Peter Bjurling

Tacrine restores cholinergic nicotinic receptors and glucose metabolism in alzheimer patients as visualized by positron emission tomography

Three patients with Alzheimers disease, a 68-year-old woman with mild dementia and 2 men (aged 64 and 72 years) with moderate dementia were treated orally with the cholinesterase inhibitor tacrine (tetrahydroaminoacridine), 80 mg daily, for several months. The patients were investigated using positron emission tomography (PET) prior to, and after 3 weeks and 3 months of treatment. The PET studies involved a multi-tracer system consisting of [18F]-fluoro-deoxy-glucose (18F-FDG) (tracer for glucose metabolism); 11C-butanol (cerebral blood flow) and (S)(-)- and (R)(+)-[N-11C-methyl]-nicotine (nicotinic receptors; cholinergic neural activity). Tacrine treatment increased the uptake of 11C-nicotine to the brain. Significant reduced difference in uptake between the two enantiomers (S)(-)- and (R)(+)11C-nicotine was observed in the frontal and temporal cortices after tacrine treatment in all three patients. The kinetic analysis indicated increased binding of (S)(-)11C-nicotine in brain compatible with a restoration of nicotinic cholinergic receptors. The most pronounced effect was observed after 3 weeks and 3 months treatment in the patient with mild dementia. An increase in cerebral glucose utilization was found in the 68-year-old patient with mild dementia but also slightly in the 64-year-old man with moderate dementia when treated with tacrine for 3 months. Tacrine administration did not affect cerebral blood flow. The PET data obtained after 3 weeks of tacrine treatment was paralleled by improvement in neuropsychological performance. This study shows in vivo by PET neurochemical effects induced in brain by treatment with tacrine to Alzheimer patients. Intervention with tacrine in the early course of the disease might be necessary for clinical improvement.

Positron emission tomography with 5-hydroxytryprophan in neuroendocrine tumors.

PURPOSE Carcinoid tumors, especially those of midgut origin, produce serotonin via the precursors tryptophan and 5-hydroxytryptophan (5-HTP). We have evaluated the usefulness of positron emission tomography (PET) with carbon-11-labeled 5-HTP in the diagnosis and treatment follow-up evaluation of patients with neuroendocrine tumors. PATIENTS AND METHODS PET using 11C-labeled 5-HTP was compared with computed tomography (CT) in 18 patients (14 midgut, one foregut, one hindgut carcinoid, and two endocrine pancreatic tumors [EPT]). In addition, 10 of 18 patients were monitored with PET examinations during treatment. RESULTS All 18 patients, including two with normal urinary 5-hydroxyindole acetic acid (U-5-HIAA), had increased uptake of 11C-labeled 5-HTP in tumorous tissue as compared with normal tissue. Liver metastases, as well as lymph node, pleural, and skeletal metastases, showed enhanced 5-HTP uptake and PET could detect more lesions than CT in 10 patients and equal numbers in the others. Tumor visibility was better for PET than for CT due to the high and selective uptake of 5-HTP with a high tumor-to-background ratio. Binding studies indicated an irreversible trapping of 5-HTP in the tumors. Linear regression analyses showed a clear correlation (r = .907) between changes in U-5-HIAA and changes in the transport rate constant for 5-HTP during treatment. CONCLUSION PET with 11C-labeled 5-HTP demonstrated high uptake in neuroendocrine gastrointestinal tumors and thereby allowed improved visualization compared with CT. The in vivo data on regional tumor metabolism, as expressed in 11C-5-HTP uptake and transport rate, provided additional information over conventional radiologic techniques. The close correlation between the changes in 11C-5-HTP transport rate and U-HIAA during medical treatment indicates the potential of 11C-5-HTP-PET as a means to monitor therapy.

Manganese induced brain lesions inMacaca fascicularis as revealed by positron emission tomography and magnetic resonance imaging

A series of positron emission tomography scans was made on two monkeys during a 16-month period when they received manganese(IV)oxide by subcutaneous injection. The distribution of [11C]-nomifensine uptake, indicating dopamine terminals, was followed in both monkey brains. The brain distributions of [11C]-raclopride, demonstrating D2 dopamine receptors, and [11C]-l-dopa, as a marker of dopamine turnover, were followed in one monkey each. The monkeys developed signs of poisoning namely unsteady gait and hypoactivity. The [11C]-nomifensine uptake in the striatum was reduced with time and reached a 60% reduction after 16 months exposure. This supports the suggestion that dopaminergic nerve endings degenerate during manganese intoxication. The [11C]-l-dopa decarboxylation was not significantly altered indicating a sparing of [11C]-l-dopa decarboxylation during manganese poisoning. A transient decrease of [11C]-raclopride binding occurred but at the end of the study D2-receptor binding had returned to starting values. The magnetic resonance imaging (MRI) revealed that the manganese accumulated in the globus pallidus, putamen and caudate nucleus. There were also suggestions of gliosis/edema in the posterior limb of the internal capsule. MRI might be useful to follow manganese intoxication in humans as long as the scan is made within a few months of exposure to manganese, i. e. before a reversal of the manganese accumulation.

Unilateral MPTP lesion in a rhesus monkey: effects on the striatal dopaminergic system measured in vivo with PET using various novel tracers

We have produced in one monkey a unilateral lesion of the dopaminergic nigrostriatal pathway by slowly infusing 1-methyl-4-phenyl-1.2.3.6-tetrahydropyridine (MPTP) into the right internal carotid artery, resulting in contralateral hemiparkinsonism. This procedure was combined with a series of positron emission tomography scans before and after the lesion, using several dopaminergic tracers in parallel. We show that specific binding of [11C]nomifensine in the lesioned striatum disappears to a large extent (80-90%) as a result of the lesion, indicating a corresponding loss of striatal dopamine re-uptake binding sites and thus of the dopamine nerve terminal pool. The uptake of radioactivity in the striatum contralateral to the lesion remained unchanged. In parallel, an early increase in ipsilateral [11C]raclopride binding, indicating upregulation of dopamine D2 receptors, was seen following the presynaptic lesion. [11C]Deprenyl uptake, indicating monoamine oxidase type B enzyme concentration, did not change after the lesion.

Low brain uptake of L-[11C]5-hydroxytryptophan in major depression: a positron emission tomography study on patients and healthy volunteers

The precursor of serotonin, L‐5‐hydroxytryptophan (L‐5‐HTP), was radiolabelled with 11C in the β‐position, yielding [β‐11C]serotonin after decarboxylation, allowing positron emission tomography studies of L‐5‐HTP uptake across the blood‐brain barrier. We studied 8 healthy volunteers and 6 patients with histories of DSM‐III major depression, 2 with repeated examinations after clinically successful treatment. We report a significantly lower uptake of [11C]5‐HTP across the blood‐brain barrier in depressed patients, irrespective of phase of illness. The findings emphasize that serotonin is involved in depressive pathophysiology and support earlier suggestions that the transport of 5‐HTP across the blood‐brain barrier is compromised in major depression.

Amphetamine effects on dopamine release and synthesis rate studied in the Rhesus monkey brain by positron emission tomography

SummaryPositron emission tomography (PET) was used in a multitracer protocol to evaluate D-amphetamine induced effects on dopamine biosynthesis rate and release in propofol anesthetized Rhesus monkeys.l-[β-11C]DOPA was used as biochemical probe to study the brain dopamine biosynthesis rate whilst dopamine release was followed by the binding displacement of the [11C]-radiolabelled dopamine receptor antagonists, raclopride and N-methylspiperone. Studies were performed with either a constant rate intravenous infusion of D-amphetamine aiming at plasma concentrations of 0.2 to 25 ng/ml or with intravenous bolus doses of 0.1 and 0.4 mg/ kg. Decreased binding of the dopamine receptor antagonists was measured in both modes of D-amphetamine administration but notably [11C]N-methylspiperone was less able to sense D-amphetamine induced release of dopamine. At plasma concentrations aimed above 1 ng/ml a levelling off of the binding of [11C]raclopride at 68 ± 8.1% of the baseline value indicated that displacement was only possible from a fraction of the binding sites. Amphetamine was observed to increase the rate constant forl-[β-11C]DOPA utilization in the brain. This was most likely due to an acutely induced subsensitivity of presynaptic dopamine receptors.l-[β-11C]DOPA and [11C]raclopride were found suitable to indicate changes in dopamine synthesis rate and release respectively using PET and can be used to mirror drug-induced changes of brain dopaminergic function.

Brain kinetics of L-[beta-11C]dopa in humans studied by positron emission tomography.

The in vivo dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA) labelled with11 C in the Β position has been used for positron emission tomography studies of L-DOPA utilization in the brain. The brain uptake and kinetics of L-[11 C]DOPA-derived radioactivity were studied in healthy male volunteers, and the specific utilization, i.e. decarboxylation rate of L-[11 C]DOPA in different brain areas, was quantified using a brain region devoid of specific L-[11C]DOPA utilization as reference. Total uptake of L-[11 C]DOPA-derived radioactivity measured in the brain varied two- to threefold between subjects, with highest radioactivity in the striatal region. Specific utilization of L-[11C]DOPA radioactivity in the striatal region and in the prefrontal cortex varied twofold between subjects. No specific utilization was observed in other regions of the brain. The uptake of radioactivity in the brain increased dose-dependently with the simultaneous administration of unlabelled L-DOPA up to 10 mg. On the other hand, a decrease in brain radioactivity uptake was measured after pretreatment with 1 mg/kg oral L-DOPA, indicating competition for transport across the blood-brain barrier. Benserazide 0.5 mg/ kg orally increased somewhat the radioactivity uptake to the brain. None of these pharmacological perturbations demonstrated any clearcut effect on specific utilization of L-[11C]DOPA. Thus,11C-labelled L-DOPA is introduced as an alternative to the well-established L-6-[18 F]fluoro-DOPA methodology in clinical studies on brain L-DOPA uptake and dopamine synthesis.

Demonstration of [11C] 5-hydroxy-L-tryptophan uptake and decarboxylation in carcinoid tumors by specific positioning labeling in positron emission tomography

In three patients with carcinoid liver and/or lymph node metastases, we studied the process of tumor tracer uptake and decarboxylation by means of positron emission tomography (PET) using 5-hydroxy-L-tryptophan (5-HTP) 11C-labeled in the beta-position (HTP) and later the same day with 5-HTP 11C-labeled in the carboxyl group (HTC). With HTP, in which the 11C-label follows the molecule through decarboxylation to form 11C-serotonin, a high tumor accumulation of the tracer was found. With HTC, in which the label is rapidly eliminated from the tissues as 11CO2 if decarboxylation takes place, there was virtually no uptake by the tumors. By utilizing data from PET scanning with both tracers, we could quantify the decarboxylation rate and tissue accumulation of [11C]-serotonin and hence the enzymatic action of aromatic amino acid decarboxylase.

Pyridoxine effect on synthesis rate of serotonin in the monkey brain measured with positron emission tomography

The influence of the co-factor pyridoxine, vitamin B6, on the activity of aromatic amino acid decarboxylase enzyme was studied by positron emission tomography, PET in the brain of the Rhesus monkey using the precursor for serotonin synthesis 5-hydroxy-L-tryptophan (5-HTP) radiola-belled with11C in the β-position. The rate constant for the formation of serotonin in the corpus striatum was calculated using a two tissue compartment model with reference area in the brain. In baseline investigations, the mean rate constants (±S.D:) for selective utilization of [11C]5-HTP to form [11C]serotonin in the corpus striatum was 0.0080 ± 0.0011 min−1. Pretreatment with intravenous pyridoxine hydrochloride 10 mg/kg bodyweight before doing a second PET study resulted in an enhanced rate constant by a mean of 20%. The rate increase was statistically significant. The increase varied considerably in different monkeys from no effect to more than 60%. The effect of pyridoxine on aromatic amino acid decarboxylase activity supported a regulatory role of pyridoxine on the synthesis of neurotransmitter in vivo, and may be of importance in diseases with deficiencies in neurotransmitter function.

Estimation of regional cerebral utilization of [11C]-L-3,4-dihydroxy-phenylalanine (DOPA) in the primate by positron emission tomography.

Tedroff J, Aquilonius S‐M, Hartvig P, Lundqvist H, Bjurling P, Långström B. Estimation of regional cerebral utilization of [11C]‐L‐3,4‐dihydroxy‐phenylalanine (DOPA) in the primate by positron emission tomography. Acta Neurol. Scand 1992: 85: 166‐173.