Joakim Tedroff

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.

Monoamine re‐uptake sites in the human brain evaluated in vivo by means of 11C‐nomifensine and positron emission tomography: the effects of age and Parkinson's disease

ABSTRACT— Six patients with Parkinsons disease, selected to cover a range of clinical features, and 7 healthy volunteers aged 24–81 years, were examined by positron emission tomography after i.v. injection of racemic 11C‐nomifensine, a catecholamine re‐uptake blocking drug. After injection the radiotracer, radioactivity was rapidly distributed to the brain. The highest accumulation of radioactivity was found in areas rich in dopaminergic and noradrenergic innervation, such as the striatum and the thalamus. In regions with negible dopaminergic and noradrenergic innervation, such as the cerebellum, radioactivity was lower and evenly distributed. In all investigated brain regions a marked age‐related decline in 11C‐nomifensine‐derived radioactivity relative to the cerebellum was observed in the group of healthy volunteers. Parkinsonian patients did not show such a decline with age. In the group of parkinsonian patients with mainly unilateral involvement, the contralateral putamen exhibited the most pronounced decrease. Only the 3 parkinsonian patients aged 63 and younger showed markedly lower 11C‐nomifensine binding in striatal areas than age‐matched healthy volunteers. 11C‐nomifensine seems to be a valuable tool for investigating noradrenergic and dopaminergic re‐uptake sites in vivo. Further achievements will most likely be made when the active enantiomer becomes available.

NMDA‐Receptor Activity Visualized with (S)‐[N‐Methyl‐11C]Ketamine and Positron Emission Tomography in Patients with Medial Temporal Lobe Epilepsy

Summary: Purpose: To determine whether neurochemical activation of the N‐methyl‐D‐aspartate (NMDA) receptor‐gated ion channel shows quantitative changes, measured as binding of 11C‐labeled (S)‐[N‐methyl]ketamine, in patients with medial temporal lobe epilepsy (MTLE).

Striatal kinetics of [11C]-(+)-nomifensine and 6-[18F]fluoro-L-dopa in Parkinson's disease measured with positron emission tomography

The kinetics in brain of the dopamine reuptake blocking agent [11C]‐(+)‐nomifensine and the L‐dopa analogue 6‐[18F]fluoro‐L‐dopa were compared in 3 patients with idiopathic Parkinsons disease and age‐matched healthy volunteers using positron emission tomography. Regional uptake was analyzed and quantified according to a 3‐compartment model. Retention of both tracers in striatal regions of the parkinsonian patients were reduced compared with the healthy volunteers mainly in the putamen, while the caudate nucleus was only mildly affected. The reductions were considerably less than the decrease previously reported postmortem for striatal dopamine content in the basal ganglia of patients with Parkinsons disease. A fairly constant ratio between 6‐[18F]fluoro‐L‐dopa utilization and [11C]‐(+)‐nomifensine binding in the caudate nucleus and the putamen were found in both groups unrelated to the size of the estimated parameters. This indicates that a limiting factor for the utilization of exogenous levodopa in Parkinsons disease may be a reduced transport capacity for the amino acid into the dopaminergic terminals.

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.

Efficacy and Safety of the Dopaminergic Stabilizer Pridopidine (ACR16) in Patients With Huntington's Disease.

Objectives:To evaluate the efficacy and safety of the dopaminergic stabilizer pridopidine (ACR16) in patients with Huntingtons disease (HD). Methods:In a randomized, double-blind, placebo-controlled, 4-week trial, patients with HD received pridopidine (50 mg/d, n = 28) or placebo (n = 30). The primary outcome measure was the change from baseline in weighted cognitive score, assessed by cognitive tests (Symbol Digit Modalities, verbal fluency, and Stroop tests). Secondary outcome measures included changes in the Unified Huntingtons Disease Rating Scale, Hospital Anxiety and Depression Scale, Leeds Sleep Evaluation Questionnaire, Reitan Trail-Making Test A, and Clinical Global Impression of Change. Safety assessments were also performed. Results:There was no significant difference between pridopidine and placebo in the change from baseline of the weighted cognitive score. However, secondary measures such as affective symptoms showed trends toward improvement, and there was significant improvement in voluntary motor symptoms compared with placebo (P < 0.05). Pridopidine was well tolerated, with a safety profile similar to placebo. Conclusions:Pridopidine shows promise as a treatment for some of the symptoms of HD. In this small-scale study, the most notable effect was improvement in voluntary motor symptoms. Larger, longer-term trials are warranted.

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.

Altered pattern of brain dopamine synthesis in male adolescents with attention deficit hyperactivity disorder

BackgroundLimited data from positron emission tomography (PET) studies of subjects with attention-deficit/hyperactivity disorder (ADHD) indicate alterations in brain dopamine neurotransmission. However, these studies have used conventional univariate approaches that are less sensitive to detect complex interactions that may exist between different brain dopamine pathways and individual symptoms of ADHD. We aimed to investigate these potential interactions in adolescents with ADHD.MethodsWe used a 3D PET scan to measure utilization of native L-[11C]-DOPA to map dopamine presynaptic function in various cortical, striatal and midbrain regions in a group of 8 male adolescents with ADHD and 6 age matched controls. To evaluate the interactions between the studied brain regions, multivariate statistical methods were used.ResultsAbnormal dopaminergic function was found in multiple brain regions of patients with ADHD. A main finding was lower L-[11C]-DOPA utilization in adolescent with ADHD as compared to control subjects, especially in subcortical regions. This pattern of dopaminergic activity was correlated specifically with symptoms of inattention.ConclusionDopamine signalling in the brain plays an important modulatory role in a variety of motor and cognitive functions. We have identified region-specific functional abnormalities in dopaminergic function, which may help better account for the symptoms of ADHD.