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Biomedical subjects

J Hietala

Publications and source records attributed to J Hietala.

At least 37 records · Page 2Linked to original sources
PubMed2003

Measurement of striatal and thalamic dopamine D2 receptor binding with 11C-raclopride.

11C-Raclopride is a widely used positron emission tomography (PET) tracer for measurement of striatal D2 dopamine receptor binding characteristics. Recently, 11C-raclopride has also been used for quantification of thalamic D2 receptor binding. We studied reproducibility and validity issues on the thalamic D2 binding measurements using healthy volunteer test-retest data and simulated data. Eight healthy male volunteers received 11C-raclopride as a bolus injection in a standard test-retest design using 3-dimensional PET. The displacement of thalamic 11C-raclopride binding by the D2 receptor antagonist haloperidol was studied in two female schizophrenic patients. With regards to reproducibility and reliability, thalamic 11C-raclopride binding could be described with a simplified reference tissue model resulting in binding potentials (BPs) between 0.38 and 0.66. In comparison, the model failed to describe 11C-raclopride binding consistently in temporal cortex due to low specific signal. Measurement of thalamic 11C-raclopride BP was reproducible with a test-retest variability of 7.6+/-6.2% and reliable with an intraclass correlation coefficient (ICC) of 0.87. Comparable ICCs were observed in caudate and putamen (0.84-0.96). With regard to validity, subchronic low dose haloperidol treatment reduced specific 11C-raclopride binding equally in putamen and thalamus but a higher dose induced clearly higher D2 receptor occupancy in putamen than in thalamus. Noise simulations indicated that this can partly be explained by an over-estimation of thalamic D2 receptor BP in noisy conditions (low signal, high occupancy). The D2 receptor BP in putamen was clearly more resistant to noise. We conclude that the reproducibility and reliability of thalamic 11C-raclopride BP is good and equal to, or only slightly less than, those observed in caudate or putamen. However, the signal-to-noise ratio for quantification may become too low especially in receptor occupancy-type studies, leading to an artefactual underestimation of measured D2 receptor occupancy.

Adult↗
PubMed2002

Structural magnetic resonance imaging in patients with first-episode schizophrenia, psychotic and severe non-psychotic depression and healthy controls. Results of the schizophrenia and affective psychoses (SAP) project.

BACKGROUND: Structural brain abnormalities are prevalent in patients with schizophrenia and affective disorders. AIMS: To study how regional brain volumes and their ratios differ between patients with schizophrenia, psychotic depression, severe non-psychotic depression and healthy controls. METHOD: Magnetic resonance imaging scans of the brain on first-episode patients and on healthy controls. RESULTS: Patients with schizophrenia had a smaller left frontal grey matter volume than the other three groups. Patients with psychotic depression had larger ventricular and posterior sulcal cerebrospinal fluid (CSF) volumes than controls. Patients with depression had larger white matter volumes than the other patients. CONCLUSIONS: Left frontal lobe, especially its grey matter volume, seems to be specifically reduced in first-episode schizophrenia. Enlarged cerebral ventricles and sulcal CSF volumes are prevalent in psychotic depression. Preserved or expanded white matter is typical of non-psychotic depression.

Adult↗
PubMed2001

Decreased striatal dopamine transporter binding in vivo in chronic schizophrenia.

We have previously reported that average striatal dopamine transporter (DAT) binding in vivo is unaltered in neuroleptic-naive first-episode schizophrenic patients [Laakso et al., Am. J. Psychiatry 157 (2000) 269]. However, as it has been suggested that some of the brain changes in schizophrenia may vary depending on the illness phase, we studied DAT density in eight stable, medicated chronic schizophrenic patients and eight matched controls using positron emission tomography and [18F]CFT, a marker of dopamine nerve terminals. [18F]CFT binding potentials were significantly lower in chronic schizophrenic patients than in controls, both in the caudate and the putamen (-9 to -16%). Together with the finding of unchanged average striatal DAT levels in first-episode patients and relative insensitivity of striatal [18F]CFT binding to endogenous dopamine and neuroleptic drugs, the result is in line with a relative loss of striatal dopaminergic nerve terminals and/or decreased expression of DAT in a subset of chronic schizophrenic patients.

Adult↗
PubMed2001

A morphometric MRI study of the hippocampus in first-episode, neuroleptic-naïve schizophrenia.

Magnetic resonance imaging (MRI) studies have frequently, although not unambiguously, reported hippocampal volume deficit in schizophrenia. Data on the hippocampal volumes in first-episode schizophrenia, however, are sparse. In addition, a recent topographic MRI study proposed a regionally specific volume loss in the hippocampus of chronic schizophrenics, but to date no reports have replicated this finding. In this study two-dimensional MRI-based topographic brain mapping was used to study the possibility of regional changes in the hippocampus of 22 controls and 18 patients with first-episode, neuroleptic-naïve schizophrenia. Compared to controls, there were no significant differences between hippocampal volumes, regional volumes, or length of the hippocampus in the patients with schizophrenia. These data are at odds with the previous reports on hippocampal volume loss in first-episode schizophrenia, and with the hypothesis of regionally specific hippocampal volume deficit in schizophrenia.

Adult↗
PubMed2001

Sertindole is a serotonin 5-HT2c inverse agonist and decreases agonist but not antagonist binding to 5-HT2c receptors after chronic treatment.

RATIONALE: Sertindole is a novel antipsychotic drug with high affinity for dopamine D2, alpha-1-adrenoceptors and serotonin 5-HT2A and 5-HT2c receptors. The 5-HT2c receptor component of sertindole may be clinically relevant as this receptor subtype is implicated in regulation of anxiety, cognition/memory and brain plasticity. OBJECTIVE: To characterise the interaction of sertindole with the 5-HT2C receptor using rat choroid plexus as a physiological receptor source. RESULTS: Sertindole had nanomolar affinity for the 5-HT2c receptor in vitro. Sertindole antagonised 5-HT-stimulated phosphoinositide (PI) hydrolysis and, like clozapine, also inhibited basal PI hydrolysis suggesting that sertindole is a 5-HT2C receptor inverse agonist. The effect of repeated sertindole dosing on 5-HT2C receptors was studied in rats treated for 21 days with sertindole (20, 300 and 1250 microg/kg/day). Clozapine (25 mg/kg/day) was used as a comparison drug. 5-HT2C receptor binding in the choroid plexus was measured with antagonist and agonist ligands ([3H]mesulergine and [125I]DOI) using quantitative autoradiography 8 days after withdrawal. Clozapine decreased 5-HT2C receptor antagonist and agonist binding sites equally by 36% and 32%, respectively. Sertindole did not induce significant changes in the total number of 5-HT2C receptors, but the highest dose of sertindole lowered the affinity of [3H]mesulergine for 5-HT2C receptors. This was most likely due to residual sertindole levels in the brain which was supported by direct concentration measurements. In contrast, sertindole induced a highly significant and dose-related decrease in 5-HT2C agonist binding (up to 77%). Neither drug affected striatal D2 receptor binding. CONCLUSIONS: Sertindole, like clozapine, was found to be a serotonin 5-HT2C receptor inverse agonist. The preferential downregulation of 5-HT2C receptor agonist (G-protein-coupled) sites by chronic administration seemed to differentiate sertindole from clozapine at these dose regimens. The 5-HT2c receptor downregulation during repeated dosing may contribute to therapeutic efficacy and/or side effects of sertindole treatment.

Animals↗
PubMed2001

Measurement of cortical dopamine d1 receptor binding with 11C[SCH23390]: a test-retest analysis.

[11C]SCH 23390 is a standard ligand for positron emission tomography (PET) studies on striatal dopamine D1 receptors. Its usefulness for cortical D1 receptor quantification in human PET studies has been questioned but has not been addressed previously. The authors tested the reproducibility of [11C]SCH 23390 binding potential (BP) in cortical areas in five healthy volunteers using three-dimensional PET. Measurement of D1 receptor BP was reproducible in basal ganglia, as well as in all cortical areas studied (intraclass correlation coefficients between 0.81 and 0.92). The absolute variability in cortical areas was 9.21% +/- 0.07%. The reproducibility of cortical D1 receptor BP measurement with [11C]SCH 23390 is equal to that observed with a more recent D1-ligand, [11C]NNC 112. [11C]NNC 112 produces slightly higher specific-to-nonspecific binding ratios but has markedly slower kinetics resulting in a need for a longer scan time. These aspects should be considered when designing studies on the cortical D1-like receptors.

Adult↗
PubMed2001

Sex differences in extrastriatal dopamine d(2)-like receptors in the human brain.

OBJECTIVE: The study examined gender differences in extrastriatal dopamine D2-like receptor levels in the human brain in vivo. METHOD: [(11)C]FLB 457, a high-affinity radioligand for extrastriatal D(2)-like receptors, and a three-dimensional positron emission tomography system were used to measure D(2)-like receptor binding potentials in frontal cortex, temporal cortex, and thalamus in 12 healthy men and 12 healthy women. RESULTS: Women had higher D(2)-like receptor binding potentials than men in the three brain regions studied, and the difference in the frontal cortex was statistically significant. In a more detailed regional analysis, the difference between the sexes was most pronounced for the left and right anterior cingulate cortex. CONCLUSIONS: This study provides in vivo evidence for a gender difference in dopamine D(2)-like receptor levels, which could be reflected in gender-associated differences in clinical disorders linked to the dopamine system.

Adult↗
PubMed2000

Lack of association between the functional variant of the catechol-o-methyltransferase (COMT) gene and early-onset alcoholism associated with severe antisocial behavior.

Addictive drugs, including ethanol, increase the brain's dopaminergic transmission, and catechol-o-methyltransferase (COMT) enzyme has a crucial role in dopamine inactivation. A common functional polymorphism in the COMT gene results in a three- to four-fold variation in enzyme activity. In a previous study, we found an association between type 1 (with late-onset but without prominent antisocial behavior) alcoholism and the low activity allele of the COMT gene. In this work we analyzed whether the COMT polymorphism has any effect on the development of type 2 (with early-onset and habitual impulsive violent behavior) alcoholism. The COMT genotype was determined in 62 impulsive violent recidivist offenders with early-onset (type 2) alcoholism, 123 late-onset nonviolent (type 1) alcoholics, and 267 race and gender-matched controls. The allele and genotype frequencies of these groups were compared with each other and also with previously published data from 3,140 Finnish blood donors. The type 2 alcoholics did not differ from either the blood donors or the controls. The low activity (L) allele frequency was higher among type 1 alcoholics (chi(2) = 4.98, P = 0.026) when compared with type 2 cases. The odds ratio for type 1 alcoholism as compared with type 2 alcoholism for those subjects with the LL genotype versus the HH genotype was 3.0 (95% confidence interval 1.1-8.4, P = 0.017). The results suggest that COMT genotype has no major role in the development of early-onset alcoholism with severe antisocial behavior.

Adult↗
PubMed2000

Extrastriatal dopamine D2 and D3 receptors in early and advanced Parkinson's disease.

OBJECTIVE: To investigate whether dopamine D2 and D3 receptor subtypes (D2/3Rs) outside the caudate-putamen are affected in PD. BACKGROUND: Alterations in striatal D2-like dopamine receptors in PD have been extensively demonstrated using PET, but there are no studies focusing on extrastriatal D2/3Rs. METHODS: Fourteen unmedicated patients with idiopathic early PD with predominantly left-sided symptoms, 14 levodopa-medicated patients with advanced PD, and 20 normal age-matched controls were examined using PET. PET scanning was performed with a novel high-affinity D2/3R radioligand ([11C]FLB 457) and a PET scanner in three-dimensional mode. RESULTS: In advanced PD, the binding potential of [11C]FLB 457 in the dorsolateral prefrontal cortex was decreased by 40% (p < 0.01), in the anterior cingulate cortex by 20% (p < 0.01), and in the medial thalamus by 17% (p < 0.05) compared with healthy controls. In early PD, the extrastriatal [11C]FLB 457 binding potentials were not significantly different compared with the control group. However, the binding potential in the anterior cingulate cortex (29%; p < 0. 05) was higher in early PD compared with advanced PD. CONCLUSIONS: These results imply that the D2/3 receptor subtypes outside the striatum are affected in advanced PD but not in the early stages of the disease, and that this receptor decline is present in the anterior cingulate cortex, the dorsolateral prefrontal cortex, and the thalamus.

Brain↗
PubMed2000

Measurement of extrastriatal D2-like receptor binding with [11C]FLB 457--a test-retest analysis.

[11C]FLB 457 is a radioligand for positron emission tomography (PET) that possesses high affinity to D2/D3 receptors. It has been suggested to be useful for quantification of low-density dopamine D2 receptor populations, e.g. in cortical and limbic brain areas. We explored the reproducibility of five methods for measuring extrastriatal D2-like receptor binding potential with [11C]FLB 457. Seven healthy male volunteers were examined twice with [11C]FLB 457 (high specific radioactivity) on the same day, at least 3 h apart. Four brain areas, frontal cortex, nucleus thalamus, temporal cortex and cerebellar cortex, were examined. Binding potentials (BPs) were derived from (1) a target to cerebellum distribution volume ratio, (2/3) two reversible reference tissue compartment models and (4) a transient equilibrium approach. For comparison, BP values were also calculated with the standard three-compartment kinetic model that does not assume a receptor-free reference region. The use of the standard three-compartment model did not result in reproducible BP estimates. The distribution volume (DV) ratio, reference tissue compartment models and the transient equilibrium method all had good to excellent intraclass correlation coefficients (ICCs) in the studied brain areas ranging from 0.56 to 0.93. Absolute variability was also relatively low, ranging from 5.3% to 10.4%. There were no marked differences in the ICC or absolute and relative variability between the four methods based on a reference tissue (cerebellum). In addition, we did not observe systematic differences in the BP between the first and the second scan. These data indicate that the reproducibility of the DV ratio, reference tissue models and the transient equilibrium method is good or excellent. However, each of these methods includes assumptions affecting their validity. Thus, the choice of method will be critically dependent on the purpose of the study.

Adult↗
PubMed2000

Quantification of [Carbonyl-(11)C]WAY-100635 binding: considerations on the cerebellum.

The specific binding of [carbonyl-(11)C]WAY-100635 to 5-hydroxytryptamine(1A) receptors was quantitated using different kinetic models. Ten healthy subjects were studied using a GE Advance PET scanner. We suggest that tissue heterogeneity explains part of the nonspecific binding seen in cerebellum, which leads to an underestimation of binding potential with reference tissue methods. The nonlinear three-compartmental model with metabolite-corrected plasma input provides accurate estimates of receptor binding because of the favorable kinetics of tracer in the brain and circulation.

Adult↗
PubMed2000

Striatal dopamine transporter binding in neuroleptic-naive patients with schizophrenia studied with positron emission tomography.

OBJECTIVE: Recent in vivo imaging studies indicate a dysregulated presynaptic function of the striatal dopaminergic system in patients with schizophrenia. To further explore the basis of this phenomenon, the authors studied brain dopamine transporter binding in vivo in patients with first-episode, never-medicated schizophrenia. METHOD: Nine patients with schizophrenia and nine healthy matched comparison subjects were recruited. Striatal dopamine transporter binding was measured with positron emission tomography and a specific dopamine transporter ligand, [(18)F]CFT, a radiolabeled form of 2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane. RESULTS: Average caudate and putamen dopamine transporter binding potentials were almost identical in the patients and comparison subjects, but the patients lacked the right-left asymmetry of the caudate dopamine transporter binding seen in the comparison group. CONCLUSIONS: Average striatal dopamine transporter density is unaltered in neuroleptic-naive patients with schizophrenia. However, patients lack asymmetry in caudate dopamine transporter binding, which conforms with disrupted brain lateralization in this disorder.

Adult↗
PubMed2000

Prediction of detached personality in healthy subjects by low dopamine transporter binding.

OBJECTIVE: Low striatal dopamine D(2) receptor binding in healthy human subjects has been associated with detached personality in studies using positron emission tomography (PET) and the Karolinska Scales of Personality questionnaire. The authors investigated whether a similar correlation exists between striatal dopamine transporter binding and detached personality. METHOD: Eighteen healthy volunteers participated in a PET study with the specific dopamine transporter ligand [(18)F]CFT ([(18)F]WIN 35,428) and completed the Karolinska Scales of Personality questionnaire form. RESULTS: Age-corrected dopamine transporter binding in the putamen, but not in the caudate, correlated negatively with detachment personality scores, especially in the right hemisphere. CONCLUSIONS: This finding supports the hypothesis that low dopaminergic neurotransmission is associated with detached personality. Furthermore, since [(18)F]CFT binding is thought to reflect the density of dopaminergic nerve terminals in the brain, the authors suggest that the neurodevelopmental formation of the brain dopaminergic system may influence adult personality traits.

Adult↗
PubMed2000

High levels of dopamine activity in the basal ganglia of cigarette smokers.

OBJECTIVE: The authors' goal was to study presynaptic dopamine activity in smoking and nonsmoking human subjects in vivo. METHOD: [(18)F]Fluorodopa ([(18)F]DOPA) uptake K(i) values in the basal ganglia of nine smoking and 10 nonsmoking healthy men were measured with positron emission tomography. RESULTS: Significantly higher [(18)F]DOPA uptake was observed in both the putamen (average 17.3% higher) and the caudate (average 30.4% higher) of smokers than in those of nonsmokers. CONCLUSIONS: Smoking is related to greater dopamine activity in the human basal ganglia. Nicotine-induced dopamine activity may be a relevant mechanism in dependence on cigarette smoking.

Adult↗
PubMed2000

PET studies of brain monoamine transporters.

Monoamine transporters are proteins mainly located on nerve terminals of dopaminergic, noradrenergic and serotonergic neurons. They are members of a larger sodium dependent transporter family and represent a major mechanism terminating the action of released neurotransmitter in the synaptic cleft. In addition to being important target molecules for many antidepressive drugs and substances of abuse, transporter proteins are good markers for the integrity of monoaminergic innervation. Therefore, there is a growing interest for in vivo imaging studies using positron emission tomography (PET) or single photon emission computed tomography (SPECT) and ligands selective for monoamine transporters. In this review, the use of monoamine transporter ligands (or tracers) for imaging studies of cocaine dependence, neurodegenerative diseases and mechanism of antidepressant drug action is discussed, with special focus on the use of PET for evaluating possible new pharmacological innovations.

Animals↗
PubMed1999

Morning versus evening dosing of ibuprofen using conventional and time-controlled release formulations.

Many functions of the human body vary considerably during a day. These variations can lead to changes in drug plasma concentrations. In the study on healthy volunteers described here it was determined whether ibuprofen plasma levels following single oral doses of immediate-release and press-coated time-controlled release tablet formulations depend on time of drug administration (08:00 or 22:00 h). The difference between morning and evening dosing of the immediate-release formulation was minimal. The results with the press-coated formulation were unexpected having regard to results of previous studies on non-steroidal anti-inflammatory analgesics. Time to peak concentration was 6 h after morning administration, 4 h after evening administration. Both the rate and extent of bioavailability of ibuprofen were lower when dosing took place at 08:00 h than when dosing took place at 22:00 h. The influence of food on the pharmacokinetic profile of an evening dose of the press-coated formulation was also studied. When tablets were administered with a meal the ratio C(max)/AUC and t(max) and AUC values indicated that bioavailability was reduced. The main conclusion was that the chronopharmacokinetic behaviour of the press-coated ibuprofen tablet is related to the formulation, not the drug substance as such.

Adult↗
PubMed1999

Depressive symptoms and presynaptic dopamine function in neuroleptic-naive schizophrenia.

We have previously reported aberrations in the striatal presynaptic dopamine function in neuroleptic-naive schizophrenic patients compared to healthy controls (Hietala, J., Syvälahti, E., Vuorio, K. et al., 1995. Lancet 346, 1130-1131). In this extended study we explore whether the altered presynaptic dopamine function correlates with the clinical symptomatology in schizophrenia. Striatal dopamine synthesis capacity (6-[18F]fluorodopa (FDOPA) uptake, Ki values) was studied with positron emission tomography in 10 neuroleptic-naive schizophrenic patients and 13 healthy controls. The clinical symptomatology was characterized with the Positive and Negative Symptom Scale (PANSS). The patients had an increased FDOPA uptake in striatum and lacked the asymmetry in caudate FDOPA uptake (p = 0.0005), confirming our earlier results. Left striatal FDOPA uptake (Ki) values correlated negatively with depressive symptoms in a highly significant manner. On the other hand, paranoid symptomatology correlated positively with right putamen FDOPA uptake at a trend level (rho = 0.73, p < 0.02). The lack of asymmetry in caudate Ki values did not associate with any dimension of psychopathology. The major finding in this study is that depressive symptoms in neuroleptic-naive first-admission schizophrenia are associated with low presynaptic dopamine function. This link appears to be hemisphere-related and may have drug-treatment implications, e.g., in prediction of response to D2 receptor blocking antipsychotic drugs. A possible connection between paranoid symptomatology and subcortical hyperdopaminergia is suggested, but this remains to be further verified.

Adolescent↗