SENILE CHANGES IN CIRCADIAN RHYTHMS AND BEHAVIOR

睡眠障碍和其他行为障碍是常见的抱怨

Sleep disorders and other behavioral disturbances are common complaints among patients with Alzheimer's disease (AD) and their families, and frequently result in institutionalization. Evidence from previous investigations suggests that these clinical problems may be due in part to age- and disease-related disturbances in one or more components of the human circadian timing system. The long-term goals of our research are two-fold and complementary: 1. To determine the pathophysiology of sleep and behavioral disturbances in AD as these related to abnormalities of structure and function in the circadian timing system; 2. To elucidate the mechanisms by which structural components of the circadian timing system affect behavior, using a pathological condition (AD) as an experiment of nature. The specific aims of this research are: 1. To employ a constant routine protocol to determine the amplitude and phase of the endogenous circadian pacemaker in AD, free of those masking influences present under natural conditions; 2. To assess the relationship between amplitude and phase changes in AD and objective measures of sleep fragmentation and agitated behavior; 3. To establish the relationship between the amplitude and phase of the endogenous circadian pacemaker and the size, cellularity and neuropathology of the suprachiasmatic nucleus (SCN), the putative anatomic location of that pacemaker. To accomplish these aims, we will conduct longitudinal clinical evaluations, followed by post-mortem neuropathological studies, of 90 carefully diagnosed AD patients. A control population of 18 matched healthy elderly subjects will be studied under identical conditions. Clinical measures of sleep and agitation will be obtained by direct, continuous behavioral observation by trained raters for 72 hours. Subjects then will be evaluated during a constant routine protocol to determine the amplitude and phase of their endogenous circadian pacemaker, independent of the masking influences of sleep, activity, posture, meals and lighting. Statistical comparisons will be made with controls, and with the behavioral observation data. Patients will be followed longitudinally until autopsy, and a neuropathological examination will be performed to establish the dementia diagnosis. Morphometric and immunocytochemical techniques will be used to determine the glial/neuron ratio and vasopressin cellularity of the SCN. Statistical correlations between these indices of SCN degeneration in patients with pathologically-confirmed AD and the amplitude and phase of the endogenous circadian pacemaker will be tested.