A 5-year longitudinal study of the relationships between stress, coping, and immune cell β2-adrenergic receptor sensitivity
Introduction
A growing body of literature demonstrates detrimental health effects from caring for a loved-one with Alzheimer's disease (AD) (Shaw et al., 1997). For example, this care has been associated with increased likelihood of developing hypertension (Shaw et al., 1999), elevated sympathetic arousal (Irwin et al., 1997), increased risk for cardiovascular disease (Lee et al., 2003, Mausbach et al., in press-b), and worsened immune system functioning (Kiecolt-Glaser et al., 1991, Kiecolt-Glaser et al., 1996, Kiecolt-Glaser et al., 1995, Kiecolt-Glaser et al., 2003). Each of these harmful effects provides potential mechanisms by which caregivers are at increased risk for mortality compared with non-caregivers (Schulz and Beach, 1999).
While the mechanisms associated with physical morbidity in caregivers are complex, a number of studies have examined the relationship between stress and peipheral blood mononuclear cell (PBMC) β2-adrenergic receptor functioning (Dimsdale et al., 1994, Mausbach et al., 2007b, Mills et al., 2004, Redwine et al., 2004). Among other functions, the β2-adrenergic receptor mediates vascular smooth muscle relaxation (Fitzgerald and Goldfien, 2004), resulting in vasodilation. A number of authors have speculated that blunted β2-adrenergic receptor sensitivity paired with unaffected or enhanced α-adrenergic sensitivity may contribute to the development of hypertension (Bertel et al., 1980, Cleophas and Kauw, 1994, de Champlain et al., 1989). Such an imbalance could potentially increase peripheral resistance resulting in elevated blood pressure. It is possible that a simultaneous desensitization of vascular alpha- and vascular beta-adrenergic receptors could leave blood pressure relatively unchanged, although alpha-adrenergic receptors are typically more resistant to desensitization and/or down-regulation than beta-adrenergic receptors, thus leaving this potential scenario not frequently observed (Zhao et al., 1996). Moreover, research suggests that, among the elderly, hypertension may exhibit a differential physiological profile. Specifically, previous research has found that aging tends to be associated with a profile of low cardiac output combined with heightened total peripheral resistance, as well as reduced beta-adrenergic sensitivity (Feldman et al., 1984, Kawamoto et al., 1989, Sowers, 1987).
In addition to playing a role in the development of vascular reactivity and hypertension, β2-adrenergic receptors aid in the production of cytokines, which influence not only immune cell function but also other processes including glial cell proliferation (Giulian and Lachman, 1985) and neuron survival (Schwartz et al., 1991). Further, β2-adrenergic receptors aid in the regulation of T-cell and natural killer cell functioning (Kohm and Sanders, 2001). β2-adrenergic receptors play an important role in healthy immune system functioning and a blunting of the β2-adrenergic receptors can result in both cardiovascular and immune system destabilization, potentially increasing caregivers' risk for a number of health consequences (Schulz and Beach, 1999, Shaw et al., 1997).
Desensitization of β2-adrenergic receptors may occur by way of excessive activation of the autonomic nervous system via caregiving stress (Kohm and Sanders, 2001, Kühlwein et al., 2001). Indeed, Alzheimer caregivers, especially if they are distressed, are prone to exhibit exaggerated sympathetic arousal (Mausbach et al., 2005) and reduced β2-adrenergic receptor sensitivity (Mausbach et al., 2007b, Mills et al., 1997). Cross-sectional studies by Mills and colleagues (Mills et al., 2004, Mills et al., 1997) have demonstrated associations between stress, sympathoadrenomedullary (SAM) arousal, and β2-adrenergic receptor sensitivity in AD caregivers. Previous research in other populations further confirms the link between increased SAM tone and decreased β2-adrenergic receptor sensitivity and density (Bertel et al., 1980, Fraser et al., 1981, Sztajzel et al., 2006). As a whole, these data suggest the possibility that the stresses of caregiving may be associated with SAM hyperarousal and concomitant β2-adrenergic receptor desensitization.
Although stress, particularly chronic stress such as seen in caregiving, may potentially impact vascular and immune system functioning, recent data suggest that positive coping factors may help maintain general well-being and possibly protect against deleterious effects of stress. For example, longitudinal studies among caregivers suggest that coping strategies are related to long-term mental and physical health benefits (Dimsdale et al., 1994, Goode et al., 1998, Hooker et al., 2002, Strang and Haughey, 1999). One coping factor receiving increased attention has been personal mastery. This construct represents an individual's belief that he/she can control the circumstances of his/her life (Pearlin and Schooler, 1978). Mastery likely exerts its benefits via initiation of positive behaviors in the face of environmental and psychological stressors. A greater sense of mastery has been associated with improved psychological (Boss et al., 1990, Hobfoll et al., 2003, Semple, 1992) and physical health (Lachman and Weaver, 1998), reduced risk for mortality (Penninx et al., 1997), and restored β2-adrenergic receptor sensitivity (Mausbach et al., 2007b). While these studies point to the importance of mastery in one's overall health, they are largely cross-sectional in nature. In addition to the study by Penninx et al., (1997), one recent longitudinal study found hat mastery was associated with reduced longitudinal risk for disability among women (Penninx, 2000), while another found a positive effect of mastery on both mental and physical health outcomes in Alzheimer caregivers (Mausbach et al., 2007d). Longitudinal examination of the relations between stress, coping, and β2-adrenergic sensitivity are therefore needed to illuminate the potential mechanisms underlying the development of health problems among elderly individuals under stress (e.g., cardiovascular disease) and to explore coping factors which may prevent such outcomes from manifesting.
The purpose of this study was to examine the longitudinal relations between stress, coping, and β2-adrenergic receptor sensitivity in a sample of 115 spousal caregivers of individuals with Alzheimer's disease. Based on previous cross-sectional evidence showing a negative relationship between stress and β2-adrenergic receptor sensitivity, we predicted that decreased receptor sensitivity would be associated with increased reports of stress over time. Alternatively, given our previous cross-sectional finding that higher levels of mastery are associated with increased β2-adrenergic receptor sensitivity, we predicted a positive relationship between β2-adrenergic receptor sensitivity and mastery over time.
Section snippets
Participants
Participants were 115 spousal caregivers of patients with AD who were enrolled in a study examining the psychobiological effects of stress. Caregivers were primarily elderly (mean age = 72.6 ± 8.8 years), female (68.7%), and Caucasian (92.2%). The duration that caregivers had been providing care when they enrolled ranged from 4 months to 15 years. Inclusion/exclusion criteria included provision of in-home care to a spouse with a documented diagnosis of Alzheimer's disease, minimum age of 55 years,
Results
Baseline demographic and health characteristics of the sample are presented in Table 1. Over the course of the study, 5 assessments were made. Dropout information is as follows: Of the 115 participants enrolled in the study, 97 were assessed at the 1-year follow-up; 74 at the 2-year follow-up; 34 at the 3-year follow-up; and 11 at the 4-year follow-up.
Discussion
Over a 5-year longitudinal study, elderly dementia caregivers exhibited age-independent decreases in β2-adrenergic receptor sensitivity. Furthermore, increases in caregiver stress and decreases in personal mastery were associated with reduced receptor sensitivity. These longitudinal findings are consistent with our previous cross-sectional study on the relations between stress, mastery, and β2-adrenergic receptor sensitivity (Mausbach et al., 2007b), and further strengthen a mechanistic
Acknowledgements
This research was supported by the National Institute on Aging award AG 15301. Support was also provided by NIA awards AG 23989 and AG 08415, the National Institute of Mental Health award M01RR00827, and the Veterans Affairs Center for Excellence on Stress and Mental Health (CESAMH).
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