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G Sedvall

Publications and source records attributed to G Sedvall.

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

Three-dimensional visualization and quantification of the benzodiazepine receptor population within a living human brain using PET and MRI.

Positron emission tomography (PET) in combination with receptor-selective high-affinity radioligands allows the characterization of neuroreceptor distributions in the living human brain. Thus far, the visualization and quantification of receptors with PET have been limited to series of two-dimensional (2D) image planes of the anatomic receptor distribution. The development of high-resolution PET has increased the number of planes to approximately 50, supplying an excessive amount of image information from a single experiment. The inherent limitations of 2D techniques make them insufficient to apprehend and efficiently analyze this cumbersome amount of data. In the present communication we describe procedures to visualize and quantify in three dimensions (3D) the total image information from the compound set of 47 2D planes of a PET experiment using commercially available software. Three-dimensional computer graphic and volume rendering techniques were used to analyze and display the results. For the experimental application the benzodiazepine (BZ) antagonist [11C]flumazenil was used as radioligand to visualize the BZ receptor (BZR) population in the brain of a healthy human subject. Three-dimensional images of the radioligand binding receptor population were displayed with regard to volume and form in relation to the corresponding anatomic structures in the brain reconstructed from MR images. The volume-rendering technique allowed the inspection of PET signals representing BZR populations in the interior of the hemisphere as viewed from the medial projection. Thresholding and seeding techniques were used to define volumes and quantities. Using the PET data and volume rendering, the total amount of cerebral BZRs (NCerebrum) and the apparent volume they take into account (V(BZR, Cerebrum)app) could he calculated for the first time using an automated procedure. The cerebrum of the healthy subject contained 17.6 nmol of BZRs in a volume of approximately 1.25 L. The principles and application of the technical development described offer new dimensions to clinical neuroscience and should be practically useful for automated quantitative determination of neuroreceptor number in brain regions of patients with neuropsychiatric disorders and in relation to drug treatment.

Adult↗
PubMed1997

Autoradiographic comparison of [125I]epidepride and [125I]NCQ 298 binding to human brain extrastriated dopamine receptors.

Extrastriatal D2-dopamine receptors can be visualised in the monkey and human brain using the benzamides [11C]- and [76Br]FLB 457 in PET and [123I]epidepride in SPECT but not with the salicylamide analogues [76Br]FLB 463 and [123I]NCQ 298. To clarify the background for the differences in binding seen in vivo, we have compared the in vitro binding of [125I]epidepride and [123I]NCQ 298, using human whole hemisphere autoradiography. The images obtained with any radioligand showed detailed distribution with very dense binding in the putamen and the caudate nucleus and with the same detailed extrastriatal distribution. Thus, the divergent results obtained in vivo cannot be explained by different binding properties of the extrastriatal receptors.

Autoradiography↗
PubMed1997

[125I] beta-CIT-FE and [125I] beta-CIT-FP are superior to [125I] beta-CIT for dopamine transporter visualization: autoradiographic evaluation in the human brain.

The binding of the three dopamine transporter radioligands ([125I] beta-CIT, [125I] beta-CIT-FE, and [125I] beta-CIT-FP) was studied using whole-hemisphere autoradiography on postmortem human brains. The autoradiograms revealed an intense and homogeneous labeling of the nucleus caudatus and putamen but also to varying extent to serotonergic and noradrenergic transporters of neocortex and thalamus. The order of specificity estimated (striatum over neocortex ratios) was beta-CIT-FP > beta-CIT-FE > > beta-CIT, suggesting that beta-CIT-FE and beta-CIT-FP should be preferred for in vivo studies of the dopamine transporter in the human brain.

Autoradiography↗
PubMed1997

PET study of the pre- and post-synaptic dopaminergic markers for the neurodegenerative process in Huntington's disease.

PET and: markers for the pre- and postsynaptic neurons were used to study the dopamine system in vivo in Huntington's disease. The radioligands used were [11C]SCH 23390 for D1-receptors, [11C]raclopride for D2-receptors and [11C]beta-CIT for dopamine transporters. Five patients with Huntington's disease and five matched controls were recruited. Brain anatomy was examined by MRI. The findings in patients were as follows. Postsynaptic D1- and D2-receptor densities were similarly reduced in the striatum. A reduction in D1-receptor density was shown in the temporal cortex; it draws attention to the cortical degeneration in relation to the cognitive deficits observed in Huntington's disease. The reduction of D1- and D2-receptor binding potentials in the striatum correlated significantly with increasing duration of illness. The correlation between the duration of illness and decline of D1- and D2-receptors make these receptors valuable as quantitative markers for the Huntington's disease degenerative process. Besides postsynaptic changes, a significant 50% decrease of [11C]beta-CIT binding to the dopamine transporter was found in the striatum. A reduced striatal blood flow in Huntington's disease cannot be excluded and could account for a small part of the decrease in [11C]beta-CIT binding. We suggest that the finding reflects a loss of presynaptic terminals or a reduced expression of dopamine transporter in the nigrostriatal dopaminergic system in Huntington's disease.

Adult↗
PubMed1997

Ciliary neurotrophic factor null mutation and schizophrenia in a Swedish population.

According to the maldevelopmental hypothesis, the neurotrophic factor system represents an important area which might be genetically and neurochemically involved in the etiopathogenesis of schizophrenic psychoses. Patients suffering from schizophrenic psychoses and control persons were genotyped for a null mutation of the ciliary neurotropic factor gene. There were no significant differences in the allelic and genotypic distributions in the total schizophrenic and control samples. However, there was a negative association with a family history of psychosis. Thus, it cannot be excluded that this genetic variant represents a vulnerability marker for specific schizophrenic subtypes. The development of valid diagnostic instruments based on biological criteria is crucial for schizophrenia research; more homogeneous subgroups are more likely to represent distinct nosological entities than the heterogenous group of diseases presently categorized as schizophrenia.

Alleles↗
PubMed1997

Localization of neuropeptide Y Y1 mRNA in the human brain: abundant expression in cerebral cortex and striatum.

Many neurobiological functions have been ascribed to the NPY Y1 receptor subtype, but autoradiographic analysis has failed to detect Y1 binding sites in most human brain areas, in contrast to the rat. We examined the regional distribution of Y1 mRNA-containing cells in the post-mortem human brain to clarify if there is a major species difference in terms of the existence of Y1 receptors in the human telencephalon, in particular the striatum and cortex. In situ hybridization experiments revealed widespread distribution of Y1 mRNA signals in all layers of most limbic and neocortical regions, predominantly in layer IV (most cortical regions) and layer VI. The striatum showed moderate Y1 receptor mRNA expression levels with intensely expressing cells localized to the nucleus accumbens. The highest Y1 receptor mRNA expression was apparent within the dentate gyrus, and the lowest in the subiculum, parahippocampal gyrus, cerebellum, and thalamus. In vitro autoradiography using [125I]Leu31Pro34-PYY and [125I]PYY with NPY (13-36) or Leu31Pro34-NPY, confirmed the presence of low Y1-like binding in the human brain despite abundant Y1 mRNA expression. However, using a rat model of the human autopsy process, it was apparent that the inability to reveal high Y1- versus Y2-like receptors in the human brain was related in part to marked reductions of Y1-like, but not Y2-like, receptors within a 4 h post-mortem delay. Altogether, the results indicate that the Y1 receptor gene is abundant in the human brain and this receptor may have important roles in cognitive, limbic and motor function.

Adult↗
PubMed1997

Schizophrenia and neurotrophin-3 alleles.

Studies of brain anatomy and premorbid functioning indicate that schizophrenia may be of neurodevelopmental origin. In the neurotrophic factor neurotrophin-3 (NT-3) gene, the A3/147-bp allele in a dinucleotide repeat polymorphism located in the promoter region was found to be associated with schizophrenia in a Japanese study. Another NT-3 polymorphism (Glu63Gly) indicated an association with schizophrenic patients with a putative neurodevelopmental form of the disease. We examined Swedish schizophrenic patients (n = 109) and control subjects (n = 78) for the same two NT-3 polymorphisms, as well as a third silent exonic polymorphism (at Pro55). No significant difference was found between the two groups. However, in a meta-analysis including the present and previous studies of Caucasian subjects, the A3/147-bp allele frequency was found to be significantly higher in the schizophrenic patients. In the present study, carriers of the A3/147 bp allele tended to have an earlier age of onset and to display more extrapyramidal symptoms. In the silent exonic polymorphism (at Pro55), female schizophrenic patients had higher adenine and lower guanine allele frequencies than control female subjects. Together with previous studies, the results provide some support for an association between the NT-3 gene and certain forms of schizophrenia. This warrants further investigation of NT-3 and other neurotrophic factors with additional polymorphisms and larger patient samples.

Adult↗
PubMed1997

Tyrosine hydroxylase and dopamine D4 receptor allelic distribution in Scandinavian chronic alcoholics.

Associations of polymorphic genetic markers at the tyrosine hydroxylase (TH) and dopamine D4 receptor (DRD4) loci were examined in Scandinavian chronic alcoholics (n = 72) and control subjects (n = 67). Patients were divided into subgroups with regard to the presence of parental alcoholism and age of onset. Neither the TH nor the DRD4 allele distributions were significantly different when alcoholic samples were compared with control subjects. However, a tendency to high prevalence for 1 of the 5 TH alleles assayed (TH-K3) was observed in a subsample of 44 alcoholics characterized by late onset when compared with control subjects (27.3% vs. 10.6%, p = 0.041). Results suggest that no major influence on alcoholism is exerted through genes associated with the DRD4 or TH allelic markers examined.

Adult↗
PubMed1997

Prodynorphin allelic distribution in Scandinavian chronic alcoholics.

Two regions of the human prodynorphin gene, the exon 4-region coding for the opioid peptides and the putative promotor/exon 1-region were analyzed for possible presence of polymorphisms. No polymorphism was detected in the exon 4-region, whereas a GC/AT base-pair exchange was observed 301 base pairs upstream of the exon 1/intron A boundary. This polymorphic marker was examined in Scandinavian chronic alcoholics (n = 70) and control subjects (n = 55). Prodynorphin allelic distributions were not significantly different in alcoholic patients and control subjects. The results suggest that no major influence on alcoholism is exerted through genes associated with this prodynorphin allelic marker.

Adult↗
PubMed1996

Dopamine-related genes and their relationships to monoamine metabolites in CSF.

Monoamine metabolite (MM) levels in lumbar cerebrospinal fluid (CSF) are extensively used as indirect estimates of monoamine turnover in the brain. In this study we investigated genotypes for DNA polymorphisms in the D2 (DRD2), D3 (DRD3), and D4 (DRD4) dopamine receptor and tyrosine hydroxylase (TH) genes and their relationships to CSF MM in healthy volunteers (n = 66). Concentrations of homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) were corrected for back length, a confounding variable. Corrected MM levels were not related to age, gender, height, weight heredity, season or atmospheric pressure at sampling. Individuals with specific DRD2 and TH allele and genotype configurations significantly differed in HVA and MHPG concentrations. DRD3 homo- and heterozygotic genotypes had significantly different CSF 5-HIAA levels. DRD4 genotypes were not related to MM concentrations. The results suggest that specific DRD2, DRD3, and TH genotypes participate in the regulation of monoamine turnover in the central nervous system. Accordingly monoamine receptors and synthesizing enzyme genotypes appear to be variance factors influencing MM concentrations in CSF. The relationships found in this study support MM concentrations as markers for monoamine transmission in the human brain.

Adult↗
PubMed1996

Autoradiographic localization of extrastriatal D2-dopamine receptors in the human brain using [125I]epidepride.

Epidepride is a benzamide with high affinity for central D2- and D3-dopamine receptors. The anatomical distribution of [125I]epidepride binding was examined by autoradiography, using postmortem human whole-hemisphere cryosections. The density of [125I]epidepride binding sites was high in caudate nucleus and putamen. [125I]epidepride also labeled receptors in extrastriatal region such as in the pallidum, some thalamic nuclei, the neocortex, and the substantia nigra. The neocortical binding was heterogeneously distributed. In most cortical regions, binding sites were located in superficial layers (I-II). However, in basal levels of the occipital cortex, [125I]epidepride binding was located in a deeper layer, probably corresponding to layer V. Competition studies indicated that most of the [125I]epidepride binding represented predominantly D2-dopamine receptors, in striatal as well as in extrastriatal regions. The presence of extrastriatal D2-dopamine receptor populations is of particular interest for research on schizophrenia and antipsychotic drug action.

Aged↗
PubMed1996

Lack of association between schizophrenia and the apolipoprotein E epsilon 4 allele.

The association between the epsilon 4 allele of the apolipoprotein E (APOE) gene and Alzheimer's disease (AD) has been reported. In order to examine if the epsilon 4 allele may play a role also in schizophrenia, another mental disorder, patients (n = 87) and control subjects (n = 57) were genotyped for APOE. No significant difference was found between the groups. The data indicate that the APOE gene is not of major importance for the genesis of schizophrenia.

Adult↗
PubMed1996

A search for association between schizophrenia and dopamine-related alleles.

Dopamine receptor dysfunction and altered tyrosine hydroxylase activity have both been implicated in the pathophysiology of schizophrenia. Schizophrenic patients and control subjects were examined for allele frequencies in the tyrosine hydroxylase and dopamine D2 and D4 receptor genes. No significant differences of allele or genotype frequencies were found between the two groups after adjustment for multiple comparisons. Neither were any significant relationships observed between allele frequencies and a number of clinical variables within the schizophrenic subsample. When no adjustment was made for multiple testing a few significant tendencies were obtained which warrant further research in extended patient and control materials. The results are compatible with the view that the tyrosine hydroxylase, dopamine receptor D2 and D4 gene polymorphisms examined are not of major importance in the aetiology or pathophysiology of schizophrenia.

Adult↗
PubMed1996

Autoradiographic localisation of D3-dopamine receptors in the human brain using the selective D3-dopamine receptor agonist (+)-[3H]PD 128907.

The selective D3-dopamine receptor agonist 4aR, 10bR-(+)-trans-3,4,4a, 10b-tetrahydro-4-[N-propyl-2,3-3H]-2H,5H-[1] benzopyrano[4,3-b]-1,4-oxazin-9-ol ([3H]PD 128907) was used to visualise D3-dopamine receptors in whole hemisphere cryosections from post-mortem human brain. [3H]PD 128907 has an 18- to 40-fold selectivity for D3- over D2-dopamine receptors as compared to a 7- to 24-fold selectivity of the more commonly used ligand [3H]7-OH-DPAT. [3H]PD 128907 accumulated markedly in the nucleus accumbens and in the ventral parts of caudate nucleus and putamen, with a slightly heterogeneous (patch-matrix like) distribution. The binding in the lateral parts of caudate nucleus and putamen was much less dense. No binding was obtained in any other regions. A very high proportion of [3H]PD 128907 was specifically bound, as judged from the low binding remaining in the presence of the D2/D3-dopamine receptor antagonist raclopride. This gives the ligand a potential for the detection of low density D3-dopamine receptors in the human brain. The binding obtained with [3H]PD 128907 was qualitatively similar to that using [3H]7-OH-DPAT in the presence of GTP. However, [3H]7-OH-DPAT labelled, in contrast to [3H]PD 128907, also D3-dopamine receptors in neocortex. The new compound [3H]PD 128907 appears to be a suitable radioligand for autoradiographic examination of the D3-dopamine receptor localisation in the human brain, and should also be useful for pharmacological studies of this receptor subtype.

Adult↗