Alzheimer Disease: Ancoli-Israel S

Ancoli-Israel S, Alessi C. · No affiliation provided · Am J Geriatr Psychiatry. · Pubmed #15879581 No free full text.

This publication has no abstract.

Martin JL, Ancoli-Israel S. · Veteran's Affairs Greater Los Angeles Healthcare System, Geriatric Research, Education and Clinical Center, 16111 Plummer Street, North Hills, CA 91343, USA. · Clin Geriatr Med. · Pubmed #18035230 links to  free full text

Abstract: Nighttime sleep disruption is characteristic of long-term care residents, is typically accompanied by daytime sleepiness, and may be caused by a multitude of factors. Causal factors include medical and psychiatric illness, medications, circadian rhythm abnormalities, sleep disordered breathing and other primary sleep disorders, environmental factors, and lifestyle habits. There is some suggestion that these factors are amenable to treatment; however, further research on the implementation of treatments within the long-term care setting is needed. Additional work is also needed to understand the administrative and policy factors that might lead to systemic changes in how sleep is viewed and sleep problems are addressed in long-term care settings.

Yesavage JA, Friedman L, Ancoli-Israel S, Bliwise D, Singer C, Vitiello MV, Monjan AA, Lebowitz B. · Sierra-Pacific Mental Illness Research, Education, and Clinical Center, Palo Alto VA Health Care System, Palo Alto, CA 94304, USA. · J Geriatr Psychiatry Neurol. · Pubmed #12967054 No free full text.

Abstract: This article proposes new standards for identifying, defining, and naming sleep/wake cycle disturbances associated with Alzheimer's disease (AD) to aid in more effective research, including the development and testing of potential treatments. Many AD patients develop sleep/wake cycle disturbances associated with distress, depression, and sleep disturbances in the caregiver, as well as early nursing home placement for the patient. The Food and Drug Administration Psychopharmacological Drugs Advisory Committee has emphasized the need for a comprehensive diagnostic system. A key point made by the committee was that behavioral problems associated with dementia (including sleep and chronobiological disturbances) are scientifically and clinically valid targets of pharmacologic treatment. However, current diagnostic criteria preclude development of FDA-acceptable studies of pharmacological interventions because they do not include the required specific indications for treatment. This article attempts to develop better-defined provisional criteria with the goal of promoting epidemiological, physiological, and, especially, pharmacological research on sleep/wake disturbances.

Cooke JR, Loredo JS, Liu L, Marler M, Corey-Bloom J, Fiorentino L, Harrison T, Ancoli-Israel S. · Department of Medicine, University of California, San Diego, California, USA. · Drugs Aging. · Pubmed #16872233 No free full text.

Abstract: BACKGROUND AND OBJECTIVE: Studies suggest that some acetylcholinesterase inhibitors (AChEIs) increase rapid eye movement (REM) sleep and nightmares in patients with Alzheimer's disease (AD) but few have studied their effect on other sleep parameters. The objective of this study was to examine differences in sleep architecture in AD patients taking different AChEIs. METHODS: 76 participants (51 men, 25 women) [mean age = 78.2 years; SD = 7.7] with mild to moderate AD underwent medication history screening as well as polysomnography to determine the percentage of each sleep stage. Participants were divided into groups based on AChEI used: donepezil (n = 41), galantamine (n = 15), rivastigmine (n = 8) or no AChEI (n = 12). General univariate linear model analyses were performed. RESULTS: AChEI therapy had a significant effect on the percentage of stage 1 (p = 0.01) and stage 2 (p = 0.03) sleep. Patients in the donepezil group had a significantly lower percentage of stage 1 sleep than patients in the galantamine group (mean = 17.3%, SD = 11.7 vs 29.2%, SD = 15.0, respectively; p = 0.01), but there was no significant difference between the donepezil group and the rivastigmine (mean = 25.0%, SD = 12.3) or no AChEI groups (mean = 27.6%, SD = 17.7) in this respect. No significant differences in percentage of stage 1 between other groups were seen. Patients in the donepezil group also had a significantly higher percentage of stage 2 sleep than patients in the no AChEI group (mean = 63.6%, SD = 14.4 vs 51.4%, SD = 16.9, respectively; p = 0.04), but there was no significant difference between the donepezil group and either the galantamine group (mean = 56.5%, SD = 8.7) or the rivastigmine group (mean = 59.9%, SD = 8.4). There were no significant differences between groups in terms of percentage REM sleep or other sleep parameters. CONCLUSION: Subgroups of AD patients (classified according to AChEI treatment) in this study differed with respect to the amount of stage 1 and stage 2 sleep experienced, with the donepezil-treated group having the lowest percentage of stage 1 sleep and the highest percentage of stage 2 sleep. There was no significant difference in the amount of REM sleep between the groups. Our data suggest that sleep architecture may be affected by the use of donepezil in patients with AD. Although not elicited in this study because of the small sample size, there may be a class effect of AChEIs on sleep architecture. Double-blind, placebo-controlled studies are needed to better understand causality and the effect of each AChEI on sleep architecture in patients with AD.

Ancoli-Israel S, Gehrman P, Martin JL, Shochat T, Marler M, Corey-Bloom J, Levi L. · Department of Psychiatry 116A, University of California, Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA. · Behav Sleep Med. · Pubmed #15600135 No free full text.

Abstract: Sleep in the nursing home environment is extremely fragmented, possibly in part as a result of decreased light exposure. This study examined the effect of light on sleep and circadian activity rhythms in patients with probable or possible Alzheimer's disease. Results showed that both morning and evening bright light resulted in more consolidated sleep at night, as measured with wrist actigraphy. Evening light also increased the quality of the circadian activity rhythm, as measured by a 5-parameter extended cosine model (amplitude, acrophase, nadir, slope of the curve, and relative width of the peak and trough). Increasing light exposure throughout the day and evening is likely to have the most beneficial effect on sleep and on circadian rhythms in patients with dementia. It would behoove nursing homes to consider increasing ambient light in multipurpose rooms where patients often spend much of their days.

Ancoli-Israel S, Martin JL, Gehrman P, Shochat T, Corey-Bloom J, Marler M, Nolan S, Levi L. · Department of Psychiatry, University of California, San Diego, Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA. · Am J Geriatr Psychiatry. · Pubmed #12611749 No free full text.

Abstract: OBJECTIVE: Preliminary data suggest that morning bright light might improve symptoms of agitation, a serious problem in patients with dementia. The authors expand on an earlier pilot study by evaluating the effect of bright light therapy on agitated behavior in a large sample of patients with severe dementia. METHODS: Ninety-two patients were randomly assigned to morning bright light, morning dim red light, or evening bright light. Agitation was rated by research staff who observed the patients every 15 minutes throughout the treatment period and by caregivers at one time-point before and one time-point after treatment. RESULTS: Morning bright light delayed the acrophase of the agitation rhythm by over 1.5 hours. Bright light was associated with improved caregivers' ratings but had little effect on observational ratings of agitation. CONCLUSION: Although the result that light shifted the peak of the agitated behavior might be generalizable to patients with milder forms of AD, the fact that agitation was not ameliorated might not be. Because the suprachiasmatic nucleus (SCN) of patients with severe AD is likely to be more degenerated, and the circadian activity rhythms deteriorate as the disease progresses, it is still possible that patients with more intact SCNs, that is, patients with mild or moderate AD, might benefit from light treatment even more than those with severe AD.

Gehrman PR, Connor DJ, Martin JL, Shochat T, Corey-Bloom J, Ancoli-Israel S. · Department of Psychiatry, Hospital of the University of Pennsylvania, Philadelphia, PA, USA. · Am J Geriatr Psychiatry. · Pubmed #19155748 No free full text.

Abstract: OBJECTIVES: Patients with Alzheimer dementia often display both agitated behavior and poor sleep. Given that the disease is often associated with low endogenous levels of melatonin, exogenous melatonin administration may lead to improvements in sleep and agitation. DESIGN: Randomized, placebo-controlled study. SETTING: Nursing homes in San Diego, CA, metropolitan area. PARTICIPANTS: Subjects were patients with probable Alzheimer disease. INTERVENTION: Melatonin (8.5 mg immediate release and 1.5 mg sustained release) (N = 24) or placebo (N = 17) administered at 10:00 P.M. for 10 consecutive nights. The protocol consisted of baseline (3 days), treatment (10 days), and posttreatment (5 days) phases. MEASUREMENTS: Sleep was measured continuously using actigraphy. Agitation was rated using both the Agitated Behavior Rating Scale and the Cohen-Mansfield Agitation Inventory. Treatment effects were examined both across the 24-hr day and separately by nursing shift. RESULTS: There were no significant effects of melatonin, compared with placebo, on sleep, circadian rhythms, or agitation. CONCLUSION:: This study failed to find a beneficial effect of exogenous melatonin, consistent with a number of other studies. The lack of efficacy may be related to the absence of a true treatment effect or to the superphysiologic dose of melatonin used.

Aschbacher K, Roepke SK, von Känel R, Mills PJ, Mausbach BT, Patterson TL, Dimsdale JE, Ziegler MG, Ancoli-Israel S, Grant I. · Department of Psychiatry, University of California, San Diego, USA. · J Affect Disord. · Pubmed #19131112 No free full text.

Abstract: BACKGROUND: Depressive symptoms and caregiving stress may contribute to cardiovascular disease (CVD) via chronic platelet activation; however, it remains unclear whether this elevated activation constitutes a trait or state marker. The primary objective was to investigate whether persistent depressive symptoms would relate to elevated platelet activation in response to acute psychological stress over a three-year period. METHODS: Depressive symptoms (Brief Symptom Inventory) were assessed among 99 spousal dementia caregivers (52-88 years). Platelet P-selectin expression was assessed in vivo using flow cytometry at three time-points over the course of an acute stress test: baseline, post-stress, and after 14 min of recovery. Two competing structural analytic models of depressive symptoms and platelet hyperactivity with three yearly assessments were compared. RESULTS: Although depressive symptoms were generally in the subclinical range, their persistent elevation was associated with heightened platelet reactivity and recovery at all three-years while the change in depressive symptoms from the previous year did not predict platelet activity. LIMITATIONS: These results focus on caregivers providing consistent home care, while future studies may extend these results by modeling major caregiving stressors. CONCLUSIONS: Enduring aspects of negative affect, even among those not suffering from clinical depression are related to hemostatic changes, in this case platelet reactivity, which might be one mechanism for previously reported increase in CVD risk among elderly Alzheimer caregivers.

Ancoli-Israel S, Palmer BW, Cooke JR, Corey-Bloom J, Fiorentino L, Natarajan L, Liu L, Ayalon L, He F, Loredo JS. · Departments of Psychiatry, University of California, San Diego, La Jolla, California, USA. · J Am Geriatr Soc. · Pubmed #18795985 No free full text.

Abstract: OBJECTIVES: To examine whether treatment of obstructive sleep apnea (OSA) with continuous positive airway pressure (CPAP) in patients with Alzheimer's disease (AD) results in better cognitive function. DESIGN: Randomized double-blind placebo-controlled trial. Participants were randomized to therapeutic CPAP for 6 weeks or placebo CPAP for 3 weeks followed by therapeutic CPAP for 3 weeks. SETTING: General clinical research center. PARTICIPANTS: Fifty-two men and women with mild to moderate AD and OSA. INTERVENTION: CPAP. MEASUREMENTS: A complete neuropsychological test battery was administered before treatment and at 3 and at 6 weeks. RESULTS: A comparison of subjects randomized to 3 weeks of therapeutic versus placebo CPAP suggested no significant improvements in cognition. A comparison of pre- and posttreatment neuropsychological test scores after 3 weeks of therapeutic CPAP in both groups showed a significant improvement in cognition. The study was underpowered to make definitive statements about improvements within specific cognitive constructs, although exploratory post hoc examination of change scores for individual tests suggested improvements in episodic verbal learning and memory and some aspects of executive functioning such as cognitive flexibility and mental processing speed. CONCLUSION: OSA may aggravate cognitive dysfunction in dementia and thus may be a reversible cause of cognitive loss in patients with AD. OSA treatment seems to improve some cognitive functioning. Clinicians who care for patients with AD should consider implementing CPAP treatment when OSA is present.

Mausbach BT, Aschbacher K, Mills PJ, Roepke SK, von Känel R, Patterson TL, Dimsdale JE, Ziegler MG, Ancoli-Israel S, Grant I. · Department of Psychiatry, University of California at San Diego, La Jolla, CA, USA. · Psychiatry Res. · Pubmed #18708265 No free full text.

Abstract: Caring for a spouse with Alzheimer's disease (AD) is associated with overall health decline and impaired cardiovascular functioning. This morbidity may be related to the effects of caregiving stress and impaired coping on beta(2)-adrenergic receptors, which mediate hemodynamic and vascular responses and are important for peripheral blood mononuclear cell (PBMC) trafficking and cytokine production. This study investigated the longitudinal relationship between stress, personal mastery, and beta(2)-adrenergic receptor sensitivity assessed in vitro on PBMC. Over a 5-year study, 115 spousal AD caregivers completed annual assessments of caregiving stress, mastery, and PBMC beta(2)-adrenergic receptor sensitivity, as assessed by in vitro isoproterenol stimulation. Heightened caregiving stress was associated with significantly decreased receptor sensitivity, whereas greater sense of personal mastery was associated with significantly increased receptor sensitivity. These results suggest that increased stress may be associated with a desensitization of beta(2)-receptors, which may contribute to the development of illness among caregivers. However, increased mastery is associated with increased receptor sensitivity, and may therefore serve as a resource factor for improved health in this population.

Roepke SK, Mausbach BT, Aschbacher K, Ziegler MG, Dimsdale JE, Mills PJ, von Känel R, Ancoli-Israel S, Patterson TL, Grant I. · Department of Psychiatry, University of California at San Diego, La Jolla, CA 92093-0680, USA. · Am J Geriatr Psychiatry. · Pubmed #18378556 No free full text.

Abstract: OBJECTIVES: Spousal caregivers of Alzheimer's disease patients are at increased risk for cardiovascular disease, possibly via sympathetic response to stressors and subsequent catecholamine surge. Personal mastery (i.e., belief that one can manage life's obstacles) may decrease psychological and physiological response to stressors. This study examines the relationship between mastery and sympathetic arousal in elderly caregivers, as measured by norepinephrine (NE) reactivity to an acute psychological stressor. DESIGN: Cross-sectional. SETTING: Data were collected by a research nurse in each caregiver's home. PARTICIPANTS: Sixty-nine elderly spousal Alzheimer caregivers (mean age: 72.8 years) who were not taking beta-blocking medication. INTERVENTION: After assessment for mastery and objective caregiving stressors, caregivers underwent an experimental speech task designed to induce sympathetic arousal. MEASUREMENTS: Mastery was assessed using Pearlin's Personal Mastery scale and Alzheimer patient functioning was assessed using the Clinical Dementia Rating Scale, Problem Behaviors Scale, and Activities of Daily Living Scale. Plasma NE assays were conducted using pre- and postspeech blood draws. RESULTS: Multiple regression analyses revealed that mastery was significantly and negatively associated with NE reactivity (B = -9.86, t (61) = -2.03, p = 0.046) independent of factors theoretically and empirically linked to NE reactivity. CONCLUSIONS: Caregivers with higher mastery had less NE reactivity to the stressor task. Mastery may exert a protective influence that mitigates the physiological effects of acute stress, and may be an important target for psychosocial interventions in order to reduce sympathetic arousal and cardiovascular stress among dementia caregivers.

Galvin JE, Cornblatt B, Newhouse P, Ancoli-Israel S, Wesnes K, Williamson D, Zhu Y, Sorra K, Amatniek J. · Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA. · Alzheimer Dis Assoc Disord. · Pubmed #18317244 No free full text.

Abstract: Deficits in attention are present early in the course of Alzheimer disease (AD). Acetylcholine receptors are appealing molecular targets for intervention as cholinergic pathways are involved in the neurobiology of attention. For this reason, measures of attention were included in 2 independent, multicenter, randomized, parallel, controlled trials in subjects with AD comparing the effects of galantamine, an acetylcholinesterase inhibitor and postulated nicotinic receptor modulator, and donepezil, an acetylcholinesterase inhibitor. The attention battery of the Cognitive Drug Research computerized assessment system was used in both trials. Small magnitude, positive signals were observed for simple and choice reaction times for both compounds. Attention task performance tended to improve early for galantamine-treated subjects. A consistent temporal pattern of improvement was not observed in donepezil-treated subjects. Quantitative findings appeared more pronounced in subjects with moderate AD. Galantamine's proposed action as a nicotinic receptor modulator may bear on these findings. Improved attention may have positive effects on cognitive and functional outcomes for AD patients, although this hypothesis requires further study and validation.

Mausbach BT, Patterson TL, Von Känel R, Mills PJ, Dimsdale JE, Ancoli-Israel S, Grant I. · Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093-0680, US. · Aging Ment Health. · Pubmed #18074251 No free full text.

Abstract: The objectives of this study were to evaluate the impact of personal mastery and caregiving stress on caregiver depressive symptoms and health over time and to examine the moderating effect of mastery on the relations between stress and these outcomes. A total of 130 spousal Alzheimer caregivers completed yearly assessments of personal mastery, role overload, health symptoms and depressive symptoms. Random regression was used to evaluate the relations between time-varying values for stress and mastery in predicting depressive and health symptoms. It was found that variation in depressive symptoms over time was significantly related to role overload (p<0.05) and personal mastery (p<0.001). A significant overload-by-mastery interaction was found for predicting depressive symptoms (p=0.002) and caregiver health (p=0.008), whereby mastery attenuated the effect of stress on these outcomes. We conclude that personal mastery appears to reduce the effects of stress on depression and health outcomes over time.

Aschbacher K, von Känel R, Mills PJ, Hong S, Roepke SK, Mausbach BT, Patterson TL, Ziegler MG, Dimsdale JE, Ancoli-Israel S, Grant I. · Department of Psychiatry, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0680, USA. · Psychosom Med. · Pubmed #17991824 No free full text.

Abstract: OBJECTIVE: To investigate the combined effects of caregiving and hormone replacement therapy (HRT) on platelet hyperactivity to acute psychological stress. Both HRT and the chronic stress of caregiving have been associated with increased cardiovascular risk, potentially through a mechanism of platelet hyperactivity. METHODS: A total of 78 elderly postmenopausal women (51 caregivers (CG) and 27 noncaregivers (NC)) were assessed for platelet activation in response to a laboratory speech test. Half the sample was taking HRT. Blood was sampled at baseline, post speech, and after 14 minutes of recovery. Platelet activation was assessed through whole blood flow cytometry assays of % aggregates (Agg), and expression of % fibrinogen receptors (FbR) and % P-selectin (P-sel) on platelet surface. RESULTS: Multivariate repeated-measures analysis of variance revealed that CG taking HRT exhibited significantly prolonged platelet activation in response to acute stress. There was an interaction between HRT and CG on recovery from stress for Agg (F (1,71) = 5.260, p = .025), P-Sel (F(1,71 = 6.426, p = .013), and FbR (F(1,71 = 6.653, p = .012), controlling for age, cardiovascular disease, and aspirin. Among HRT users, regression analysis revealed that CG had delayed recovery of Agg (beta = 0.354, t(34) = 2.154, p = .038) and P-sel (beta = 0.498, t(34)=3.126, p = .004) from stress relative to NC. No caregiving effects on recovery were present among non-HRT users. In addition, these effects were maintained after controlling for health behaviors, medications, and medical conditions. CONCLUSION: Chronic dementia caregiving stress in combination with HRT may impair recovery of platelet activation after acute mental stress (i.e., activation levels do not quickly return to resting levels), thereby potentially increasing cardiovascular risk among CG who take HRT.

Mausbach BT, von Känel R, Aschbacher K, Roepke SK, Dimsdale JE, Ziegler MG, Mills PJ, Patterson TL, Ancoli-Israel S, Grant I. · Department of Psychiatry (0680), University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0680, USA. · Psychosom Med. · Pubmed #17942832 No free full text.

Abstract: OBJECTIVE: To determine if caregivers of spouses with Alzheimer's disease demonstrate greater increase in tissue plasminogen activator (t-PA) antigen relative to noncaregiving controls. Caring for a spouse with Alzheimer's disease has been associated with increased mortality and reduced time to developing cardiovascular disease (CVD), possibly due to impaired fibrinolysis resulting from chronic stress. METHODS: Annual in-home assessments of plasma t-PA antigen were collected from 165 participants (112 caregivers and 53 noncaregivers) enrolled in the University of California, San Diego Alzheimer caregiver study. Participants were married, living with their spouses, at least 55 years of age, and free of serious medical conditions (e.g., cancer). Caregivers provided in-home care for their spouse with Alzheimer's disease at the time of enrollment. Exclusion criteria included taking anticoagulant medication or evidenced severe hypertension (>200/120 mm Hg). Mixed (random effects) regression was used to assess slopes for t-PA antigen over the study period at the same time controlling for medical and demographic characteristics associated with t-PA antigen. RESULTS: Caregivers demonstrated significantly greater increases in t-PA antigen over the 5-year study period compared with noncaregiving controls (p = .02), even when controlling for body mass index, mean blood pressure, age, gender, and use of CVD medication. CONCLUSIONS: The accelerated rate of developing a prothrombotic environment including elevated t-PA antigen may provide one mechanism by which caregiving is associated with greater morbidity and mortality and the development of CVD.

Mausbach BT, Aschbacher K, Patterson TL, von Känel R, Dimsdale JE, Mills PJ, Ancoli-Israel S, Grant I. · Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093-0680, USA. · J Psychosom Res. · Pubmed #17383495 No free full text.

Abstract: OBJECTIVE: We examined the impact of Alzheimer caregiver transitions (i.e., placement and bereavement) on psychological outcomes and on plasma D-dimer levels, an end product of the coagulation cascade associated with increased cardiovascular risk. METHODS: This was a prospective study in which 126 spousal caregivers of Alzheimer's patients were assessed each year for 5 years. We used random regression models to evaluate discontinuous change in our outcomes over time, with emphasis on the impact of caregiver transitions on psychological and physical well-being. RESULTS: Caregivers experienced immediate improvement in overload and mastery following transitions, and these improvements were maintained over time. There was also a significant drop in depressive symptoms immediately following placement of spouses. D-dimer rose significantly over time but began to significantly decline at 6-months posttransitions. CONCLUSIONS: Caregiver transitions appear to produce immediate and long-term "normalization" of psychological health in caregivers. This normalization also appears related to "downstream" reductions in D-dimer.

Cooke JR, Liu L, Natarajan L, He F, Marler M, Loredo JS, Corey-Bloom J, Palmer BW, Greenfield D, Ancoli-Israel S. · Department of Medicine, University of California, San Diego, Veterans Affairs San Diego Healthcare System, CA, USA. · Behav Sleep Med. · Pubmed #17083302 No free full text.

Abstract: Patients with Alzheimer's disease (AD) commonly have poor sleep and a high reported incidence of sleep-disordered breathing (SDB). This study examined how the presence of SDB affected sleep stages in AD patients. Sixty-six volunteers with mild - moderate AD underwent home polysomnography. Results showed that patients with SDB spent less of the night in REM sleep than those with no SDB, but there were no differences in other sleep stages. The findings suggest that the decreased amount of REM sleep may be due to the presence of AD and SDB. Treating these patients' SDB may increase their amount of REM sleep, which may result in improved daytime functioning. Controlled trials of SDB treatment in AD are needed to answer this question.

Mausbach BT, Ancoli-Israel S, von Känel R, Patterson TL, Aschbacher K, Mills PJ, Ziegler MG, Dimsdale JE, Calleran S, Grant I. · Department of Psychiatry, University of California, San Diego, CA 92093-0682, USA. · Sleep. · Pubmed #17068989 No free full text.

Abstract: STUDY OBJECTIVE: Caregiving for a relative with Alzheimer disease has been associated with sympathoadrenal medullary arousal and morbidity and mortality. In this study, we examined if sleep disturbance of elderly caregivers was associated with physiologic markers of cardiovascular risk, including plasma norepinephrine, epinephrine, and the hemostasis marker D-dimer. DESIGN: Cross-sectional. SETTING: Community-based sample of elderly caregivers of spouses with Alzheimer disease assessed within their homes. PARTICIPANTS: A sample of 40 elderly spousal caregivers of patients with Alzheimer disease. MEASUREMENTS AND RESULTS: Participants underwent in-home full-night polysomnography and had plasma assayed for norepinephrine and epinephrine. Using multiple regression analyses and controlling for a number of cardiovascular risk factors (e.g., age, sex, blood pressure, body mass index), increased wake after sleep onset was positively associated with norepinephrine levels (beta = .35; t = 2.45, df = 32, p = .020) and plasma D-dimer (beta = .31; t = 2.18, df = 29, p = .038). Further, plasma norepinephrine was significantly associated with D-dimer (beta = .34; t = 2.11, df = 29, p = .044). Additional analyses indicated that norepinephrine accounted for 28% of the relationship between wake after sleep onset and D-dimer. No association was observed between sleep variables and epinephrine. CONCLUSIONS: These findings provide preliminary evidence that sleep disturbance may contribute to morbidity in caregivers through sympathoadrenal medullary arousal and downstream physiologic effects such as altering the hemostasis environment.

Mausbach BT, Mills PJ, Patterson TL, Aschbacher K, Dimsdale JE, Ancoli-Israel S, von Känel R, Grant I. · Department of Psychiatry, University of California at San Diego, La Jolla, CA 92093-0680, U.S.A. · Int Psychogeriatr. · Pubmed #17018181 No free full text.

Abstract: BACKGROUND: A growing body of literature suggests that caregiving burden is associated with impaired immune system functioning, which may contribute to elevated morbidity and mortality risk among dementia caregivers. However, potential mechanisms linking these relationships are not well understood. The purpose of this study was to investigate whether stress-related experience of depressive symptoms and reductions in personal mastery were related to alterations in ss2-adrenergic receptor sensitivity. METHODS: Spousal Alzheimer's caregivers (N = 106) completed measures assessing the extent to which they felt overloaded by their caregiving responsibilities, experienced depressive symptoms, and believed their life circumstances were under their control. We hypothesized that caregivers reporting elevated stress would report increased depressive symptoms and reduced mastery, which in turn would be associated with reduced ss2- adrenergic receptor sensitivity on peripheral blood mononuclear cells (PBMC), as assessed by in vitro isoproterenol stimulation. RESULTS: Regression analyses indicated that overload was negatively associated with mastery (beta = -0.36, p = 0.001) and receptor sensitivity (beta = -0.24, p = 0.030), whereas mastery was positively associated with receptor sensitivity (beta = 0.29, p = 0.005). Finally, the relationship between overload and receptor sensitivity diminished upon simultaneous entry of mastery. Sobel's test confirmed that mastery significantly mediated some of the relationship between overload and receptor sensitivity (z = -2.02, p = 0.044). CONCLUSIONS: These results suggest that a reduced sense of mastery may help explain the association between caregiving burden and reduced immune cell ss2-receptor sensitivity.

von Känel R, Dimsdale JE, Mills PJ, Ancoli-Israel S, Patterson TL, Mausbach BT, Grant I. · Department of General Internal Medicine, Division of Psychosomatic Medicine, University Hospital, Switzerland. · J Gerontol A Biol Sci Med Sci. · Pubmed #16960028 No free full text.

Abstract: BACKGROUND: Elevated plasma levels of interleukin (IL)-6, C-reactive protein (CRP), and D-dimer belong to the biological alterations of the "frailty syndrome," defining increased vulnerability for diseases and mortality with aging. We hypothesized that, compatible with premature frailty, chronic stress and age are related in predicting inflammation and coagulation activity in Alzheimer caregivers. METHODS: Plasma IL-6, CRP, and D-dimer levels were measured in 170 individuals (mean age 73 +/- 9 years; 116 caregivers, 54 noncaregiving controls). Demographic factors, diseases, drugs, and lifestyle variables potentially affecting inflammation and coagulation were obtained by history and adjusted for as covariates in statistical analyses. RESULTS: Caregivers had higher mean levels of IL-6 (1.38 +/- 1.42 vs 1.00 +/- 0.92 pg/mL, p =.032) and of D-dimer (723 +/- 530 vs 471 +/- 211 ng/mL, p <.001) than controls had. CRP levels were similar between groups (p =.44). The relationship between caregiver status and D-dimer was independent of covariates (p =.037) but affected by role overload. Age accounted for much of the relationship with IL-6. After controlling for covariates, the interaction between caregiver status and age was significant for D-dimer (beta =.20, p =.029) and of borderline significance for IL-6 (beta =.17, p =.090). Post hoc regression analyses indicated that, among caregivers, age was significantly correlated with both D-dimer (beta =.50, p <.001) and IL-6 (beta =.38, p =.001). Among controls, however, no significant relationship was observed between age and either D-dimer or IL-6. CONCLUSIONS: The interaction between caregiving status and age for D-dimer and IL-6 suggests the possibility that older caregivers could be at risk of a more rapid transition to the frailty syndrome and clinical manifestations of cardiovascular diseases.

Aschbacher K, von Känel R, Dimsdale JE, Patterson TL, Mills PJ, Mausbach BT, Allison MA, Ancoli-Israel S, Grant I. · Department of Psychiatry, School of Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. · Am J Geriatr Psychiatry. · Pubmed #16861374 No free full text.

Abstract: BACKGROUND: The procoagulant factor D-dimer has been shown to be associated with thrombus formation and degradation as seen with conditions such as myocardial infarction and unstable angina. Research has demonstrated that spousal dementia caregivers have elevated levels of D-dimer relative to their non-caregiving peers. OBJECTIVE: The objective of this study was to determine the relationship of basal level and laboratory stressor-induced concentration of D-dimer to severity of dementia in spousal care recipients. METHODS: Seventy-one elderly caregivers were compared with a comparison group of 37 non-caregivers (average age: 71 years). Clinical Dementia Rating (CDR), a global measure of dementia, was used to assess severity of spousal dementia. Plasma D-dimer was measured at baseline and in response to an acute speech stressor. RESULTS: Regression analysis revealed a significant positive association between severity of spousal dementia and caregiver D-dimer, both at baseline and in response to acute stress, while controlling for age. The model examined an exponential relationship, with D-dimer increasing progressively across the span of dementia stages. DISCUSSION: Dementia severity of the care recipient was associated with increasing hypercoagulability among elderly caregivers. Effect size estimates suggest that such D-dimer increases may have clinical implications, particularly among late-stage caregivers.

Chong MS, Ayalon L, Marler M, Loredo JS, Corey-Bloom J, Palmer BW, Liu L, Ancoli-Israel S. · Department of Psychiatry, Univeristy of California at San Diego, San Diego, CA 92161, USA. · J Am Geriatr Soc. · Pubmed #16696743 No free full text.

Abstract: OBJECTIVES: Studies have reported that 33% to 70% of patients with Alzheimer's disease (AD) have sleep-disordered breathing (SDB). Continuous positive airway pressure (CPAP) treatment has been shown to reduce daytime sleepiness and improve health-related quality of life in nondemented older people with SDB. The effect of therapeutic CPAP treatment on daytime sleepiness in patients with mild-moderate AD with SDB was assessed. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Patients' home and the University of California San Diego, General Clinical Research Center, J. Christian Gillin Laboratory of Sleep and Chronobiology. PARTICIPANTS: Thirty-nine community-dwelling elderly patients with mild-moderate probable AD with SDB. INTERVENTION: Patients were randomly assigned to receive 6 weeks of therapeutic CPAP or 3 weeks of sham CPAP followed by 3 weeks of therapeutic CPAP. MEASUREMENTS: Epworth Sleepiness Scale (ESS) was administered at baseline, 3 weeks, and 6 weeks. Changes in daytime sleepiness in subjects who received optimal therapeutic CPAP were compared with changes in the sham CPAP group. RESULTS: Within the therapeutic CPAP group, ESS scores were reduced from 8.89 during baseline to 6.56 after 3 weeks of treatment (P=.04) and to 5.53 after 6 weeks of treatment (P=.004). In the sham CPAP group, there was no significant difference after 3 weeks of sham CPAP but a significant decrease from 7.68 to 6.47 (P=.01) after 3 weeks of therapeutic CPAP. CONCLUSION: These data provide evidence of the effectiveness of CPAP in reducing subjective daytime sleepiness in patients with AD with SDB.

Mausbach BT, Aschbacher K, Patterson TL, Ancoli-Israel S, von Känel R, Mills PJ, Dimsdale JE, Grant I. · Department of Psychiatry, University of California at San Diego, San Diego, California 92093-0680, USA. · Am J Geriatr Psychiatry. · Pubmed #16582038 No free full text.

Abstract: OBJECTIVE: Caring for a loved one with Alzheimer disease is a highly stressful experience that is associated with significant depressive symptoms. Previous studies indicate a positive association between problem behaviors in patients with Alzheimer disease (e.g., repeating questions, restlessness, and agitation) and depressive symptoms in their caregivers. Moreover, the extant literature indicates a robust negative relationship between escape-avoidance coping (i.e., avoiding people, wishing the situation would go away) and psychiatric well-being. The purpose of this study was to test a mediational model of the associations between patient problem behaviors, escape-avoidance coping, and depressive symptoms in Alzheimer caregivers. METHODS: Ninety-five spousal caregivers (mean age: 72 years) completed measures assessing their loved ones' frequency of problem behaviors, escape-avoidance coping, and depressive symptoms. A mediational model was tested to determine if escape-avoidant coping partially mediated the relationship between patient problem behaviors and caregiver depressive symptoms. RESULTS: Patient problem behaviors were positively associated with escape-avoidance coping (beta = 0.38, p < 0.01) and depressive symptoms (beta = 0.26, p < 0.05). Escape-avoidance coping was positively associated with depressive symptoms (beta = 0.33, p < 0.01). In a final regression analysis, the impact of problem behaviors on depressive symptoms was less after controlling for escape-avoidance coping. Sobel's test confirmed that escape-avoidance coping significantly mediated the relationship between problem behaviors and depressive symptoms (z = 2.07, p < 0.05). CONCLUSION: Escape-avoidance coping partially mediates the association between patient problem behaviors and depressive symptoms among elderly caregivers of spouses with dementia. This finding provides a specific target for psychosocial interventions for caregivers.

von Känel R, Dimsdale JE, Ancoli-Israel S, Mills PJ, Patterson TL, McKibbin CL, Archuleta C, Grant I. · Department of General Internal Medicine, University Hospital, Berne, Switzerland. · J Am Geriatr Soc. · Pubmed #16551309 No free full text.

Abstract: OBJECTIVES: To determine whether objective measures of sleep correlate with plasma levels of the proinflammatory cytokine interleukin (IL)-6 and the procoagulant marker fibrin D-dimer in caregivers of patients with dementia. DESIGN: Cross-sectional study. SETTING: Subjects' homes. PARTICIPANTS: Sixty-four community-dwelling spousal caregivers (69% women, mean age+/-standard deviation 72+/-9) and 36 sex-matched noncaregiving controls. MEASUREMENTS: All participants underwent in-home full-night polysomnography. Demographic and lifestyle factors, depression, diseases, and medication that could affect inflammation, coagulation, and sleep were controlled for in analyses regressing sleep variables and caregiver status and their interaction on plasma levels of IL-6 and D-dimer. RESULTS: Caregivers had higher levels of D-dimer (781+/-591 vs 463+/-214 ng/mL, P=.001) and IL-6 (1.42+/-1.52 vs 0.99+/-0.86 pg/mL, P<.06) and lower levels of total sleep time (369+/-70 vs 393+/-51 minutes, P=.049) and sleep efficiency (77+/-11 vs 82+/-9%, P=.04) than controls. After controlling for age and body mass index, longer wake time after sleep onset (change in coefficient of determination (DeltaR2)=0.039, P=.04) and the interaction between caregiver status and higher apnea-hypopnea index (DeltaR2=0.054, P=.01) were predictors of IL-6. Controlling for age, caregiver status independently predicted D-dimer levels (DeltaR2=0.047, P=.01). Controlling for age and caregiver status, lower sleep efficiency (DeltaR2=0.032, P=.03) and the interaction between caregiver status and more Stage 2 sleep (DeltaR2=0.037, P=.02) independently predicted plasma D-dimer levels. CONCLUSION: Poor sleep was associated with higher plasma IL-6 and D-dimer levels. These effects were most pronounced in caregivers of subjects with Alzheimer's disease. The findings suggest a mechanism that may explain how disturbed sleep might be associated downstream with cardiovascular risk, particularly in older people under chronic stress.

Ayalon L, Ancoli-Israel S, Stepnowsky C, Marler M, Palmer BW, Liu L, Loredo JS, Corey-Bloom J, Greenfield D, Cooke J. · Department of Psychiatry, University of California, San Diego, San Diego, CA, and Veterans Affairs San Diego Health Care System, San Diego, CA 92161, USA. · Am J Geriatr Psychiatry. · Pubmed #16473983 No free full text.

Abstract: OBJECTIVE: This analysis examined whether patients with Alzheimer disease (AD) tolerate continuous positive airway pressure (CPAP). METHOD: Thirty patients with AD were randomized to CPAP or sham CPAP and completed sleep, depression, and quality-of-life questionnaires. Participants could choose to continue treatment after the trial. RESULTS: Patients wore CPAP for 4.8 hours per night. More depressive symptoms were associated with worse adherence (rS=-0.37; N=30, p<0.04). Patients who continued using CPAP had fewer depressive symptoms (t [19]=2.45, p=0.02) and better adherence (t [19]=2.32, p=0.03) during the trial. CONCLUSION: Patients with AD with obstructive sleep apnea can tolerate CPAP. Adherence and long-term use may be more difficult among those patients with more depressive symptoms.