Biomedical subjects

T L Perry

Publications and source records attributed to T L Perry.

At least 37 records · Page 2Linked to original sources

PubMed1990

What excitotoxin kills striatal neurons in Huntington's disease? Clues from neurochemical studies.

Amino acid analyses of both caudate nucleus and putamen obtained at autopsy from patients dying with Huntington's disease (HD), and from control subjects, showed significantly decreased mean glutamate contents in the HD patients. In addition, the mean glutamate concentration was significantly increased in the CSF of living HD patients as compared with controls. Neurochemical studies also showed that neither aspartic acid, proline, 5-oxoproline, nor homocysteic acid is likely to act as a causative excitotoxin in HD. Excessive striatal glycine content, or deficient glutathione content, is unlikely to contribute to the effects of a causative excitotoxin in HD. We suggest that glutamic acid may be the proximate causative neurotoxin in the striatum in HD, as a result of an unexplained failure in the reuptake mechanism for glutamate released there as an excitatory neurotransmitter.

Adult↗

PubMed1990

Dominantly inherited apathy, central hypoventilation, and Parkinson's syndrome: clinical, biochemical, and neuropathologic studies of 2 new cases.

We describe 2 new patients from a family in which 10 persons in 3 successive generations had a dominant neuropsychiatric disorder characterized by apathy, central hypoventilation, and parkinsonism. Neuropathologically, both patients showed severe neuronal loss and reactive gliosis in the substantia nigra. Neurochemical studies showed a marked depletion of dopamine in substantia nigra, putamen, and caudate nucleus, as well as reduction in serotonin content in the substantia nigra. Glutamate contents were low in frontal cortex and thalamus, and gamma-aminobutyric acid (GABA) contents were low in thalamus and substantia nigra of both patients. In addition, phosphoethanolamine contents were reduced in all brain regions of both patients, especially in the substantia nigra. One patient with severe symptoms had low levels of homovanillic acid, 5-hydroxyindoleacetic acid, and GABA in his CSF repeatedly for 3 years before death (aged 58), while the 2nd patient died (aged 51) of an unrelated cause before developing any symptoms of the familial disorder. Because brain deficiencies of multiple neurotransmitters appear to be involved, this disorder is unlikely to respond to treatment; however, neurochemical studies of CSF may make presymptomatic diagnosis feasible.

Adult↗

PubMed1989

Schizophrenia, tardive dyskinesia, and brain GABA.

We measured the contents of gamma-aminobutyric acid (GABA) and of other amino compounds in five regions of autopsied brain from 18 patients with schizophrenia and from a large group of adult control subjects dying without any neurological or psychiatric disorder. In addition, concentrations of GABA were measured in the cerebrospinal fluid (CSF) of living schizophrenic patients and control subjects. No deficiency of GABA was found in the frontal cortex, caudate nucleus, putamen, nucleus accumbens, or medial dorsal thalamus of patients dying with schizophrenia, nor were GABA concentrations low in the CSF of living schizophrenic patients. These results do not confirm our earlier report of low levels of GABA in the nucleus accumbens and thalamus of some schizophrenic patients. We do not find neurochemical evidence favoring an involvement of GABAergic neuronal hypofunction in the etiology either of schizophrenia or of neuroleptic-induced tardive dyskinesia.

Adult↗

PubMed1989

An unusual aminoacidopathy associated with mitochondrial encephalomyopathy.

Five patients from two unrelated pedigrees are affected by an inherited form or forms of mitochondrial encephalomyopathy in which the exact site of the block in the respiratory chain has yet to be identified. All five patients regularly exhibit an unusual aminoacidopathy evident both in fasting plasma and in CSF. Alanine concentrations are elevated, reflecting high tissue pyruvate and lactate levels. Concentrations of the four essential amino acids threonine, methionine, tryptophan and lysine are substantially reduced, as are those of citrulline, ornithine and arginine. This pattern of amino-acid deficiency is apparently not due to failure to absorb the dibasic amino acids, to any abnormality of the urea cycle, to excessive synthesis and turnover of creatine, or to protein malnutrition. The aminoacidopathy presumably is a metabolic consequence of one or more impairments in the electron transport chain in mitochondria. A detailed explanation of its aetiology needs to be sought.

Adolescent↗

PubMed1989

Dominantly inherited olivopontocerebellar atrophy from eastern Cuba. Clinical, neuropathological, and biochemical findings.

A form of dominantly inherited olivopontocerebellar atrophy (OPCA) occurs commonly in persons of Spanish ancestry in northeastern Cuba. Its prevalence in the Province of Holguin is 41 per 100,000, a figure much higher than that found in western Cuba or in other parts of the world. The high prevalence is probably the result of a founder effect, but might be due to an interaction between a mutant gene and an unidentified environmental neurotoxin. We describe the clinical features of this disorder, and the neuropathological abnormalities in 7 autopsied patients. In addition, we report biochemical findings in plasma, cerebrospinal fluid (CSF) and urine obtained from 10 living OPCA patients. Quantitation of amino acids in fasting plasma showed a number of differences between the Cuban patients and healthy Canadian controls, but these are likely to have been caused by dietary differences. Amino acid concentrations in the CSF of the Cuban OPCA patients were similar to those of healthy Cuban controls, except for a decreased concentration of ethanolamine. Mean concentrations of dopamine metabolites were significantly low in the CSF of the OPCA patients, corresponding to neuronal depletion observed in the substantia nigra of autopsied cases. Examination of the patients' urines provided no evidence that either cyanide or 3-acetylpyridine is involved in causing this form of OPCA.

Adult↗

PubMed1989

Beta-N-methylamino-L-alanine. Chronic oral administration is not neurotoxic to mice.

Repeated dietary consumption of the neurotoxic amino acid beta-N-methylamino-L-alanine (BMAA), found in the seeds of Cycas circinalis, has been postulated as causing both amyotrophic lateral sclerosis (ALS) and the parkinsonism-dementia syndrome (PD) that were formerly very prevalent among the indigenous people of the Marianas Islands. Cynomolgus monkeys fed BMAA have been reported to develop behavioral and neuropathological changes like those found in human ALS. We gave large amounts of BMAA, totaling 15.5 g/kg of the L-isomer, by gavage to mice over 11 weeks without observing any behavioral abnormalities. When killed, these animals showed none of the neurochemical or neuropathological changes that would be expected in ALS or Parkinson's disease. Their striatal dopamine contents were normal, and there were no reductions in the contents of glutamate and aspartate in cerebral cortex like those encountered in sporadic human ALS. The results of this experiment do not support chronic ingestion of BMAA as the causative factor for Guamanian ALS or PD.

Administration, Oral↗

PubMed1989

Mitochondrial encephalomyopathy with associated aminoacidopathy in a male sibship.

We report two brothers with a previously undescribed type of mitochondrial encephalomyopathy and associated aminoacidopathy. Both have growth failure, progressive intellectual decline, deafness, neurologic dysfunction, exercise intolerance, lactic acidosis, and abnormal plasma and cerebrospinal fluid amino acid levels (elevated levels of alanine and low levels of threonine, methionine, citrulline, tryptophan, ornithine, arginine, and lysine). A muscle biopsy specimen taken from the younger, more severely affected brother showed abnormal mitochondrial morphology. Activities of the following enzymes in cultured fibroblasts from both boys were normal: pyruvate dehydrogenase, pyruvate carboxylase, phosphoenolpyruvate carboxykinase, cytochrome oxidase, reduced nicotinamide-adenine dinucleotide-cytochrome c reductase, and succinate cytochrome c reductase. Fibroblast mitochondria from the younger boy showed undetectable (less than 1% of control values) adenosine triphosphate synthesis with pyruvate and malate, whereas adenosine triphosphate synthesis with succinate was 70% of control values. These data indicate probably deficient activity of complex I of the electron transport chain. The boys' mother has progressive neurosensory hearing loss; their sister is clinically normal. Both mother and sister have many of the biochemical abnormalities found in the boys. It is possible, but not proved, that this disorder is inherited through maternal mitochondria.

Amino Acid Metabolism, Inborn Errors↗

PubMed1989

Stereoselective disposition of racemic E-10-hydroxynortriptyline in human beings.

The disposition and elimination kinetics of the enantiomers of E-10-hydroxynortriptyline (E-10-OH-NT) were studied in six rapid and four slow hydroxylators of debrisoquin after a single oral dose of 75 mg racemic E-10-OH-NT hydrogen maleate. The plasma levels and the AUC of unconjugated (-)E-10-OH-NT were two to five times higher than those of (+)E-10-OH-NT. The plasma half-lives of both enantiomers were 8 to 9 hours. A significantly higher proportion of the given dose of (+)E-10-OH-NT (64.4% +/- 12.1%) than of (-)E-10-OH-NT (35.3% +/- 9.7%) was recovered in urine as glucuronide conjugate, but more (-)E-10-OH-NT was recovered unchanged in urine. The total oral plasma clearance and the metabolic clearance by glucuronidation were significantly (p less than 0.0001) higher for (+)E-10-OH-NT than for (-)E-10-OH-NT. The findings indicate that first-pass glucuronidation of E-10-OH-NT is enantioselective in human beings in vivo, with preference for (+)E-10-OH-NT. The renal clearance of unbound (-)E-10-OH-NT (0.57 +/- 0.16 L.kg-1.hr-1), on the other hand, exceeded that of (+)E-10-OH-NT (0.44 +/- 0.14 L.kg-1.hr-1) (p less than 0.005), which suggests enantioselective tubular secretion. The debrisoquin hydroxylation status was not associated with any of the investigated kinetic processes that relate to E-10-OH-NT.

Administration, Oral↗

PubMed1988

Tetrahydroisoquinoline lacks dopaminergic nigrostriatal neurotoxicity in mice.

1,2,3,4-Tetrahydroisoquinoline (TIQ) has been reported to occur in human brain, with its content being 10-fold higher in the brain of a patient with Parkinson's disease (PD) than in that of a control subject. This congener of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) could be formed in brain by the condensation of phenylethylamine with metabolically formed formaldehyde. Phenylethylamine contents are greatly increased in the tissues of untreated patients with phenylketonuria. We injected C57 black mice repeatedly with maximal tolerated doses of TIQ, but later found no reduction in the contents of dopamine and its metabolites in their striata. We doubt that TIQ is a cause of PD, especially since the disorder has not been reported to occur in elderly patients with phenylketonuria.

Animals↗

PubMed1988

Brain neurotransmitters in glycine encephalopathy.

We measured neurotransmitter markers in autopsied brain of infants with glycine encephalopathy (GE). Because patients with GE develop intractable seizures, special attention was devoted to those neurotransmitter systems implicated in human epilepsy. Mean levels of glycine in the frontal cortex of GE patients were three times higher than control values. No abnormalities were observed for concentrations of gamma-aminobutyric acid (and related receptors), other major neurotransmitter amino compounds, or activities of cholineacetyltransferase and aspartate aminotransferase. Mean acetylcholinesterase activity was significantly elevated by 46%. As experimental data suggest, glycine markedly potentiates the action of the excitatory neurotransmitter glutamic acid. To the extent that the brain seizures in patients with GE can be explained by this mechanism, pharmacotherapy with excitatory amino acid antagonists may represent a new approach to the treatment of GE.

Amino Acid Metabolism, Inborn Errors↗

PubMed1988

2-Phenylpyridine and 3-phenylpyridine, constituents of tea, are unlikely to cause idiopathic Parkinson's disease.

Idiopathic Parkinson's disease (PD) is likely to be caused by one or more unidentified neurotoxins, present in the environment or formed endogenously, which progressively damage dopaminergic nigrostriatal neurons. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is an experimental neurotoxin which produces biochemical and neuropathological changes in lower primates and mice and in humans inadvertently exposed to it that closely resemble those found in PD. 2-Phenylpyridine (2-PP) and 3-phenylpyridine (3-PP), both of them present in tea, are the only MPTP analogues that are known to be present in the human diet. We exposed C57 black mice, animals very sensitive to the dopaminergic neurotoxicity of MPTP, to prolonged parenteral and oral administration of large doses of 2-PP, and to prolonged parenteral administration of the N-methylated tetrahydro derivatives of 2-PP and 3-PP. The latter are closer chemical analogues of MPTP than are 2-PP and 3-PP themselves. None of these MPTP analogues lowered the contents of dopamine and its metabolites in the striatum of mice. We speculate that the neurotoxins which cause PD are unlikely to resemble MPTP structurally, and we suggest that the search for chemical causes of PD should be directed to a wider variety of compounds encountered by humans.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1988

Cerebrospinal fluid values for monoamine metabolites, gamma-aminobutyric acid, and other amino compounds in Rett syndrome.

We measured concentrations of 3-methoxy-4-hydroxy-phenylglycol, 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid--the metabolites of noradrenaline, dopamine, and serotonin used as central neurotransmitters--in the cerebrospinal fluid (CSF) specimens of five girls with Rett syndrome. These patients met the clinical criteria for both inclusion and exclusion of the diagnosis of Rett syndrome. In contrast to previous reports, cerebral monoamine metabolites were present in normal concentrations in CSF. In addition, concentrations of gamma-aminobutyric acid and of a large number of other amino acids and related compounds were normal in the CSF of patients with the syndrome. We doubt that an underlying biochemical cause for this disorder has yet been discovered.

Adolescent↗

PubMed1988

Brain amino acids and glutathione in progressive supranuclear palsy.

We measured amino acid contents in autopsied brains of seven patients with progressive supranuclear palsy (PSP) and in control subjects dying without brain disease. Glutathione was also quantitated in rapidly frozen brains of PSP patients, Parkinson's disease (PD) patients, and controls. In PSP, we found glutamic acid markedly increased in the nucleus accumbens; taurine significantly increased in nucleus accumbens, substantia nigra, and globus pallidus; and gamma-aminobutyric acid significantly increased in nucleus accumbens and putamen. Glycerophosphoethanolamine contents were significantly increased in most regions. Glutathione, which is significantly decreased in substantia nigra in PD, was increased in this brain region in PSP, suggesting that different mechanisms may be responsible for destruction of dopaminergic nigrostriatal neurons in these two disorders.

Aged↗

PubMed1987

4-phenylpyridine and three other analogues of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine lack dopaminergic nigrostriatal neurotoxicity in mice and marmosets.

C57 black mice were injected repeatedly with maximal tolerated doses of 2 chemical analogues of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); 4-phenylpyridine and 4-phenyl-1,2,3,6-tetrahydropyridine. Although both compounds were clearly acutely toxic to mice, neither caused any reduction in striatal dopamine content after chronic exposure. Two MPTP analogues which may be formed endogenously during the metabolism of brain monoamines, 2-methyl-1,2,3,4-tetrahydroisoquinoline and 2-methyl-1,2,3,4-tetrahydro-beta-carboline, were injected repeatedly into common marmosets. Again, although both compounds appeared highly toxic, neither caused any reduction in striatal dopamine content. It appears unlikely that any of these 4 MPTP analogues causes idiopathic Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1987

Exposure to cigarette smoke does not decrease the neurotoxicity of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice.

Epidemiological surveys have repeatedly shown that idiopathic Parkinson's disease (PD) occurs less frequently in persons who have smoked cigarettes for many years than among age-matched non-smokers. Since PD might be caused by neurotoxins chemically similar to N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), we explored the possible protective effect of repeated exposure to cigarette smoke against MPTP neurotoxicity in the C57 black mouse. Mice given MPTP and exposed to cigarette smoke suffered just as great a depletion of striatal dopamine as did mice treated only with MPTP. We discovered also that different lots of C57 black mice obtained from a single supplier can have markedly different sensitivities to MPTP.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1987

Amino acids, glutathione, and glutathione transferase activity in the brains of patients with Alzheimer's disease.

We measured the contents of amino acids and related amino compounds in autopsied brain from 22 patients with Alzheimer's disease (AD) and in cortical biopsy specimens from 2 other patients. The diagnosis of AD was established neuropathologically in all 24 patients by the presence of both neurofibrillary tangles and neuritic plaques in neocortex. The mean contents of gamma-aminobutyric acid (GABA), and of the GABA dipeptide homocarnosine, were significantly reduced in frontal and occipital cortices and in hippocampus of the autopsied brains of AD patients compared to control patients without neurological disease. However, GABA contents were normal in frontal cortex in biopsy samples from 2 patients. Phosphoethanolamine contents were significantly reduced at autopsy in frontal and occipital cortex, and in the substantia innominata. We found no evidence of a deficiency of glutamate, aspartate, or taurine in AD brain, as has been claimed. Glutathione contents and glutathione transferase activities were normal in frontal cortex and substantia innominata. The mechanism of neuronal death in patients with AD is unlikely to involve either insufficient synthesis of glutathione or failure to conjugate free radicals with glutathione.

Adolescent↗

PubMed1987

Brain choline acetyltransferase reduction in dominantly inherited olivopontocerebellar atrophy.

We measured the activity of choline acetyltransferase, the cholinergic marker enzyme, in the brains of 17 patients from five established pedigrees with dominantly inherited olivopontocerebellar atrophy (OPCA). OPCA is a group of cerebellar ataxia disorders in which serious intellectual impairment is not typically considered to be an accompanying feature. Patients from all five pedigrees demonstrated markedly reduced choline acetyltransferase activity in the cerebral cortex, with less severe changes in the hippocampus. Although the magnitude of the cortical choline acetyltransferase deficit is comparable to that seen in the brains of patients with Alzheimer's disease, none of our OPCA patients appeared, on last examination, to have severe global dementia of the Alzheimer type. Determination of the clinical significance of our biochemical data must await the results of studies in which the cognitive status of OPCA individuals has been accurately assessed.

Brain↗

PubMed1987

A controlled trial of isoniazid therapy for action tremor in multiple sclerosis.

Ten patients with clinically definite multiple sclerosis (MS) and action tremor were treated with isoniazid (INH) in a double-blind single crossover trial. The daily dose of INH administered during the 4-week treatment phase of the trial was determined by acetylator phenotype with slow acetylators receiving 12 mg/kg per day and rapid acetylators 20 mg/kg per day. Six of eight patients who completed the trial showed clinical improvement in the postural (alternating) tremor while on INH but the degree was minimal in all cases. Results of tremograms indicated that improvement also occurred in the intentional (synchronous) component of three patients while on INH, but this did not achieve statistical significance. Cerebrospinal fluid (CSF) levels of gamma-aminobutyric acid (GABA) homocarnosine and ornithine were markedly elevated with INH therapy (providing evidence for substantial inhibition of GABA aminotransferase activity and increase in GABA in the CNS), but no correlation was found between the degree of GABA elevation in the CSF and the clinical response. Side effects were minimal and well tolerated. Although INH appears to have a limited therapeutic role, a trial is warranted in MS patients with postural tremor.

Adult↗