Biomedical subjects

E D Bird

Publications and source records attributed to E D Bird.

At least 55 records · Page 3Linked to original sources

PubMed1988

Amino acid and neuropeptide neurotransmitters in Huntington's disease cerebellum.

Several neuropathologic studies have suggested that there may be pathologic involvement of the cerebellum in Huntington's disease (HD). To investigate this further, we measured concentrations of neurotransmitter amino acids and the neuropeptides, somatostatin, neuropeptide Y and substance P, in HD cerebellar cortex and dentate nucleus. Twenty-seven pathologically confirmed cases of HD were compared with 20 controls. There were no significant changes in concentrations were significantly increased by 21% in HD cerebellar cortex. In the dentate nucleus, there were small significant increases of neuropeptide Y-like immunoreactivity and substance P-like immunoreactivity. The meaning of the neurotransmitter changes found is unclear: however, the lack of change in GABA and glutamate concentrations argues against a substantial loss of intrinsic cerebellar neurons.

Aged↗

PubMed1988

Predictive testing for Huntington's disease with use of a linked DNA marker.

The probability of carrying the gene for Huntington's disease can in many cases be estimated in the children of affected persons by identifying a specific DNA marker that is genetically linked to the gene. We studied 47 persons at 50 percent risk of inheriting Huntington's disease who requested a presymptomatic or prenatal genetic-linkage test between September 1986 and January 1988. The participants were given pre-test counseling and psychological and neurologic evaluations. Nineteen persons later voluntarily withdrew from the protocol, including one who would have been excluded anyway, and one person was from a family that was too small to allow testing. Three D4S10 restriction-fragment-length polymorphisms produced by the HindIII, EcoRI, and Bg/I enzymes were used for all tests, and the probability that a subject was a Huntington's disease carrier was calculated. The accuracy of the test was compromised by a 4 percent recombination frequency between D4S10 and the Huntington's disease gene. Fifteen presymptomatic tests and one prenatal test were completed. Four yielded positive results, seven yielded negative results, and five were uninformative; seven persons are awaiting test results. All participants with positive tests experienced intermittent depression, but none required hospitalization, and no suicide threats were reported. Five participants received a diagnosis of Huntington's disease on the basis of the neurologic assessment. We conclude that some persons in the early stages of Huntington's disease may seek presymptomatic testing rather than neurologic evaluations.

Adult↗

PubMed1988

Somatostatin and neuropeptide Y concentrations in pathologically graded cases of Huntington's disease.

Somatostatin and neuropeptide Y concentrations have previously been reported to be increased in the basal ganglia in Huntington's disease (HD). In the present study we have extended these findings by examining both somatostatin-like immunoreactivity (SLI) and neuropeptide Y-like immunoreactivity (NPYLI) in cases of HD, which were graded according to the severity of pathological degeneration in the striatum. In addition, we surveyed a large number of subcortical nuclei and cortical regions for alterations. Both SLI and NPYLI were significantly increased about threefold in the caudate, putamen, and the nucleus accumbens. Increases in mild and severe grades were similar, which is consistent with a relative but not absolute sparing of striatal aspiny neurons in which somatostatin and neuropeptide Y are colocalized. Significant increases of NPYLI were also found in the external pallidum, subthalamic nucleus, substantia nigra compacta, claustrum, anterior and dorsomedial thalamus, bed nucleus of the stria terminalis, and locus ceruleus. SLI was significantly increased in the external pallidum, red nucleus, and locus ceruleus. Measurements of both neuropeptides were made in 24 regions of the cerebral cortex. Significant increases in both NPYLI and SLI were found in the frontal cortex (Brodmann areas 6, 8, 9, 10, 11, and 45) and temporal cortex (Brodmann area 21), whereas NPYLI was also increased in Brodmann areas 12, 20-22, 25, and 42. Alterations in the cerebral cortex were as pronounced in cases with mild striatal pathological changes as in those with severe striatal pathological changes. These alterations may occur early in HD and could reflect a selective sparing of somatostatin-neuropeptide Y cortical neurons combined with cortical atrophy.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1988

A detailed examination of substance P in pathologically graded cases of Huntington's disease.

Substance P concentrations have been found to be reduced in the basal ganglia in Huntington's disease (HD). In order to further examine this finding in the present study we measured substance P-like immunoreactivity (SPLI) in cases of HD which had been graded as to the severity of pathological changes in the striatum. Marked significant reductions of SPLI were found in all striatal nuclei which were significantly correlated with the percentage of neuronal loss in the varying pathologic grades. Similar changes were found in the projection sites of striatal substance P neurons, the globus pallidus interna and the substantia nigra. These changes are consistent with a loss of striatal substance P containing projection neurons in HD. Significant reductions in SPLI were also found in the external pallidum, bed nucleus of the stria terminalis and the subthalamic nucleus. Small significant increases in SPLI (20-30%) were found in 3 frontal cortical regions (Brodmann areas 6, 8 and 9). The finding of neurochemical changes in the subthalamic nucleus is of particular interest since lesions in this nucleus are known to result in chorea and therefore might contribute to the chorea which is a cardinal symptom of HD.

Aged↗

PubMed1988

Receptor affinity, neurochemistry and behavioral characteristics of the enantiomers of thioridazine: evidence for different stereoselectivities at D1 and D2 receptors in rat brain.

The binding characteristics of the enantiomers of thioridazine were assessed in the brain of the rat using competitive radioreceptor assays with tritiated ligands selective for dopamine D1 (SCH-23390), D2 (spiperone), norepinephrine alpha-1 (prazosin) and muscarinic (quinuclinidinyl benzilate) receptors. (+)-Thioridazine was shown to have 2.7 and 4.5 times higher affinity than (-)-thioridazine for D2 and alpha-1 receptors, respectively. In contrast, (-)-thioridazine had 10 times higher affinity for the D1 receptor. Both enantiomers showed similar affinities for the muscarinic receptor. In a second experiment, thioridazine, dopamine, norepinephrine, serotonin and their metabolites were assayed in the brain of the rat after acute administration of the enantiomers of thioridazine and the assessment of catalepsy. (+)-Thioridazine was 4.1 times as potent as (-)-thioridazine in elevating the turnover of dopamine in the striatum, but neither enantiomer affected the other monoamines. The concentration of thioridazine and its metabolites in the brain, for a given dose, was similar for both enantiomers. (-)-Thioridazine induced slightly more catalepsy than (+)-thioridazine and appeared to be more toxic at large doses. While racemic thioridazine had an intermediate effect between that of its two enantiomers in the binding and neurochemical assays, it appeared to induce more catalepsy than either enantiomer, suggesting a synergistic effect in this behavioral assay. It was concluded that (+)- and (-)-thioridazine act as partially selective D2 and D1 antagonists, respectively. Therefore, clinical administration of only one enantiomer of thioridazine, rather than the currently prescribed racemate, may result in an improved therapeutic profile and so be worthy of further investigation.

Animals↗

PubMed1988

Concentration and distribution of thioridazine and metabolites in schizophrenic post-mortem brain tissue.

Thioridazine (THD) and its major metabolites, mesoridazine (MES), sulforidazine (SULF), and northioridazine (norTHD) accumulate at a predictable rate in human brain tissue after chronic medication. Although the concentration of THD is normally lower than or the same as its major metabolite, MES, in the plasma, it was found to be up to five times as concentrated in the brain tissue of treated patients. THD and its metabolites were evenly distributed throughout all regions of the brain in chronically medicated patients. Brain concentrations of THD were also compared with those of chlorpromazine (CPZ) when both drugs had been given at the same dose before death, and were shown to be up to 10 times more concentrated in brain at doses greater than 300 mg/day. Because some of the metabolites of THD are pharmacologically active, it is important to know how they accumulate in the brain in relation to the parent compound to understand how this drug mediates its clinical effect.

Aged↗

PubMed1988

Growth-associated protein GAP-43 is expressed selectively in associative regions of the adult human brain.

GAP-43 is a neuron-specific phosphoprotein that has been linked with the development and functional modulation of synaptic relationships. cDNAs for the human GAP-43 gene were used to reveal high overall levels of GAP-43 mRNA in a number of integrative areas of the neocortex, but low levels in cortical areas involved in the initial processing of sensory information, in several brainstem structures, and in caudate-putamen. Neurons expressing highest levels of GAP-43 mRNA were found by in situ hybridization to be concentrated in layer 2 of association cortex and in hippocampal pyramidal cells. Control studies showed that several other RNAs had regional distributions that were different from GAP-43, although the mRNA encoding the precursor of the Alzheimer amyloid beta protein followed a similar pattern of expression. These results suggest that a restricted subset of cortical and hippocampal neurons may be specialized for synaptic remodeling and might play a role in information storage in the human brain.

Association Learning↗

PubMed1988

3-Hydroxyanthranilate oxygenase activity is increased in the brains of Huntington disease victims.

An excess of the tryptophan metabolite quinolinic acid in the brain has been hypothetically related to the pathogenesis of Huntington disease. Quinolinate's immediate biosynthetic enzyme, 3-hydroxyanthranilate oxygenase (EC 1.13.11.6), has now been detected in human brain tissue. The activity of 3-hydroxyanthranilate oxygenase is increased in Huntington disease brains as compared to control brains. The increment is particularly pronounced in the striatum, which is known to exhibit the most prominent nerve-cell loss in Huntington disease. Thus, the Huntington disease brain has a disproportionately high capability to produce the endogenous "excitotoxin" quinolinic acid. This finding may be of relevance for clinical, neuropathologic, and biochemical features associated with Huntington disease.

3-Hydroxyanthranilate 3,4-Dioxygenase↗

PubMed1988

Clinical and neuropathologic assessment of severity in Huntington's disease.

Clinical records were evaluated for 163 Huntington's disease patients in whom postmortem brain specimens had been graded for degree of neuropathologic involvement in the striatum. Juvenile/adolescent onset (4 to 19 years of age) was associated with very severe neuropathologic involvement produced by an apparent rapid degenerative process. Cases of early (20 to 34 years) and midlife (35 to 49 years) onset had respectively less severe striatal involvement, suggesting a slower degenerative progression. High correlations among the grade of neuropathologic involvement, cell counts of neurons, and a rating of physical disability suggest that each represents a common underlying degenerative process of the disease. The relationship between the age at onset and the extent of neuropathologic involvement suggests that a single mechanism may determine both onset and rate of degenerative disease progression.

Aging↗

PubMed1987

The amyloid beta protein gene is not duplicated in brains from patients with Alzheimer's disease.

Complementary DNAs (cDNAs) encoding portions of the amyloid beta protein were used to investigate possible amyloid gene duplication in sporadic Alzheimer's disease. A strategy employing two Eco RI restriction fragment length polymorphisms (RFLPs) detected by the amyloid cDNAs was used. RFLPs allow the detection of a 2:1 gene dosage in the DNA of any individual who is heterozygous for a particular RFLP. The amyloid gene regions homologous to the cDNAs used were not duplicated in the DNA from brains of individuals with sporadic Alzheimer's disease. Similar results were also obtained with a strategy employing a test for 3:2 gene dosage.

Alleles↗

PubMed1987

EC array sensor concepts and data.

The use of multiple parameter assays of entire metabolic pathways is potentially a powerful tool for unraveling mechanisms of disorders or drug action and classification of neurological diseases. Coulometric electrode series array sensors, coupled with liquid chromatography (n-ELC), provide a route to multiplying the resolving power of conventional LC by factors of 10 to 50. Since the original description of the n-ELC concept by Matson et al. (1), fundamental issues of optimizing sensor design and integration with computer controlled LC systems have been addressed. Femtogram level potential time (ET) separations can now be performed for multiple components in both isocratic and gradient modes. A 56-component isocratic method for the study of the kynurenine system in Huntington's Disease (HD) is presented as an indication of the analytical definitions and nomenclature used to qualify an n-ELC procedure, and an indication of the implications of multiparameter data bases on data handling and experimental design.

Amino Acids↗

PubMed1987

An analysis of the arrangement of neurons in the cingulate cortex of schizophrenic patients.

A series of computer-assisted stereomorphometric analyses of the spatial arrangements of neurons and glia in postmortem cerebral cortex specimens has been developed and applied to both control subjects and schizophrenic patients. The data suggest that the anterior cingulate cortex of schizophrenic patients may contain domains or aggregates of neurons, particularly in layer II, which are smaller in size and separated by wider distances than those observed in the control group. Verification of the inferences made from the computer-generated data has been obtained by direct microscopic visualization and measurement of neuronal aggregates of layer II in Nissl-stained cingulate specimens from the control and schizophrenic groups. Statistical correction of the data, using multivariate statistics, for effects of age, hypoxia, postmortem interval, fixation, and neuroleptic exposure does not eliminate the differences in size and separation of neuronal aggregates in layer II of schizophrenic patients. The possible relevance of these findings to our understanding of schizophrenic symptomatology is discussed.

Aged↗

PubMed1987

Increased vertical axon numbers in cingulate cortex of schizophrenics.

Data generated from an earlier study have suggested a model in which greater numbers of long, vertical, associative axons may occur in the anterior cingulate cortex of schizophrenic patients relative to control subjects. This hypothesis has now been tested using neuron-specific antibodies raised against the 200-kilodalton neurofilament subunit, a component of neuronal cytoskeleton, to immunostain axons of human postmortem cingulate cortex. A manual method for counting axons in the region of layer II and sublamina IIIA has been designed and applied blindly to parallel control and schizophrenic immunoprocessed specimens. The results show that there are 25% more vertical axons in the schizophrenic than in the control specimens. Preferentially higher numbers of both long vertical axons (62%) and axons associated with blood vessels (52%) have also been noted in the schizophrenic specimens. By contrast, the number of large-caliber horizontal axons was the same in the two groups; therefore, the greater number of vertical axons in schizophrenic specimens does not appear to represent a nonspecific effect. When these data are corrected for the effects of several confounding variables using analysis of covariance, the overall pattern of the results persists. These findings suggest the possibility that there might be an increase of associative inputs into the anterior cingulate cortex of schizophrenic patients, although it is not clear at present whether the differences noted, if replicative, may be primarily or perhaps only secondarily related to the disorder.

Axons↗

PubMed1987

Human brain dopamine receptors in children and aging adults.

Since spontaneous oral dyskinesias are more prevalent in the elderly, and since these movements may be controlled by the balance of brain dopamine D1 and D2 dopamine receptors, we measured the densities of these receptors in 247 postmortem brain striata. In childhood, the densities of D1 and D2 dopamine receptors in the brain striatum rise and fall together. After age 20 years, D1 receptors disappear at 3.2% per decade while D2 receptors disappear at about 2.2% per decade. Overall, therefore, the D1/D2 ratio falls with age. Since perioral motion in rats is dominated by a high D1/D2 ratio, the observed decline in the human D1/D2 ratio with age suggests that the perioral control mechanisms for humans and rats may be different.

Aged↗

PubMed1987

Somatostatin and neuropeptide Y are unaltered in the amygdala in schizophrenia.

Although a biochemical abnormality has been postulated in the etiology of schizophrenia, evidence supporting this hypothesis has been conflicting. Because of the presence of somatostatin-like immunoreactivity (SLI) in limbic system nuclei of the brain, we examined postmortem concentrations of SLI in patients dying with schizophrenia and in normal controls. Concentrations of SLI in Brodmann cortical area 38, hippocampus, caudate, putamen, nucleus accumbens, and both segments of the globus pallidus were not significantly different from controls. In addition, we examined both SLI and neuropeptide-Y-like immunoreactivity (NPYLI) in subnuclei of the amygdala and the substantia innominata. There were no significant alterations in either neuropeptide as compared with controls.

Amygdala↗

PubMed1987

Human brain D1 and D2 dopamine receptors in schizophrenia, Alzheimer's, Parkinson's, and Huntington's diseases.

Because dopamine D2 receptors are known to be elevated in schizophrenic brain striata, this study examined whether a similar dopamine receptor elevation occurred in other diseases including neuroleptic-treated Alzheimer's and Huntington's diseases. The average D1 density in postmortem striata from Alzheimer's patients was 17.6 +/- 0.1 pmol/g, similar to an age-matched control density of 16.6 +/- 0.4 pmol/g. The average D1 density in schizophrenia patients was 19.0 +/- 0.6 pmol/g, similar to the age-matched control density of 17.9 +/- 0.6 pmol/g. In Parkinson's disease patients, however, the D1 receptor density was elevated, with values of 22.8 +/- 1.2 pmol/g (in patients not receiving L-DOPA) and 19.6 +/- 1.5 pmol/g (in patients receiving L-DOPA) compared to the age-matched control density of 16.0 +/- 0.4 pmol/g. The D2 receptors in Alzheimer's striata averaged 13.4 +/- 0.6 pmol/g (in patients who had not received neuroleptics), almost identical to the control density of 12.7 +/- 0.3 pmol/g. The average D2 density in neuroleptic-treated Alzheimer's striata was 16.7 +/- 0.7 pmol/g, an elevation of 31%, the individual values of which had a normal distribution. In Parkinson's disease patients, the D2 densities were elevated in tissues from patients not receiving L-DOPA (19.9 +/- 1.5 pmol/g in putamen and 14.8 +/- 1.2 pmol/g in striatum) compared to the age-matched control values of 13.0 +/- 0.4 pmol/g and 12.6 +/- 0.3 pmol/g, respectively. In Huntington's disease patients, the D2 density averaged 7.5 +/- 0.4 pmol/g in patients who had not received neuroleptics, but was 10.3 +/- 0.6 pmol/g in those who had. Although all of the D1 and D2 densities in each of the above diseases and subgroups revealed a normal distribution pattern, the D2 densities in schizophrenia displayed a bimodal distribution pattern, with 48 striata having a mode at 14 pmol/g, and the other 44 striata having a mode at 26 pmol/g. Thus, compared to the neuroleptic-induced and unimodal elevations in D2 of 31% in Alzheimer's disease and 37% in Huntington's disease, the schizophrenic striata with a mode of 26 pmol/g (105% above control) appear to contain more D2 receptors than can be accounted for by the neuroleptic administration alone.

Adult↗

PubMed1987

Amino acid neurotransmitter abnormalities in Huntington's disease and the quinolinic acid animal model of Huntington's disease.

Concentrations of gamma-aminobutyric acid (GABA), glutamate, aspartate, and taurine were measured in postmortem tissue from the brains of patients with Huntington's disease (HD) and in the quinolinic acid (QA) lesioned rat striatum. The aim of the study was to assess further the ability of the QA model of HD to reproduce the neurochemical features of the disease. Nine cortical and 9 subcortical regions were examined from 17 pathologically graded cases of HD and 10 controls. Significant reductions in both GABA and glutamate were found in HD striatum. The reductions were greater in the more severely affected grades of HD, and there was a gradient of amino acid loss across the striatal nuclei (caudate greater than putamen greater than nucleus accumbens) which was consistent with the known pattern of pathological involvement. Taurine and aspartate concentrations showed no significant change. GABA reductions were found in both segments of the globus pallidus (external greater than internal) and both parts of the substantia nigra (reticulata greater than compacta). In advanced cases of HD, there were significant reductions in glutamate in Brodmann cortical areas 3-1-2, 6, 9, and 17, but GABA, aspartate, and taurine were unaltered in the cortex. The QA lesions reproduced the striatal deficits of both GABA and glutamate but, in contrast to HD, there was a decrease in taurine, possibly due to species differences. Chronic QA lesions resulted in a secondary dying back of corticostriatal glutamatergic terminals, but did not produce a change in cortical glutamate concentration. This suggests that reductions in cortical glutamate in HD may reflect a primary loss of glutamatergic neurons. Our findings extend previous observations on amino acid neurotransmitters in HD and, with the exception of taurine, confirm the general applicability of the QA model.

Amino Acids↗

PubMed1987

Morphologic and histochemical characteristics of a spared subset of striatal neurons in Huntington's disease.

We have previously found that a biochemically distinct subset of neurons, containing nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d), is selectively resistant to the degenerative process that affects the striatum in Huntington's disease (HD). We report the morphologic and histochemical characteristics of these striatal neurons and their distribution with respect to the histochemical compartments as defined by acetylcholinesterase (AChE) activity. Sections of striatum were stained histochemically for NADPH-d and AChE and immunocytochemically for somatostatin and neuropeptide Y-like immunoreactivity. The diaphorase end-product was contained within medium-sized neurons which corresponded morphologically to a category of aspiny interneurons. Combined techniques showed that NADPH-d, somatostatin, and neuropeptide Y coexisted within the same neurons in controls and patients with HD. The density of these neurons was greater in the ventral putamen and the nucleus accumbens than in the remainder of the striatum. The distinctive AChE pattern of high and low enzyme activity was altered in HD. The AChE-rich matrix zone was markedly reduced in size, while the total area of zones of low enzyme activity was not different from that found in control striatum. The relation between these AChE chemical compartments and the distribution of preserved diaphorase neurons remained intact; NADPH-d neurons were predominantly observed in the matrix zone.

Acetylcholinesterase↗