Per Hartvig

Nerve growth factor affects11C-nicotine binding, blood flow, EEG, and verbal episodic memory in an Alzheimer patient (Case Report)

SummaryBased on animal research suggesting that nerve growth factor (NGF) can stimulate central cholinergic neurons, the known losses of cholinergic innervation of the cortices in Alzheimers disease (AD), and our experience of infusing NGF to support adrenal grafts in parkinsonian patients, we have initiated clinical trials of NGF infusions into the brain of patients with AD. Here we report a follow-up of our first case, a 69-year-old woman, with symptoms of dementia since 8 years. Intraventricular infusion of 6.6 mg NGF during three months resulted in a marked transient increase in uptake and binding of11C-nicotine in frontal and temporal cortex and a persistent increase in cortical blood flow as measured by PET as well as progressive decreases of slow wave EEG activity. After one month of NGF, tests of verbal episodic memory were improved whereas other cognitive tests were not. No adverse effects could be ascribed to the NGF infusion. Taken together, the results of this case study indicate that NGF may counteract cholinergic deficits in AD, and suggest that further clinical trials of NGF infusion in AD are warranted.

Increased dopamine synthesis rate in medial prefrontal cortex and striatum in schizophrenia indicated by L-(β-11C) DOPA and PET

BACKGROUND The aim of the present study was to investigate dopamine synthesis in the brain of drug-free schizophrenic patients, not only in the striatum but also in extrastriatal areas like the prefrontal cortex, brain areas that for a long time has been in focus of interest in the pathophysiology of schizophrenia. METHODS PET was performed in 12 drug-free (10 drug-naive) psychotic schizophrenic patients and 10 healthy volunteers matched for age and gender using 11C-labelled L-DOPA as the tracer. The time-radioactivity curve from occipital cortex (located within Brodman area 17 and 18) was used as input function to calculate L-DOPA influx rate, Ki images, that were matched to a common brain atlas. A significant overall increase of the Ki values was found in the schizophrenic group as compared with healthy controls. RESULTS In particular, significantly higher Ki were found in the schizophrenic patients compared to the controls in the caudate nucleus, putamen and in parts of medial prefrontal cortex (Brod 24). The Ki value reflect an increased utilization of L-DOPA, presumably due to increased activity of the amino acid decarboxylate enzyme. CONCLUSIONS The results indicate that the synthesis of dopamine is elevated within the striatum and parts of medial prefrontal cortex in schizophrenia.

Patient-controlled Analgesic Therapy, Part III: Pharmacokinetics and Analgesic Plasma Concentrations of Ketobemidone

SummaryThe effects of anaesthesia and surgery on the pharmacokinetics of ketobemidone were studied in 12 patients. Plasma ketobemidone concentrations were assayed with a mass-fragmentographic method. The peroperative Vdarea was 5.9±2.6L/kg and the terminal half-life was 3.9 ± 1.7h. In the postoperative period Vdarea decreased to 3.7 ±0.4L/kg and the terminal half-life to 2.1 ±0.4h. Plasma clearance (Clp) did not change significantly, peroperative Clp being 18±4.3ml/min/kg and postoperative Clp being 22 ±7.5ml/min/kg. The pharmacokinetics of ketobemidone were not influenced by the addition of a spasmolytic agent in the commercial combination ketobemidone preparation ‘Ketogin’.Postoperative pain was relieved in 15 patients by patient-controlled intravenous administration of ketobemidone by means of a programmable drug injector. The mean ketobemidone consumption was 2.3 ± 0.8mg/h, which produced a mean plasma concentration of 28 ± 11ng/ml. Pseudosteady-state plasma concentrations of ketobemidone were established with a mean minimum effective concentration (MEC) of 25 ± 11ng/ml. Ketobemidone ‘plain’ and ‘Ketogin’ did not differ significantly in these respects. Analgesia was considered by all patients to be satisfactory.

Kinetic analysis of regional (S)(-)11C-nicotine binding in normal and Alzheimer brains--in vivo assessment using positron emission tomography.

SummaryA compartment model has been developed and validated for the kinetic analysis of (S)(-)11C-nicotine binding in the brain including a compensation for the influence of regional cerebral blood flow (rCBF). The model was applied to eight patients with Alzheimer disease (AD) and three age-matched healthy volunteers who received intravenous injections of (S)(-)11C-nicotine and 11C-butanol. The uptake and time course of radioactivity in different brain regions were assessed by positron emission tomography (PET). The rate constant k* was formulated by dividing the K2 rate constant for 11C-nicotine with the K, rate constant for 11C-butanol and thereby minimizing the influence of CBF on the quantitated binding of 11C-nicotine. The rate constant k2* for 11C-nicotine giving a quantitative measure of binding in the brain tissue was significantly higher in the temporal and frontal cortices as well as in the hippocampus of AD brains as compared with controls, indicating deficits in specific nicotinic binding in these brain areas of AD patients. A significant and negative correlation was obtained between cognitive function (Mini-Mental State Examination) and k2* of 11C-nicotine in the temporal and frontal cortices as well as in the hippocampus. The described kinetic model allowed in vivo quantification of nicotinic receptor binding in brain, which will be of importance in the future for evaluation of diagnosis, progress of disease, as well as the therapeutic effects in the treatment of AD.

Somatotopic organization along the central sulcus, for pain localization in humans, as revealed by positron emission tomography.

Abstract Regional cerebral blood flow was measured with positron emission tomography (PET) in six healthy volunteers at rest and during experimentally induced, sustained cutaneous pain on the dorsum of the right hand or on the dorsum of the right foot. Pain was inflicted by intracutaneous injection of capsaicin, providing a mainly C-fibre nociceptive stimulus. Statistical analysis showed significant activations along the central sulcus (SI) area when comparing pain in the hand to pain in the foot. Separate comparison of both pain states to a baseline revealed different locations along the central sulcus for hand pain and foot pain. The encountered differences are consistent with what is previously known about the somatotopics of non-painful stimuli. When comparing painful stimuli to baseline, the contralateral anterior cingulate gyrus, the ipsilateral anterior insular cortex and the ipsilateral prefrontal cortex were implicated. The results are consistent with an involvement of SI in the spatial discrimination of acute cutaneous pain.

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.

Decreased uptake and binding of11C-nicotine in brain of Alzheimer patients as visualized by positron emission tomography

SummaryPositron emission tomography of the brain following intravenous injection of (+) (R) and (−) (S) N-[11C-methyl]nicotine showed a marked reduced uptake of both isomers, especially the (R) form, in Alzheimer patients as compared to age-matched controls. The significantly larger difference between the uptake values of the (S)- and (R)-enantiomers of11C-nicotine in Azheimer brains may be of diagnostic value.

In vivo evaluation of striatal dopamine reuptake sites using 11C-nomifensine and positron emission tomography

Abstract In vitro nomifensine demonstrates high affinity and specificity for dopamine reuptake sites in the brain. In the present study 11C‐nomifensine was administered i.v. in trace amounts (10–50μg) to ketamine anaesthetized Rhesus monkeys (6–10 kg b.w.) and the time‐course of radioactivity within different brain regions was measured by positron emission tomography (PET). Six base‐line experiments lasting for 60–80 min were performed. The procedure was repeated after pretreatment with nomifensine (2–6 mg/kg i.v.), another reuptake inhibitor, mazindol (0,3 mg/kg i.v.), desipramine (0.5 mg/kg i.v) or spiperone (0.3 mg/kg i.v.) before the administration of a second 11C‐nomifensine dose. The highest radioactivity uptake was found in the dopamine innervated striatum and the lowest in a region containing the cerebellum, known to be almost devoid of dopaminergic neurons. The difference between striatal and cerebellar uptake of 11C‐nomifensine derived radioactivity was markedly reduced after nomifensine and mazindol but not after desipramine and spiperone. These results indicate that in vivo the striatal uptake of 11C‐nomifensine, as measured with PET, involves specific binding with the dopamine reuptake sites. In the first human applications of 11C‐nomifensine and PET in a healthy volunteer, the regional uptake of radioactivity was similar to that in base‐line experiments with Rhesus monkeys. In the healthy subject the striatal/cerebellar ratio was 1.6, 50 min after the injection of 11C‐nomifensine. In a hemi‐parkinsonian patient this ratio was 1.1 contralaterally and 1.3 ipsilaterally to the affected side. 11C‐nomifensine and PET seems to be an auspicious method to measure the striatal dopaminergic nerve terminals of man in vivo.

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.

Patient-controlled Analgesic Therapy, Part II: Individual Analgesic Demand and Analgesic Plasma Concentrations of Pethidine in Postoperative Pain

Summary20 surgical patients were allowed to self-administer small intravenous doses of pethidine to relieve pain after major abdominal surgery. Pethidine injections were given by means of a programmable drug injector. Pethidine consumption varied from 12 to 50mg/h with a mean ± SD of 26 ± 10mg/h. The mean measured plasma concentration of pethidine during self-administration was 551 ± 182ng/ml, with a range of 132 to 896ng/ml. Minimum effective concentrations averaged 455 ± 174ng/ml. Individual pethidine consumption and mean plasma concentrations did not differ between men and women, and were not correlated to variations in age, anthropometric factors, plasma clearance or elimination rate constant for pethidine. Individual consumption of pethidine was consistent, with stable plasma concentrations throughout most of the trial period. Pseudo-steady-state plasma concentrations of pethidine were established and maintained at widely different levels. 19 of the 20 patients obtained subjectively satisfactory analgesia.