Dementia severity and Lewy bodies affect circadian rhythms in Alzheimer disease

Abstract

Sleep disturbance is a symptom shared by all neurodegenerative, dementing illnesses, such as Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB), and its presence frequently precipitates decisions to seek institutional care for patients. Although the sleep disturbances of AD and DLB are qualitatively similar, they appear to be more prominent in patients with DLB. Disturbance of the circadian rhythm has been noted and is a potential factor underlying the nocturnal sleep fragmentation and daytime sleepiness observed in these patients. We studied the circadian variation of core-body temperature and motor activity in a total of 32 institutionalized patients with probable AD by NINCDS-ADRDA criteria, 9 of whom also met pathologic criteria for DLB. Eight, healthy, elderly male controls were studied on a clinical research unit designed to simulate the hospital environment where the dementia patients were studied. Circadian variables generally had greater deviations from normal associated with increasing AD pathology, as measured by postmortem-determined Braak stage, supporting the hypothesis that central changes mediate circadian disturbances in AD and DLB. Patients with a postmortem diagnosis of DLB manifested greater disturbances of locomotor activity circadian rhythms than patients with AD, possibly reflecting the greater sleep disturbances seen in this population, but the differences from normal in the circadian rhythms of the AD and DLB patients were qualitatively similar.

Introduction

Sleep–wake regulation in normal adults can best be characterized as an interaction between two discrete processes. The first, circadian process promotes alertness as a function of time of day. The second, homeostatic process builds need to sleep as a function of the duration of prior wakefulness [5], [11]. Aging has been shown to contribute to a deterioration in sleep quality and an increased incidence of reported sleep disturbance [34], including increased wakefulness and decreased time in slow-wave and REM sleep [19], [28]. Age-associated changes in sleep appear to be a consequence of changed homeostatic [8] rather than altered circadian function [12].

Sleep disturbance is a frequent symptom in patients clinically diagnosed with age-associated, neurodegenerative dementias such as Alzheimer’s disease [21], [28], (AD) and Pick’s disease [26], and its presence often precipitates decisions by families and others to seek institutional care [27]. Patients diagnosed with probable AD also show direct circadian disturbances including reduced amplitude and phase-delay of circadian variation of core-body temperature and activity [30], [35] that could be contributing to the sleep disturbance.

These studies have not addressed the question of whether the circadian abnormalities and sleep–wake disturbances seen in patients with probable AD stem from endogenous or exogenous influences. Dementia patients in nursing homes [1], [9], and other institutional environments specializing in the care of patients with neurodegenerative dementia [35] have been found to have lower diurnal and greater nocturnal exposure to light than community-dwelling elderly. These changes have been linked to sleep disturbance in residents of these facilities [31], where opportunities for social interaction and other environmental time cues may be reduced and impact the sleep of nursing home patients. These exogenous influences, however, are distinct from the endogenous, neurodegenerative features of dementing illnesses normally thought to cause the emergence of behavioral symptoms, such as sleep and circadian rhythm disturbances. Evidence to date from the limited literature addressing this question, implicates endogenous factors as a prime contributor to circadian disturbances in patients with AD [18]. Patients studied at the same institution, yet with different dementia diagnoses, have demonstrably different circadian abnormalities [18] supporting the hypothesis that the different neurodegenerative patterns of these illnesses had a major influence on the ultimate, observed circadian disturbances.

However, a diagnostic distinction, that has not yet been examined for circadian disturbance, is dementia with Lewy bodies (DLB), a relatively recently defined nosological entity [24]. Lewy bodies are spherical, eosinophilic, neuronal inclusions composed of low molecular-weight neurofilaments and, when seen in the substantia nigra, are the pathological hallmark of Parkinson’s disease. In DLB, however, Lewy bodies are seen in cortical as well as in subcortical regions of the brain outside of the substantia nigra. AD and DLB share some neuropathological features such as beta-amyloid plaques, however, patients with DLB often lack the neurofibrillary tangles generally seen in AD [17]. This intricate relationship between DLB and AD makes for great difficulties in accurately distinguishing DLB and AD clinically [15], [22].

Patients with DLB have sleep disturbances similar to those with other neurodegenerative dementias, however DLB patients are noted to have greater overall sleep disturbance than patients with AD [16]. Manifestations of their sleep disturbance include some clearly non-circadian phenomena such as a greater incidence of REM sleep behavior disorder, a syndrome characterized by the loss of the ability to maintain muscle atonia during REM sleep [4], [13]. The increased daytime sleepiness and nightime arousals seen in DLB compared to AD could have a source in circadian regulation [16].

In the present study, therefore, we further test the hypothesis that endogenous, disease-specific factors are responsible for the circadian disturbances in AD. First, if central, disease-related processes govern the circadian alterations in AD then the more severe the changes, the more profound the circadian disturbances should be. Braak staging of Alzheimer-related changes [6] provides a standardized assessment tool for the evaluation of severity of pathology which correlates well with clinical progression of the illness [3]. Second, if environmental influences are most important, circadian disturbances in DLB should resemble those seen in AD.