Klaus Wienhard

The ECAT EXACT HR: Performance of a new high resolution positron scanner

Objective The ECAT EXACT HR is a newly designed CTI–Siemens PET scanner with high spatial resolution. Its physical performance with respect to resolution, count rate efficiency, and scatter was investigated and evaluated with phantom studies. Materials and Methods The new tomograph consists of three rings of 112 BGO block detectors (50 mm x 23 mm x 30 mm deep) each, covering an axial field of view of 15 cm with a patient port of 56 cm diameter. Each block is sawed into an 8 x 7 matrix giving 24 detector rings with 784 crystals each. Results Total sensitivity for a 20 cm cylinder phantom is 177 kcps/μCi/ml in two-dimensional (2D) mode and increases to 1.46 Mcps/μCi/ml in 3D mode. Count rate performance was investigated for different low energy discriminator thresholds. Smaller detector blocks improve noise equivalent counts by ∼50% compared with the EXACT system both in 2D and in 3D mode. Scatter fractions vary in 2D from 0.09 to 0.13 for energy thresholds from 450 to 250 keV for line sources in a 20 cm diameter phantom. In 3D mode an increase of scatter by a factor of 3 is observed. Transaxial spatial resolution varies from 3.6 mm full width at half-maximum (FWHM) at the center to 4.5 mm FWHM tangentially and 7.4 mm FWHM radially at R = 20 cm. Average axial resolution changes from 4.0 mm FWHM at center to 6.7 mm FWHM at R = 20 cm. Conclusion Due to its special properties, the EXACT HR can be equally applied to routine clinical brain and whole-body imaging and to noninvasive experimental studies of regional tracer concentrations in medium-sized animals.

Progressive Derangement of Periinfarct Viable Tissue in Ischemic Stroke

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.

The ECAT HRRT: performance and first clinical application of the new high resolution research tomograph

The ECAT HRRT is a three-dimensional (3-D) only dedicated brain tomograph employing the new scintillator lutetium-oxy-orthosilicate (LSO) and using depth of interaction (DOI) information to achieve uniform isotropic resolution across a 20-cm diameter volume. With its unique technological innovations it represents the prototype of a new generation of high-resolution brain tomographs. The physical performance with respect to count rate, live time, scatter, sensitivity, and resolution was evaluated with phantom studies and measurements with a point source. The HRRTs imaging performance was tested with phantoms and fluorodeoxyglucose (FDG) scans performed in animal and human brains. We find that due to the significantly improved resolution and the large solid angle covered by the panel detectors, several issues that have been adequately solved for older generation scanners demand new attention for the HRRT, like acquiring and handling large amounts of data effectively, strategies for optimal reconstruction, shielding, and correction of random coincidences.

Performance Evaluation of the Positron Scanner ECAT EXACT

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/μCi/ml for a 20 cm cylinder phantom in 2D. This increases to 1.5 Mcps/μCi/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 μCi/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 tomography demonstrate the versatility of its applications without compromising on physical performance.

Dynamic Penumbra Demonstrated by Sequential Multitracer PET after Middle Cerebral Artery Occlusion in Cats

Experimental models of focal cerebral ischemia have provided important data on early circulatory and biochemical changes, but typically their correspondence with metabolic and hemodynamic findings in stroke patients has been poor. To fill the gap between experimental studies at early time points and rather late clinical studies, we repeatedly measured CBF, CMRO2, oxygen extraction fraction (OEF), cerebral blood volume (CBV), and CMRglc in six cats before and up to 24 h after permanent middle cerebral artery (MCA) occlusion (MCAO), using the 15O steady state and [18F]fluorodeoxyglucose methods and a high-resolution positron emission tomography (PET) scanner. Likewise, three sham-operated control cats were studied during the same period. Final infarct size was determined on serial histologic sections. In the areas of final glucose metabolic depression that were slightly larger than the histologic infarcts, mean CBF dropped to ∼40% of control values immediately on arterial occlusion. It further decreased to <20% during the course of the experiment. This progressive ischemia was most conspicuous in border zones. CMRO2 fell to a lesser degree (55%), eventually reaching ∼25% of its control level. At early stages, OEF increased mainly in the center of ischemia. With time, areas of increased OEF moved from the center to the periphery of the MCA territory. Concurrently, progressive secondary decreases in OEF in conjunction with further reductions of CBF and CMRO2 indicated the development of central necrosis. The findings are highly suggestive of a dynamic penumbra. In five cats with complete MCA infarcts, CBF decreased and OEF increased in the contralateral hemisphere after 24 h, suggesting whole-brain damage. This effect may be explained by the widespread brain edema found histologically in addition to the nonspecific CBF reductions and OEF elevations observed also in the sham-operated controls after 1 day in the experimental condition. In one cat, cortical OEF increased only transiently. Normal CMRO2 and CMRglc were eventually restored, and the final infarct was small. This study demonstrates that acute regional pathophysiologic changes can be repeatedly assessed by multivariate PET in cats. Viable tissue can be detected up to several hours after MCA occlusion, and the transition of misery-perfused regions into necrosis or preserved tissue can be followed over time. The present results support the concept of a dynamic penumbra, in which for up to 24 h tissue damage spreads progressively from the center to the periphery of ischemia. Sequential high-resolution PET provides insight into the dynamics of regional pathophysiology and may thus further the development of rational therapeutic strategies.

Regional Kinetic Constants and Cerebral Metabolic Rate for Glucose in Normal Human Volunteers Determined by Dynamic Positron Emission Tomography of [18F]-2-Fluoro-2-Deoxy-D-Glucose

Using dynamic [18F]fluorodeoxyglucose (FDG) positron emission tomography with a high-resolution, seven-slice positron camera, the kinetic constants of the original three-compartment model of Sokoloff and co-workers (1977) were determined in 43 distinct topographic brain regions of seven healthy male volunteers aged 28–38 years. Regional averages of the cerebral metabolic rate for glucose (CMRglu) were calculated both from individually fitted rate constants (CMRglukinetic) and from activity maps recorded 30–40 min after FDG injection, employing a four-parameter operational equation with standard rate constants from the literature (CMRgluautoradiographic). Metabolic rates and kinetic constants varied significantly among regions and subjects, but not between hemispheres. k1 ranged between 0.0485 ± 0.00778 min−1 in the oval center and 0.0990 ± 0.01347 min−1 in the primary visual cortex. k2 ranged from 0.1198 ± 0.01533 min−1 in the temporal white matter to 0.1472 ± 0.01817 min−1 in the cerebellar dentate nucleus. k3 was lowest (0.0386 ± 0.01482 min−1) in temporal white matter and highest (0.0823 ± 0.02552 min−1) in the caudate nucleus. Maximum likelihood cluster analysis revealed four homogeneous groups of brain regions according to their respective kinetic constants: (1) white matter and mixed brainstem structures; (2) cerebellar gray matter and hippocampal formations; (3) basal ganglia and frontolateral and primary visual cortex; and (4) other cerebral cortex and thalamus. Across the entire brain, k1 and k2 were positively correlated (r = 0.79); k1 and k3 showed some correlation (r = 0.59); but no significant linear association was found between k2 and k3. A strong correlation with CMRglu could be demonstrated for k1 (r = 0.88) and k3 (r = 0.90), but k2 was loosely correlated (r = 0.56). CMRglu kinetic ranged from 17.0 ± 2.45 μmol/100 g/min in the occipital white matter to 41.1 ± 5.62 μmol/100 g/min in the frontolateral cortex. In most regions the mean values of CMRglu kinetic did not differ significantly from CMRglu autoradiographic. With few exceptions, however, within-region variance was significantly less for CMRglu kinetic than for CMRglu autoradiographic, suggesting greater individual reliability of results obtained by the kinetic approach.

Comparative Regional Analysis of 2-Fluorodeoxyglucose and Methylglucose Uptake in Brain of Four Stroke Patients. With Special Reference to the Regional Estimation of the Lumped Constant

The glucose metabolic rate of the human brain can be measured with labeled deoxyglucose, using positron emission tomography, provided certain conditions are fulfilled. The original method assumed irreversible trapping of deoxyglucose metabolites in brain during the experimental period, and it further requires that a conversion factor between deoxyglucose and glucose, the “lumped constant,” be known for the brain regions of interest. We examined the assumption of irreversible trapping of fluorodeoxyglucose metabolites in brain of four patients in 365 normal and 4 recently infarcted regions. The average net, steady-state rate of fluorodeoxyglucose (KD) accumulation in normal regions of the four patients was 0.025 ml g−1 min−1. We also examined the variability of the lumped constant. We first confirmed that methylglucose is not phosphorylated in the human brain. We then estimated the lumped constant from the regional distribution of labeled methylglucose in brain. The average (virtual) volume of distribution of labeled methylglucose in the normal regions was 0.46 ml g−1 and was the same in both gray and white matter structures. The average brain glucose content corresponding to this value was 1.3 μmol g−1, assuming a Michaelis constant (Kt) of 3.7 mM for glucose transport across the blood–brain barrier. The lumped constant varied insignificantly between 0.4 and 0.5 in most regions, with an overall average of 0.44. It did not vary significantly between the patients and was the same in gray and white matter structures, but was inversely related to the calculated metabolic rate. This observation indicates that metabolic rates calculated with a fixed lumped constant (e.g., 0.40) would be slightly underestimated at high metabolic rates and slightly overestimated at low metabolic rates. The average glucose metabolic rates of the 365 normal regions, in which gray matter regions prevailed by 20:1, was 32 μmol 100 g−1 min−1. The average glucose phosphorylation rate in white matter was 20 μmol 100 g−1 min−1 with a lumped constant of 0.45. In the recently infarcted areas, the lumped constants varied from 0.37 to 2.83, corresponding to glucose metabolic rates varying from 2 to 18 μmol 100 g−1 min−1. Two infarct types were identified. In one type, the phosphorylation-limited type, glucose content and the lumped constant were close to normal (1 μmol g−1 and 0.40, respectively). In the other, the transport/flow-limited type, the glucose content was low (0.2 μmol g−1), and the lumped constant in excess of unity. The evidence from the present study upholds the model of Sokoloff et al. in every detail.

Estimation of Local Cerebral Glucose Utilization by Positron Emission Tomography of [18F]2-Fluoro-2-deoxy-D-glucose: A Critical Appraisal of Optimization Procedures

Various approaches estimating local cerebral glucose utilization by positron emission tomography of labeled deoxyglucose are compared. Autoradiographic methods that predict the glucose utilization rate from a single scan are unreliable in pathologic tissue because of abnormal values of the model rate constants. A normalization procedure using the ratio of measured tissue activity to activity calculated with standard rate constants is proposed to readjust the values of the rate constants. Reliable estimates of metabolic rates can be obtained from dynamic recordings of tracer uptake. In the graphic approach, metabolic rate can be derived from the slope of a segment of a transformed uptake curve, which becomes linear at 15–20 min after intravenous tracer injection, with an accuracy comparable with that in complete dynamic studies. However, by recording and analyzing full-length uptake curves, in addition to metabolic rate, the model rate constants can be determined regionally. The physiological significance of those parameters is demonstrated in crossed cerebellar deactivation in 30 patients with supratentorial infarcts. Mild hypometabolism both within the ischemic lesion and in the morphologically intact cerebellum is accompanied by a reduction of the phosphorylation rate only. Severe metabolic depression, by contrast, affects both cerebellar transport and phosphorylation processes, whereas in the cerebrum, only the rate constant k1 is significantly correlated with the degree of metabolic disturbance.

Individual Functional Anatomy of Verb Generation

Examination of the individual functional anatomy of language is of particular interest in clinical neurology to explain the variability of aphasic symptoms after focal lesions and to avoid damage of language-related brain areas by surgery. For a silent verb generation task, we examined whether activation PET with 3D data acquisition, multiple replication of conditions, and coregistration with MRI provides results that are consistent and reproducible enough to be useful clinically. Visual analysis was performed on PET-MRI fusion images, including renderings of the brain surface. Quantitative analysis was based on volumes of interest. In seven right-handed normals, activation of the triangular part of the left inferior frontal cortex [Brodman area (BA) 45] was the most significant finding that was present in each subject. Two subjects showed minor anatomical variants of the ascending or horizontal ramus of the sylvian fissure that were associated with the least activation of BA 45. In the left hemisphere the other frontal gyri, the superior temporal and posterior part of the middle temporal gyrus, and the paracingulate gyrus were also significantly activated. There was significant bilateral cerebellar activation, but it was significantly more intense on the right than on the left side. The consistency and high interindividual reproducibility of these findings suggest that this technique may be useful for clinical assessment of language-related areas.

Early [11C]Flumazenil/H2O Positron Emission Tomography Predicts Irreversible Ischemic Cortical Damage in Stroke Patients Receiving Acute Thrombolytic Therapy

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.