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Biomedical subjects

H N Wagner

Publications and source records attributed to H N Wagner.

At least 37 records · Page 2Linked to original sources
PubMed1997

D2-like dopamine receptor density in Tourette syndrome measured by PET.

UNLABELLED: Tourette syndrome (TS) is a chronic neurologic disorder characterized by the presence of involuntary motor and phonic tics. There is evidence that TS is associated with an abnormality of the dopaminergic system, involving postsynaptic D2 receptors. We tested the hypothesis that D2-like dopamine receptors are elevated in TS. METHODS: Twenty-nine adult patients with TS were studied by PET imaging with [11C]3-N-methylspiperone ([11C]NMSP). Two methods of data analysis were used. The first was a caudate-to-cerebellar ratio, measured at 45 min. The second method, applied in 20 subjects, was a two-PET scan procedure. Both used high specific activity [11C]NMSP, but the second scan was preceded by a dose of unlabeled haloperidol, which partially occupied the D2-like dopamine receptors. This was done to provide an absolute measure of receptor density (Bmax). All patients were compared to age- and sex-matched controls. RESULTS: Neither group showed significant differences from their control group in caudate-to-cerebellar ratio. However, the two-PET scan Bmax measurement demonstrated that 4 of the 20 patients had significantly elevated D2-like receptors. In this group of 20 patients, multiple linear regression analysis revealed a trend between the severity of vocal tics and Bmax values. This Bmax measure also revealed a significant (p < 0.05) association with performance on the Wisconsin Card Sorting Test. CONCLUSION: These findings suggest that not all patients with TS have an abnormality of D2-like receptors, but a subgroup of TS subjects has a significant D2-like dopamine receptor elevation. These findings also support the importance of applying a more quantitative method for Bmax determination to PET imaging analysis. The Bmax findings in the subgroup do not exclude an effect of intrasynaptic dopamine competition, but this effect may be less likely due to the high affinity of [11C]NMSP.

Adult↗
PubMed1997

Longer occupancy of opioid receptors by nalmefene compared to naloxone as measured in vivo by a dual-detector system.

UNLABELLED: Surgical procedures usually involve the administration of narcotic drugs as anesthetics or adjuvants. To reverse the effects of anesthesia, opioid antagonists such as naloxone are commonly used. Due to its short lasting effects, patients receiving naloxone must be monitored carefully. Nalmefene, a pure opiate antagonist with a longer duration of action than naloxone, has shown promise in the reversal of opioid anesthesia. METHODS: A simple dual-detector positron radiation detector system and [11C]carfentanil were used to compare the duration of blockade of cerebral mu opioid receptors by naloxone and nalmefene in eight normal volunteers. Carbon-11-carfentanil brain kinetics were monitored for 5 min and 2, 4, 8 and 24 hr after the administration of either nalmefene (1 mg or 1 microg/kg) or naloxone (2 mg or 2 microg/kg). Blood samples were obtained at the same times for plasma determinations. RESULTS: Clearance half-times from opioid receptors were 28.7 +/- 5.9 hr for 1 mg of nalmefene and 2.0 +/- 1.6 hr for 2 mg of naloxone. Brain clearance times were about 21.1 and 3.4 times slower than plasma clearance times for nalmefene and naloxone, respectively. CONCLUSION: These findings suggest that the prolonged effects of nalmefene are related to the slow dissociation of nalmefene from opioid receptors, which are not reflected in the plasma curve. This longer blockade of opioid receptors by nalmefene represents an advantage in the clinical management of postsurgical reversal of narcotic anesthesia and opioid side effects as well as the reversal of opioid overdose.

Adult↗
PubMed1997

Imaging nicotinic acetylcholine receptors with fluorine-18-FPH, an epibatidine analog.

UNLABELLED: Nicotinic acetylcholine receptors (nAChRs) have been implicated in a variety of central processes, such as learning and memory and analgesia. These receptors also mediate the reinforcing properties of nicotine in tobacco products and are increased in postmortem samples of brains of smokers. On the other hand, brains of individuals who have died from dementia of the Alzheimer type show abnormally low densities of nAChRs. In this study, the distribution and kinetics of [(+/-)-exo-2-(2-[18F] fluoro-5-pyridyl)-7-azabicyclo[2.2.1]heptane (18F-FPH), a high-affinity nAChR agonist, was evaluated in a baboon using PET. METHODS: After intravenous injection of 5 mCi [185 MBq] 18F-FPH into a 25-kg anesthetized baboon, sequential quantitative tomographic data were acquired over a period of 150 min. Regions of interest were placed and time-activity curves were generated. Brain kinetics of the radiotracer were calculated, and the in vivo regional binding in the baboon brain was compared with the known in vitro regional distribution of nAChRs in the rat and human brain. RESULTS: Brain activity reached a plateau within 60 min after injection of the tracer, and the binding was reversible. Elimination of 18F-FPH was relatively rapid from the cerebellum (clearance t[1/2] = 3 hr), intermediate from the hypothalamus/midbrain (t[1/2] = 7 hr) and slow from the thalamus (t[1/2] = 16 hr). Radioactivity due to 18F-FPH at 130 min postinjection was highest in the thalamus and hypothalamus/midbrain, intermediate in the neocortex and hippocampus and lowest in the cerebellum. Subcutaneous injection of 1 mg/kg cytisine 45 min after injection of the radiotracer reduced brain activity at 130 min by 67%, 64%, 56% and 52% of control values in the thalamus, hypothalamus/midbrain, hippocampus and cerebellum, respectively. The regional binding of 18F-FPH at 130 min was highly correlated with the known densities of nAChR measured in vitro in human (r = 0.81) and rat brain (r = 0.90). CONCLUSION: These results demonstrate the feasibility of imaging nAChRs in vivo. Fluorine-18-FPH appears to be a suitable tracer to study nAChRs in the human brain.

Animals↗
PubMed1996

Striatal dopamine D2 receptor quantification and superior temporal gyrus: volume determination in 14 chronic schizophrenic subjects.

Chronic schizophrenic (n = 14) and normal subjects (n = 15) were studied with resonance imaging (MRI) and positron emission tomography (PET). Two PET scans were carried out to estimate caudate dopamine D2 receptor densities. MRI was used to measure the volume of the superior temporal gyrus. Average striatal D2 receptor density (Bmax) was significantly higher in the schizophrenic group than in the normal group. Average left superior temporal gyral volume was significantly smaller in the schizophrenic group than in the normal group, and the same tendency was found for the right superior temporal gyrus. Thus, the main finding of this combined analysis of functional and structural neuroimaging techniques was an inverse relationship between reduced superior temporal gyral volume and elevated striatal D2 receptor Bmax values. These preliminary findings require confirmation in larger groups of patients and control subjects.

Adult↗
PubMed1996

Assessing neuroreceptor occupancy by continuous infusion of carbon-11 labeled radioligands.

In carbon-11 labeled radiotracer studies of neuroreceptors in the brain, a state of practical equilibrium, monitored with a simple dual-probe detector system, was achieved by injection of a bolus of tracer followed by a continuous infusion of the tracer. After investigating several different bolus-to-infusion activity ratios, we observed that a practical equilibrium state could be achieved with a slope of 0.02+/-0.001 cpsxkg/microCi/min for [11C]carfentanil studies in normal human beings. The usefulness of this approach to assess neuroreceptor occupancy was demonstrated in two cases.

Adult↗
PubMed1996

The future.

Within the next 20 years, nuclear medicine could become a major focus of medical practice and biomedical research as medicine enters a new age of certainty, in which surgery, radiation, and chemotherapy will only be used when a benefit is certain to result from the treatment. Not only in neuropsychiatric disease, but also in other diseases, such as cancer, disease will be viewed as molecular dissonance, or, a communication disorder. Cells become cancerous and people become anxious, neurotic, or even psychotic because specific tissue cells or neurons either do not get the right messages because of a deficiency in DNA transcription and wrong messages are produced, or because of a failure in reception of the correct messages carried to cells. Nuclear medicine makes it possible to characterize these transmitters and receptors as they are distributed throughout various parts of the living human body. No field of clinical medicine is better equipped to transfer the advances in molecular biology and genetics to the care of the sick. Nuclear medicine takes a physiological and biochemical, rather than an anatomical or ontological, view of disease. Disease is characterized as a statistically defined deviation of one or more functions or regional biochemical processes from those of healthy people under circumstances as close as possible to those of a person of the same sex and age as the patient. The emission of photons from radioactive tracers that can penetrate from the inside of the body to external radiation detectors is what makes it possible to examine molecular interactions involving picomolar concentrations of molecules involved in biochemical interactions between macromolecular recognition sites, enzymes, and substrates within different parts of the living body. Perturbations (stress tests) will be increasingly used to detect abnormal responsiveness to external forces early in the course of a disease. Movement of the diagnostic process from an orientation toward anatomy to a more fundamental level, the molecular level, will be the hallmark of medicine in the next millennium. Gross or histopathologic changes will no longer suffice. Radiotracers will be able to characterize plasma membrane and intracellular recognition sites and will also provide in vivo probes, making it possible to identify changes in specific genes, as well as their molecular expression, even before the disease or disorder has manifest itself by symptoms and physical signs. Such molecular characterization of disease in situ will make it possible to treat the patient as an individual and not just as a representative member of a group of patients who have similar problems and have been labeled as having a particular disease. Diagnosis will become increasingly specific despite the heterogeneity of the present diagnostic labels.

Biochemistry↗
PubMed1995

In vivo D2 dopamine receptor density in psychotic and nonpsychotic patients with bipolar disorder.

BACKGROUND: A prior positron emission tomographic study from The Johns Hopkins University, Baltimore, Md, using N-methylspiperone labeled with carbon 11 reported elevated basal ganglia D2 dopamine receptor density (Bmax) values in neuroleptic-naive schizophrenic patients compared with controls. We have now extended these studies to include patients with bipolar disorder. METHODS: Patients with bipolar disorder (n = 14) either had never received neuroleptic medication or had been neuroleptic-free for more than 6 months, and they met DSM-III criteria for currently symptomatic affective disorder. Patients with bipolar disorder were compared with matched schizophrenic patients and normal controls. All received two positron emission tomographic scans, the second of which was preceded by oral administration of haloperidol lactate, to permit the calculation of D2 dopamine receptor Bmax. RESULTS: Diagnostic groups differed in Bmax by analysis of variance (P < .0001); post hoc tests showed higher Bmax values for psychotic patients with bipolar disorder and schizophrenic patients compared with normal controls and for schizophrenic patients and psychotic patients with bipolar disorder compared with nonpsychotic patients with bipolar disorder. Among patients with bipolar disorder, Bmax values correlated significantly with the severity of psychotic symptoms (r = .63) on the Present State Examination but not with the severity of nonpsychotic mood symptoms. CONCLUSIONS: We conclude that, like schizophrenic patients, patients with psychotic bipolar disorder have elevations of D2 dopamine receptor Bmax values and that such elevations in affective disorder are more closely associated with the presence of psychosis than with mood abnormality. Elevations in dopamine receptor values thus may occur in psychiatric states that are characterized by psychotic symptoms rather than being specific to schizophrenia.

Adult↗
PubMed1995

Intrastriatal dopamine infusion reverses compensatory increases in D2-dopamine receptors in the 6-OHDA lesioned rat.

Direct infusion of dopamine into the corpus striatum has been proposed as a potential approach for the treatment of Parkinson's disease. The present study examined the effect of intrastriatal dopamine infusion on D2-dopamine receptors in the 6-hydroxydopamine (6-OHDA) lesioned rat brain. The completeness of the 6-OHDA-induced nigrostriatal injury was confirmed using [3H]-mazindol autoradiography and apomorphine-induced behaviour. Intrastriatal infusion of three different dopamine doses significantly reduced the apomorphine-induced behaviour. [3H]-spiperone autoradiography performed one day after the termination of dopamine infusion into the striatum revealed a dramatic reduction of D2-dopamine receptor binding. The mean +/- SEM percent reduction of D2 receptor binding in the affected areas of the striatum was 28.8 +/- 1.0% for 4.74 micrograms dopamine/h infusion rate, 35.0 +/- 1.6% for 9.48 micrograms dopamine/h infusion rate and 33.3 +/- 5.0% for 14.22 micrograms dopamine/h infusion rate when compared to the unlesioned side. Infusion of vehicle alone did not have any effect. The present results support the concept that intrastriatal dopamine infusion may be a useful therapeutic approach for the treatment of Parkinson's disease.

Animals↗
PubMed1995

An improved method for the synthesis of radiolabeled McN5652 via thioester precursors.

An improved procedure that facilitates routine production and increases the radiochemical yield of [11C]McN5652 (trans-1,2,3,5,6,10b-hexahydro-6-[4-([11C]methylthio)-phenyl]pyrrolo- [2,1-alpha]-isoquinoline) is presented. Specifically, thiol acetate, butyrate, and benzoate derivatives of McN5652 were prepared as the precursors for the [11C]McN5652 synthesis. These thioesters offer greater stability than the previously used thiol precursor (desmethyl McN5652) and enable a single batch of material to be used for multiple radiolabelings. Hydrolysis of the thioester functionality (tetrabutylammonium hydroxide, 10 min) unmasked the free thiol which, without purification, was reacted with [11C]iodomethane in DMF at 40-45 degrees C for 1 min. The average decay-corrected radiochemical yield for [11C]McN5652 was 26% with an average specific activity of 2290 mCi/mumol (end of synthesis). This facile radiolabeling method, utilizing the butyrate thioester of McN5652, was also employed in the preparation of [3H](+)- and (-)McN5652 [trans-1,2,3,5,6S (or 6R),10bR, (or 10bS)-hexahydro-6-[4-([3H]methylthio)phenyl]pyrrolo-[2,1,alpha]- isoquinoline] from [3H]iodomethane.

Carbon Radioisotopes↗
PubMed1995

Positron emission tomography of 5-HT transporter sites in the baboon brain with [11C]McN5652.

[11C]McN5652 is a new radioligand specific for 5-hydroxytryptamine (5-HT; serotonin) transporters. In this study we used [11C]McN5652 to image the 5-HT transporter sites in baboon brain by positron emission tomography (PET). Dynamic PET studies were performed in three Papio anubis baboons. The animals were injected intravenously first with 11C-labeled (+)-McN5652([11C](+)McN5652), then with pharmacologically inactive enantiomer 11C-labeled (-)-McN5652 ([11C](-)McN5652); two animals received a third study with [11C](+)McN5652 after pretreatment with the specific 5-HT uptake site inhibitor fluoxetine (5 mg/kg). Initial uptake into the brain was similar for both [11C](+)McN5652 and [11C](-)McN5652. At later times (45-120 min after injection), only [11C](+)McN5652 showed a distribution characteristic for 5-HT uptake sites. In contrast, in studies with [11C](-)McN5652 and in those with [11C](+)McN5652 after 5-HT uptake site blockade with fluoxetine, 11C radioactivity concentrations were significantly lower and the distribution pattern was relatively even. The differences between [11C](+)-and (-)McN5652 were calculated for the time interval 95-125 min postinjection and used to estimate specific binding. Specific binding correlated well (r = 0.95, p < 0.001) with the known density of 5-HT uptake sites in human brain. These results indicate that [11C](+)McN5652 is suitable for PET imaging of 5-HT uptake sites in primate brain.

Animals↗
PubMed1995

Quantitative measurement of vascularization and vascular ingrowth rate of coralline hydroxyapatite ocular implant by Tc-99m MDP bone imaging.

Complete fibrovascular ingrowth of the hydroxyapatite ocular implant is necessary for peg drilling, the secondary procedure that couples the mobile sphere to the ocular prosthesis providing it with motility. This study was conducted to determine the usefulness of the bone scan for the evaluation and relative quantification of the vascularization of coralline hydroxyapatite ocular implants. In 23 patients (32 scans), vascularization of the ocular implant was measured by three-phase bone scintigraphy. There were 16 patients with left, and 7 with right orbital implants. At followup 0.5 to 8 months after successful hydroxyapatite implantation, the mean implant to normal intraorbital activity ratio on delayed bone scans in anterior view was 2.73 +/- 0.73 (mean +/- SD) with a range of 1.42-4.2. The normal right to left and left to right intraorbital bone activity ratios determined in anterior view from 10 normal delayed bone scans were 0.98 +/- 0.05 (mean +/- SD) and 1.02 +/- 0.05 (mean +/- SD) respectively, with a range of 0.93-1.07. The difference of the activity (count) ratios among the successfully implanted group and normals was statistically significant (P < 0.0001). A hydroxyapatite ocular implant to contralateral intraorbital bone activity ratio of greater than 1.12 with a homogeneous tracer distribution throughout the implant suggests adequate and diffuse vascularization is present. The progressive increase in activity ratio of the orbital implants seen in the early postimplantation period, which is indicative of the progression of vascularization, reaches a plateau after 1 month and remains relatively stable thereafter.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗