Lennart Widén

Head Fixation Device for Reproducible Position Alignment in Transmission CT and Positron Emission Tomography

A head-positioning device allowing accurate position transference between computed tomography and positron emission tomography is described. A base plate is fixed to the patients head through either an individual mold or screws into the calvarium. This base plate fits onto the headholders of the two devices, thus ensuring that scans are taken at the same level. Using the regular software, the coordinates of an anatomic structure may be determined and transferred between the two images.

Changes in Regional Cerebral Oxidative Metabolism Induced by Tactile Learning and Recognition in Man

We measured the regional cerebral oxidative metabolism (rCMRO2) with positron emission tomography in normal healthy volunteers in three different stages: rest, tactile learning, and tactile recognition of complicated geometrical objects. The frequency of manipulatory movements during tactile recognition was twice that of tactile learning. Tactile recognition with the right hand increased rCMRO2 in six prefrontal cortical areas, bilaterally in the supplementary motor areas, the premotor areas and supplementary sensory areas, in the left primary motor and primary sensory area, in the left anterior superior parietal lobule, bilaterally in the secondary somatosensory area, the anterior insula, lingual gyri, hippocampus, basal ganglia, anterior parasagittal cerebellum, and lobus posterior cerebelli. These structures have in other studies been found to participate in manipulatory movements and analysis of somatosensory information. Tactile learning increased rCMRO2 in the same structures as did tactile recognition. Thus we found no differences in the anatomical structures participating in storage and retrieval. However the rCMRO2 increases in the left premotor cortex, supplementary motor area, and left somatosensory hand area were larger during tactile recognition in accordance with the higher frequency of manipulatory movements and higher flux of somatosensory information from the periphery during recognition. Despite this the rCMRO2 was significantly higher in the neocerebellar cortex during tactile learning. Since there were no learning effects on the manipulatory movements, this extra metabolic activity in the lateral cerebellum was attributed to energy demanding processes associated with climbing fibre activity during storage of somatosensory information.

Feasibility of reversing benzodiazepine tolerance with flumazenil

To examine whether the benzodiazepine antagonist flumazenil can reverse tolerance to benzodiazepines but without precipitating withdrawal seizures, the antiepileptic effect of flumazenil itself and its ability to reverse tolerance at a dose that would leave sufficient receptors free for the binding of benzodiazepines were investigated. Electroencephalographic studies in 6 patients with partial and 6 with generalised seizures showed that flumazenil had a short (20 min) non-dose-dependent suppressant effect on epileptic discharges in those with partial seizures. Receptor occupancy studies in 12 patients showed that 1.5 mg flumazenil given intravenously occupied 55% receptors, whereas 15 mg occupied nearly all receptors. When 3 patients with partial seizures who had become tolerant to clonazepam were given 1.5 mg flumazenil, they were seizure-free for 6-21 days after the injection. The value of intermittent therapy with a benzodiazepine antagonist for preventing or reversing tolerance to benzodiazepine agonists ought to be investigated further.

Rapid Feasibility Studies of Tracers for Positron Emission Tomography: High-Resolution PET in Small Animals with Kinetic Analysis

The development of methods for production of a radiotracer for use in human studies with positron emission tomography (PET) is often a time-consuming process of optimizing radiolabelling yields and handling procedures. Sometimes the radiotracer is not the original drug, but rather a derivative with unknown in vivo pharmacological properties. We have developed a fast and simple method of testing putative new PET tracers in vivo in small animals. The procedure has been validated in rats with different PET tracers with known kinetic and pharmacological properties ([2-18F]2-fluoro-2-deoxy-d-glucose, [N-methyl-11C]Ro 15-1788, and [15O]butanol). The tracer concentration in arterial blood was continuously measured to obtain the brain input function. Following image reconstruction of the scans, time–activity curves of selected regions of interest were generated. Estimations of CMRglc (1.0 ± 0.2 μmol g−1 min−1), CBF (1.4 ± 0.4 ml g−1 min−1) and transport rate constants for [N-methyl-11C]Ro 15-1788 (K1 = 0.44 ± 0.01 ml g−1 min−1 and k2 = 0.099 ± 0.005 min−1) as well as calculated first pass extraction (0.32 ±0.1) are in reasonable agreement with literature values. Small animal studies require minimal amounts of radioactivity and can be performed without sterility and toxicology tests. They may serve as a preliminary basis for radiation safety calculations because whole body scans can be performed even with a head scanner. The major advantage of this procedure in comparison to ex vivo autoradiography is that very few experiments are necessary to reliably determine the properties of the blood–brain barrier transport of the radiotracer and the possible whole brain receptor binding characteristics.

Positron Emission Tomographic Measurements of Cerebral Glucose Utilization Using [1-11C]D-Glucose

Regional CMRglc was measured in seven healthy volunteers with positron emission tomography using [1-11C]D-glucose. Regional CBF was measured using [11C]fluoromethane. The arteriovenous differences of unlabeled glucose and oxygen together with 11C metabolites were also measured. In addition to the loss of [11C]CO2, a loss of acidic 11C metabolites was also detected. A three-compartment model was applied to the tracer data in the time interval 0–24 min. After correction for the loss of 11C metabolites, the tracer method gave an average CMRglc of 26.4 ± 1.9 (SD) μmol/100 g/min, close to the value obtained with the Fick principle. After correction for the loss of [11C]CO2 only, the tracer method gave 23.6 ± 2.1 μmol/100 g/min, compatible with (1/6) CMRO2, obtained with the Fick principle. These results and the time course of the loss of acidic 11C metabolites are consistent with the presence of nonoxidative metabolism of glucose that causes an early loss of mainly [11C]lactate after a bolus injection of the tracer. This implies that [1-11C]D-glucose measures the rate of glucose oxidation rather than the total CMRglc. The experiments using [1-11C]D-glucose were compared to five analogous experiments using [U-11C]D-glucose together with [15O]H2O as a flow tracer. After correction for the loss of [11C]CO2, the two glucose tracers gave similar global values of CMRglc and other parameters associated with glucose utilization, but with labeling in the carbon-1 position, the loss of [11C]CO2 was substantially delayed and the contrast between gray and white matter was improved. A kinetic model for [1-11C]D-glucose for use in PET studies without the simultaneous measurement of rCBF and the loss of 11C metabolites is proposed.

Facilitated transport of glucose from blood to brain in man and the effect of moderate hypoglycaemia on cerebral glucose utilization

The effect of steady-state moderate hypoglycaemia on human brain homeostasis has been studied with positron emission tomography using [U-11C]-D-glucose as tracer. To rule out any effects of insulin, the plasma insulin concentration was maintained at the same level under normo- and hypoglycaemic conditions. Reduction of blood glucose by 55% increased the glucose clearance through the blood-brain barrier by 50% and reduced brain glucose consumption by 40%. Blood flow was not affected. The results are consistent with facilitated transport of glucose from blood to brain in humans. The maximal transport rate of glucose from blood to brain was found to be 62±19 (mean±SEM) μmol hg−1 min−1, and the half-saturation constant was found to be 4.1 + 2.3 mM.

CORTICAL BENZODIAZEPINE RECEPTOR BINDING IN PATIENTS WITH GENERALIZED AND PARTIAL EPILEPSY

Summary: Impaired cortical inhibition may be involved in epileptogenic mechanisms. In a positron‐emission tomography (PET) study, we demonstrated a reduction of the cortical benzodiazepine (BZD) receptor density in the epileptic foci of patients with partial epileptic seizures. In the present study, we used the same method in 10 patients with primary generalized epilepsy to determine whether an altered BZD receptor binding could also be demonstrated in this patient group. The [11C]‐labeled BZD receptor antagonist Ro 15–1788 was used as ligand. Receptor affinities and densities were calculated in various cortical regions and then compared with the values from corresponding “nonepileptic” regions in the previously examined partial epilepsy patients. Focal alterations of the BZD receptor density or affinity were not demonstrated in patients with generalized epilepsy. This patient group had a slight tendency toward lower mean cortical BZD receptor density, however, as compared with corresponding values from 10 patients with partial epilepsy. Our results strongly suggest that a focal alteration of cortical inhibition is not a prominent feature of human generalized epilepsy. The observed tendency toward lower mean cortical BZD receptor density may be a consequence of diffusely impaired cortical inhibition. Further investigations of this issue are therefore indicated.

Positron emission tomographic studies of central cholinergic nerve terminals

The aim of this study was to develop a quantitative method for the study of cholinergic nerve terminals in vivo. An 18F-labeled analogue of vesamicol ([18F]FMV) that binds with high affinity to synaptic vesicles from Torpedo electric organ was synthesized and evaluated in vivo in rats and monkeys by positron emission tomography (PET). In rats, the tracer was rapidly cleared from the blood and highly extracted into the brain, where it was specifically and irreversibly bound. In monkeys, a specific binding of the tracer was observed in brain regions known to contain cholinergic nerve terminals. Preinjection of non-labeled vesamicol prevented the cerebral binding of [18F]FMV to a high affinity site in both species. Our results are a major step towards quantitative human in vivo studies of presynaptic cholinergic functions.

In vivo distribution of [11C]-busulfan incynomolgus monkey and in the brain of a human patient

SummaryThe in vivo distribution of the antileukemic agent busulfan labeled with the positron-emitting radionuclide carbon 11 was investigated in cynomolgus monkeys and in a human patient using positron emission tomography. After i.v. injection of the radiotracer, its regional uptake was monitored for about 1 h in the monkeys body and in a separate experiment, in the monkeys brain. The concentration of radioactivity in the liver, which showed the highest levels of all the organs scanned, increased throughout the experiment and was 9-fold that in the brain at the end of the experiment. [11C]-Busulfan rapidly crossed the blood-brain barrier. The radioactivity peaked in both the cortex and the white matter showing a ratio of 1.25, at 3 min but declined quickly to yield a ratio of approximately 1 after 30 min. In the human brain, radioactivity in the cerebellum, cortex, and white matter reached a maximum within 5 min showing a cortex:white matter ratio of 1.6. The activity in the cortex declined to yield a ratio of 1 within 30 min. Of the delivered dose, 20% penetrated into the brain.

Striatal D2/acetylcholine interactions: PET studies of the vesamicol receptor.

The regional cerebral distribution of [18F]NEFA, an aminobenzovesamicol (ABV), was studied in primates with PET. The binding was stereoselective and could be blocked but not displaced with vesamicol. The regional distribution pattern at late times, striatum > cortex > cerebellum, was corroborated by in vitro autoradiography using [3H]ABV and is consistent with known patterns of cholinergic innervation. Pretreatment with sigma 1 or D1 antagonists did not affect the striatal uptake, whereas D2 antagonists markedly augmented the uptake. This is consistent with the known induction of acetylcholine turnover in the striatum in response to D2-receptor blockade and demonstrates that the amount of [18F]-(-)-NEFA incorporated was influenced by the cholinergic activity in the target neurones.