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Biomedical subjects

T L Perry

Publications and source records attributed to T L Perry.

At least 73 records · Page 4Linked to original sources
PubMed1984

Elevation of gamma-aminobutyric acid in human brain may increase dopaminergic neuronal function.

Studies in experimental animals have yielded conflicting findings as to the influence of gamma-aminobutyric acid (GABA) on the activity of nigrostriatal and mesolimbic dopaminergic neurons. We measured cerebrospinal fluid (CSF) concentrations of GABA and homovanillic acid (HVA) in 19 patients before and during treatment with isoniazid. CSF GABA concentrations increased markedly during isoniazid administration, presumably reflecting increases in brain GABA content. At the same time, HVA concentrations in CSF rose significantly. The net effect of elevating brain GABA content in humans appears to be to increase dopamine release from dopaminergic neurons.

Brain↗
PubMed1984

Benzodiazepine receptor binding in cerebellar cortex: observations in olivopontocerebellar atrophy.

Benzodiazepine receptor binding was measured in cerebellar cortex of 15 patients with dominantly inherited olivopontocerebellar atrophy (OPCA). The majority of these patients had a moderate to marked Purkinje cell loss, as judged by the lowered levels of dentate nucleus gamma-aminobutyric acid (GABA), a marker of Purkinje cells. Despite the reduction in Purkinje cell number cerebellar cortical benzodiazepine receptor density was either normal or slightly elevated in the OPCA patients. These results are in contrast to the findings in a mutant strain of mice deficient in Purkinje cells in which the concentration of benzodiazepine receptors in cerebellum is greatly reduced. Our data indicate that in the human, cerebellar cortical benzodiazepine receptors are either not significantly associated with Purkinje cells or that in OPCA Purkinje cell loss triggers a de novo synthesis of extra benzodiazepine binding sites. It is concluded that, in contrast with the rodent, in the human benzodiazepine receptor binding may not serve as a marker for cerebellar Purkinje cells.

Atrophy↗
PubMed1984

Nigrostriatal dopaminergic neurons remain undamaged in rats given high doses of L-DOPA and carbidopa chronically.

Rats were fed maximally tolerated doses of L-3,4-Dihydroxyphenylalanine (L-DOPA) and carbidopa daily for 120 days in order to achieve a sustained elevation in brain dopamine levels. Some animals were also given buthionine sulfoximine, a gamma-glutamylcysteine synthetase inhibitor, in an unsuccessful effort to reduce brain glutathione contents. L-DOPA- and carbidopa-treated animals displayed no behavioral changes suggestive of nigrostriatal dopaminergic neuronal loss. When sacrificed 60 days after L-DOPA treatment ended, all rats had normal tyrosine hydroxylase activities and dopamine contents in their striata, and cell counts were normal in the substantia nigra. It therefore seems unlikely that a model of Parkinson's disease, suitable for exploring the etiological importance of glutathione deficiency, can be produced in rats merely by administering the largest tolerable doses of L-DOPA.

Animals↗
PubMed1984

Tyrosinemia and intractable seizures.

A child with intractable seizures from the age of 10 months and developmental retardation developed jaundice and hepatosplenomegaly at 23 months. She died at the age of 25 months. Methionine and tyrosine were elevated in urine, plasma, CSF, and brain. These elevations were more marked in the CNS than in the blood. 4-Hydroxyphenylpyruvate dioxygenase, an enzyme involved in the metabolism of tyrosine, was undetectable in skin fibroblasts and liver. This finding together with other biochemical data suggest that our case had an inherited disorder of tyrosine metabolism, in the category of tyrosinemia I. Disturbances of tyrosine and methionine metabolism in the CNS in tyrosinemia I may be more important than has been realized. The disorder should be considered in children with unexplained epilepsy and in those who develop hepatic dysfunction while on anticonvulsants.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed1984

Neurochemical abnormalities in a patient with ataxia-telangiectasia.

We describe biochemical abnormalities found in autopsied brain of a patient with ataxia-telangiectasia. Neuropathologic changes were limited to the cerebellum and spinal cord. The atrophic cerebellum showed marked loss of Purkinje's and granule cells, and moderate loss of stellate and basket cells. Glutamic acid content was markedly reduced, and taurine content somewhat reduced in the cerebellar cortex, while gamma-aminobutyric acid (GABA) content was greatly reduced in the dentate nucleus. GABA receptor binding was reduced by 70% in cerebellar cortex. Phosphoethanolamine content was greatly reduced in the cerebellar cortex and inferior olivary nucleus. This compound was also deficient in 10 other brain regions and was the only extracerebellar neurochemical abnormality observed.

Ataxia Telangiectasia↗
PubMed1983

Increased GABA receptor binding in dominantly-inherited cerebellar ataxias.

We measured gamma-aminobutyric acid (GABA) receptor binding in the cerebellar cortex of 14 patients with dominantly-inherited cerebellar ataxias. Most of these patients had moderate to marked Purkinje cell loss as judged from the subnormal dentate nucleus GABA levels. Mean GABA receptor binding (at 25 nM GABA concentration) was elevated significantly by 37% in the total group of 14 patients studied and by 60% in the largest subgroup (n=6) analyzed. Possible explanations for the enhanced binding include glial proliferation, exposure of normally unexposed receptor sites consequent to neuronal degeneration, and/or denervation supersensitivity.

Cerebellar Ataxia↗
PubMed1983

Neuronal [3H]benzodiazepine binding and levels of GABA, glutamate, and taurine are normal in Huntington's disease cerebellum.

Alterations in one subunit of the proposed GABA receptor complex, namely, the GABA receptor, have been observed in Huntington's disease cerebellum. We measured binding to a second subunit, the benzodiazepine binding site, in the autopsied cerebellum of 12 patients dying with adult-onset Huntington's disease. Neuronal benzodiazepine ([3H]flunitrazepam) binding density (Bmax) and affinity in cerebellar cortex of the Huntington's disease patients were not significantly different from control values. Similarly, maximal GABA stimulation of benzodiazepine binding was normal in the Huntington's disease cerebellum. In addition, no significant changes were observed in the concentrations of GABA, glutamate, and taurine in cerebellar cortex, nor of GABA in the dentate nucleus.

Amino Acids↗
PubMed1983

Striatal GABAergic neuronal activity is not reduced in Parkinson's disease.

The content of gamma-aminobutyric acid (GABA) and the activities of glutamic acid decarboxylase (GAD) and tyrosine hydroxylase (TH) were measured in whole putamen obtained at autopsy from 13 patients dying with idiopathic Parkinson's disease and 13 appropriate control subjects. Mean GABA content was significantly elevated (by 28%) in the putamen of the Parkinson's disease patients. TH activity was markedly reduced, while there was no significant reduction of GAD activity in the putamen of these patients. GABA content was also measured in both sides of the striatum in rats which had received unilateral injections of 6-hydroxydopamine (6-OHDA) in the vicinity of the axons of the nigrostriatal projection. Mean GABA content was found significantly elevated (by 33%) in the ipsilateral striatum. Loss of dopaminergic nigrostriatal neurons, in both human Parkinson's disease and in the rat 6-OHDA model, is accompanied by increased striatal GABA content. The assumption that GABAergic neurotransmission is reduced in the striatum in Parkinson's disease may not be correct.

Amino Acids↗
PubMed1983

Hyperasparaginemia in a schizophrenic patient.

A man with a chronic schizophrenia-like psychotic disorder had fasting plasma asparagine concentrations that were consistently 4 to 8 SD above the normal level. Asparagine levels were also high in his cerebrospinal fluid (CSF) and erythrocytes. Ornithine, proline, and glutamate concentrations were irregularly high in fasting plasma, and gamma-aminobutyric acid (GABA) concentrations were elevated in CSF. Whether or not these biochemical abnormalities were related to the psychotic disorder is unclear. However, increased asparagine concentrations, possibly due to an enzymatic deficiency of asparaginase, could lead to deregulation of polyamine biosynthesis and to excessive production of GABA from putrescine. These biochemical changes could in turn cause disordered brain function. A search in mentally ill patients for metabolic abnormalities involving asparagine, or other amino acids, might hasten elucidation of the biochemical basis of the schizophrenias.

Adult↗
PubMed1982

Parkinson's disease: a disorder due to nigral glutathione deficiency?

Amino acid analysis of autopsied human brain showed reduced glutathione (GSH) content significantly lower in the substantia nigra than in other brain regions. GSH was virtually absent in the nigra of patients with Parkinson's disease. Oxidative degradation of L-DOPA and dopamine in vivo may generate reactive oxygen species (hydrogen peroxide, superoxide, hydroxyl radical, or singlet oxygen) which can damage membranes and other cellular components. Since GSH is an important natural antioxidant, a deficiency of GSH in the substantia nigra could make this region vulnerable to oxidative injury. If confirmed, the hypothesis that loss of nigrostriatal dopaminergic neurons results from a regional GSH deficiency could have important therapeutic implications for the management and prevention of Parkinson's disease.

Adult↗
PubMed1982

Normal cerebrospinal fluid and brain glutamate levels in schizophrenia do not support the hypothesis of glutamatergic neuronal dysfunction.

A recently proposed hypothesis to explain schizophrenia is based on reports of reduced concentrations of glutamic acid in the cerebrospinal fluid (CFS) of schizophrenic patients. This hypothesis suggests that there may be a dysfunction of glutamatergic neurons in schizophrenia, with either a degeneration of these neurons, or their failure to release glutamate as a neurotransmitter. Direct measurement of glutamate levels in CSF and autopsied brain of schizophrenic patient showed no differences from glutamate levels in suitable adult control subjects. The data presented here do not offer support for the new hypothesis.

Adult↗
PubMed1982

Human CSF GABA concentrations: revised downward for controls, but not decreased in Huntington's chorea.

gamma-Aminobutyric acid (GABA) concentrations were measured in CSF specimens from two large groups of control subjects, one without neurological or psychiatric disease, and one with a variety of neurological disorders not known to involve altered GABAergic function in brain. CSF GABA was also measured in patients with Huntington's chorea and in patients with other choreiform disorders. GABA was measured in CSF by a modification of the ion exchange-fluorometric method that featured use of a relatively large cation exchange column, and a markedly decreased quantity of sulfosalicylic acid for deproteinization of CSF. Mean BABA concentrations in CSF were 87 and 77 nmol/liter for neurologically normal and abnormal control subjects, 82 nmol/liter for the Huntington's chorea patients, and 105 nmol/liter for patients with other forms of chorea. The mean concentration of homocarnosine was not reduced in CSF of Huntington's chorea patients as compared with controls. Mean CSF GABA concentrations found in control subjects were less than half the lowest control means previously reported. These low values are attributable in part to a reduction in on-column hydrolysis of conjugated forms of GABA in CSF, which can be produced by excessive sulfosalicylic acid, and in part to improved chromatographic resolution of GABA from other unknown o-phthalaldehyde-reactive compounds in CSF. Analysis of free GABA in CSF does not appear useful for diagnosis of suspected Huntington's chorea, nor as a possible predictive test for persons genetically at risk for Huntington's chorea.

Carbon Radioisotopes↗
PubMed1982

Concentrations of GABA and other amino acids in CSF from torsion dystonia patients.

Free amino acid concentrations were measured by conventional amino acid analysis, and gamma-aminobutyric acid (GABA) concentrations were determined, by an ion-exchange fluorometric technique, in CSF specimens from 16 patients with torsion dystonias and in CSF from a large number of control subjects. The mean CSF GABA concentration of the dystonia patients (97 +/- 11 nmol/L) did not differ significantly from the means for CSF GABA in two groups of adult control subjects. Mean concentrations of all commonly determined amino compounds were normal in the CSF of torsion dystonia patients, except for ornithine, which was modestly but significantly reduced.

Adolescent↗
PubMed1982

A double-blind clinical trial of isoniazid in Huntington disease.

Isoniazid (INH) was given to nine patients with Huntington disease (HD) in a double-blind, placebo-controlled crossover trial. In an earlier open trial, three of six patients had improved, and one of them remained improved after 7 years on INH. Only one patient benefited in the present trial. All patients excreted small amounts of hydrazine in their urine while taking INH, and it is this INH metabolic that elevates GABA content in brain. GABA concentrations were markedly increased in CSF during INH therapy. Lack of clinical improvement in most HD patients despite elevation of brain GABA content suggests that in the minority who are benefited, INH may be acting by some mechanism other than increase of GABAergic neuronal function.

Adult↗
PubMed1981

Cystinylglycine in plasma: diagnostic relevance for pyroglutamic acidemia, homocystinuria, and phenylketonuria.

Cystinylglycine, recently identified as a normal small peptide in human plasma, has diagnostic importance for several genetically determined disorders. We found cystinylglycine absent from the plasma of a patient with pyroglutamic acidemia, and the peptide was either absent or greatly reduced in plasma from patients with homosyctinuria. In the latter disorder, a different small peptide replaced cystinylglycine. It was identified as the mixed disulfide of homocysteine and cysteinylglycine. The mean plasma concentration of cystinylglycine was 13.6 +/- 3.6 mumol/l in adult control subjects, and concentrations of the mixed disulfide of homocysteine and cysteinylglycine varied between 2 and 10 mumol/l in the plasma of homocystinuric patients. Failure to separate cystinylglycine from phenylalanine with many rapid amino acid analyzer systems can lead to a misclassification of persons as heterozygotes for the phenylketonuria gene when heterozygosity testing is based on the phenylalanine/tyrosine molar ratio in fasting plasma.

Autoanalysis↗
PubMed1981

Mild elevations of plasma ornithine in homocystinuria.

Hyperornithinemia was found on many occasions during monitoring of amino acids in the fasting plasma of homocystinuric patients. Ornithine concentrations were elevated 2- to 3-fold above the normal mean value. Hyperornithinemia was of much less marked degree than that seen in gyrate atrophy of the choroid and retina, and was not accompanied by overflow ornithinuria or hypolysinemia. Elevations in plasma ornithine concentrations in homocystinuric patients were generally proportional to elevations in the plasma concentration of homocystine, but not that of methionine.

Adolescent↗