Lesions of the putamen: their relevance to dystonia.

Two patients with acquired dystonia were studied by computed imaging techniques and found to have lesions predominantly involving the putamen. The implications of these findings are discussed, and it is concluded that, for the genesis of dystonia, a relative increase of other inputs to the pallidum may be important, such as those from the caudate and subthalamic nuclei.

Positron emission tomography and histopathology in Pick's disease.

PET using 18F-2-fluoro-2-deoxyglucose was carried out on a case of Pick's disease established by necropsy. A sharply decreased cortical metabolic rate for glucose was obtained in specific gyri, especially in the frontal lobes, where there was extensive gliosis and neuronal loss. More moderate decreases were found in areas with numerous Pick bodies and inflated neurons but less gliosis. The PET pattern was sufficiently distinctive to suggest that it might be possible to distinguish Pick's from Alzheimer's disease premortem.

Comparison of PET, MRI, and CT with pathology in a proven case of Alzheimer's disease.

Positron emission tomography (PET) with fluorodeoxyglucose (FDG), magnetic resonance imaging (MRI), and CT were carried out in a patient with Alzheimer's disease 16 months before he died. At autopsy, the gross appearance of the brain correlated with MRI and CT, which showed some regional atrophy. These were much less revealing than PET, which correlated with microscopic findings of neuronal loss and proliferation of glia. In areas of moderately impaired local cerebral metabolic rate of glucose, as revealed by reduced FDG uptake, there was some gliosis, primarily around the numerous senile plaques. In areas of severe metabolic impairment, there was a profound loss of neurons, extensive gliosis, and a diminished appearance of plaques. PET-FDG is a better measure of the severity of Alzheimer's disease than MRI or CT, because it reflects the degree of neuronal pathology.

MRI and PET studies of manganese-intoxicated monkeys.

Using MRI and PET, we investigated the consequences of manganese intoxication in a primate model of parkinsonism and dystonia. Three rhesus monkeys were injected intravenously with doses of 10 to 14 mg/kg of MnCl2 on seven occasions, each a week apart. Two animals became hypoactive with abnormal extended posturing in the hind limbs. These motor disturbances did not improve with administration of levodopa. In all three monkeys, T1-weighted MRI demonstrated high signal intensities in the regions of the striatum, globus pallidus, and substantia nigra. No significant changes were found on [18F]6-fluoro-L-dopa, [11C]raclopride, or [18F]fluorodeoxyglucose PET. These results are consistent with the pathologic findings, which were primarily confined to the globus pallidus, and indicate that manganese intoxication is associated with preservation of the nigrostriatal dopaminergic pathway, despite clinical evidence of parkinsonian deficits. Chronic manganese intoxication may cause parkinsonism by damaging output pathways downstream to the nigrostriatal dopaminergic pathway. This is consistent with the demonstrated lack of therapeutic response to levodopa.

The use of positron emission tomography in pion radiotherapy.

The radioactive debris produced by pion radiotherapy can be imaged by the technique of Positron Emission Tomography (PET) as a method of non-invasive in situ verification of the pion treatment. This paper presents the first visualization of the pion stopping distribution within a tumor in a human brain using PET. Together with the tissue functional information provided by the standard PET scans using radiopharmaceuticals, the combination of pion with PET technique can provide a much better form of radiotherapy than the use of conventional radiation in both treatment planning and verification.

Routine synthesis of L-[18F]6-fluorodopa with fluorine-18 acetyl hypofluorite.

The synthesis of L-[18F]6-fluorodopa (2.4-10.6 mCi) was done by passing gaseous [18F]acetyl hypofluorite through a solution of L-methyl-N- acetyl-[beta-(3-methoxy-4-acetoxyphenyl)]alaninate in acetic acid at room temperature followed by the hydrolysis of the intermediate products with concentrated hydriodic acid. The desired fluorodopa isomer was isolated in 8% EOB radiochemical yield by high performance liquid chromatography in an overall synthesis time of 100 min.

Routine synthesis of carbon-11-carboxyl-labeled L-dopa.

Carbon-11-carboxyl-labeled L-dopa has been synthesized by the modified Bucherer-Strecker method. The reaction mixture was first purified by chiral HPLC followed by deprotection using hydriodic acid. The entire procedure was performed in a remotely operated system which gave the product in 28% radiochemical yield (decay corrected) in an overall synthesis time of 55-60 min.

The reproducibility of striatal uptake data obtained with positron emission tomography and fluorine-18-L-6-fluorodopa tracer in non-human primates.

Cynomolgus and rhesus monkeys have been studied via PET with [18F]-L-6 fluorodopa tracer. Striatal fluorodopa uptake rate constants have been derived by graphical analysis of transaxial slice images centered on the striata. The differences between pairs of values of the rate constant, obtained from two scans on the same monkey separated by two weeks or more, exhibited a relative standard deviation of 34.4%. If the two scans were conducted one immediately after the other, with the position of the monkey undisturbed, the standard deviation was reduced to 14.0%. The utility of this technique was demonstrated by comparing the effects on the scans of halothane and pentobarbital anesthesia and by the administration of NSD 1015, a peripheral and central inhibitor of L-aromatic amino-acid decarboxylase, between back-to-back scans. With NSD 1015, the fluorodopa uptake constant was reduced by an average of 76.0%.

Recovery of the human striatal signal in a slice oriented positron emission tomograph.

The human striatum is small enough for partial volume effects to be important when imaged in positron tomographs with slice widths 10 mm or greater. The combination of interslice distance and slice width in such tomographs results in an axial undersampling of the striatal activity which introduces the additional problem of variation of axial recovery as a function of position of the striatum along the tomograph axis. Using striatal phantoms, we have developed a method that corrects the recovered striatal signal to a maximum value equivalent to that measured when the object is centered with respect to a slice. This makes the recovery independent of the axial position of the striatum. The method also provides an estimate of the total striatal activity by integrating the axial image intensity distribution along the tomograph axis. The method is able to detect and correct for relative axial tilt of the left and right striatum. We applied it to 26 human [18F]-6-L-fluorodopa scans and obtained an average uptake rate constant k value of 0.25 +/- 0.05 ml/min/striatum and a left to right k value percentage asymmetry of 0.1% +/- 6.3%.

Graphical analysis of 6-fluoro-L-dopa trapping: effect of inhibition of catechol-O-methyltransferase.

UNLABELLED: Graphical methods to analyze tracer time-course data allow reliable quantitation of the rate of incorporation of tracer from plasma into a "trapped" kinetic component, even when the details of the kinetic model are unknown. Applications of the method over long time periods often expose the slow reversibility of the trapping process. In the extended graphical method, both trapping rate and a presumed first-order loss rate constant are estimated simultaneously from the time-course data. METHODS: We applied the extended graphical method to 6-fluoro-L-dopa (6-FD), simultaneously estimating the rate of uptake (Ki) and the rate constant for loss from the trapped component (K(loss)) in a single fitting procedure. We applied this approach to study the effects of two catechol-O-methyl-transferase inhibitors on the kinetics of 6-FD in cynomolgus monkeys. RESULTS: Inhibition of peripheral O-methylation with either inhibitor, confirmed by high-performance liquid chromatography analysis of labeled compounds in arterial plasma, had no significant effect on Ki, in agreement with previously reported studies. In contrast, tolcapone, a catechol-O-methyl-transferase inhibitor, having central effects in addition to peripheral effects at the dosage used, decreased K(loss) by 40% from control values (p < 0.002), whereas nitecapone, which has no known central activity, had no significant effect. CONCLUSION: This method provides insight into the neurochemical basis for the kinetic behavior of 6-FD in both health and disease and may be used to define the action of centrally active drugs that influence the metabolism of dopamine.

Effects of monoamine oxidase and catechol-O-methyltransferase inhibition on dopamine turnover: a PET study with 6-[18F]L-DOPA.

The consequences of monoamine oxidase and catechol-O-methyltransferase inhibition on the effective turnover of dopamine were investigated using 6-[18F]L-3-4-dihydroxyphenylalanine (6-[18F]L-DOPA) and positron emission tomography. The effective dopamine turnover was expressed as the ratio between the rate of reversibility of 6-[18F]L-DOPA trapping (k[loss]) and the rate of uptake of 6-[81F]L-DOPA (Ki) in the striatum of normal cynomolgus monkeys. The monkeys received 6-[18F]L-DOPA scans, untreated or after pretreatment with either the peripheral catechol-O-methyltransferase inhibitor nitecapone; the peripheral and central catechol-O-methyltransferase inhibitor tolcapone; the monoamine oxidase inhibitors deprenyl or pargyline; a combination of tolcapone and the monoamine oxidase inhibitors. Tolcapone alone or combined with the monoamine oxidase inhibitors produced a significant decrease in the dopamine turnover (55 to 65%). Neither nitecapone nor monoamine oxidase inhibition alone produced significant changes. These results may have implications for the use of central catechol-O-methyltransferase inhibitors added to routine levodopa therapy in parkinsonian patients.

A new device for the quantitative assessment of dopaminergic drug effects in unilateral MPTP-lesioned monkeys.

Non-human primates exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) have been employed to study the clinical features of parkinsonism. Monkeys lesioned by unilateral intracarotid administration of MPTP display spontaneous and drug responsive turning behavior. However this seems to correlate poorly with their clinical deficits. We describe an objective measurement of arm movement velocity, applied in 4 cynomolgus monkeys before and after unilateral administration of MPTP. Reduced movement velocities correlated with clinical signs of unilateral flexed arm posture, rigidity, tremor and bradykinesia and could be reversed with L-DOPA therapy. This measurement technique has advantages for the quantitative assessment of parkinsonian deficits and will permit the evaluation of dopaminergic therapy and transplantation in non-human primates.

Routine determination of [18F]-L-6-fluorodopa and its metabolites in blood plasma is essential for accurate positron emission tomography studies.

A batch-contact alumina-extraction method has been used to separate [18F]-L-6-fluorodopa (FD) from its principal metabolite, 3-O-methyl-[18F]-6-fluorodopa (3-OMe-FD), in arterial blood plasma samples collected from subjects pretreated with carbidopa during positron emission tomography (PET) scans. The time course of the metabolite-corrected blood plasma activity is then used as an input function for kinetic analysis of striatal FD uptake. Results obtained from using the batch-contact alumina-extraction method were compared with those from high performance liquid chromatography, and also with those from a chromatographic alumina cartridge technique developed in this laboratory. In 60 human subjects including normal healthy volunteers and patients diagnosed as having a movement disorder, arterial blood plasma samples were collected after FD injection during a two-hour PET scan and analyzed by the batch-contact alumina-extraction method. The activity ratio (metabolites/FD) increased linearly with time for all subjects. However, there was a wide variation in the slope of the plot of the activity ratio (metabolites/FD) versus time among the subjects. No significant linear or curved relationship was observed between the slope and the age of the subject. Separation of FD from its metabolites is therefore necessary for each PET-FD study conducted.

Routes of administration and effect of carbidopa pretreatment on 6-[18F]fluoro-L-dopa/PET scans in non-human primates.

In 6-[18F]fluoro-L-dopa (Fdopa)/positron emission tomography (PET) studies, carbidopa pretreatment increases the Fdopa bioavailability to the brain and enhances the intensity of striatal PET images. Different PET research teams have used various carbidopa doses and routes of administration in non-human primate studies. The purpose of this study was to examine the plasma profiles of carbidopa and the effect of the route of administration of carbidopa on a Fdopa/PET scan. Cynomolgus monkeys were given carbidopa either orally (5 mg/kg), intraperitoneally (2.5 and 5 mg/kg) or intravenously (5 mg/kg) 60-90 min prior to the Fdopa injection. Carbidopa-treated monkeys were compared to monkeys without carbidopa treatment. No carbidopa was detected in the plasma samples when it was given orally, possibly due to poor absorption in the gastrointestinal tract. In addition, the striatal and cortical activities were not statistically different from those of the untreated monkeys, indicating that little or no inhibition of the peripheral decarboxylation of Fdopa by carbidopa had taken place. When carbidopa was given intraperitoneally at a dose of 2.5 and 5 mg/kg and intravenously at 5 mg/kg, plasma carbidopa concentrations at the time of Fdopa injection were 0.95 +/- 0.26, 2.22 +/- 0.23 and 2.79 +/- 0.26 micrograms/ml, respectively. Because of inhibition of peripheral decarboxylation of Fdopa by carbidopa, more Fdopa was available for transport into the brain and as a result, both the striatal and cortical activities were significantly higher than those of the untreated monkeys. Carbidopa administration had no effect on either the striatal-to-cortical activity ratio or the striatum uptake value.

Effects of detector wobble motion on image noise in positron emission tomography.

The effects of detector wobble motion on image variance is described analytically and verified by simulation studies. Simulation results in the form of variance images are presented for various phantoms, sampled under both uniform and wobble-motion conditions. It is shown that under most measurement conditions in a typical PET study, the image precision is degraded due to the nonuniform projection variance introduced by the wobble motion. Using the wobble parameters of the UBC-TRIUMF development of PETT VI, the rms noise is found to be increased by 9 percent due to wobbling.

Design of an efficient position sensitive gamma ray detector for nuclear medicine.

The shortcomings of conventional scintillation cameras are analysed theoretically with a view towards improving performance at gamma ray energies above 140 keV. A camera design is proposed which incorporates several new features to obtain good spatial resolution from thicker crystals of sodium iodide. Computer simulations show that in addition to having good efficiency and spatial resolution, the new design allows parallax error correction and (possibly) Compton scattering correction at gamma energies up to 511 keV.

Cerebral glucose metabolism in Parkinson's disease.

Local cerebral glucose utilization was measured in patients with predominantly unilateral Parkinson's disease using 18F-2-fluoro-deoxyglucose and positron emission tomography. Preliminary results indicate the presence of asymmetric metabolic rates in the inferior basal ganglia. The structure comprising the largest portion of basal ganglia at this level is globus pallidus. These findings are consistent with metabolic studies on animals with unilateral nigrostriatal lesions in which pallidal hypermetabolism on the lesioned side has been demonstrated. Increased pallidal activity is likely secondary to a loss of inhibitory dopaminergic input to the striatum from substantia nigra.

The spatial distribution of zinc and cobalt in single human head hairs.

The concentration patterns of indigenous zinc and of zinc and cobalt absorbed from radiotracer solutions have been measured via flameless AA and radioactivity assay, respectively, in individual human head hairs. Patterns for indigenous zinc were found to be relatively flat and featureless. Patterns for absorbed zinc (like those for indigenous and absorbed copper in the same subjects) showed increasing concentrations with increasing distance from the root, plus zones of locally increased concentrations at positions different from those for zones of increased copper concentrations. In bleached hair, indigenous zinc concentrations were decreased, and absorbed zinc and cobalt concentrations were increased compared to values in normal hair. The data for absorbed zinc and cobalt were interpreted in terms of a variable concentration of metal-binding sites in the hair structure, coupled with an increased porosity induced by hair bleaching. The flat patterns for the indigenous zinc content were interpreted as indicating the importance of dietary zinc and incorporation via the follicle, and the unimportance of external contamination as the source of this zinc. The forensic implications of the data have been discussed.

The absorption of arsenic into single human head hairs.

Single head hairs from several subjects have been soaked in arsenic radiotracer solution and the arsenic absorbed on 2-mm hair segments has been determined by radioactivity assay. The absorption patterns were characterized for some subjects by regions of high uptake where (in other hairs from the same subject) regions of low uptake of copper and zinc were found, and vice versa. These data have been interpreted in terms of varying densities of binding sites in the hair structure, with specific chemical character. Arsenic absorption patterns for other subjects were highly structured, showing zones of very high and very low absorption. The dangers of interpreting similar patterns for the indigenous arsenic content of hair in terms of the dates on which elevated arsenic ingestion took place have been discussed.

Absorption patterns for 33P phosphate into single human and animal hairs.

Absorption of phosphate into single human and animal hair shafts has been studied by means of 32P radiotracer techniques. Nondestructive radioassay permitted repetitive experiments on the same hair specimen. Phosphate concentration patterns were shown to be complementary to those for zinc absorption and sometimes to exhibit prominent concentration peaks extending over regions of the shaft 10 to 20 mm in length. Appearance of such peaks was shown to be favored by pH decreasing below 7 but not by migration of phosphate along the hair shaft, which was unimportant.