before thrombolysis. Conclusions —These findings suggest that imaging of benzodiazepine receptors by FMZ PET distinguishes between irreversibly damaged and viable penumbra tissue early after acute stroke.

Recently new high resolution brain PET and PET/SPECT tomographs have been discussed using phoswich detectors. The detector design is based on two layers of scintillation crystals in the z-axis with different physical properties, such as light decay time or light yield. This makes it feasible to assign the depth of interaction (DOI) information in order to be able to correct for spatial degradation in PET or to operate the detector in PET or SPECT mode. The pixel DOI detectors are cost effectively arranged in a block design. In this work the authors discuss the possibility of separating events from the two different layers in the time domain using pulse shape discrimination or in the energy domain using pulse height discrimination. Furthermore, the authors have investigated the feasibility of interdetector scatter suppression using pulse shape discrimination. The measurements have been done using a LSO/LSO high resolution PET detector, a LSO and GSO crystal in coincidence and a NaI(TI)/LSO combined PET/SPECT detector. The investigations show, that the pulse shape discrimination technique has a significant higher identification probability compared to the pulse height discrimination and does make a interdetector scatter detection feasible.

To improve the spatial resolution and uniformity in modern high resolution brain PET systems over the entire field of view (FOV), it is necessary to archive the depth of interaction (DOI) information and correct for spatial resolution degradation. In this work the authors present the performance results of a high resolution LSO/GSO phoswich block detector with DOI capability. This detector design will be used in the new CTI High Resolution Research Tomograph, ECAT HRRT. The two crystal layer (19/spl times/19/spl times/7.5 mm/sup 3/) and a light guide are stacked on each other and mounted on a (2/spl times/2) PMT set, so that the corners of the phoswich are positioned over the PMT centers. The crystal phoswich is cut into a 8/spl times/8 matrix of discrete crystals. The separation of the LSO and the GSO layer by pulse shape discrimination allows discrete DOI information to be obtained. The high light output and the light guide design results in an accurate identification of the 128 single crystals per block. Flood source measurements document a very good homogeneity of events, energy centroid stability and energy resolution (14-20% FWHM) per single crystal. An intrinsic resolution of /spl sim/1.3 mm and the DOI feasibility is extracted by coincidence measurements with a single GSO crystal.

Management of low-grade gliomas continues to be a challenging task, because CT and MRI do not always differentiate from nontumoral lesions. Furthermore, tumor extent and aggressiveness often remain unclear because of a lack of contrast enhancement. Previous studies indicated that large neutral amino acid tracers accumulate in most brain tumors, including low-grade gliomas, probably because of changes of endothelial and blood-brain barrier function. We describe 11C-methionine uptake measured with PET in a series of 196 consecutive patients, most of whom were studied because of suspected low-grade gliomas. Uptake in the most active lesion area, relative to contralateral side, was significantly different among high-grade gliomas, low-grade gliomas, and chronic or subacute nontumoral lesions, and this difference was independent from contrast enhancement in CT or MRI. Corticosteroids had no significant effect on methionine uptake in low-grade gliomas but reduced uptake moderately in high-grade gliomas. Differentiation between gliomas and nontumoral lesions by a simple threshold was correct in 79%. Recurrent or residual tumors had a higher uptake than primary gliomas. In conclusion, the high sensitivity of 11C-methionine uptake for functional endothelial or blood-brain barrier changes suggests that this tracer is particularly useful for evaluation and follow-up of low-grade gliomas.

Background and Purpose —Therapy of acute ischemic stroke can only be effective as long as neurons are viable and tissue is not infarcted. Since γ-aminobutyric acid receptors are abundant in the cortex and sensitive to ischemic damage, specific radioligands to their subunits, the central benzodiazepine receptors (BZR), may be useful as indicators of neuronal integrity and as markers of irreversible damage. To test this hypothesis we studied the binding of the BZR ligand [ 11 C]flumazenil (FMZ) early after ischemic stroke in comparison to the extent of final infarcts and hypometabolic cortical areas. Methods —In 10 patients cerebral blood flow, cerebral metabolic rate for oxygen (CMRO 2 ), oxygen extraction fraction (OEF), and FMZ binding were studied by positron emission tomography 3.5 to 16 hours after onset of their first hemispheric stroke. Early changes in flow, oxygen metabolism, and FMZ binding were compared with permanent disturbances in glucose metabolism, and the size of the final infarcts was determined on MRI or CT 12 to 22 days after the stroke. Results —In all patients except one cerebral blood flow was disturbed, with marked decreases in eight and a hyperperfusion in one patient corresponding to the location of neurological deficits. In these areas CMRO 2 was also reduced but to a variable degree, inducing highly variable OEF. Areas with markedly decreased CMRO 2 ( Conclusions —These results demonstrate that permanently and irreversibly damaged cortex can be detected by reduced FMZ binding early after stroke. Since FMZ distribution additionally images regional cerebral perfusion, BZR radioligands have a potential as clinically useful tracers in patients with acute ischemic stroke. The evidence of tissue damage furnished by these tracers might be of relevance for the selection of individual therapeutic strategies.

Background and Purpose Ligands for cerebral benzodiazepine receptors were used in the past to indicate the intactness of cortical neurons in subacute to chronic states after stroke and thus to differentiate among brain regions with complete or incomplete infarction and with functional deactivation. For planning acute interventional therapy, however, a marker of irreversible damage in early ischemia is needed. We studied the applicability of [ 11 C]flumazenil (FMZ) for differentiation between tissue with and without potential of recovery in the first hours after focal experimental ischemia. Methods In 11 cats, cerebral blood flow, cerebral metabolic rate for oxygen, oxygen extraction fraction, and FMZ binding were studied repeatedly by positron emission tomography before, during, and up to 12 hours after transient middle cerebral artery occlusion (MCAO) (30 minutes in 2, 60 minutes in 7, and 120 minutes in 2 cats, respectively). Development of the defects in energy metabolism were compared with the defects in FMZ binding (2 to 3 hours and 8 to 9 hours after MCAO), with the pattern of disturbed glucose metabolism (determined 12 hours after MCAO), and with the size of the infarcts (determined ≈15 hours after MCAO). Results Irrespective of the level of reperfusion, defects in FMZ binding (2 to 3 hours after MCAO) were closely related to areas with severely depressed oxygen consumption and predicted the size of the final infarcts, whereas preserved FMZ binding indicated intact cortex. Depression of glucose metabolism was in all animals larger than the defects in FMZ binding and the infarcts, indicating functional deactivation of brain areas beyond the permanent morphological damage. In addition, FMZ distribution within 2 minutes after injection was significantly correlated to flow and yielded reliable perfusion images. Conclusions The reduction of FMZ binding early after focal ischemia reflects irreversible neuronal damage that otherwise only can be detected by multitracer studies. Our experimental data and first clinical applications suggest that FMZ has potential as an indicator of developing infarction. Since FMZ distribution additionally images perfusion, this tracer might be useful for the selection of patients who would benefit from acute therapeutic intervention.

Concepts of basal ganglia organization suggest structually and functionally segregated pathways that link putamen and caudate function to motor and cognitive performance, respectively.To investigate whether motor and cognitive impairment in Parkinson disease is attributable to selective disturbance in nigrostriatal, dopaminergic function and regional cerebral glucose metabolism.Twenty patients with probable Parkinson disease underwent positron emission tomographic measurements of dopaminergic, nigrostriatal function (positron emission tomography with fluorodopa F 18), regional glucose metabolism (positron emission tomography with fludeoxyglucose F 18), memory testing, and evaluation of locomotor disability.Memory performance in the patient cohort strongly correlated with the individual disease duration and degree of locomotor disability (P.05). Striatal uptake rates of fluorodopa F 18 were significantly reduced in all patients (P.05) compared with those in normal control subjects, and putaminal rates correlated significantly with the patients' degree of locomotor disability (P.01) but not with memory performance. In the patients with an advanced stage of disease, there was a significant correlation between reduced caudate uptake rates of fluorodopa F 18 and the patients' impairment in delayed recall performance of the memory task (P.05) but not with the individual degree of locomotor disability. No changes were found for regional glucose metabolic rates in the patients compared with the controls.The present study provides evidence for the hypothesis that on the level of the striatum, motor impairment in Parkinson disease may be assigned to altered dopamine neuronal integrity in the putamen but not in the caudate, whereas memory impairment in the more advanced cases may be attributed to caudate but not putaminal dysfunction.

In temporal lobe epilepsy (TLE) patients without lesions, major hippocampal sclerosis, or atrophy on magnetic resonance imaging (MRI), the localizing power of [11C]flumazenil (FMZ) and 2-[18F]fluoro-2-deoxy-D-glucose (FDG) was compared using high-resolution positron emission tomography (PET) studies and individually coregistered MRI scans. Following complete clinical, neuropsychological, and electrophysiological evaluation, benzodiazepine receptor density was assessed using the FMZ equilibrium method. Thirty minutes later, interictal FDG-PET was performed under resting conditions. PET images were matched to three-dimensionally coregistered, T1-weighted MRI. Each temporal lobe (TL) was divided into 12 volumes of interest. The regional FMZ data were normalized with respect to average cortical values. For each patient the right-left asymmetries of rCMRGlc and normalized FMZ data were calculated. In 7 to 10 patients, mesial TL structures showed reduced FMZ binding, with a decrease by at least 10% in the affected TL. Reductions of 10% or more of rCMRGlc usually were more widespread than FMZ reductions and often involved lateral temporal cortex. The regions of most pronounced disturbances are not necessarily identical in both methods. Three patients had a complex correspondence of lateralization with PET, neuropsychological, and EEG data. In 4 patients, lateralization was less clear from EEG or neuropsychological results but was still consistent with lateralization by PET. In 3 of 10 patients, however, major discrepancies were found. These data suggest that the combination of neuropsychological testing, EEG, and MRI-guided FMZ- and FDG-PET will help to select patients with clearly defined epileptogenic foci especially in mesial TLE. Even in cases without MRI lesions, TL epileptic foci can be lateralized with consistency across the methods; FMZ-PET shows the pathologic focus more circumscribed than FDG-PET.

As a result of the limited spatial resolution of positron emission tomographic scanners, the measurements of physiological parameters are compromised by tissue heterogeneity. The effect of tissue heterogeneity on a number of parameters was studied by simulation and an analytical method. Five common tracer models were assessed. The input and tissue response functions were assumed to be free from noise and systematic errors. The kinetic model was assumed to be perfect. Two components with different kinetics were mixed in different proportions and contrast with respect to the model parameters. Different experimental protocols were investigated. Of three methods investigated for the measurement of cerebral blood flow (CBF) (steady state, dynamic, integral), the second one was least sensitive to errors caused by tissue heterogeneity and the main effect was an underestimation of the distribution volume. With the steady state method, errors in oxygen extraction fraction caused by tissue heterogeneity were always found to be less than the corresponding errors in CBF. For myocardial blood flow the steady state method was found to perform better than the bolus method. The net accumulation of substrate (i.e. rCMRglc in the case of glucose analogs) was found to be comparatively insensitive to tissue heterogeneity. Individual rate constants such as k2 and k3 for efflux and metabolism of the substrate in the pool of unmetabolized substrate in the tissue, respectively, were found to be more sensitive. In studies of radioligand binding, using only tracer doses, the effect of tissue heterogeneity on the parameter kon.Bmax could be considerable. In studies of radioligand binding using a protocol with two experiments, one with high and one with low specific activity, Bmax was found to be insensitive while Kd was very sensitive to tissue heterogeneity.

Congenital lactic acidosis with neurological symptoms may be due to a variety of disorders of energy metabolism. We investigated whether positron emission tomography (PET) and proton magnetic resonance spectroscopy (1H MRS) are capable of demonstrating specific changes to facilitate diagnosis. A corresponding increase of cerebral lactate (with MRS) and rate of glycolysis (with PET) was observed in 2 children with biochemical evidence of defective mitochondrial respiration. No such increase was noted in a child with lactic acidosis due to stress and exercise but normal respiratory chain activity, and in a control case with an epilepsy syndrome without evidence of primary changes of energy metabolism. The results suggest that defects of oxidative phosphorylation may cause a massive increase of glycolysis to cover energy requirements, with corresponding accumulation of lactate in brain tissue. This mechanism can now be demonstrated in vivo and, with further experience, may potentially be used as a diagnostic marker of respiratory chain disorders in brain tissue.

The anatomical localization of brain areas involved in repeating words was examined in six right-handed non-aphasic subjects. Their individual metabolic activation was studied with positron emission tomography (PET) and [18F]2-fluoro-2-deoxy-D-glucose (FDG) using a new data processing technique that includes three-dimensional coregistration with magnetic resonance images. Left superior temporal gyrus (cortical convexity surface, Brodmann area 22), right superior temporal lobe (superior temporal sulcus and bottom of transverse sulcus), sensorimotor cortex (vocalization area) bilaterally, and supplementary motor cortex were consistently activated in each individual. Cerebellar activation was more variable. In contrast to previous blood flow activation studies with averaging across subjects, this new technique permits the anatomical localization and quantitation of activated areas in each individual. It can therefore also be applied to patients with brain lesions.

An automatic control device for the administration of 15O labelled gaseous PET tracers with constant dose per time (continuous inhalation) is presented. The system controls the flow through the target, the flow to the patient and the dose to the patient simultaneously. The desired values for the dose and the flow to the patient are variable. The dose to the patient is kept constant within ±4% even if the beam current raises or if the beam is off for some seconds.

We evaluated 7 pairs of twins (2 monozygotic and 5 dizygotic) discordant for Parkinson's disease (PD), of whom the cotwins showed no signs of motor impairment on neurological examination. All subjects underwent positron emission tomographic measurements of cerebral glucose metabolism and dopaminergic, nigrostriatal function following injection of 2-[18F]fluoro-2-deoxy-D-glucose and L-6-[18F]fluorodopa ([18F]dopa), respectively, as well as testing for anterograde, verbal episodic, and semantic memory performance. Statistical analysis demonstrated significant reduction of striatal [18F]dopa uptake not only in the twin patients with PD but also in all of the cotwins, who showed significantly (p < 0.05) impaired [18F]dopa metabolism in at least one of the striatal measures including caudate, putaminal, and the rostrocaudal putaminal gradient of [18F]dopa uptake. Compared with age-matched controls, regional glucose metabolism was unchanged in all the twins. Neuropsychological testing showed significant (p < 0.05) impairment in verbal memory processing in the twin patients with PD and in 6 of the cotwins. Semantic memory skills were affected in 2 twin patients only. A significant correlation was found between scores obtained in Buschke's Selective Reminding Test and striatal [18F]dopa uptake, further substantiating the role of dopaminergic pathways in memory processing. The present study is the first to reveal not only significant disturbance of nigrostriatal dopaminergic function in verbal episodic memory that is known to be affected in PD. Larger studies with a longitudinal design will be necessary to answer the question of whether cognitive changes found in the cotwin group are signs of incipient PD.

A simple model to describe data losses in PET cameras is presented. The model is not intended to be used primarily for dead time corrections in existing scanners, even if this may be possible. Instead the model is intended to be used for data simulations in order to determine the figures of merits of future camera systems based on data handling state-of-art solutions. The model assumes the data loss to be factorized into two components, one describing the detector or block-detector performance and the other the remaining data handling such as coincidence determinations, data transfer and data storage. Two modern positron camera systems have been investigated in terms of this model. These are the new Siemens-CTI systems, Ecat Exact and Ecat Exact HR, both with an axial field-of-view (FOV) covering around 15 cm. They both have retractable septa and can acquire data from the whole volume within the FOV and can reconstruct volume image data. An example is given how to use the model for live time calculations in a futuristic large axial FOV cylindrical system. >

Diseases and dysfunction of the central nervous system are often associated with regional changes in cerebral glucose metabolism, which can be measured in vivo by PET using 18F-FDG as the tracer. For quantification, the arterial tracer input function must be determined. For rodents in particular, direct measurement of blood radioactivity concentration is scarcely feasible for follow-up of individual animals because of the invasiveness of blood sampling. We show that the whiskers area of the rat9s muzzle serves as an extracerebral reference region. The derived model also takes into account local variations of the lumped constant, which is crucial in pathologic tissue. Methods: In 11 rats, the reference tissue kinetic parameters were determined from PET data and measured whole blood radioactivity concentration. Parametric images of cerebral kinetic rate constants were calculated using the directly measured input function, the reference tissue time–activity curve with individually fitted reference kinetic parameters, and the reference time–activity curve with fixed reference kinetic parameters calculated from the fitted parameters averaged over all animals. The need for kinetic modeling in disease models is demonstrated in 5 rats subjected to acute focal cerebral ischemia. 18F-FDG metabolism and transport rate constants and local cerebral glucose metabolic rates were calculated. Results: Cerebral kinetic constants derived from the 3 methods corresponded closely. The maximum difference in whole-brain kinetic parameters observed between the directly measured input function and the reference tissue time–activity curve with individually fitted reference kinetic parameters was less than 5%. Taking fixed reference parameters (the reference time–activity curve with fixed reference kinetic parameters calculated from the fitted parameters averaged over all animals) still provided whole-brain kinetic parameters with an accuracy of approximately 90%. In the rats subjected to focal cerebral ischemia, 18F-FDG kinetic parameters in healthy tissue were not significantly different from whole-brain kinetic parameters in naive rats. The ischemic region was characterized by preserved glucose metabolism, although 18F-FDG uptake was elevated significantly—that is, the lumped constant in the ischemic region was different from that of healthy brain tissue. Conclusion: The method presented here allows for the quantitative noninvasive determination of cerebral glucose consumption in rats, takes into account local variations of the lumped constant, and is suitable for follow-up measurements of individuals.

A simple and reliable system for the single-breath inhalation and for short-term rebreathing of radioactive gases used in positron emission tomography is described. It comprises a collection- and radioactivity measurement-device, an inhalation bag for single-breath application, a modified anaesthetic system for rebreathing and a patient exhaled gas management system. The system is mainly used with 15O-labelled gases, but allows also the use of longer lived tracers such as methyl fluoride labelled with 18F or 11C.

The Cologne Special is a prototype of the ECAT EXACT (model 921), a new generation of Siemens-CTI PET scanners. It consists of three rings of 48 BGO block detectors each, covering an axial field of view of 16.2 cm with a patient port of 56.2 cm diameter. This results in a total of 24 rings with 384 crystals each, giving 47 contiguous image planes in two-dimensional (2D) mode. Total system sensitivity is 216 kcps/microCi/ml for a 20 cm cylinder phantom in 2D. This increases to 1.5 Mcps/microCi/ml in 3D. Data are acquired in the stationary mode only (no wobble motion), resulting in a transaxial spatial resolution of better than 6 mm full width at half-maximum (FWHM) at the center, which degrades to 7.5 mm tangentially and 9.6 mm radially at a radius of 20 cm. Average axial resolution changes from 5.0 mm FWHM at the center to 8.1 mm at R = 20 cm. Count rate performance was investigated at different low energy discriminator settings and found to be linear up to 2.5 microCi/ml with a 20 cm phantom. The magnitude and distribution of scatter were evaluated for both septa-extended and septa-retracted conditions for a range of energy thresholds. Brain, heart, and whole-body studies with the new tomograph demonstrate the versatility of its applications without compromising on physical performance.

Sixteen patients were studied by multitracer positron emission tomography (PET) within 6–48 (mean of 23) h of onset of a hemispheric ischemic stroke and again 13–25 (mean of 15.6) days later. Cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral metabolic rate of oxygen (CMRO2), oxygen extraction fraction (OEF), and cerebral metabolic rate of glucose (CMRglc) were measured each time by standard methods, and the sets of brain slices obtained at the two studies were matched using a three-dimensional alignment procedure. On matched brain slices, regions of interest (ROIs) for infarct and peri-infarct tissue, contralateral mirror regions, and major brain structures were outlined. In the core of infarction, blood flow and metabolism were significantly lower than in the corresponding contralateral regions at the first study, and did not change during the observation period. In the peri-infarct tissue, CMRO2 was moderately decreased at the first measurement; over time, the CMRO2 deteriorated progressively while flow did not change. When peri-infarct regions were selected on the basis of increased OEF (25 ± 29.8% above corresponding contralateral regions) on the early scans, the CBF was significantly decreased (23 ± 6.6%) while the CMRO2 showed only a slight difference from the mirror region. Within the observation period, the CBF improved but the CMRO2, OEF, and CMRglc deteriorated. Only in a few regions with increased OEF and slightly impaired CMRO2 was metabolism preserved close to normal values. These data from repeat PET studies in reproducibly defined tissue compartments furnish evidence of viable tissue in the border zone of ischemia up to 48 h after stroke. While this viable peri-infarct tissue exhibits some potential for effective treatment of ischemic stroke, therapeutic routines available today cannot prevent subsequent metabolic derangement and progression to necrosis. Multitracer PET studies identifying viable tissue could be of value in the development of effective treatment of ischemic stroke.

Four schizophrenic patients were investigated with dynamic positron emission tomography (PET) using (18F)fluorodeoxyglucose (FDG) and (18F)methylspiperone (MSP) as tracers. Two schizophrenics were on haloperidol therapy at the time of MSP PET. The other two schizophrenics were treated with clozapine, in one of them MSP PET was carried out twice with different daily doses (100 mg and 450 mg respectively). Neuroleptic serum levels were measured in all patients. Results were compared with MSP PET of two drug-free male control subjects and with a previous fluoroethylspiperone (FESP) study of normals. Three hours after tracer injection specific binding of MSP was observed in the striatum in all cases. The striatum to cerebellum ratio was used to estimate the degree of neuroleptic-caused striatal D2 dopamine receptor occupancy. In the haloperidol treated patients MSP binding was significantly decreased, whereas in the clozapine treated patients striatum to cerebellum ratio was normal. Even the increase of clozapine dose in the same patient had no influence on this ratio. Despite the smaller number of patients the study shows for the first time in humans that striatal MSP binding reflects the different D2 dopamine receptor affinities of clozapine and haloperidol.

A comparative PET study of [18F]2-fluoro-2-deoxy-D-glucose (FDG) and [18F]2-fluoro-2-deoxy-D-mannose (FDM) uptake was performed in 13 patients with focal brain lesions. Differences between FDG and FDM with respect to model rate constants, lumped constant, and estimated metabolic rate for glucose were determined on a regional basis. Across whole brain, the transport rate constant K*1 was almost unchanged, whereas k*2, describing the transport back from tissue to plasma, was 6% higher, and the phosphorylation rate constant k*3 was 9% lower for FDM compared to FDG. This implies a 20% lower lumped constant for FDM. No significant regional variability of this differential tracer behavior was observed in normal or in lesioned brain tissue. Thus, results from previous FDG studies, where the radiotracer was not 100% pure FDG but contained varying amounts of FDM, can easily be corrected by adjustment of the lumped constant employed in metabolic quantitation.

We used the ligand 3-N-(2′-F 18)fluoroethylspiperone (FESP) and positron emission tomography (PET) to quantify in vivo serotonin S2 neuroreceptor density and affinity in the baboon frontal cortex. In the cortex, FESP binds specifically and exclusively to S2 receptors, and an equilibrium is reached when the rate of ligand-receptor association and dissociation become equal. Using multiple studies in the same baboon, an equilibrium (saturation) analysis approach provided a linear Hill plot with a slope of 1.02 (r2 =0.988,P

PET studies of dopamine D2-receptor binding were performed in thirty patients with various disorders related to the dopaminergic system and in six healthy controls. Uptake of [18F]fluoroethylspiperone in caudate over three hours was analyzed in terms of several indices of receptor binding:caudate-to-cerebellum activity ratio, concentration of ligand as percentage of injected dose, caudate-to-blood radioactivity ratio, slope of tracer uptake curves, binding potential, kinetic constants of a three compartment model. In 14 patients brain glucose metabolism was also measured. Data on medicated patients demonstrate that the average values of most of the above parameters indicate the decreased number of available D2-receptors whereby, besides an age dependent decline, the caudate-to-cerebellum ratio affords the relatively best distinction among diagnostic groups. In individual cases, large variability among subjects permits only the classification of severe pathologies. Morphological damage and neuronal loss in the striatum may also cause abnormal low values both for the indices of receptor binding and for glucose consumption, thus providing a possible pathogenetic link between receptor dysfunction and impaired energy metabolism.

Group studies using PET and other types of neuroimaging require some means to achieve congruence of brain structures across subjects, such that scans from individuals varying in brain shape and gyral anatomy can be analyzed together. Volume registration methods are the most widely used approach to achieve this congruence. They are fast and typically require little manual interaction, but, unfortunately, it is difficult to achieve a good match between cortical areas in volume space, especially where folding patterns vary across subjects. Cortical flattening is a recent, alternative strategy: Its key features are explicit definition of cortex, such that white matter or cerebrospinal fluid compartments are largely excluded from the analysis volume, and subsequent registration of the cortical sheet in its natural, 2-dimensional topology. This type of registration has been demonstrated to provide better matching of congruent cortical structures than volume methods and, thus, offers a potentially more robust way of analyzing PET data. Methods: Here, we explore the applicability of cortical flattening of coregistered MRI to 18F-FDG PET on the HRRT system (high-resolution research tomograph), the highest-resolution whole-head scanner available to date. Results: We report average values and SD of cortical metabolism in a pilot study of the dominant hemisphere in 9 control subjects and provide estimates of group sizes necessary for studies using this technique. Conclusion: We conclude that cortical flattening with subsequent surface registration is a feasible and promising strategy for group studies on the HRRT, providing the highest fidelity maps of human cortical glucose consumption to date.

Positron emission tomography with 11C-N-methyl-4-piperidyl-acetate (MP4A) was applied in eight healthy volunteers and two patients with mild Alzheimer's disease (AD) to assess acetylcholine esterase (AChE) activity in magnetic resonance imaging-identified brainstem nuclei. Uptake ratios in lateral dorsal tegmental and pedunculopontine nuclei relative to cerebellum yielded reproducible values for the AChE activity in controls and reduced values in AD, more marked in a patient with complaints of disturbed sleep. Cortical AChE activity was related to the extent of cognitive impairment which was more severe in the AD patient without sleep disturbance. This preliminary observational study demonstrates the feasibility to image and assess AChE activity in small nuclei of the brain stem. This approach may be helpful to investigate the interaction of various nuclei in the complex network regulating sleep and wakefulness in representative patient groups with documented sleep disturbance.

To develop efficient and safe gene therapy approaches, the herpes simplex virus type 1 thymidine kinase gene (HSV-1- tk ) has been shown to function as a marker gene for the direct noninvasive in vivo localization of thymidine kinase (TK) expression by positron emission tomography (PET) using radiolabeled nucleoside analogues as specific TK substrates. Moreover, the gene encoding dopamine type 2 receptor ( d2r ) could be used as a PET marker gene using specific radiolabeled receptor binding compounds. Here we describe the quantitative colocalization of d2r and HSV-1- tk gene expression mediated from a universal HSV-1 amplicon vector in a subcutaneous human Gli36dEGFR glioma model by PET. The HSV-1 amplicon vector was constructed using a bicistronic gene cassette to contain (1) the d2r80A mutant, which is able to bind its ligand racloprid but unable to activate downstream signal transduction pathways, and (2) the tk39 mutant with enhanced enzymatic activity toward guanosine analogues fused to the green fluorescent protein gene ( tk39gfp ) serving as a marker gene in cell culture. After infection of human Gli36dEGFR glioma cells with the HSV- d2r80A IRES tk39gfp (HSV-DITG) amplicon vector in cell culture, D2 receptor expression and its targeting to the cell surface were determined by Western blotting and immunolabeling. Vector application in vivo served for quantitative colocalization of d2r80A - and tk39gfp -derived PET signals employing the specific D2 receptor binding compound [ 11 C]racloprid and the specific TK39 substrate 9-(4-[ 18 F]fluoro-3-hydroxymethylbutyl)guanine. Our results demonstrate that for the range of gene expression studied in vivo, both enzymatic and receptor binding assays give comparable quantitative information on the level of vector-mediated gene expression in vivo. The d2r80A in combination with a specific binding compound passing the intact blood-brain barrier might be an alternative marker gene for the noninvasive assessment of vector-mediated gene expression in the brain using PET.