M. Mirmiran

Indirect bright light improves circadian rest-activity rhythm disturbances in demented patients

Light is known to be an important modulator of circadian rhythms. We tested the hypothesis than an enduring increase in the daytime environmental illumination level improves rest-activity rhythm disturbances in demented patients. Actigraphy was performed before, during, and after 4 weeks of increased illumination in the living rooms of 22 patients with dementia clinically diagnosed as probable Alzheimers disease, multi-infarct dementia, dementia associated with alcoholism, or normal pressure hydrocephalus. The results indicated that during increased illumination, the stability of the rest-activity rhythm increased in patients with intact vision, but not in visually impaired patients.

Alterations in the circadian rest-activity rhythm in aging and Alzheimer's disease

The suprachiasmatic nucleus, considered to be the endogenous circadian clock in the mammalian brain, shows morphological changes with aging, which become even more pronounced in Alzheimers disease (AD). In order to assess possible functional implications of these alterations, circadian rest-activity rhythms of 6 young and 13 old volunteers and of 12 AD patients were studied with a recently developed ambulatory rest-activity monitor (RA24). Young and old volunteers showed no differences in their rest-activity rhythm in any of the variables studied. Comparison of old controls versus AD patients revealed that (1) rest-activity rhythm was markedly disturbed in many of the AD patients and tended to be correlated with the severity of the dementia; (2) disturbances were most pronounced in subjects using sedating drugs; (3) disturbances in the latter group did not result from medication as no differences were found in the rest-activity patterns before and after administration of sedating drugs; (4) negative findings reported in the literature concerning circadian disturbances in AD may well have resulted from selection criteria that excluded the group of patients with the most severely affected rest-activity rhythm; and (5) rest-activity monitors offer a practical and fruitful approach for the study of circadian rhythms in humans.

Circadian rest—activity rhythm disturbances in alzheimer's disease

Previous studies showed circadian rhythm disturbances in patients with Alzheimers disease. Rest-activity rhythm disturbances manifest themselves through a fragmentation of the rhythm, a weak coupling with Zeitgebers, and high levels of activity during the night. The aim of the present study was to investigate which factors contribute to the presence of these disturbances. Therefore, several rest-activity rhythm, constitutional, and environmental variables were assessed in a heterogeneous group of 34 patients with Alzheimers disease, including presenile and senile patients living at home or in a nursing home, as well as in 11 healthy controls. Circadian rest-activity rhythm disturbances were most prominent in institutionalized patients. Regression analyses showed the involvement of the following variables. First stability of the rest-activity rhythm is associated with high levels of daytime activity and high levels of environmental light resulting from seasonal effects as well as from indoor illumination. Presenile onset contributed to instability of the rhythm. Second, fragmentation of periods of activity and rest is associated with low levels of daytime activity, and is most prominent in moderately severe dementia. Third, night-time activity level is higher during the times of the year when the days are getting shorter and lower when the days are growing longer. These findings indicate that rest-activity rhythm disturbances may improve by increasing environmental light and daytime activity, an assumption for which empirical evidence has recently been published.

Suppression of active sleep by chronic treatment with chlorimipramine during early postnatal development: effects upon adult sleep and behavior in the rat.

In an attempt to study the possible role of active sleep in brain development, male rats were injected twice daily with chlorimipramine, a potent monoamine reuptake blocker, from 1 week to 3 weeks of postnatal age. AS was reduced to less than 10% of total sleep time, the level found in mature rats. Most of the AS reduction was compensated for by quiet sleep but a slight increase in wakefulness also occurred, owing to brief interruptions of sleep at times when AS was expected. In adulthood, the AS-deprived rats showed a higher percentage of AS than did the controls, due to an increase in frequency and duration of AS epochs. Moreover, many of the epochs contained abnormally frequent and strong jerky body movements and rapid-eye-movements, reminiscent of neonatal AS patterns. In addition, the amplitude of hippocampal theta waves during AS was greater than in control rats. The chlorimipramine-treated rats also showed behavioral abnormalities in later life. On the open field test exploratory behavior was much reduced, while increased rearing and defecation occurred. Masculine sexual performance was severely deficient, primarily due to the low level of intromissions and ejaculations. Experimental animals performed less efficiently than controls on a temporal learning task (differential reinforcement of low response rate) and responded more rapidly on a spatial task (left-right alternation learning). These results demonstrate that early interference with the functioning of monoaminergic systems can have long-lasting physiological and behavioral consequences. Furthermore, they are consistent with the hypothesis that AS is an important factor in normal brain development.

Changes in vasopressin cells of the rat suprachiasmatic nucleus with aging

The suprachiasmatic nucleus (SCN) of the hypothalamus is considered to be the endogenous clock of the mammalian brain, regulating circadian rhythmicity of a great number of physiological and behavioural parameters. Numerous studies have shown that the circadian organization in the rat is progressively disturbed in senescence. However, a recent study by Peng et al.17 using conventionally stained material, revealed no decrease in overall SCN cell number of senescent rats. Their results have now been confirmed in this study. In addition, an increase in SCN volume (P = 0.02) and nucleus diameter (P = 0.001) and an overall decrease in cell density (P = 0.006) was observed. All these parameters seem to confirm the absence of a general degeneration in the senescent SCN. However, the major aim of the present study was to determine whether a well-defined population of neurons, i.e. the vasopressinergic (AVP) cells of the SCN, shows changes with aging. Immunocytochemical staining with antivasopressin and morphometry revealed a decrease of 31% (P = 0.007) in the number of these SCN neurons, whereas the remaining vasopressin cells became larger (P = 0.001). There were no statistical significant differences between rats housed in standard cages and those housed in an enriched environment in either age group, but the groups were relative small. Changes in either the number or stainability of SCN vasopressin neurons may be a morphological correlate of changed circadian rhythms in senescence.

Circadian rhythms in spontaneous neuronal discharges of the cultured suprachiasmatic nucleus.

The suprachiasmatic nucleus (SCN) is believed to play a major role in the generation and control of circadian rhythms in mammals. In order to obtain further evidence concerning this, single and multiple neuronal discharges were continuously recorded over a period of several days in neonatal rat SCN explants. These organotypic explants, which had been cultured for several weeks in a chemically defined medium, showed alternating high and low levels of spontaneous neuronal discharges with a periodicity around 24 h. Such explants can serve as a useful model to study the neuronal mechanisms underlying the generation of mammalian circadian rhythms.

Long-Term Fitness Training Improves the Circadian Rest-Activity Rhythm in Healthy Elderly Males

In old age, the circadian timing system loses optimal functioning. This process is even accelerated in Alzheimers disease. Because pharmacological treatment of day-night rhythm disturbances usually is not very effective and may have considerable side effects, nonpharmacological treatments deserve attention. Bright light therapy has been shown to be effective. It is known from animal studies that increased activity, or an associated process, also strongly affects the circadian timing system, and the present study addresses the question of whether an increased level of physical activity may improve circadian rhythms in elderly In the study, 10 healthy elderly males were admitted to a fitness training program for 3 months. The circadian rest-activity rhythm was assessed by means of actigraphy before and after the training period and again 1 year after discontinuation. As a control for possible seasonal effects, repeated actigraphic recordings were performed during the same times of the year as were the pre and post measurements in a control group of 8 healthy elderly males. Fitness training induced a significant reduction in the fragmentation of the rest-activity rhythm. Moreover, the fragmentation of the rhythm was negatively correlated with the level of fitness achieved after the training. No seasonal effect was found. Previous findings in human and animal studies are reviewed, and several possible mechanisms involved in the effect of fitness training on circadian rhythms are discussed. The results suggest that fitness training may be helpful in elderly people suffering from sleep problems related to circadian rhythm disturbances.

Non-pharmacological treatment of sleep and wake disturbances in aging and Alzheimer's disease: Chronobiological perspectives

Numerous studies indicate a deterioration of nighttime sleep and daytime cognitive performance in elderly people and Alzheimer patients. As a result of the increasing number of elderly people and Alzheimer patients in the western society, attention for these problems has grown. However, so far, the major research effort has been concentrating on the development of pharmacological therapies for an isolated age-related problem. In the present review it is argued that several age-related problems with sleep and wakefulness may reflect a dampening of circadian rhythm amplitudes. Non-pharmacological manipulation of circadian rhythms by means of various external stimuli appears to be effective in improving sleep and cognitive functioning in elderly people and Alzheimer patients.

Aging and circadian rhythms

Publisher Summary This chapter summarizes the current knowledge about the circadian system and its organization and provides an overview of chronobiological studies in which age or dementia has been treated as independent variable. It also discusses the relevance of considering circadian variations in gerontology and indicates possible fruitful future directions of the research related to aging and circadian rhythms. Circadian rhythms—that is, rhythmic changes with a periodicity of approximately 24 hours—can be observed in organisms ranging from protozoans to humans. Organization in the dimension time is a pervasive characteristic of living systems. The circadian timekeeping system appears to be changed during aging in both animals and humans. Because of the growing interest in gerontology, the number of functional systems for which age-related changes are described is continuously increasing. In contrast to some other systems sensitive to the effects of aging, the circadian timekeeping system is directly implicated in the organization of various important physiological functions. The reduction in suprachiasmatic nuclei (SCN) cell number found in old age and even stronger in Alzheimers disease represents a possible morphological correlate of circadian rhythm alterations in old age.

Age-related changes in the sleep pattern of male adult rats

In order to study whether or not the age-related changes in the sleep pattern observed in humans also occur in rats, young adult (4 months) and old (22 months) male Wistar rats were implanted with EEG and EMG electrodes for 24 h on-line registration by means of an automatic sleep-classifier. During the 12 h light period, the old rats as compared to the young adult ones showed a significant increase of the time spent awake and a decrease of active sleep time. Furthermore, the light-dark ratio was decreased in the old rats for wakefulness and active sleep. Off-line analysis of the EEG during quiet sleep and active sleep revealed no differences between the two age groups. These results suggest the existence of a number of considerable age-related changes in the sleep pattern of adult rats, which are comparable to those observed in humans.