A personal history of sleep disorders medicine.
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Animals↗
Biomedical subjects
W C Dement
Publications and source records attributed to W C Dement.
Effects of central alpha-2 adrenergic compounds on canine narcolepsy, a disorder of rapid eye movement sleep.
Recent experiments have demonstrated that pharmacological activation of central noradrenergic systems by monoaminergic stimulators or uptake blockers or through the stimulation of alpha-1 adrenergic receptors improved cataplexy, a major symptom of narcolepsy. In order to further the understanding of the control of cataplexy by noradrenergic mechanisms, the involvement of central alpha-2 adrenoceptors was examined in genetically narcoleptic Doberman pinschers using in vivo pharmacology. Yohimbine (1.5-96.0 micrograms/kg i.v.) and seven other selective and centrally acting alpha-2 adrenoceptor antagonists (rauwolscine: 1.5-96 micrograms/kg i.v.; atipemazole: 1.5-96 micrograms/kg i.v.; Wy-25309: 1.5-386 micrograms/kg i.v.; CGS-7525A: 1.5-386 micrograms/kg i.v.; idazoxan, 6-1536 micrograms/kg i.v.; piperoxan, 6-1536 micrograms/kg i.v.; and mianserin, 6-1536 micrograms/kg i.v.) significantly suppressed cataplexy. The alpha-2 mediation of this effect was demonstrated by a close correlation between drug affinities (Ki) toward the alpha-2 site (defined using [3H]yohimbine in canine cortex) and the ability of these drugs to reduce cataplexy [ED50 in nanomoles per kilogram i.v.) (r2 = 0.71, n = 8, P less than .01). The effects of six centrally acting alpha-2 agonists on canine cataplexy were also examined and two groups of compounds were distinguished on the basis of their pharmacological profile. Classical alpha-2 agonists such as clonidine (0.0625-4.0 micrograms/kg i.v.), p-aminoclonidine (0.0625-4.0 micrograms/kg i.v.) and guanfacine (0.0625-4.0 micrograms/kg i.v.) had no effect on cataplexy whereas BHT-920 (0.01875-3.0 micrograms/kg i.v.), BHT-933 (16.0-258 micrograms/kg i.v.) and xylazine (16.0-258 micrograms/kg i.v.) dramatically aggravated cataplexy.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic alpha-Agonists↗
Canine narcolepsy is associated with an elevated number of alpha 2-receptors in the locus coeruleus.
alpha 2-Receptors in the canine brain were pharmacologically characterized using [3H]yohimbine binding. Competition studies revealed a single class of binding sites in frontal cortex but two distinct subtypes in nucleus caudatus. The role of central alpha 2-receptors in narcolepsy was investigated in 5 normal and 5 narcoleptic Doberman pinschers. Scatchard analysis of [3H]yohimbine binding in different brain areas revealed an increase in the number of alpha 2-binding sites limited to the locus coeruleus. This suggests that altered autoinhibition of norepinephrine release may be associated with the narcoleptic symptomatology.
Animals↗
Central alpha 1 adrenoceptor subtypes in narcolepsy-cataplexy: a disorder of REM sleep.
The present study suggests the specific involvement within the central nervous system of an alpha 1 adrenoceptor subtype in a behavior, the control of cataplexy, a pathological analogue of rapid eye movement (REM) sleep atonia. Experiments have shown that prazosin, an alpha 1 antagonist, dramatically aggravates canine narcolepsy-cataplexy through a central mechanism, and that [3H]prazosin binding sites are increased in the amygdala of narcoleptic dogs. However, the corresponding Scatchard plots were curvilinear and best fit was obtained with a two-site model, suggesting the existence of two [3H]prazosin binding sites. These two sites (high and low affinity [3H]prazosin binding sites) met the criteria for authentic receptors and were respectively very similar to the alpha 1a and alpha 1b (high and low affinity for WB4101, respectively) subtypes recently described in the rat and rabbit. Our results of in vivo pharmacology and in vitro [3H]prazosin binding in canine narcolepsy now clearly implicate the low affinity [3H]prazosin binding site (alpha 1b) in canine narcolepsy: (1) Prazosin, an alpha 1 antagonist with similar affinity for both subtypes, was much more potent in increasing cataplexy than WB4101, a compound with more affinity for the alpha 1a receptor. (2) Chlorethylclonidine and phenoxybenzamine, two irreversible blockers of the alpha 1 receptors with more affinity for the alpha 1b receptors, aggravate cataplexy for up to two weeks. (3) The alpha 1 receptor upregulation previously reported by our group in the amygdala of narcoleptic dogs was due to a selective increase in the low affinity [3H]prazosin binding sites. A role for noradrenaline in REM sleep regulation has been suspected for many years, but has never been clearly elucidated.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic alpha-Antagonists↗
REM latency in Alzheimer's disease.
Latency to the first episode of rapid eye movement sleep (REML) has been proposed as a potential biomarker for Alzheimer's disease (AD). In this study, we compared REML values from 28 AD patients and 28 age- and sex-matched controls. We employed multiple definitions of REML and multiple cutoffs to classify patients and controls. Results indicated that the best REML definition and optimal cutoff criterion resulted in only 65% correct classifications. We discuss the longer REML in AD patients relative to controls in terms of both overall sleep disturbance and selective deterioration of the REM-cholinergic system. As REML may be relatively short in other forms of psychopathology (e.g., affective disorders), REML may still hold promise in the differential diagnosis of dementia and pseudodementia.
Aged↗
Restriction fragment length polymorphism in canine narcolepsy.
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Animals↗
Narcolepsy without unique MHC class II antigen association: studies in the canine model.
Human narcolepsy is almost exclusively associated with the major histocompatibility complex (MHC) class II antigen HLA-DR2 and is the strongest HLA-disease association described to date. Canine narcolepsy resembles the human disease in its behavioral manifestations and responses to therapeutic drugs. Therefore, mixed leukocyte culture (MLC) was used to study differences in the canine MHC class II (DLA-D) antigens present in narcoleptic dogs to determine whether an analogous, unique DLA-D antigen could be identified in canine narcolepsy. Results show at least five different DLA-D antigens appear in potential narcoleptic haplotypes among the 29 dogs studied. The data demonstrate that, unlike man, in dogs there is no unique D locus antigen associated with narcolepsy and further suggest that linkage disequilibrium with a specific MHC antigen is unlikely to be essential for the manifestation of canine narcolepsy. Because human narcolepsy is thought to be multigenic, the canine narcolepsy-MHC dissociation suggests that the dog model may help elucidate the non-MHC narcolepsy gene(s).
Animals↗
Prostaglandin E2 and its methyl ester reduce cataplexy in canine narcolepsy.
The effects of intravenous administration of prostaglandins (PGs) were investigated in genetically narcoleptic Doberman pinschers. The treatment of narcoleptic dogs with PGE2 and PGE2 methyl ester, but not PGD2 and PGD2 methyl ester, induced a dose-dependent reduction of canine cataplexy, a dissociated manifestation of rapid-eye-movement sleep. The effect was specific and not associated with any change in other behavior. Furthermore, the effect was long-lasting (up to 2 hr) and could not be explained by the acute cardiovascular changes seen after intravenous PG administration. PGE2 methyl ester, a lipophilic derivative of PGE2 with more central penetration than PGE2, was 4 times more potent than PGE2. These results indicate that PGE2 modifies cataplexy through a central effect and suggest that this prostaglandin may play a role in rapid-eye-movement sleep regulation.
Animals↗
Nerve conduction and creatinine clearance in aged subjects with periodic movements in sleep.
Periodic leg movements during sleep (PLMs) are non-epileptiform, repetitive limb movements that are highly prevalent among the geriatric population. The mechanisms underlying these movements are poorly understood. In this study we evaluated PLMs of 24 aged volunteers. We hypothesized that the high prevalence of PLMs seen in the aged would be related to (a) lower creatinine clearance and (b) slowed velocities/delayed latencies in the nerve conduction studies of such individuals. Results did not support hypothesis (a) but offered some equivocal support for hypothesis (b), inasmuch as aged subjects with higher levels of PLMs had delayed motor and sensory latencies in the upper limbs (median n., ulnar n.). Results are discussed in terms of central vs peripheral mechanisms involved in the generation of PLMs in elderly persons.
Aged↗
A method for checking interobserver reliability in observational sleep studies.
Disturbances of the sleep/wake cycle occur frequently in nursing home residents. Because of the many technical difficulties in studying sleep and rhythms in such patients, systematic behavioral observations offer an alternative approach. In this study we describe a method for determining interrater reliability of such observations. Two individuals observed 39 nursing home residents four times per hour during daytime and nighttime hours. Results indicated high interrater reliability for both sleep/wake and the presence of apnea during sleep. Both day and night observations were made reliably. We found only 101 discrepancies of 1.160 tandem observations. These results suggests that behavioral observations are a viable approach in the study of the sleep/wake cycle in nursing home settings.
Aged↗
Heart rate and blood pressure changes during sleep-waking cycles and cataplexy in narcoleptic dogs.
Cataplexy is the abrupt loss of muscle tone experienced by narcoleptics. It is usually precipitated by strong emotions or athletic activity. It has been hypothesized that cardiovascular variables have a role in the triggering of cataplexy. In the present study, we have utilized the narcoleptic canine model to directly investigate changes in heart rate and blood pressure in relation to cataplectic episodes. We found that heart rate increased 18% on average in the 20 s preceding cataplexy onset and then fell during cataplexy. Thus, from a cardiovascular standpoint, cataplexy can be subdivided into two very different periods, the cataplexy onset period with very high and declining heart rate, and the period greater than or equal to 10 s after onset, with greatly reduced heart rate. Heart rate at cataplexy onset was significantly higher than heart rate in rapid-eye-movement (REM) sleep, non-REM sleep, and quiet waking. Blood pressure did not markedly change before the onset of spontaneous cataplexies but decreased significantly during cataplexy. Although blood pressure increases did not precede spontaneous cataplexies, sudden increases in blood pressure, induced pharmacologically or by obstruction of the descending aorta, triggered cataplexy in the most severely affected subjects. A hypothesized role for cataplexy as a homeostatic reflex, triggered by interactions between blood flow, central chemoreceptors, and atonia control mechanisms in the medial medulla, is discussed.
Animals↗
Compliance and side effects in sleep apnea patients treated with nasal continuous positive airway pressure.
Nasal continuous positive airway pressure (CPAP) is an effective therapy for sleep apnea. We treated 144 patients with nasal CPAP and observed them for periods of as long as 25 months. No pneumothoraces occurred in any patient. Compliance rates were between 65% (90/139) and 83% (90/108), depending on the patient population considered. Demographic factors unrelated to discontinuing using CPAP included age, sex, and the presence of a housemate. Better-educated patients were less able to tolerate the equipment. Dry throat and nose and sore eyes were the most common side effects, but only sore eyes related to the amount of pressure. Side effects were unrelated to the number of months on the treatment, and obesity was related to higher pressures. Our study provides optimistic intermediate-term follow-up observations of patients on nasal CPAP therapy for sleep apnea. Whether adverse consequences occur over longer periods of time remains to be seen.
Adult↗
The influence of ambient temperature on sleep characteristics in the aged cat.
Sleep characteristics were compared in young adult and aged cats over a range of environmental temperatures from 5 to 35 degrees C. Although both groups exhibited sleep disruptions as ambient temperatures decreased, transient arousals were increased at temperature extremes in the aged group compared to young adults. Declining efficiency of thermoregulatory control and increased sensitivity to environmental temperature in the elderly may contribute to the changes in sleep quality which occur during the aging process.
Aging↗
Influence of freezer storage time on cerebral biogenic amine and metabolite concentrations and receptor ligand binding characteristics.
Brains from breed and age-matched canines stored at -80 degrees C for between 3 and 44 months showed a time-dependent decline in the concentration of norepinephrine in the amygdala and dopamine and norepinephrine in the caudate. No changes were seen in the density or ligand affinities of prazosin or spiperone binding sites in the same areas nor were there changes in quinuclidinyl benzylate binding sites in the frontal cortex. The changes in dopamine concentrations in the caudate were not accompanied by changes in the concentrations of dopamine metabolites. The chromatograms from which the dopamine and norepinephrine concentrations were estimated contained several unidentified, amperometrically detectable, extraneous peaks which increased in size in the older tissue samples. These results suggest that the decline in dopamine and norepinephrine concentrations was not the result of enzymatic breakdown, but probably the result of chemical decomposition. These findings have significance for the measurement of dopamine and norepinephrine concentrations in autopsied brains kept frozen in storage.
Amygdala↗
Effect of alpha 1-adrenoceptors blockade with prazosin in canine narcolepsy.
The role of central alpha 1-adrenergic receptors in cataplexy was investigated in 4 narcoleptic poodles and 6 genetically narcoleptic Doberman pinschers. Treatment of narcoleptic dogs with prazosin, a selective alpha 1-adrenergic receptor blocker, exacerbated cataplexy in both narcoleptic dog breeds. Control and heterozygous Dobermans were not affected by the drug. Binding studies using [3H]prazosin revealed an increase in alpha 1-receptor binding apparently limited to the amygdala. The present study suggests that central alpha 1-adrenoceptors, whose role is still mostly unknown, play a fundamental role in controlling mechanisms involved in cataplexy and REM sleep.
Animals↗
Effect of running wheel availability on circadian patterns of sleep and wakefulness in mice.
Sleep/wake expression in mice varies predictably with circadian phase. Such circadian rhythms are known to depend on intact suprachiasmatic nuclei (SCN) in the hypothalamus, but the mechanism by which SCN activity modulates sleep/wake expression is unknown. This paper examines the possibility that circadian patterns of sleep/wake derive partly from circadian timing of waking behaviors that are incompatible with sleep, such as locomotor activity. Voluntary locomotor activity was restricted in five mice adapted to a running wheel by locking the wheel in place. Continuous electrographic monitoring of sleep and wakefulness over multiple circadian cycles revealed: (1) during the active phase, shorter wake bouts and more frequent bouts of sleep, resulting in greater sleep/wake fragmentation and more time spent asleep; (2) during the rest phase, a small compensatory reduction in NREM sleep; (3) reduced amplitude of circadian sleep/wake rhythms and a greater amount of sleep overall. Thus, voluntary locomotor activity has an important influence on sleep/wake expression in mice, and the normal circadian pattern of sleep/wake depends on circadian timing of activity. Previous reports of damped circadian sleep/wake rhythms in rodents may therefore be explained by coincident diminutions in locomotor activity associated with age or health status. Our results also support analogous findings in human subjects, and we propose that elderly humans may benefit from therapies that augment daytime activity.
Animals↗
Nightly variation of periodic leg movements in sleep in middle aged and elderly individuals.
This study investigated night-to-night variation in periodic leg movements in sleep (PLMS). PLMS are common in the elderly, but their mechanism and significance are not understood. Forty-five aged individuals (means = 69.7 years) were studied polysomnographically for 2 or 3 nights with surface electrodes placed above the anterior tibialis. Results indicated that PLMS varied considerably from night to night within individuals, though there was not a significant difference between nights for the entire group. Some evidence indicated that individuals with less severe sleep complaints showed greater nightly variation. The nightly variation in PLMS was over four times as large as the nightly variation in breathing disturbance in sleep, another condition common in the sleep of the aged. These data suggest that studies relating PLMS to other key variables (e.g. symptoms of disturbed sleep) should rely on multiple nights of data or, if single night data are used, be particularly careful to replicate findings across samples.
Aged↗
Catastrophes, sleep, and public policy: consensus report.
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Accidents, Occupational↗