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Biomedical subjects

T Sunderland

Publications and source records attributed to T Sunderland.

At least 163 records · Page 9Linked to original sources
PubMed1987

Dementia of the Alzheimer type: clinical and family study of 22 twin pairs.

We studied 22 twin pairs in which one or both twins had dementia of the Alzheimer type (DAT). In four twins, diagnosis was confirmed by autopsy. Seven monozygotic (MZ) pairs were concordant for DAT; 10 MZ pairs were discordant. Two dizygotic (DZ) pairs were concordant for DAT, and 3 DZ pairs were discordant. The current concordance rate was 41% for MZ twins and 40% for DZ twins. The study supports the belief that, etiologically, DAT cannot be entirely accounted for by a single autosomal dominant gene. The data also suggest that in certain genetic circumstances, disease expression may be delayed in females.

Aged↗
PubMed1986

Naloxone and Alzheimer's disease. Cognitive and behavioral effects of a range of doses.

There have been conflicting reports on the effects of naloxone hydrochloride in patients with dementia of the Alzheimer type (DAT). In addition, none of the naloxone studies in DAT used doses of 2.0 mg/kg or more, the amount necessary to produce reliable cognitive and behavioral changes in young normal subjects. In a randomized, double-blind, placebo-controlled study, 12 patients with DAT were administered naloxone hydrochloride in doses of 5 micrograms/kg, 0.1 mg/kg, and 2.0 mg/kg, with detailed evaluation of its behavioral and cognitive effects using measures selected for their potential relevance to DAT and the known effects of blockade of endogenous opiate systems. None of the measures of motor performance, attention, memory, learning, or recognition showed improvement with naloxone. Increased inappropriate verbal productions were noted after 0.1 mg/kg of naloxone hydrochloride. Patients became irritably activated after this dose, which may account for the altered verbal behavior in this study and also for some of the changes suggesting cognitive improvement in prior studies. Differences in the sensitivity and dose dependency of the behavioral effects in patients with DAT compared with prior studies in young normal subjects merit further investigation.

Adult↗
PubMed1986

Diazepam-binding inhibitor. A brain neuropeptide present in human spinal fluid: studies in depression, schizophrenia, and Alzheimer's disease.

Diazepam-binding inhibitor is a novel peptide purified to homogeneity from rat and human brain. Diazepam-binding inhibitor is present, though not exclusively, in gamma-aminobutyric acid (GABA)-containing neurons where it is believed to inhibit GABAergic neurotransmission mediated by GABA by binding to the benzodiazepine-GABA receptor complex. Since an impairment of central GABAergic tone has been postulated to be associated with a number of neuropsychiatric disorders, we measured human diazepam-binding inhibitor immunoreactivity in the cerebrospinal fluid (CSF) of patients suffering from endogenous depression, schizophrenia, and dementia of the Alzheimer's type. Patients with major depression had significantly higher concentrations of human diazepam-binding inhibitor immunoreactivity in CSF when compared with age- and sex-matched normal volunteers, while no difference in CSF diazepam-binding inhibitor immunoreactivity was found in schizophrenics or patients with dementia of the Alzheimer's type when compared with controls. The possibility is discussed that the increased CSF human diazepam-binding inhibitor immunoreactivity observed in depressed patients may represent a functional disinhibition of GABAergic neurotransmission associated with depression.

Adult↗
PubMed1986

Further studies of the putative serotonin agonist, m-chlorophenylpiperazine: evidence for a serotonin receptor mediated mechanism of action in humans.

To further evaluate the effects and mechanism of action of the putative serotonin agonist m-chlorophenylpiperazine (m-CPP) in humans, changes in plasma prolactin, cortisol, growth hormone, ACTH and body temperature were studied in a group of 10 healthy volunteers following oral administration of m-CPP (0.75 mg/kg), before and after pretreatment with the serotonin receptor antagonist metergoline (MTG). M-CPP produced transient significant increases in plasma prolactin, cortisol, ACTH and in body temperature, but did not significantly alter plasma growth hormone concentration. Moreover, pretreatment with the 5HT antagonist metergoline blocked the m-CPP-induced hormonal and temperature changes. These findings provide strong support for m-CPP's effects in humans being mediated through an interaction with 5HT receptors, and thus support the usefulness of m-CPP as a pharmacologic tool for studying disease and drug-induced alterations in serotonin function in man.

Adrenocorticotropic Hormone↗
PubMed1986

Human plasma melatonin is elevated during treatment with the monoamine oxidase inhibitors clorgyline and tranylcypromine but not deprenyl.

Melatonin was measured in plasma collected between 8:00 and 8:30 a.m. from 27 depressed patients studied before and after 21- to 24-day treatment with three monoamine oxidase (MAO) inhibitors. Baseline plasma melatonin concentrations determined by radioimmunoassay were 4.0 +/- SD 4.7 pg/ml. Tranylcypromine, a nonselective MAO inhibitor given in doses of 20-40 mg/day for 3 weeks, significantly elevated plasma melatonin to 10.6 +/- SD 2.0 pg/ml. Clorgyline, given in doses of 15-30 mg/day for 3 weeks, produced a significant, approximately three-fold increase in plasma melatonin (13.6 +/- SD 13.5 pg/ml). This clorgyline dose was selective for MAO type A inhibition, as MAO-B activity measured in platelets from the same blood samples was unaffected by clorgyline. In contrast, the selective MAO-B inhibitor deprenyl (10-30 mg/day for 3 weeks) led to a 96 +/- 4% inhibition of platelet MAO-B activity but no significant change in plasma melatonin (5.1 +/- SD 4.2 pg/ml). As both serotonin and norepinephrine are preferentially metabolized by MAO-A rather than MAO-B, an increased availability of serotonin (the precursor of melatonin) or enhanced noradrenergic function might mediate the melatonin changes observed to follow MAO-A but not MAO-B inhibition.

Blood Platelets↗
PubMed1986

Pharmacologic modelling of Alzheimer's disease.

Evidence pointing to the central role of the cholinergic system in normal human memory function and disorders such as Alzheimer's disease has grown tremendously in recent years. Anticholinergic and non-cholinergic agents have been found to create transient memory impairments in young adults which mimic the changes associated with normal aging or amnesia. The rationale for using scopolamine, a centrally active anticholinergic agent, as a pharmacologic probe of memory function is reviewed using data from studies in animals and humans. The cognitive functioning of normal elderly controls given scopolamine is compared to the baseline functioning of patients with Alzheimer's disease, followed by a discussion of the use of scopolamine as a modelling agent for dementia.

Adult↗
PubMed1986

Design and interpretation of opiate antagonist trials in dementia.

In view of the reports of possible beneficial effects of naloxone in dementia, rationales and strategies for studying endogenous opiate systems are reviewed. Important considerations in the design and interpretation of clinical investigations using naloxone are also reviewed. The nature and distribution of endogenous opiate systems are summarized from an historical perspective. Endogenous opiate systems are distributed throughout the central nervous system and play important roles in a variety of brain functions, including memory and learning. In view of this, several rationales are evident for studying endogenous opiate systems in dementia, since it is a syndrome in which structures known to contain opiate systems are disturbed, functions modulated by opiate systems are disturbed, and other neurotransmitter systems (functionally linked to endogenous opiate systems) are disturbed. Different strategies for studying endogenous opiate systems are reviewed, including examination of body fluids and pharmacologic challenge studies. Naloxone hydrochloride, a competitive opiate receptor antagonist, is a commonly used pharmacologic agent. The design of a multidose naloxone study of 12 dementia patients is discussed, with reference to the pharmacokinetics, pharmacodynamics, and specificity of naloxone as well as to the nature of the dependent measures selected for this study. No cognitive benefit was observed in this study. Behavioral arousal was observed at naloxone doses, with more evident psychomotor retardation at higher doses. These findings are contrasted with the results of naloxone challenges in other studies. The varying effects of naloxone within and across populations can be conceptualized in terms of the basic and clinical considerations previously discussed. The importance of dose-finding studies is stressed for this and other drug trials.

Alzheimer Disease↗
PubMed1986

Simultaneous liquid-chromatographic determination of 3,4-dihydroxyphenylglycol, catecholamines, and 3,4-dihydroxyphenylalanine in plasma, and their responses to inhibition of monoamine oxidase.

This is a reversed-phase liquid-chromatographic method, with electrochemical detection, for simultaneously measuring, in plasma, the concentrations of the catecholamine precursor dihydroxyphenylalanine (DOPA); the endogenous catecholamines norepinephrine, epinephrine, and dopamine; and the deaminated catecholamine metabolites dihydroxyphenylacetic acid (DOPAC) and dihydroxyphenylglycol (DHPG). We used this method to assess effects of monoamine oxidase (EC 1.4.3.4) inhibition in humans. Plasma DHPG concentrations as determined by the present method (mean 826, SEM 61 ng/L) were similar to those found by other methods. Inhibition of monoamine oxidase (by administering deprenyl or tranylcypromine) decreased plasma DHPG by greater than 65%, plasma DOPAC by greater than 50%, and plasma DOPA by about 20%, without consistently affecting norepinephrine or epinephrine. Simultaneous measurement of DOPA, catecholamines, and DHPG may be useful for examining the synthesis, release, and intraneuronal metabolism of norepinephrine. The assay method is rapid, reliable, and simple, and it provides a more comprehensive assessment of noradrenergic nervous function than does measurement only of catecholamines.

Alzheimer Disease↗
PubMed1986

Rapid antidepressant effect of addition of lithium to tranylcypromine.

A chronically depressed patient who had not responded to treatment with several tricyclic antidepressants and monoamine oxidase inhibitors alone, responded within hours following the addition of lithium to ongoing tranylcypromine treatment in a double-blind medication trial. The findings are discussed in the context of reports of lithium augmentation of other antidepressants.

Depressive Disorder↗
PubMed1985

Tyramine pressor sensitivity changes during deprenyl treatment.

Deprenyl has previously been reported to be a selective monoamine oxidase (MAO) type B inhibitor, which is associated with little or no enhancement of the pressor effects of tyramine. Employing an intravenous steady-state tyramine infusion technique, the effects of different doses of deprenyl and, for comparison, the mixed inhibitor tranylcypromine on the pressor response to tyramine were studied in 11 depressed patients. After 3 weeks of treatment, deprenyl produced dose-proportionate increases in tyramine sensitivity at all three doses (10, 30, and 60 mg/day) when compared to placebo baseline tyramine responses. While only a modest (3.7-fold) increase in tyramine sensitivity was found with the 10 mg/day deprenyl dose, the increase in tyramine sensitivity at the 60 mg/day dose of deprenyl (22-fold) approached that found with tranylcypromine. Reductions in plasma 3-methoxy,4-hydroxyphenylglycol (MHPG), used as a possible index of in vivo MAO-A inhibition, were highly correlated with increases in tyramine pressor sensitivity (r = 0.82). The data suggest that deprenyl acts as a relatively selective MAO-B inhibitor at low doses, but that this selectivity is lost at higher doses, resulting in a significant "crossover" inhibition of MAO-A and increased tyramine pressor sensitivity.

Blood Pressure↗
PubMed1985

Scopolamine challenges in Alzheimer's disease.

A challenge paradigm was designed to test the functional sensitivity to anticholinergic agents in Alzheimer's disease. Ten patients with dementia of the Alzheimer type were serially administered three different intravenous doses of the centrally active anticholinergic drug scopolamine and placebo. Testing was carried out in a placebo-controlled, double-blind fashion to measure cognitive, physiologic and behavioral changes. Alzheimer patients showed a marked, dose-related behavioral and cognitive sensitivity to temporary cholinergic blockade. Scopolamine testing may serve as an index of the status of central cholinergic functional integrity, and ultimately may prove useful as a diagnostic or staging test in the evaluation of the cholinergic system in dementia. Research is currently under way with elderly age-matched controls and populations with other neuropsychiatric disorders to explore this hypothesis further.

Adult↗
PubMed1985

TRH stimulation test in dementia of the Alzheimer type and elderly controls.

Dementia of the Alzheimer type (DAT) is known to be a heterogeneous syndrome with many clinical manifestations, including depression. In the present study, the thyrotropin-releasing hormone (TRH) stimulation test, previously used as a possible biological marker of depression, was administered to 15 DAT patients and 10 elderly controls. Seven out of 15 (47%) of the patients but none of the controls showed a blunted response with maximal changes of thyroid-stimulating hormone (TSH) from baseline of less than or equal to 7 microIU/ml following injection of 500 micrograms of TRH. The degree of blunting did not correlate with concurrent depression ratings.

Adult↗
PubMed1985

Neuroendocrine effects of M-chlorophenylpiperazine, a serotonin agonist, in humans.

M-Chlorophenylpiperazine (m-CPP) produces effects on the central serotonergic system in animals compatible with direct agonist activity on postsynaptic serotonin receptors. Although it is a metabolite of the antidepressant trazodone, m-CPP has not previously been given to humans. To evaluate the neuroendocrine, behavioral, and physiological effects of m-CPP, 15 normal subjects were given 0.5 mg/kg m-CPP, orally. Administered acutely under double blind, placebo-controlled conditions, m-CPP was well tolerated by 14 of the 15 subjects; it produced significant increases in plasma PRL and cortisol and in body temperature, without changing pulse or blood pressure. The mean (SD) maximal increases over baseline for PRL, cortisol and temperature were 13.4 (9.9) ng/ml, 10.1 (6.7) micrograms/100 ml, and 0.4 (0.2) C, respectively. A small but significant increase in self-rated activation-euphoria and anxiety was noted by some subjects, whereas there were no significant effects on ratings of depression, dysphoria, altered self-reality, or functional impairment. These results are similar to those for other serotonin agonists and, thus, suggest that m-CPP merits further study as a pharmacological probe of serotonergic responsivity in humans. The results also support the hypothesis that serotonin plays a role in the regulation of PRL, cortisol, body temperature, and mood.

Adult↗
PubMed1985

Central auditory function in Alzheimer's disease.

The central auditory (dichotic) function of 38 patients with Alzheimer's disease was found to be significantly impaired when compared with a control group. Significant relationships were observed between dichotic scores and intelligence quotient, cortical atrophy in the temporal lobes, and cerebral glucose metabolism in the left temporal lobe. Comparing atrophy and glucose metabolism in the temporal lobes, we observed contralateral ear effects in dichotic performance as well as an interaction of asymmetry of atrophy with dichotic performance, consistent with previous models of dichotic listening in other forms of temporal lobe pathology.

Adult↗