Treatment of behavioural, cognitive and circadian rest-activity cycle disturbances in Alzheimer's disease: haloperidol vs. quetiapine.

This 5-wk, open-label, comparative study investigated the effects of quetiapine and haloperidol on behavioural, cognitive and circadian rest-activity cycle disturbances in patients with Alzheimer's disease (AD). Out of a total of 30 patients enrolled in the study, there were 22 completers, 11 in the quetiapine group (mean age 81.9+/-1.8 yr, mean baseline MMSE 19.9+/-1.3, mean dose 125 mg) and 11 in the haloperidol group (mean age 82.3+/-2.5 yr, mean baseline MMSE 18.1+/-1.3, mean dose 1.9 mg). As shown in the Neuropsychiatric Inventory, both medications reduced delusion and agitation, whereas quetiapine additionally improved depression and anxiety. Haloperidol worsened aberrant motor behaviour and caused extrapyramidal symptoms. In the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological test battery which assessed cognitive parameters, quetiapine improved word recall; significant interaction terms revealed differences between quetiapine and haloperidol in word-list memory and constructional praxis. According to the Nurses' Observation Scale for Geriatric Patients (NOSGER) quetiapine improved instrumental activities of daily living. Actimetry documented the circadian rest-activity cycle before and after treatment. Sleep analysis revealed that patients receiving quetiapine had shorter wake bouts during the night, whereas patients receiving haloperidol had fewer though longer immobile phases. The study provides evidence that quetiapine at a moderate dose may be efficacious in treating behavioural disturbances in AD, with better tolerability than haloperidol.

Age-related changes in the circadian modulation of sleep-spindle frequency during nap sleep.

STUDY OBJECTIVES: Sleep spindles exhibit a clear circadian modulation in healthy younger people. During the biological night (when melatonin is secreted), spindle density and spindle amplitude are high and spindle frequency and its variability are low, as compared with the biological day. We investigated whether this circadian modulation of spindle characteristics changes with age. DESIGN: A 40-hour multiple-nap paradigm under constant-routine conditions SETTING: Chronobiology Laboratory, University Psychiatric Hospitals, Basel, Switzerland PARTICIPANTS: Seventeen younger (20-31 years) and 15 older (57-74 years) volunteers. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Whereas the circadian modulation of spindle density, amplitude, duration, and intraspindle frequency variability was not greatly affected by age, we found significant changes in the circadian modulation of spindle frequency. The pronounced circadian modulation of spindle frequency in younger, but not older, subjects was phase locked with the circadian rhythm in melatonin secretion. In the latter, circadian modulation was attenuated and tended to be advanced with respect to the timing of melatonin secretion. There was no difference between age groups in the phase of the sleep-wake cycle or that of melatonin, nor did the phase angle between them differ. Although changes in the circadian modulation of spindle frequency in older subjects were accompanied by reduced amplitude in the sleep consolidation profile, there was no significant correlation between spindle frequency and sleep consolidation. CONCLUSION: This multiple-nap protocol under constant-routine conditions revealed an age-dependent weaker coupling of the circadian rhythms of spindle frequency and sleep propensity to the circadian rhythm of melatonin secretion.

Age-related attenuation of the evening circadian arousal signal in humans.

The human circadian pacemaker maintains timing and consolidation of sleep-wake behavior by opposing the build-up of homeostatic sleep pressure during the wake episode, particularly in the evening during the 'wake maintenance zone'. We tested whether age-related changes in sleep are a consequence of a weaker circadian arousal signal in the evening. Circadian rhythms and spectral components of the sleep EEG were investigated in 17 young (20-31 year) and 15 older (57-74 year) volunteers under constant posture conditions during a 40-h nap protocol (75/150 min sleep/wake schedule). Quantitative evidence for a weaker circadian arousal signal in aging arose from significantly more sleep occurring during the wake maintenance zone and higher subjective sleepiness ratings in the late afternoon and evening in the older group. In addition, we found a diminished melatonin secretion and a reduced circadian modulation of REM sleep together with less pronounced day-night differences in the lower alpha and spindle range of sleep EEG activity in the older group. Thus, our data indicate that age-related changes in sleep propensity are clearly related to a reduced circadian signal opposing the homeostatic drive for sleep.

The frontal predominance in human EEG delta activity after sleep loss decreases with age.

Sleep loss has marked and selective effects on brain wave activity during subsequent recovery sleep. The electroencephalogram (EEG) responds to sleep deprivation with a relative increase in power density in the delta and theta range during non-rapid eye movement sleep. We investigated age-related changes of the EEG response to sleep deprivation along the antero-posterior axis (Fz, Cz, Pz, Oz) under constant routine conditions. Both healthy young (20-31 years) and older (57-74 years) participants manifested a significant relative increase in EEG power density in the delta and theta range after 40 h of sleep deprivation, indicating a sustained capacity of the sleep homeostat to respond to sleep loss in ageing. However, the increase in relative EEG delta activity (1.25-3.75 Hz) following sleep deprivation was significantly more pronounced in frontal than parietal brain regions in the young, whereas such a frontal predominance was diminished in the older volunteers. This age-related decrease of frontal delta predominance was most distinct at the beginning of the recovery sleep episode. Furthermore, the dissipation of homeostatic sleep pressure during the recovery night, as indexed by EEG delta activity, exhibited a significantly shallower decline in the older group. Activation of sleep regulatory processes in frontal brain areas by an extension of wakefulness from 16 to 40 h appears to be age-dependent. These findings provide quantitative evidence for the hypothesis that frontal brain regions are particularly vulnerable to the effects of elevated sleep pressure ('prefrontal tiredness') and ageing ('frontal ageing').