Disrupted daily activity/rest cycles in relation to daily cortisol rhythms of home-dwelling patients with early Alzheimer's dementia

Abstract

Disturbed sleep cycles are the principal cause of institutionalization in dementia, and therefore represent a major clinical problem. They may arise from dysfunction within the circadian clock of the hypothalamus that times and consolidates wakefulness, or from neuropathology in output pathways and/or target sites of the clock specifically controlling sleep and wakefulness. To determine the relationship of disturbed activity cycles to other circadian clock-controlled rhythms, cross-sectional and longitudinal actigraphy and serial sampling of saliva were used to compare the impact of early Alzheimer's dementia on activity/rest and cortisol rhythms in home-dwelling subjects. Mildly demented subjects had daily activity rhythms comparable to those of healthy age-matched subjects. Moderately demented subjects exhibited a range of disturbances of the activity/rest cycle, with reduced stability, increased fragmentation and loss of amplitude. Within the moderately demented group, however, the degree of circadian disruption was not correlated with the individual severity of dementia. All groups of subjects, mild, moderate with normal activity cycles and moderate with abnormal activity cycles, exhibited robust daily profiles of salivary cortisol, with highest levels in the morning (08:00 h) and an evening nadir (20:00-24:00 h). Salivary cortisol levels tended to be higher in the moderately demented subjects in the afternoon, but this effect was not specific to those with abnormal activity/rest patterns. The actimetric data confirm that deterioration of activity/rest cycles is a common and progressive feature in home-dwelling Alzheimer's patients, occurring early in the disease but after the measurable onset of dementia. The maintenance of highly rhythmic daily cortisol profiles in association with disturbed activity profiles, both on an individual and on a group basis, demonstrates that loss of circadian control to activity/rest cycles is not a consequence of global circadian disruption in early dementia. Rather, pathology may develop in discrete elements of the circadian clockwork and/or its output systems that control activity/rest, sleep and wakefulness. Further characterization of this pathology will facilitate more effective management of sleep patterns in home-dwelling demented patients.

Melanopsin retinal ganglion cell loss in Alzheimer disease

“…The circadian measures did not correlate with dementia severity. These results are concordant with those reported by others 3, 62. The lack of significant differences compared to controls for circadian parameters may be due to the inclusion in our study of mild–moderate AD cases.…”

“…This could be due to the intrinsic nature of pathology that produces variable severity of circadian derangement in this disease, as already reported in other case series 3. In our series of mild–moderate AD patients, although we failed to detect a significant difference in terms of circadian parameters (IS, IV, and RA) between AD and controls, there was a subgroup of AD patients with pathological circadian values (>2 SD from the mean of controls).…”

“…This suggests that cognitive and circadian abnormalities may have different rates of progression, which could reflect different pathophysiological mechanisms, as suggested in previous studies 68. Moreover, the patients with the worst outcome had a significantly lower stability of circadian parameters at baseline evaluation 3. Thus, the presence of significant circadian dysfunction in the early stages of disease may be a predictive factor of poor outcome in AD patients.…”

“…Selection of mild–moderate cases was constrained by the need to have the necessary compliance for reliable OCT studies. A previous study by Hatfield and coauthors, in a 1‐year follow‐up of mild–moderate AD patients, showed that the actigraphic pattern did not deteriorate over time, even in the presence of a significant decline of cognitive functions 3. This suggests that cognitive and circadian abnormalities may have different rates of progression, which could reflect different pathophysiological mechanisms, as suggested in previous studies 68.…”

The Circadian System in Alzheimer’s Disease: Disturbances, Mechanisms, and Opportunities

“…The use of noninvasive actigraphy (usually via a wristworn accelerometer) has been beneficial in monitoring rest/ activity cycles in dementia patients since the early 1990s (14,15). Later rest/activity cycles of home-dwelling AD patients were examined over one year, and those with mild dementia displayed rhythms not significantly different from those of control subjects, whereas those with moderate dementia displayed fragmentation of the rhythm and decreased amplitude, although these effects were not correlated with the severity of the dementia (16). Van Someren et al (17) reported that rhythms were most fragmented in institutionalized AD patients and that higher levels of daytime activity predicted more coherent rhythms, whereas lower levels of daytime activity predicted rhythm fragmentation.…”