Studies with Alzheimer's patients

The common thread in many research papers is that the organic progress of Alzheimer's disease results in damage to a part of the brain - the suprachiasmatic nucleus (SCN) - that controls circadian rhythms. The combination of damaged nerve pathways caused by the disease and the eyes' natural deterioration due to ageing means that indoor levels of light are not usually strong enough to signal that it's daytime and the patient's internal body clock is not synchronised with the daily routine. This affects not only the wake-up process in the morning but also the timing of the body winding down ready for sleep that would normally start in the evening. By using bright light, disruption to the normal circadian rhythms can be reduced, making it more likely that the patient will be able to fit in with a normal daily sleep/wake cycle.

Dawn-dusk simulation light therapy of disturbed circadian rest-activity cycles in demented elderly

Exp Gerontol. 2003 Jan-Feb;38(1-2):207-16
We investigated whether low intensity dawn-dusk simulation (DDS), a 'naturalistic' form of light therapy designed to embed sleep in its accustomed phase, could improve the disturbed circadian rest-activity cycle, nocturnal sleep and and/or cognitive functions in dementia. A protocol of 3 weeks each of baseline, treatment and follow-up was completed by 13 patients (85yr old+/-5yr, MMSE 14+/-5; n=9 DDS versus n=4 'placebo' dim red light) who wore an activity/lux monitor throughout. There were no significant changes in clinical or cognitive status, nor modification of circadian stability or amplitude characteristics of the rest-activity cycle. However, two aspects of sleep responded to DDS but not to dim red light. The main sleep episode was 1:14h earlier during treatment (p=0.03) compared with before and after DDS. With respect to actimetry-determined sleep variables, the DDS group tended to have shortened 'sleep latency', longer 'sleep duration', more nocturnal immobility and less nocturnal activity than the dim red group (p<0.1). In parallel, night-time light exposure tended to be reduced (p=0.07). These promising findings - after only 3 weeks of light treatment in elderly patients with advanced dementia - suggest that the circadian timing system remains functionally responsive even to low intensity DDS light. Increasing zeitgeber strength is an important strategy for improving sleep quality and timing in dementia, and DDS light therapymay provide one of the appropriate means to do so.

This study found that dawn (and dusk) simulation was effective in improving the quality of sleep in people suffering from dementia.

Variations in circadian rhythms of activity, sleep, and light exposure related to dementia in nursing-home patients
Sleep 1997;20(1):18-23
We measured 24-hour circadian-rhythm patterns of activity and sleep/wake activity in a group of nursing-home patients (58 women and 19 men with a mean age of 85.7 years). Severely demented patients were contrasted with a composite group of moderate y, mild, or not-demented patients. Sleep/wake activity and light exposure were recorded with the Actillume recorder. Cosinor analyses were computed to determine the mesor, amplitude, acrophase, and circadian quotient of the activity rhythms. The diagnosis of dementia was based on the Mini Mental Examination and on examination of medical records. Sleep was extremely fragmented in both groups of nursing-home patients. Severely demented patients slept more both at night and during the day, but there were no significant differences in the number of awakenings during the night or in the number of naps during the day when compared to the composite group of moderate, mild, or no-dementia patients. The severely demented group had lower activity mesor, more blunted amplitude, and were more phase delayed (i.e. had later acrophases) than the other group. In addition, the severely demented patients spent less time exposed to bright light. These results confirm that circadian rhythms in nursing-home patients are disturbed with more disturbance in the severely demented. Much of the disturbance may be related not just to age but to mentalstatus.

Indirect bright light improves circadian rest-activity rhythm disturbances in demented patients
Biol Psychiatry. 1997 May 1;41(9):955-963
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 Alzheimer's 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.

[Sleep disorders and dementia]
Schweiz Rundsch Med Prax. 1997;86(35):1343-9
AB A clinically relevant sleep-wake disturbance is found in up to half the patients with dementia, and the sundowning agitation is a common cause of institutionalisation of demented geriatric patients. The circadian rhythm of demented patients is levelled off with increased daytime sleep and disrupted night sleep. Particularly in vascular dementia, Korsakow syndrome, Parkinson's disease, and depression the alteration of sleep architecture may be pronounced, whereas in Alzheimer's disease prominent hypersomnolence or insomnia is typically only found in later stages of the diseases. Greatly increased daytime sleepiness or striking insomnia at the very beginning of suspected dementia should thus prompt the search for other, possibly treatable causes of dementia. Neuropathological and neurophysiological studies support the hypothesis of a deteriorated hypothalamic suprachiasmatic nucleus (harbouring the biological clock) as a cause for the deranged circadian sleep-wake system in dementia. Management of sundowning behaviour includes restriction of daytime sleep, exposure to bright lights, and social interaction schedules during the day. The benzodiazepines and analogues usually not being sufficiently effectual, low doses of mild neuroleptics are often needed. Whether recent reports on efficacy of melatonin in elderly insomniacs also apply to demented patients is yet uncertain. The careful search and treatment of possible extracerebral physiologic factors causing reversible hypersomnia or insomnia is an important requisite. Polysomnographic studies are needed to recognise treatable sleep disturbance which could deteriorate or mimic dementia and sundowning. Particularly, a sleep-apnea-hypopnea syndrome must be searched for at the beginning of a suspected dementia, when successful treatment is still possible. Sleep studies should also identify periodic leg movements of sleep with restless legs and/or increased daytime sleepiness, and hyperkinetic parasomnias such as REM sleep behaviour disorder which may complicate or imitatesundowning.

 

[Peripheral nerve stimulation in Alzheimer's disease]
Tijdschr Gerontol Geriatr. 1997 Apr;28(2):59-68
The "use it or lose it' concept implies that stimulation of neurons might stop degenerative activities and initiate regenerative processes in aging and Alzheimer's disease (AD). Based on this concept, the effects of Transcutaneous Electrical Nerve Stimulation (TENS), tactile stimulation, and a combination of the two on memory and affective behaviour of AD patients were examined. The results suggest that, compared to AD patients of the control group, patients of the experimental group improved in visual short-term memory, verbal and visual long-term memory, and verbal fluency. Moreover, stimulated AD patients participated more independently in activities of daily life and their affective behaviour improved. As in those studies the therapist was present during the peripheral stimulation of the experimental group and the sham stimulation of the control group, interpersonal communication alone could not explain the treatment effects. However, a positive effect of the combination of TENS with personal interpersonal communication could not be excluded. Consequently, it was examined whether TENS, in the absence of the therapist, could also have a beneficial influence on the cognitive and behavioural functioning of AD patients. In addition, it was investigated whether TENS had a positive effect on the rest-activity rhythm of AD-patients. The results show that improvements in visual short- and long-term memory, verbal long-term memory, and verbal fluency are solely due to the peripheral stimulus itself. Furthermore, the independent and affective functioning of both the experimental and control group appeared to relatively improve by interpersonal communication. Moreover, the rest-activity rhythm of stimulated AD-patients improved. Peripheral nerve stimulation in AD might thus become a new treatment strategy to improve patients' qualityof life.

Morning bright light therapy for sleep and behaviour disorders in elderly patients with dementia

Disruptive behavior and actigraphic measures in home-dwelling patients with Alzheimer's disease: preliminary report
J Geriatr Psychiatry Neurol. 1997 Apr;10(2):58-62
The purpose of this preliminary report was to explore overall level and diurnal patterning of caregiver reports of abnormal behavior and to explore relationships with actigraphic measures of sleep/wake activity in Alzheimer's disease (AD) patients. Our primary behavioural measure was the Time-based Behavioural Disturbance Questionnaire (TBDQ). The overall score on this measure was shown to have adequate test-retest reliability and convergent validity with another behavioural measure. Significant correlations were obtained between the TBDQ overall score and actigraphically scored sleep efficiency (r = -.35, P < .05) and wake after sleep onset (r = .43, P < .01) in 41 subjects. The data suggest a moderate relationship between actigraphic measures of sleep/wake and disturbedbehavior in home-dwelling AD patients.

Circadian rest-activity rhythm disturbances in Alzheimer's disease
SO Journal of Geriatric Psychiatry and Neurology 1997;10(2):58-62.
AB Previous studies showed circadian rhythm disturbances in patients with Alzheimer's 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 Alzheimer's disease, including pre senile 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 institutionalised 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. Pre senile 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 evidencehas recently been published.

Phototherapy for patients with Alzheimer disease with disturbed sleep patterns: results of a community-based pilot study
Alzheimer's Disease and Associated Disorders. 1997;11(3):175-8
We examined the entraining effects of phototherapy delivered by light visors on disturbed sleep patterns of community-dwelling research subjects with Alzheimer disease (AD). The pilot project used a single subject design and activity monitoring as the primary outcome measures. The protocol consisted of a 5-day baseline monitoring period, followed by 10 consecutive days of phototherapy (2,000 lux of full spectrum bright light) delivered by light visors for 2 hours each morning; this was followed by an additional 14 days of activity monitoring. Cosinor analyses found no consistent changes in acrophase, mesor, or amplitude. Observed changes in acrophase were consistent with phase advancement of the rest-activity cycle and consistent with the biological intervention. Changes in the number of night-time awakenings were not found. One subject had a significant increase in total sleep time, whereas another had a significant decrease in total sleep time. Failure to find a consistent biological effect of light on AD subjects may be secondary to: (1) insufficient duration of light exposure; (2) timing of light administration (given at a time when circadian rhythm is refractory to the effects of light); (3) advanced stages of AD making the Y circadian pacemaker in the suprachiasmatic nucleus of the hypothalamus insensitive to the biological effects of light; and (4) inadequacyof light visors as a means of providing light.

Different manifestations of circadian rhythms in senile dementia of Alzheimer's type and multi-infarct dementia

Acta Psychiatr Scand 1994 Jan;89(1):1-7
Using an actigraph and a long-term body temperature (BT) monitoring system, we simultaneously monitored rest-activity (R-A) and BT rhythms in patients with senile dementia of Alzheimer's type (SDAT; n = 20) or multi-infarct dementia (MID; n = 21) for 5-7 consecutive days. The SDAT group exhibited a well-organized BT rhythm with significantly higher amplitude compared with the MID group. The SDAT group also showed significant positive correlation between the total daily activity as well as percentage of night-time activity and the degree of dementia, while no such tendency was observed in the MID group. The different properties of the biological rhythm disorders among the SDAT and MID groups possibly underlie theirsleep and behavioural disorders.

Non-pharmacological treatment of sleep and wake disturbances in aging and Alzheimer's disease: chronobiological perspectives
Behav Brain Res. 1993 Nov 30;57(2):235-53
Numerous studies indicate a deterioration of night-time 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 cognitivefunctioning in elderly people and Alzheimer patients.

Bright light treatment of behavioural and sleep disturbances in patients with Alzheimer's disease
Am J Psychiatry. 1992 Aug;149(8):1028-32
OBJECTIVE: The authors tested the hypothesis that evening bright light pulses would improve sleep-wake patterns and reduce agitation in patients with Alzheimer's disease who have severe sundowning (a syndrome of recurring confusion and increased agitation in the late afternoon or early evening) and sleep disorders. METHOD: Ten inpatients with Alzheimer's disease on a research ward of a veterans' hospital were studied in an open clinical trial. All patients had sundowning behavior and sleep disturbances. After a week of baseline measurements, patients received 2 hours/day of exposure to bright light between 7:00 p.m. and 9:00 p.m. for 1 week. During the baseline week, the treatment week, and a post treatment week, patients were rated by nurses for agitation, sleep-wake patterns, use of restraints, and use of prescribed-as-needed medication. On the last 2 days of each week, patients wore activity monitors. Activity counts were analysed for circadian rhythmicity. RESULTS: Clinical ratings of sleep-wakefulness on the evening nursing shift improved with light treatment in eight of the 10 patients. The proportion of total daily activity occurring during the night-time decreased during the light-treatment week. The relative amplitude of the circadian locomotor activity rhythm, a measure of its stability, increased during the light-treatment week. More severe sundowning at baseline predicted greater clinical improvement. CONCLUSIONS: Evening bright light pulses may ameliorate sleep-wake cycle disturbances in some patients with Alzheimer's disease. This effect may be mediatedthrough a chronobiological mechanism

Circadian rhythms and the suprachiasmatic nucleus in perinatal development, aging and Alzheimer's disease
Prog Brain Res 1992;93:151-162
Circadian rhythms are already present in the foetus. At a certain stage of pre-natal hypothalamic development (around 30 weeks of gestation) the foetus becomes responsive to maternal circadian signals. Moreover, recent studies showed that the foetal biological clock is able to generate circadian rhythms, as exemplified by the rhythms of body temperature and heart rate of pre-term babies in the absence of maternal or environmental entrainment factors. Pre-term babies that are deprived of maternal entrainment and kept under constant environmental conditions (e.g., continuous light) in the neonatal intensive care unit run the risk of developing a biological clock dysfunctioning. However, the fact should be acknowledged that at least in mice the development of the circadian pacemaker (i.e., SCN) does not depend on environmental influences (Davis and Menaker, 1981), although other data suggest that severe disruption of the maternal circadian rhythm indeed abolishes the circadian rhythm of the foetal SCN (Shibata and Moore, 1988). During aging and in particular in AD circadian rhythms are disturbed. These disturbances include phase advance and reduced period and amplitude, as well as an increased intradaily variability and a decreased interdaily stability of the rhythm. Among the factors underlying these changes the loss of SCN neurons seems to play a central role. Other contributory factors may be reduced amount of light, degenerative changes in the visual system and the level of activity and decreased melatonin.
PMID: 1480747, UI: 93126560

Disruption of circadian regulation by brain grafts that overexpress Alzheimer beta/A4 amyloid
Proc Natl Acad Sci. 1992 Aug 1;89(15):7090-4
Alzheimer disease patients exhibit irregularities in the patterns of normally circadian (daily) rhythms. Alzheimer-type pathology has been reported in the hypothalamus and in the suprachiasmatic nuclei, the putative site of the circadian oscillator. We examined the relationship between the neuropathology of Alzheimer disease, as modelled by an animal system, and circadian dysregulation by grafting genetically transformed cells that overexpress beta/A4 amyloid into the suprachiasmatic nuclei of adult rats. Grafts of beta/A4-positive cells, but not of control cells, significantly altered the pattern of activity of implanted rats. Although experimental conditions included light-dark cycles that normally tend to drive rats to 24-h rhythms, animals with grafts of beta/A4-positive cells showed abnormally high levels of activity during the light phase in addition to a disrupted circadian pattern. Periodogram analysis demonstrated significant rhythms outside of a circadian range. The body temperature rhythm of these animals was also weak 6 weeks after grafting; however, unlike activity patterns, body temperature regained a circadian period by 8 weeks after cell implantation. These data indicate that disruption of circadian activity is a behavioural measure of the consequences of beta/A4 accumulationin brain implants.

Another study investigated the effect of exposure to bright light on agitation and sleep disorder of AD patients. Patient were exposed to 2hrs of bright light in the evening and agitation and sleep were monitored. Light treatment decreased the proportion of total activity occurring during the night-time and increased the amplitude of the circadian locomotor activity rhythm. Light treatment also improved clinical ratings of sleep-wakefulness on the evening nursing shift and more severe sundowning at baseline predicted greater clinical improvement (Satlin, Volicer, Ross, Herz and Campbell, Am.J.Psychiatry 149:1028-1032, 1992).

In a more recent study, circadian rhythms of core-body temperature and locomotor activity were examined in 28 patients with probable AD and 10 healthy controls. The body temperature of the patients was measured by an electronic sensor inserted into the rectum. Motor activity of the patients was measured by a movement monitor worn in patient's clothing. Data were collected in a storage device for later computer analysis. AD patients had higher percent nocturnal activity than controls, corresponding to the clinical picture of fragmented sleep. The amplitude of the activity cycle on the AD patients was lower than that of controls, and the acrophase of this cycle in AD patients was 4.5 hrs later than in controls. There was no difference in the amplitude of the core-body temperature circadian rhythm, but AD patients had delayed temperature acrophases. A subgroup of AD patients with large mean time differences between acrophases of their activity and temperature cycles had lower temperature amplitudes, and greater activity during the night. These findings suggest that a subgroup of AD patients with impaired endogenous pacemaker function may have a diminished capacity to synchronise the rhythm of core-body temperature with the circadian cycle of rest-activity. This circadian rhythm dysfunction may partly explainthe fragmented nocturnal sleep exhibited by these patients.

Circadian rhythms and light therapy
The effect of dementia of the Alzheimer type (DAT) on circadian rhythms and their relationship to behavioural problems of patients suffering from DAT were investigated in several studies. We have found that patients have increased nocturnal motor activity and decreased amplitude of circadian activity rhythm (Satlin, Teicher, Lieberman, Baldessarini, Volicer and Rheaume, Neuropsychopharm. 5:115-126, 1991). In addition, DAT patients showed a marked phase-delay, with individual afternoon maxima averaging 2.1 hours later than in controls.