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Biomedical subjects

T N Chase

Publications and source records attributed to T N Chase.

At least 127 records · Page 7Linked to original sources
PubMed1993

Assessment of intellectual function in dementing disorders: validity of WAIS-R short forms for patients with Alzheimer's, Huntington's, and Parkinson's disease.

While commonly administered in the neuropsychological assessment of dementia, the Wechsler Adult Intelligence Scale-Revised (WAIS-R) is excessively long (70-90 min) and difficult for many patients. The present study examined WAIS-R data from patients with clinically distinct dementing disorders, including those with Alzheimer's, Huntington's, and Parkinson's disease (N = 148). The profiles of performance of these three patient groups across subtests were remarkably similar, suggesting that the use of a short form would not result in the loss of clinically significant information. The validity of several published short forms was reviewed. Although all of these systematically over- or underestimated Full Scale IQ for these patients, after a scaling table revision the Kaufman (1990) form appears to provide an accurate estimate of IQ. The use of this short form is therefore recommended to minimize frustration and fatigue on the part of the patient, and to allow the inclusion of other tests critical to the evaluation of dementia within a single assessment session.

Aged↗
PubMed1993

Dynorphin agonist therapy of Parkinson's disease.

Striatal dynorphin system function may be altered in Parkinson's disease. To evaluate whether treatment with a selective dynorphin agonist improves motor symptoms, four parkinsonian patients received single daily injections of spiradoline under controlled conditions. Doses ranging from 1 to 4 micrograms/kg had no discernible effect on motor performance when given alone or in combination with levodopa-carbidopa. Three patients developed dose-limiting adverse effects, especially behavioral alterations. These results suggest that dynorphin replacement strategies, using spiradoline-like kappa-1 agonists, may have limited value in the therapy of patients with Parkinson's disease.

Adult↗
PubMed1993

No evidence for altered muscle mitochondrial function in Parkinson's disease.

Recent reports indicate that reductions in mitochondrial respiratory chain function occur in substantia nigra, platelets, and muscle from patients with Parkinson's disease. To confirm and further characterise the presence of a generally distributed mitochondrial defect, mitochondrial metabolism was evaluated in muscle obtained from subjects with Parkinson's disease and from normal controls. Oxygen consumption rates in muscle mitochondria represented by complex I, complexes II-III, or complex IV did not differ between the two groups. Likewise, activities of rotenone sensitive NADH cytochrome c reductase, succinate cytochrome c reductase, or cytochrome oxidase in muscle mitochondria were not significantly different between Parkinsonian and control subjects. These findings fail to provide support for a generalised defect in mitochondrial function in Parkinson's disease but do not exclude an abnormality in respiratory function confined to the substantia nigra.

Adult↗
PubMed1993

End-of-dose dystonia in Parkinson's disease.

To evaluate the pathogenesis of end-of-dose dystonia in levodopa-treated patients with Parkinson's disease, we discontinued a steady-state optimal-dose levodopa infusion either abruptly or slowly. Although dystonic signs appeared sooner after sudden levodopa termination, in both situations dystonia emerged only when circulating drug levels had fallen to the same concentration and parkinsonian scores had declined by the same amount. Dystonia onset thus appears to reflect the degree, rather than the rate, of reduction in dopaminergic stimulation, and may involve the preferential interaction of dopamine with a receptor subpopulation that does not mediate its antiparkinsonian efficacy.

Adult↗
PubMed1993

Catechol-O-methyltransferase inhibitor tolcapone prolongs levodopa/carbidopa action in parkinsonian patients.

The wearing-off phenomenon frequently complicates levodopa therapy of Parkinson's disease (PD). These response fluctuations appear when intrasynaptic dopamine concentrations begin to reflect the swings in levodopa availability that attend standard dosing regimens. Drugs that prolong the biologic half-life of levodopa and dopamine should thus prove beneficial. We administered levodopa/carbidopa in combination with single oral doses of tolcapone (Ro 40-7592), an inhibitor of catechol-O-methyltransferase, under controlled conditions to 10 PD patients with the wearing-off phenomenon. Tolcapone prolonged the antiparkinson response to levodopa/carbidopa by about 67% at several doses ranging from 50 to 400 mg (p < 0.05). There was no significant change in the peak levodopa effect on parkinsonian signs or in the severity of dyskinesias. No dose-limiting adverse effects occurred. Multiple daily dosing with tolcapone would thus be expected to safely reduce the wearing-off phenomenon associated with levodopa/carbidopa therapy.

Adolescent↗
PubMed1993

Influence of previous exposure to levodopa on the interaction between dizocilpine and dopamine D1 and D2 agonists in rats with 6-hydroxydopamine-induced lesions.

The potential antiparkinson activity of N-methyl-D-aspartate antagonists was investigated by examining the effects of dizocilpine (MK-801) on rats with 6-hydroxydopamine-induced lesions of the nigrostriatal pathway. MK-801, when administered alone to these animals, elicited ipsilateral rotation, which could be blocked by haloperidol. MK-801, at doses that did not produce rotation when given alone, inhibited the contralateral rotation produced by the D2 receptor agonist quinpirole but had no effect on the rotation induced by the D1 agonist SKF 38393 [(+-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8- diolhydrochloride]. However, exposure to levodopa 3 days previously resulted in a subsensitive rotational response to SKF 38393 and this subsensitivity to the D1 agonist was reversed by MK-801. The subsensitive rotational response to SKF 38393 was not evident 7 days after exposure to levodopa and MK-801 had no effect on the response to SKF 38393 at this time. These data suggest that N-methyl-D-aspartate receptor blockade can exert differential effects on dopamine agonist-induced rotational behavior that depend on which dopamine receptor subtype is activated and the previous exposure of the animal to dopamine agonists.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1993

Motor response complications and the function of striatal efferent systems.

Motor response complications eventually appear in most patients with advanced Parkinson's disease being treated with levodopa. The interval between onset of parkinsonism and emergence of these adverse events appears independent of the dose or the duration of therapy. Current evidence suggests that "wearing-off" fluctuations largely reflect the loss of normally functioning dopaminergic terminals, although postsynaptic alterations contribute somewhat to the underlying decline in the duration of levodopa's antiparkinsonian action. "On-off" fluctuations and peak-dose dyskinesias, on the other hand, appear to arise mainly as a consequence of postjunctional alterations that follow exposure to nonphysiologic intrasynaptic dopamine fluctuations in patients who have lost the buffering afforded by dopaminergic terminals. Studies in rats with 6-hydroxydopamine lesions indicate that striking functional alterations occur in striatal dopaminoceptive systems as a result of dopaminergic denervation and that levodopa replacement, particularly when given intermittently, fails to normalize these changes. To the extent that similar alterations contribute to the appearance of motor complications, the successful symptomatic therapy of Parkinson's disease may require continuous dopaminergic stimulation, as well as direct pharmacologic targeting of striatal dopaminoceptive systems.

Animals↗
PubMed1992

Differential effect of subthalamic nucleus ablation on dopamine D1 and D2 agonist-induced rotation in 6-hydroxydopamine-lesioned rats.

The effect of unilateral subthalamic nucleus ablation on rotation in response to dopamine D1 and D2 agonists was examined in rats with a unilateral 6-OHDA lesion of the nigrostriatal pathway. Four to five weeks following subthalamic nucleus lesion, D2 agonist-induced rotation was reduced in subthalamic nucleus-lesioned rats relative to sham controls, although no such reduction in D1 agonist-induced circling occurred. However, 1-2 weeks following subthalamic nucleus lesion marked reductions occurred in both D1 and D2 agonist-induced rotation in subthalamic nucleus lesioned rats compared to sham controls. These results suggest that the subthalamic nucleus contributes primarily to the expression of D2-mediated motor behaviors, although ablation of the subthalamic nucleus may induce certain time-dependent compensatory mechanisms in other basal ganglia structures which affect D1-mediated actions.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1992

Dopaminergic modulation of striatal neuropeptides: differential effects of D1 and D2 receptor stimulation on somatostatin, neuropeptide Y, neurotensin, dynorphin and enkephalin.

Dopaminergic modulation of neuropeptides in rat striatum was investigated by examining the effects of prolonged D1 or D2 receptor stimulation on levels of somatostatin, neuropeptide Y, neurotensin, dynorphin and enkephalin. Rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway were treated for 7 days with either the D1 agonist SKF 38393 (12.5 mg/kg/day) or the D2 agonist quinpirole (1 mg/kg/day). Two regimens of agonist treatment were compared: continuous infusion via osmotic pump implanted i.p. and intermittent (once daily) i.p. injection. Rats were sacrificed 3 h after the last injection and peptide levels measured in the striatum bilaterally by radioimmunoassay; alterations in peptide content were observed primarily in the denervated striatum. In comparison to values from lesioned, vehicle-treated controls, intermittent administration of SKF 38393 reduced somatostatin and neuropeptide Y (down 61% and 57%, respectively), increased neurotensin (up 105%) and dynorphin (up 184%) and had no effect on enkephalin; continuous SKF 38393 decreased neuropeptide Y by 39% but did not alter levels of the other peptides. Continuous quinpirole elevated somatostatin and neuropeptide Y levels (up 43% and 33%, respectively), but reduced the lesion-induced increases in both neurotensin (down 51%) and enkephalin (down 24%) content. Conversely, intermittent quinpirole decreased somatostatin (down 35%) and neuropeptide Y (down 27%), increased neurotensin content by 79% and had no effect on enkephalin. Dynorphin levels were not altered by either continuous or intermittent quinpirole. These findings reveal the complexity of dopaminergic influences on striatal neuropeptides.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1992

Limbic system abnormalities identified in schizophrenia using positron emission tomography with fluorodeoxyglucose and neocortical alterations with deficit syndrome.

A hypothesis of psychosis localization in schizophrenia was derived from studying metabolic alterations in rat brain in response to phencyclidine hydrochloride administration. Since phencyclidine and its selective agonist dizocilpine maleate (MK801) induced overlapping and long-lasting metabolic alterations predominantly in limbic areas, the hypothesis developed that schizophrenic patients with psychosis would evidence functional abnormalities in limbic circuits compared with normal controls. Accordingly, 12 actively psychotic, drug-free patients with schizophrenia and matched normal controls underwent functional brain scans using positron emission tomography and fluorodeoxyglucose. Regions of interest were identified on five matched axial slices in each patient and control subject, and average metabolic rates were calculated. Patients with schizophrenia showed a significantly lower regional cerebral metabolic rate of glucose in the hippocampus and the anterior cingulate cortex than did normal controls, but not in neocortical areas or in the extrapyramidal system. When the group of schizophrenic patients was divided into deficit and nondeficit types, a preliminary exploratory analysis suggested thalamic, frontal, and parietal cortical hypometabolism in the deficit subgroup, with normal metabolism in the nondeficit patient group in those areas; in contrast, hippocampal and anterior cingulate cortical metabolism was reduced in both deficit and nondeficit subtypes. These results suggest that the limbic system, especially the hippocampus, is functionally involved in schizophrenic psychosis and that different manifestations of schizophrenia may involve different neuronal circuits.

Adolescent↗
PubMed1992

Continuous lisuride effects on central dopaminergic mechanisms in Parkinson's disease.

Effects of the long term, continuous administration of a dopamine agonist on motor response complications attending levodopa therapy were studied in 7 patients with advanced Parkinson's disease under controlled conditions. After a 3-month round-the-clock infusion of lisuride, the duration of antiparkinsonian action of levodopa increased by approximately 90%, and the therapeutic window for the acutely administered dopamine precursor widened by > 300%. These benefits were more than three times greater than those produced by 9 days of continuous levodopa administration. In contrast to the effects on levodopa pharmacodynamics, the continuous infusion of lisuride did not prolong its action, suggesting a lisuride effect on presynaptic as well as postsynaptic dopaminergic mechanisms. These results lend further support to the view that continuous dopamine replacement ameliorates motor fluctuations and peak-dose dyskinesias that complicate standard levodopa regimens. Our findings further suggest that alterations at both presynaptic and postsynaptic levels contributing to these motor complications tend to normalize with the more physiological stimulation afforded by continuous replacement strategies, especially when given chronically.

Adult↗
PubMed1992

Effect of aging and dopaminomimetic therapy on mitochondrial respiratory function in Parkinson's disease.

Oxygen consumption and enzyme activity were evaluated in platelet mitochondria from 17 patients with Parkinson's disease. In comparison with age-matched controls, no consistent abnormality could be discerned in complex I, complex II-III, or complex IV oxygen consumption, or in the enzyme activity of these respiratory chain complexes. Neither chronic therapy with levodopa/carbidopa alone nor in combination with deprenyl significantly affected any measure of mitochondrial respiratory function. There was no discernible relationship between patient age or disease severity and any parameter of mitochondrial respiration. Moreover, blood lactate levels following glucose loading were not different in patients and controls. These results fail to support the occurrence of a generalized defect in any mitochondrial respiratory function in Parkinson's disease.

Age Factors↗
PubMed1992

Effects of cholinergic agonists on regional brain energy metabolism in the scopolamine-treated rat.

The effects of scopolamine, physostigmine, RS86 and U-80816B on regional energy metabolism were studied in rodents by means of the 2-deoxyglucose autoradiographic technique. Scopolamine depressed metabolism in an area of cerebral cortex, focused around the parietal region. Rats treated with cholinergic direct agonists (U-80816B, RS86) as well as with the indirect agonist (physostigmine) all showed decreases in cortical energy metabolism, similar to scopolamine. They also induced an increase in thalamic metabolism. When these drugs were given in conjunction with scopolamine, metabolism tended to change in the opposite direction from the values obtained with the drug alone. These results suggest that there are complex interactions between pre- and post-synaptic muscarinic receptors. Additionally, nicotinic receptors could also be involved in some of the effects of physostigmine.

Animals↗
PubMed1992

Glutamatergic therapy of Huntington's chorea.

Preclinical evidence suggests that hypofunction of the glutamatergic subthalamopallidal tract may contribute to the hyperkinesis in Huntington's chorea. The clinical effects of milacemide, a glycine prodrug, were studied in seven patients with Huntington's disease under double-blind, placebo-controlled conditions. Oral doses of 1,200 mg/day did not alter chorea or cognitive dysfunction. Specific modulatory effects of glycine on the NMDA subtype of glutamate receptors, rather than the AMPA receptors, which may predominate among target neurons of the subthalamus, may explain the therapeutic failure of milacemide.

Acetamides↗