Biomedical subjects

E D Bird

Publications and source records attributed to E D Bird.

At least 19 recordsLinked to original sources

PubMed1992

Distribution of beta-adrenergic receptor subtypes in human post-mortem brain: alterations in limbic regions of schizophrenics.

The distribution of the beta 1 (beta 1) and beta 2 (beta 2) subtypes of the beta-adrenergic receptor was examined in rat and nondiseased control human tissue. The distribution of the beta 1 and beta 2 receptors was also examined in schizophrenic cases, with additional studies in schizophrenic suicide and nonschizophrenic suicide cases. Scatchard analysis of the binding of [125I]iodopindolol (IPIN) to cortical membranes showed a similar Kd in human (177 pM) and rat (161 pM), but a lower maximum binding site (Bmax) in the human tissue (18.7 fmol/mg protein and 55.6 fmol/mg protein). For the autoradiographic studies [125I]IPIN was used to visualize both subtypes (total) or was displaced with the selective beta 1-receptor antagonist ICI-89,406 to visualize beta 2 sites, or with the selective beta 2-receptor antagonist ICI-118,551 to visualize beta 1 sites. Important differences in the regional distribution of the two subtypes of the beta-adrenergic receptors were noted between rat and human. In the nucleus accumbens and ventral putamen (ventral striatum), a patchy distribution of beta 1 receptors was observed that was not evident in the rat. These patches were aligned with markers of the matrix compartment of the striatum. The schizophrenic cases showed significant increases in the labeling of the beta 1-receptor patches with [125I]IPIN. In contrast to the frontal cortex of the nondisease controls, the parietal and temporal cortex showed a high ratio of beta 1 to beta 2 receptors and a highly laminar organization of the subtypes. [125I]IPIN binding to beta 1 receptors was highest in the external laminae with the reverse gradient for the beta 2 subtype. The medial temporal cortex displayed an alteration in the ratio of the 2 subtypes of the beta-adrenergic receptor, with the parahippocampus and hippocampus of the human, in contrast to the rat brain, predominantly expressing the beta 2 receptor. Moreover, there were consistently higher densities of beta 2 receptors in the hippocampus of the right hemisphere than the left hemisphere of the nondisease controls. There was not a left and right hemispheric asymmetry of beta 2 receptors in the hippocampus of elderly schizophrenics or in young schizophrenics who committed suicide. The asymmetry was evident in nonschizophrenic suicides, suggesting that the lack of asymmetry in the hippocampus of schizophrenics is evident early in the disease process. Thus limbic structures show alterations in the patterning of beta 1 and beta 2 receptors in the schizophrenic cases.

Adult↗

PubMed1992

Kynurenic acid concentrations are reduced in Huntington's disease cerebral cortex.

Huntington's disease (HD) is characterized by gradually evolving selective neuronal death. Several lines of evidence suggest that an excitotoxic mechanism may play a role. Tryptophan metabolism leads to production of quinolinic acid, an N-methyl-D-aspartate (NMDA) receptor agonist, and to kynurenic acid, an antagonist at these same receptors. We recently found increased kynurenine to kynurenic acid ratios in HD postmortem putamen and decreased kynurenic acid concentrations in cerebrospinal fluid, consistent with decreased formation of kynurenic acid in HD brain. In the present study we used HPLC with 16 sensor coulometric electrochemical detection to measure kynurenic acid and 18 other electrochemically active compounds in 6 cortical regions, caudate and cerebellum from controls, HD, Alzheimer's disease (AD), and Parkinson's disease (PD) patients. Significant reductions in kynurenic acid concentrations were found in 5 of 6 cortical regions examined. Smaller reductions of kynurenic acid in the caudate, cerebellum and frontal pole were not significant. No significant reductions were found in the AD and PD patients. Both uric acid and glutathionine were significantly reduced in several regions of HD cerebral cortex, which could signify abnormal energy metabolism in HD. Since kynurenic acid is an antagonist of excitatory amino acid receptors, a deficiency could contribute to the pathogenesis of neuronal degeneration in HD.

Aged↗

PubMed1992

Neuroleptic treatment is an unlikely cause of elevated dopamine in thalamus of schizophrenic subjects.

Previous studies have indicated a marked increase in the dopamine/norepinephrine ratio in thalami of schizophrenic patients compared with those of control subjects. Since these results all came from patients who were receiving neuroleptic drugs, the possibility exists that the increased dopamine concentrations are an effect of medication. To address this question, similar analyses were done on thalami from Huntington's Disease patients who had received neuroleptic treatment. The results showed no differences between the thalami of Huntington's Disease patients and controls, strongly suggesting that chronic treatment with neuroleptic drugs does not result in an increase of endogenous dopamine in the thalami of human subjects.

Adult↗

PubMed1992

Kynurenine pathway abnormalities in Parkinson's disease.

We measured metabolites of tyrosine and tryptophan (TRP) in the frontal cortex, putamen (PT), and pars compacta of the substantia nigra (SN) of control and Parkinson's disease (PD) brain tissues. Dopamine concentrations were significantly decreased in the PT and SN of PD tissue, regardless of L-dopa therapy. However, 3-O-methyldopa (3OMD) concentration showed a significant increase in each region of the PD group treated with L-dopa (PD[+]) as compared with both the control group and the PD group without L-dopa therapy (PD[-]). Therefore, 3OMD concentration appears to be a reliable marker of L-dopa therapy. Serotonin concentration was lower in each region of the PD groups than in the control group. Although the magnitude of decrease was greater in the PD(+) group, there was no statistical significance between the two PD groups. The same patterns of decrease were present in kynurenine (KYN) and kynurenic acid (KYA) concentrations, but the molar ratios of TRP to KYN and KYN to KYA were unchanged among three groups. In contrast, 3-hydroxykynurenine (3OHKY) concentration was increased in the PT PD(-) group and in three regions of the PD(+) group. Since the KYN pathway leads to formation of nicotinamide-adenine dinucleotide (NADH), the present results may be a further indication of a defect in NADH:ubiquinone oxidoreductase (complex I) in mitochondria in PD.

Aged↗

PubMed1992

Increased GABAA receptor binding in superficial layers of cingulate cortex in schizophrenics.

Recent investigations of postmortem brain from schizophrenic patients have revealed reduced numbers of neurons in several different corticolimbic brain regions. In the prefrontal and anterior cingulate cortices, more specific decreases in the numbers of interneurons, but not pyramidal cells, have been reported to occur preferentially in layer II. Based on this latter finding, a loss of inhibitory basket cells leading to a compensatory upregulation of the GABAA receptor has been hypothesized to occur in schizophrenic patients and to be a contributory factor in the pathophysiology of this disorder. We now report the results of a high-resolution quantitation of GABAA receptor binding in anterior cingulate cortex of postmortem specimens from normal and schizophrenic cases. The results indicate a preferential increase in bicuculline-sensitive 3H-muscimol binding on neuronal cell bodies of layers II and III, but not layers V and VI, of the schizophrenic cases. There was no difference in the size of neurons in any of the layers examined when the control and schizophrenic groups were compared. The neuropil of layer I also showed significantly greater GABAA binding in schizophrenics. The differences seen in the schizophrenic group did not appear to be the result of exposure to antipsychotic medication because one patient who was medication naive and a second who had received minimal exposure to antipsychotic drugs also showed elevated GABAA receptor binding. Since information processing depends on corticocortical integration in outer layers I-III, a disturbance of inhibitory activity in these superficial layers of limbic cortex may contribute to the defective associative function seen in schizophrenia.

Adult↗

PubMed1992

[Huntington disease: 7 cases with relatively preserved neostriatal islets].

Seven cases of Huntington's disease (HD) showing unusual neostriatal findings are reported. In these patients, the neostriatum contained scattered islets of relatively intact parenchyma. We attempted to determine whether these cases might represent a clinico-pathological entity, and also sought to acquire a better understanding of the neostriatal degenerative changes in HD. Cell counts showed that the number of neurons in the islets was the same as in the normal neostriatum, but there was an increased number of astrocytes. The nature of these islets is poorly understood. Analysis of their topography and of the morphometric data indicates that they probably do not represent preserved striosomes. In HD patients with preserved neostriatal islets, the symptoms appear earlier, and the course of the disease is more rapid than in HD patients with the usual neostriatal lesions. The exceptional neuropathological phenotype of our seven HD cases probably indicates a different genotype.

Adult↗

PubMed1991

Factors associated with slow progression in Huntington's disease.

The rate of disease progression was assessed for 42 persons affected by Huntington's disease who had been neurologically examined at least six times and followed up for at least 3 years. Disease progression was assessed by a disability rating scale administered at each examination. Slow progression was associated with older age at onset of disease and with heavier weight (body mass index) at the first examination. Men tended to have a slower disease progression than did women, and this was particularly evident among men inheriting Huntington's disease from affected mothers. Neither the butyrophenone haloperidol nor the tricyclic antidepressant imipramine were related to rate of progression. Assessments of depression, hostility, and tobacco use were also unrelated to rate of progression. Clinical trials in Huntington's disease should consider these factors when designing therapeutic studies.

Adolescent↗

PubMed1991

Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients.

A recent report suggested that neurons in the prefrontal, anterior cingulate, and primary motor cortex of the brains of schizophrenic subjects may be less dense than those in the brains of nonschizophrenic subjects. We have determined whether pyramidal neurons and/or interneurons are preferentially reduced in schizophrenic subjects. Twelve control subjects and 18 schizophrenic subjects were studied in a blind, quantitative analysis of the density of pyramidal cells, interneurons, and glial cells in each of the six layers of the anterior cingulate and prefrontal cortex. The results showed that numbers of small neurons (interneurons) were reduced in most layers of the cingulate cortex in schizophrenic subjects compared with nonschizophrenic subjects, with the differences being greatest in layer II. In the prefrontal area, interneuronal density was also lower in layer II and, to a lesser extent, in layer I in schizophrenic subjects compared with control subjects. In most cases, the differences were similar, although more significant, in schizophrenic subjects who had had superimposed mood disturbances than in schizophrenic subjects who had not had such comorbidity. Numbers of pyramidal neurons generally were not different between control and schizophrenic subjects, except in layer V of the prefrontal area, where schizophrenic subjects showed higher densities of these neurons. Glial numbers did not differ between the control and schizophrenic subjects, suggesting that a neurodegenerative process did not cause the reduced interneuronal density observed. Using multiple regression analysis and analysis of covariance, decreases in the density of layer II interneurons could not be adequately explained by the effects of various confounding variables, such as age, postmortem interval, duration of specimen fixation, or administration of neuroleptic agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Count↗

PubMed1991

Cerebral amyloid angiopathy without and with cerebral hemorrhages: a comparative histological study.

To identify those factors associated with cerebral hemorrhage among brains with cerebral amyloid angiopathy (CAA), we undertook a comparative postmortem histopathological study of amyloid-containing vessels in the brains of patients with and without hemorrhage. Those without hemorrhage were represented by the following two groups: (1) elderly patients from a large general hospital (n = 66; age range, 75-107 years) and (2) patients with various neuropsychiatric disorders (n = 70; age range, 27-96 years). CAA was found in 45% of the first group and in 54% of the second group. The findings in these patients were compared with those in 17 brains in which both CAA and cerebral hemorrhage were present. We found that CAA was more severe in the brains with cerebral hemorrhage than in those without, and that fibrinoid necrosis was seen only in the brains with cerebral hemorrhage (12 of the 17 brains). Microaneurysms occurred only in the presence of severe, rather than moderate or mild, CAA. Serial sections in 2 brains of patients with cerebral hemorrhage showed fibrinoid necrosis, microaneurysms, and vascular rupture in close association with the hemorrhage. In 2 patients, hemorrhage was precipitated by trauma, and in 1, it was secondary to metastatic carcinoma. The features of brains from patients with CAA that are most consistently related to cerebral hemorrhage are (1) a severe degree of CAA and (2) the presence of fibrinoid necrosis, with or without microaneurysms.

Adult↗

PubMed1991

Evidence for axonal loss in regions occupied by senile plaques in Alzheimer cortex.

The studies described have sought to determine what, if any, relationship exists between axons and the senile plaque, a hallmark histopathological feature of Alzheimer's disease. A double stain was performed on both early and late Alzheimer frontal cortex tissues in order to examine the interaction between axons stained with antibodies against the 200,000 mol. wt neurofilament subunit (NFP-200) of the axon cytoskeleton and Thioflavin-S, a fluorescent dye that stains plaques. Serial photomicrographs of plaques were taken and axon and plaque profiles were three-dimensionally reconstructed. Analysis of computer-processed images revealed that there were fewer axons within plaques than in regions lying one and two plaque distances away. When axons were observed passing through plaques, swelling and disruption of normal morphology was frequently present. Statistical analyses of axon counts within and around placques showed a gradient of axon density, with increased numbers occurring at progressive distances from the placque. Similar patterns were seen for early and late stages of the disease. The results of this study indicate that disruption of the axonal cytoskeleton may occur within the regions occupied by plaques.

Alzheimer Disease↗

PubMed1991

Reduced neuronal size in posterior hippocampus of schizophrenic patients.

The hippocampus, an integral component of the corticolimbic circuitry of the brain, has been recently implicated in the pathophysiology of schizophrenia. This article has employed quantitative morphometric techniques to determine whether abnormalities of posterior hippocampal cross-sectional area, as well as the number, size, and degree of disarray of pyramidal neurons were present in 9 control and 14 schizophrenic subjects. Seven schizophrenic patients showed evidence of superimposed mood disturbance (schizoaffective type), while the remaining seven were a mixture of paranoid, undifferentiated, and catatonic types. All morphometric measurements were conducted under strictly blind conditions; stepwise multiple regression and analyses of covariance were used to evaluate the effects of various confounding variables. There were no differences in the cross-sectional size of the hippocampus or degree of neuronal disarray between the two groups. Similarly, the number of pyramidal neurons was also the same in sectors Cornu Ammonis (CA) 2, CA 3, and CA 4 for the controls and schizophrenic subjects. In CA 1, the schizophrenic subjects without mood disturbances showed a significant reduction (36%) of pyramidal neuron numbers when compared with those of both controls and patients with mood disturbance. Pyramidal neurons were smaller in all sectors of the schizophrenic specimens, CA 1 (p less than or equal to 0.01), CA 2 (p less than or equal to 0.01), CA 3 (p less than or equal to 0.01), and CA 4 (p less than or equal to 0.005), but there were no differences with respect to the presence of mood disturbances. Corrections for the effects of age, postmortem interval, fixation interval, hypoxia, and neuroleptic exposure did not alter the pattern in the data. The significance of a smaller size of hippocampal pyramidal neurons in this group of schizophrenic specimens is unclear, but it is consistent with the suggestions of other laboratories that there may be altered function of this brain region in chronically psychotic individuals.

Affective Disorders, Psychotic↗

PubMed1991

Decreased neuronal and increased oligodendroglial densities in Huntington's disease caudate nucleus.

Decreased density of neurons was found throughout the head of the caudate nucleus in Huntington's disease (HD), with the most severe neuronal loss early in the disease in the medial region. The density of reactive astrocytes is inversely proportional to the neuronal loss. In cases of mild Huntington's disease which had no identifiable abnormality on conventional neuropathologic evaluation (grade 0), there is a reduction in neuron density without an accompanying reactive astrocytosis. The pattern for decrease in neurons and accompanying astrocytosis suggests that the earliest changes occur in the most medial portion of the head of the caudate nucleus and subsequently sweep laterally across the caudate nucleus to the internal capsule. An increased density of oligodendrocytes is observed in the head of the caudate nucleus for the lower grades (0, 1 and 2). The decreased neuronal and increased oligodendroglial densities may be of significance in understanding the pathogenesis of HD. These altered densities, observed in the absence of reactive astrocytosis, suggest that these changes may not represent recent effects of disease, but rather that HD gene expression may influence brain cell densities from early in the life of the gene carrier.

Aged↗

PubMed1991

Morphometric analysis of the prefrontal cortex in Huntington's disease.

We performed a morphometric analysis of cresyl violet-stained sections from the dorsolateral prefrontal cortex of 81 patients with Huntington's disease (HD) (grades 2, 3, and 4) and 23 age-matched normal controls. We counted large pyramidal neurons, small neurons, astrocytes, oligodendroglia, and microglia under the guidance of a specifically predefined set of morphologic criteria for each cell type and recorded the thickness of each cortical layer. Our results demonstrate a selective and progressive loss of a subset of the large pyramidal neurons in cortical layers III, V, and VI of HD patients, and a decrease in the thickness of the respective cortical laminae. A genetically determined, cell-autonomous degeneration of cortical neurons could constitute the primary pathologic process. However, the loss of only a fraction of pyramidal cells suggest a parallel, or an alternative, possibility of a retrograde degeneration of cortical neurons that project solely, or principally, to the site of primary degeneration in caudate nuclei.

Adult↗

PubMed1990

Basic fibroblast growth factor in Alzheimer's disease.

We have examined the presence of basic fibroblast growth factor (FGF) in normal and in Alzheimer brains, studied the distribution of the mitogen by immunohistochemical techniques, measured the quantities of growth factor in selected areas of the brain (Brodmann areas 10/11 and 20/21), characterized the molecular forms by Western blotting and determined its sites of synthesis by in situ hybridization. Although the same molecular forms of basic FGF are found in control and Alzheimer brains, basic FGF is increased in the brains of Alzheimer's patients. Furthermore, basic FGF is not distributed in an identical fashion to normal and Alzheimer brains, but is found in association with the lesions that characterize this disease. In normal controls (n = 5), basic FGF was found to be widely distributed throughout the three brain regions examined (prefrontal cortex, hippocampus, and hypothalamus). Immunoreactivity was observed within astrocytes in both the grey and white matter, as well as within neuronal perikarya. Brain tissues that were obtained from Alzheimer patients (N = 4) showed a substantial increase in the overall specific staining of astrocytes and neurons, particularly in areas of reactive gliosis. Focal concentration of immunoreactive basic FGF was evident within the neuritic plaques, and could be clearly seen in association with the neurofibrillary tangles present within neuronal perikarya. The possibility that basic FGF expression in the CNS is linked to the pathogenesis of the disease is discussed.

Alzheimer Disease↗

PubMed1990

Lysosomal proteinase antigens are prominently localized within senile plaques of Alzheimer's disease: evidence for a neuronal origin.

To investigate the role of proteolysis in amyloid formation, we studied the localization of the proteolytic enzymes, cathepsin D and cathepsin B, in the prefrontal cerebral cortex and hippocampus of human postmortem brains from patients with Alzheimer's disease and from individuals free of neurological disease. In control and Alzheimer brains, cathepsin immunoreactivity within cells was localized to lysosome-related structures, which were particularly abundant in neuronal perikarya. In Alzheimer brain, cathepsin immunoreactivity was also heavily concentrated extracellularly within senile plaques. Cathepsin immunoreactivity associated with plaques was not confined to lysosomes and was distributed throughout the plaque. Isolated amyloid cores, however, were not immunostained. Cathepsin-laden perikarya of degenerating neurons were frequently seen within senile plaques and, in the more advanced stages of degeneration, cathepsin immunoreactivity was present throughout the cytoplasm. Other identified constituents of senile plaques appeared to be less significant sources of cathepsin immunoreactivity, including astrocytes, degenerating neurites, microglia and macrophages. These results demonstrate that lysosomal proteinases are major constituents of the senile plaque and that degenerating neuronal perikarya are a principal source of the cathepsin immunoreactivity. We propose that the unregulated action of extracellular cathepsins liberated from degenerating neurons may lead to abnormal processing of the amyloid precursor protein and to the formation of amyloid locally within senile plaques in Alzheimer's disease.

Aged↗

PubMed1990

Laminar distributions of muscarinic acetylcholine, serotonin, GABA and opioid receptors in human posterior cingulate cortex.

Experimental animal studies have demonstrated a number of receptor localizations on specific cortical afferents and neurons. The present study of human posterior cingulate cortex evaluates the laminar distributions of particular receptors and their likely association with components of the neuropil. Coverslip autoradiographic and single grain counting techniques were used followed by heterogeneity analysis in which the layer of peak binding and an index of heterogeneity were determined for each ligand. The index was calculated by determining specific binding by layer as a percentage of binding in all layers. The differences from an absolutely homogeneous distribution, i.e. 11.1% for each of nine layers, were subtracted and the absolute laminar differences summed to form the index. High indices of over 15 reflected heterogeneous binding patterns in neocortex. The binding of ligands for muscarinic acetylcholine, serotonin, opioid, GABA and beta adrenoceptors was evaluated. Pirenzepine binding peaked in layer II of area 23a but was extremely homogeneous with an index of heterogeneity of 8.9. In contrast, oxotremorine-M binding had a peak in layer IIIc and an index of 16.4, while AF-DX 116 binding peaked in layer IIIa-b and had an index of 30.6. Of the ligands for serotonin uptake and receptor binding paroxetine binding was evenly distributed in layers I-III and had a low index of heterogeneity of 9.8. Ketanserin binding was also homogeneous and, since it had an index of 8.9, this pattern was virtually the same as that for paroxetine. In contrast, serotonin and 8-hydroxy-2-(di-n-propylamino)tetralin binding peaked in layer II and had very high indices of 20.8 and 50.3, respectively, suggesting only a limited association with that of the paroxetine distribution. Finally, there were three layers which contained peaks in binding for ligands for opioid, GABA and beta adrenoceptors. Firstly, layer Ia had peak dynorphin-A binding, the latter of which had an index of 22.6. Secondly, Tyr-D-Ala-Gly-MePhe-Gly-ol and 2-D-penicillamine-5-D-penicillamine-enkephalin binding peaked in layer II and had indices of 8.6 and 17.4, respectively. Thirdly, muscimol and (-)-cyanopindolol binding peaked in layer IIIa-b and had indices of 29.6 and 11.1, respectively. When viewed in the context of experimental animal studies, it is likely that heterogeneities in oxotremorine-M and paroxetine binding are associated with the termination of the thalamic and raphe nuclei, respectively. While serotonin 2 receptors are co-distributed with serotonin uptake sites, serotonin 1A receptors have a significant mismatch with these sites.(ABSTRACT TRUNCATED AT 400 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1990

Kynurenine pathway measurements in Huntington's disease striatum: evidence for reduced formation of kynurenic acid.

Recent evidence suggests that there may be overactivation of the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptors in Huntington's disease (HD). Tryptophan metabolism by the kynurenine pathway produces both quinolinic acid, an NMDA receptor agonist, and kynurenic acid, an NMDA receptor antagonist. In the present study, multiple components of the tyrosine and tryptophan metabolic pathways were quantified in postmortem putamen of 35 control and 30 HD patients, using HPLC with 16-sensor electrochemical detection. Consistent with previous reports in HD putamen, there were significant increases in 5-hydroxyindoleacetic acid, 5-hydroxytryptophan, and serotonin concentrations. Within the kynurenine pathway, the ratio of kynurenine to kynurenic acid was significantly (p less than 0.01) increased twofold in HD patients as compared with controls, consistent with reduced formation of kynurenic acid in HD. CSF concentrations of kynurenic acid were significantly reduced in HD patients as compared with controls and patients with other neurologic diseases. Because kynurenic acid is an endogenous inhibitor of excitatory neurotransmission and can block excitotoxic degeneration in vivo, a relative deficiency of this compound could directly contribute to neuronal degeneration in HD.

Aged↗

PubMed1985

The effects of a single acute dose of dexamethasone on monoamine and metabolite levels in rat brain.

Twenty male Sprague-Dawley rats were injected intraperitoneally with either 20 micrograms of dexamethasone or an equivalent volume of saline. The rats were then sacrificed at either one or four hours after the injections and their brains analyzed for monoamine and metabolite content using High Performance Liquid Chromatography with Electrochemical Detection. Significant effects were seen in dopaminergic and serotonergic systems, but these effects varied depending on the area of rat brain studied. Significant increases in dopamine (DA) levels were seen in the hypothalamus and nucleus accumbens of the dexamethasone treated rats when compared with saline treated rats. There was no significant effect of dexamethasone on DA levels in frontal or striatal brain areas. In the dexamethasone treated rats a significant increase in serotonin (5-HT) was observed in the hypothalamus; a significant decrease in 5-HT was observed in the frontal cortex. Biological and clinical implications of these findings are discussed.

3,4-Dihydroxyphenylacetic Acid↗