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Published online before print October 17, 2007, 10.1097/PSY.0b013e318157d461
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Psychosomatic Medicine 69:816-822 (2007)
© 2007 American Psychosomatic Society

ORIGINAL ARTICLES

Spousal Caregivers of Patients With Alzheimer's Disease Show Longitudinal Increases in Plasma Level of Tissue-Type Plasminogen Activator Antigen

Brent T. Mausbach, PhD, Roland von Känel, MD, Kirstin Aschbacher, MS, Susan K. Roepke, BA, Joel E. Dimsdale, MD, Michael G. Ziegler, MD, Paul J. Mills, PhD, Thomas L. Patterson, PhD, Sonia Ancoli-Israel, PhD and Igor Grant, MD

From the Department of Psychiatry (B.T.M., R.v.K., K.A., S.K.R., J.E.D., P.J.M., T.L.P., S.A.-I., I.G.), University of California, San Diego, La Jolla, California; Department of General Internal Medicine (R.v.K.), University Hospital Berne, Berne, Switzerland; Department of Medicine (M.G.Z.), University of California, San Diego, La Jolla, California; Veterans Affairs San Diego Healthcare System (S.A.-I.), San Diego, California.

Address correspondence and reprint requests to Brent T. Mausbach, Department of Psychiatry (0680), University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0680. E-mail: bmausbach{at}ucsd.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
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.

Key Words: cardiovascular disease • chronic stress • fibrinolysis • aging

Abbreviations: CVD = cardiovascular disease; IL-6 = interleukin-6; t-PA = tissue plasminogen activator; PAI-1 = plasminogen activator inhibitor; CHD = coronary heart disease; MAP = mean arterial pressure; BMI = body mass index; BP = blood pressure; HAM-D = Hamilton Scale for Depression.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
The stresses associated with caring for a loved one with Alzheimer's disease have been associated with compromised physical health (1,2). For example, compared with noncaregivers, those who provide care to a loved one with dementia are at increased risk for poorer immune response to influenza vaccines (3), slower wound healing (4), and the development of hypertension (5,6). The stresses of caregiving have further been associated with the development of cardiovascular disease (CVD) (7, 8) and increased risk for overall mortality over a 4-year period (9).

Prior studies identified a number of molecular and cellular changes that may explain caregivers' increased risk for developing CVD. For example, caregivers tend toward a prothrombotic and proinflammatory state as demonstrated by elevated concentrations of the procoagulant molecule D-dimer (10,11) and proinflammatory cytokine interleukin (IL)-6 (12). Longitudinal studies further suggest that caregivers demonstrate significant increases in both D-dimer (13) and IL-6 (14) over time, with possible reversal in this trend on cessation of caregiving duties (13).

Intravascular fibrin accumulation due to activated coagulation and inadequate clearing of fibrin clots from circulation by the fibrinolytic system could both give rise to atherothrombotic events with chronic stress such as imposed by dementia caregiving (15). One fibrinolytic factor rarely studied among caregivers is tissue plasminogen activator (t-PA). The t-PA is a glycoprotein produced primarily by vascular endothelial cells (16,17) that is involved in lysis of fibrin clots. The t-PA antigen in plasma reflects inactive t-PA bound to its major endogenous inhibitor plasminogen activator inhibitor (PAI)-1 (16) which, in turn, has potent antifibrinolytic properties (18). Consequently, an elevated t-PA antigen level has been shown to be an important marker of impaired fibrinolysis that is associated with increased cerebral infarction risk in older adults (19,20) and stroke among young women (21). Moreover, prospective studies have linked elevated t-PA antigen to coronary heart disease (CHD) among middle-aged and older adults (22–24), healthy adults (25,26), and postmenopausal women (27). In a meta-analysis, Lowe et al. (16) determined that t-PA antigen levels of >13.5 ng/ml placed individuals at 50% greater risk for developing CHD than those with t-PA levels <8.0 ng/ml. Studies examining the relationship between chronic stress and t-PA antigen levels are few. However, Jern and colleagues demonstrated that acute mental stress causes significant increases in t-PA antigen levels, both in young, healthy males (28) and females (29). Other studies have demonstrated t-PA antigen rise during competition stress (30). Two cross-sectional studies have demonstrated that noncaregivers experiencing vital exhaustion have elevated t-PA levels relative to nonexhausted controls (31,32). A third study did not find a relationship between vital exhaustion and t-PA levels (33). As a whole, these reports suggest that chronic stress (i.e., vital exhaustion) is associated with elevated t-PA. However, longitudinal studies are needed to examine rise in t-PA over lengthy periods of time (i.e., months or years).

Among caregiver populations who experience chronic stress, we are aware of only one study that has examined levels of t-PA antigen (10). In that study, t-PA antigen levels in caregivers of patients with Alzheimer's disease were cross-sectionally compared with a sample of noncaregiving controls, and no differences were observed between the two groups. However, the chronic stresses of caring for a loved one with Alzheimer's disease persists over years, so a longitudinal study of the fibrinolytic system can reveal events not apparent in a cross-sectional study. Therefore, this study compared the rates of change in t-PA over 5 years among a sample of 112 Alzheimer caregivers and 53 noncaregiving control subjects. Compatible with the notion that chronic stress contributes to impaired fibrinolysis (15), we hypothesized that, compared with control subjects, caregivers would demonstrate greater increase in plasma concentrations of t-PA antigen over time.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Participants
Between 2001 and 2005, 165 participants (112 caregivers and 53 noncaregiving controls) were part of a longitudinal study of the biopsychosocial consequences of caregiving stress. Caregivers were recruited through the University of California, San Diego (UCSD) Alzheimer's Disease Research Center, community support groups, local senior centers and medical clinics, and senior service professionals. Control participants were recruited through a snowball technique in which caregivers identified married individuals who were not caring for a loved one with dementia or any other debilitating condition (i.e., living with "healthy" spouses). Caregivers were permitted to identify multiple potential control participants, and many caregivers did not identify any potential controls. To be eligible, all participants must have been married and living with their spouses, be at least 55 years of age, and free of serious medical conditions (e.g., cancer). In addition, caregivers were required to be providing in-home care for their spouse with Alzheimer's disease at the time of enrollment. Participants were excluded if they were taking anticoagulant medication or evidenced severe hypertension (>200/120 mm Hg). The UCSD Institutional Review Board approved the research protocol and all participants provided written informed consent before enrolling in the study. All participants were paid volunteers and were assessed in their homes at approximately yearly intervals. Because the purpose of this study was to examine the longitudinal effects of chronic caregiving stress, caregivers were maintained in the analysis only for years in which they were providing continued in-home care for their spouses (i.e., years in which the patient with Alzheimer's disease was either placed into an inpatient facility or deceased were not included in the present analysis).

Measures
Tissue-Type Plasminogen Activator Assays
Venous blood samples were obtained annually by a trained research nurse at each subject's home. Blood was drawn via an indwelling 22-gauge catheter placed in the subject's forearm while he/she rested in a supine position. The first 5 ml of blood was discarded, with the remaining blood transferred to polypropylene tubes containing 3.8% sodium citrate. Within 3 hours of blood draws, plasma samples were centrifuged for 10 minutes at 1600 g at room temperature. Plasma was aliquoted and stored at –80°C until assayed. The t-PA antigen was assayed using a commercially available enzyme-linked immunosorbent assay kit (Asserachrom, Stago, Asnieres, France).

Medical Data
While at each subject's home, the research nurse conducted a medical history examination to obtain data on health characteristics potentially associated with t-PA antigen. For example, all subjects reported whether they were current or past smokers and the total number of days per week they consumed alcoholic beverages. With regard to smoking history, a contrast code of +0.5 was assigned to those participants reporting a history of smoking, whereas those who never smoked received a code of –0.5. In addition, all subjects provided nurses with a list of current prescription medications. These medications were classified as cardiovascular in nature, and a contrast code was assigned to each participant (+0.5 = yes; –0.5 = no) as to whether or not they took a medication of this type.

Systolic and diastolic blood pressure was obtained in triplicate using an adult/pediatric noninvasive blood pressure monitor (Critikon Dinamap 8100, GE Medical Systems Information Technologies, Tampa, FL). We calculated mean arterial pressure (MAP) using the following formula: (2/3 x diastolic BP) + (1/3 x systolic BP). Also, given a high correlation between body mass index (BMI) and t-PA antigen, we calculated each subject's BMI as the ratio between weight in kilograms and height in meters squared.

Nurses also administered an Interim Medical History questionnaire (IMED), which assesses overall health status of the participants. Specifically, participants were asked if they had experienced a variety of medical symptoms over the past 6 months associated with 14 major systems typically found in a review of systems (e.g., eyes, ears, nose, throat, chest). An overall health score is created by summing the symptoms experienced (range = 0–96), with higher scores indicating worse health.

Assessment of Stress and Depressive Symptoms
All participants completed the Role Overload scale developed by Pearlin and associates (34). This scale assesses global burden associated with life stressors and consists of 4-items rated on a 4-point scale from 1 = "not at all" to 4 = "completely." Scores were summed and higher scores indicated greater stress. Depressive symptoms were assessed using the 17-item Hamilton Scale for Depression (HAM-D) (35). This scale was administered and scored by a research nurse, and higher scores reflected greater depressive symptoms.

Data Analysis
The {chi}2 tests and t tests were used to compare caregivers and controls on baseline demographic and health characteristics. A mixed (random-effects) regression analysis was conducted to examine the impact of caregiving status and health factors on t-PA antigen over time. Mixed model regression allows us to estimate an intercept and slope for each participant based on all available data for that individual, augmented by the data from the entire sample. Therefore, as missing data are common at one or more time-points in longitudinal studies, the use of mixed models allows individual slopes to be estimated using available data for that participant. To increase interpretability of regression coefficients and to diminish problems associated with multicollinearity, Kraemer and Blasey (36) strongly recommended that independent variables be centered before conducting analysis. Therefore, we centered all independent variables with the exception of caregiver status which was dummy coded as "0" = noncaregiver and "1" = caregiver, and time in years, which was linear in nature with the baseline assessment coded as "0". Linear variables were centered around their grand means. Our mixed regression model included t-PA antigen as the dependent variable and BMI, MAP, use of CVD medication, alcohol consumption, and hours of sleep per night entered as time-varying covariates. In addition, time (years), age at baseline, gender, smoking history, and caregiver status were entered as fixed effects. Because caregiver status was coded as "0" = noncaregiver and "1" = caregiver, the estimate for "time" therefore represented the slope for noncaregivers and the corresponding p value indicated whether this slope was significant. The "time x caregiver" interaction estimate was the differential in slope for caregivers. Random effects in the model included random intercepts and slopes. Optimal model fit, as per Akaike's Information Criteria, was achieved using an unstructured covariance matrix.

Because one assumption of this study was that the stresses of caregiving were chronic, we also compared caregivers and noncaregivers on levels of stress and depressive symptoms over the course of the study. For these analyses, we utilized mixed regression models examining the effect of caregiving status, time, and the time-by-caregiving status interaction, and explored contrasts for each year in the study to determine if caregivers and controls reported greater stress and depressive symptoms across the 5-year study period.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 NOTES
 REFERENCES
 
Demographic and Health Characteristics
Table 1 shows baseline demographic and health characteristics for caregivers and controls. Statistical comparison of baseline demographic and health characteristics showed that caregivers were older (t = 3.96, df = 163, p < .001), had higher MAP (t = 2.32, df = 163, p = .02), and tended to use more CVD medication ({chi}2 = 3.73, df = 1, p = .053). Caregivers and noncaregivers did not differ in terms of BMI, smoking history, or alcohol consumption. Among caregivers, the mean years spent caregiving at initial participation was 3.5 (standard deviation = 1.1).


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  		TABLE 1. Baseline Demographic and Health Factors of Caregivers of Loved Ones With Alzheimer's Disease and Controls

 

Dropouts/Missing Data
Of the 165 participants, data were unavailable for 28 (25.0%) caregivers and 13 (24.5%) noncaregivers at the 1-year follow-up assessment. At the 2-year follow-up assessment, data were not available for 50 (44.6%) caregivers and 18 (34.0%) noncaregivers. For the 3-year follow-up, 89 (79.4%) caregivers and 34 (64.2%) noncaregivers were missing data. Finally, 105 (93.8%) caregivers and 48 (90.5%) noncaregivers were missing data at the 4-year follow-up assessment. We examined our data to determine whether missing data occurred at random. Our first analysis compared whether caregivers were ever more likely to miss a visit than noncaregivers. A series of Fisher's exact tests indicated that caregivers were not more likely to miss a visit at any of the assessment years (all p > .05; see numbers for caregivers and noncaregivers above). Similarly, males and females did not differ at any time point in terms of missing data as per Fisher's exact test results (all p > .05). Specifically, 34.7% (n = 17) of males and 20.7% (n = 24) of females missed the 1-year follow-up; 42.9% of males (n = 21) and 40.5% of females (n = 47) missed the 2-year follow-up; 71.4% (n = 35) and 75.9% (n = 88) of males and females missed the 3-year follow-up, respectively; and 87.8% of males (n = 43) and 94.8% of females (n = 110) missed the 4-year follow-up. A series of additional t tests examined whether participants who missed an assessment had higher values on any of the study variables during the previous and following assessments than those who did not miss. For example, statistical comparisons of participants who missed their 2-year follow-up assessments with those who did not revealed no significant differences in their year 1 values for t-PA (t = 0.11, df = 163, p = .91), MAP (t = 0.54, df = 163, p = .59), overload (t = 1.84, df = 163, p = .07), depressive symptoms (t = –0.06, df = 163, p= .95), or BMI (t = 0.14, df = 163, p =89). Similarly, among participants missing their 2-year follow-up, there were no differences in year 3 values for t-PA (t = –0.89, df = 95, p = .38), MAP (t = –1.11, df = 95, p = .27), overload (t = 1.08, df = 91, p = .29), depressive symptoms (t = 0.79, df = 94, p = .44), or BMI (t = –1.68, df = 95, p=.10). These results held true for all assessment visits, lending support to the assumption that data were missing at random.

Change in t-PA Antigen Over Time
Results of our mixed model analysis are shown in Table 2. Because caregiver status was coded as "0" = noncaregiver and "1" = caregiver, the estimate and p value for "time" therefore represented the slope for noncaregivers (i.e., the group coded as "0"), whereas the corresponding p value indicated whether this slope was significant. The slope representing change in t-PA over time among caregivers was obtained by adding the "time x caregiver" interaction estimate (i.e., the differential in slope for caregivers) to the time estimate. Because time was entered such that baseline values corresponded to a value of "0," noncaregivers had an average baseline t-PA level of 8.46 ng/ml. The coefficient for caregiver status (B = –0.08) was not significant, indicating that at baseline (i.e., time = "0"), caregivers and noncaregivers showed no significant differences in t-PA antigen (t = –0.15, df = 172.22, p = .88). The time-varying value for BMI was a significant predictor of t-PA antigen (t = 6.14, df = 201.65, p < .001). Participants using CVD medication also had lower t-PA antigen levels (p = .048). As hypothesized, caregivers increased t-PA antigen levels over time compared with noncaregivers (t = 2.33, df = 50.24, p = .02). The mean ± standard error of the mean (SEM) t-PA antigen slopes for caregivers was 0.97 ± 0.21, which was significant (p < .001). However, the mean ± SEN slope for noncaregiving controls was 0.31 ± 0.19, which was not significant (p = .12). On average, the caregiver rate of increase was three times as great as that of noncaregivers. A graphic depiction of the rate of change in t-PA antigen for caregivers vs. controls is shown in Figure 1.


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  		TABLE 2. Regression Equation Predicting Tissue Plasminogen Activator (t-PA) Antigen (ng/ml)

 

Figure 116
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  		Figure 1. Estimated 5-year rate of change in tissue-type plasminogen activator (t-PA) antigen for caregivers versus controls (mean ± standard error of the mean). The slope for caregivers (0.97 ± 0.21) was significant (p < .001), whereas the slope for noncaregiving controls (0.31 ± 0.19) was not (p = .12), with the average caregiver rate of increase three times as great as noncaregivers. Participants available at each assessment were as follows: Baseline = 165; 1-year follow-up = 124; 2-year follow-up = 97; 3-year follow-up = 42; 4-year follow-up = 12.

 

Because health differences between caregivers and noncaregivers may better explain change in t-PA over time, we conducted an additional analysis which tested a main effect of medical symptoms (i.e., IMED scores) and an interaction between medical symptoms and time. Results of these analyses indicated that neither the main effect (p = .62) nor the interaction term (p = .59) was significant, whereas the caregiver x time interaction remained significant (p = .04). These results suggest that differences in t-PA over time were not better attributed to health symptoms.

Stress and Depressive Symptoms Over Time
We conducted an additional mixed model analysis examining the mean differences in overload and HAM-D scores over time. In the first analysis, we included caregiver status as a predictor of these outcomes. Results indicated that the overload grand mean (mean ± SEM) was significantly higher for caregivers (10.18 ± 0.69) than for noncaregivers (6.20 ± 1.01) (t = 3.25, df = 159.32, p = .001). Similarly, the HAM-D grand mean was significantly higher for caregivers (4.42 ± 0.32) than for noncaregivers (2.14 ± 0.45). To determine whether caregivers and noncaregivers differed in overload or depression over time, a second set of analyses examined the interaction between caregiver status and time. Results of these analyses indicated nonsignificant interactions for both overload (t = –0.60, df = 181.76, p = .55) and depressive symptoms (t = 0.74, df = 57.98, p = .46). A final set of analyses examined differences between caregivers and noncaregivers at each year in the project. Caregivers reported greater overload scores than noncaregivers across each of the 5 years of this study, with group differences of p < .001 at all yearly assessment points. Similarly, caregivers scored significantly higher on the HAM-D than controls at each of the 5-yearly assessments (all p < .001). These analyses indicate that caregivers, as a whole, were significantly more stressed over the course of the study than their noncaregiving pears. Mean overload and HAM-D scores across time are presented in Figure 2.


Figure 216
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  		Figure 2. Mean ± standard error of the mean Hamilton Scale for Depression (HAM-D) (A) and Role Overload (B) scores for caregivers and noncaregivers over time.

 

These data suggest that caregivers experience chronic stress over time relative to noncaregivers, which may in turn be responsible for their steeper t-PA slopes. Because overload is an indicator of overall distress, we conducted a final analysis in which caregiver status was replaced by individual overload means (i.e., within-person centered) over time. In addition to a main effect of overload, an "overload x time" interaction was included. All other covariates from our initial model were included. Results of this analysis indicated a significant overload-by-time interaction (t = 1.99, df = 272.61, p = .048), suggesting that participants with higher mean overload scores throughout the study demonstrated steeper t-PA slopes.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
NOTES
 REFERENCES
 
Caregivers of patients with dementia who experience strain die prematurely (9). This may be due, in part, to the effects of stress on the cardiovascular system (7, 8). The stresses of caregiving are associated with greater hemodynamic response to stress (37,38), increased sympathetic nervous system activity (39), elevated concentrations of IL-6 over time (14), and a tendency toward a hypercoagulant milieu (10,11). We are not aware of any other study demonstrating that caregiving may also be prospectively associated with impaired fibrinolysis, as indicated by increases in plasma concentrations of t-PA antigen over time.

We speculate that this differential rate of increase in plasma t-PA antigen is due to the multiple stresses associated with caregiving. Previous studies have linked acute stress to significant rise in plasma concentrations of t-PA antigen (28–30), suggesting that t-PA is sensitive to stressful stimuli. Further, chronic stress (i.e., vital exhaustion) has been cross-sectionally linked to elevated t-PA in noncaregiving populations (31,32). Our study extends these previous findings to a caregiving population and demonstrates a longitudinal rise in t-PA likely due to caregivers' experience of chronic stress. The caregivers in our study reported considerable chronic stress, with significantly greater levels of overload and depressive symptoms at every one of the annual assessments. Further, the differential rate of change in t-PA antigen between caregivers and noncaregivers remained even when controlling for time-varying classical risk factors known to be associated with t-PA antigen including age, BMI, alcohol use, smoking history, and blood pressure (16). Despite our finding that caregivers had elevated concentrations of t-PA antigen over time relative to controls, we did not study additional confounders of t-PA antigen such as glucose, total cholesterol, and triglyceride levels (16). However, we covaried for BMI, and greater obesity has been associated with dyslipidemia and glucose intolerance (40). Furthermore, we did not have extensive measures of other health behaviors that might explain why caregivers demonstrated a differential rise in t-PA (e.g., poor exercise, poor diet). However, we did control for both BMI and MAP, which often become elevated as a consequence of these health behaviors. Nonetheless, future studies may want to provide added control for these factors to determine if these factors better explain the rise in t-PA over time. Notably, caregivers and noncaregivers had similar baseline t-PA values, i.e., when caregivers had spent, on average, 3.5 years in the caregiving role. This finding concurs with our previous study on BP increase over time in a sample of caregivers who had cared for individuals with Alzheimer's disease for a mean duration of 1.9 years at study entry (5). Although BP measurements were not significantly different between caregivers and their noncaregiving counterparts at baseline, caregivers had significantly more hypertensive BP recordings during the 6-year follow-up than noncaregivers (5). Altogether, these data may suggest that several years of exposure to caregiving stress may be required to elicit biological changes of significance in chronically stressed caregivers.

Because active t-PA is released from vascular endothelium, becoming inactivated by circulating PAI-1, future studies may wish to examine the role of chronic stress on endothelial functioning. Previous research suggests that acute stress is associated with impaired endothelial functioning (41,42) among otherwise healthy individuals, and that t-PA antigen is highly correlated with risk markers associated with endothelial dysfunction (e.g., C-reactive protein) (16). Studies examining whether chronic stress, in the context of caregiving, contributes to endothelial dysfunction over time would therefore be of value. Such studies might be done either through direct assessments of endothelial functioning such as flow mediated dilation, or through examination of endothelial activity markers in plasma (e.g., soluble forms of cellular adhesion molecules).

Individuals vary with respect to their use of over-the-counter medications, particularly those that may affect clotting factors. However, we did not assess the impact of over-the-counter medications, including aspirin, nonsteroidal anti-inflammatory drugs, vitamin E, ginseng, and ginkgo. Therefore, we recommend that future researchers control for the impact of these medications on t-PA levels over time.

Across the 5-year study, caregivers experienced more depressive symptoms and overload than noncaregivers, although neither group experienced significant changes in these factors over time. This finding suggests the possibility that the effects of psychological distress on t-PA antigen may be better captured by a model that investigates the cumulative impact of chronic distress on fibrinolysis over time, rather than a model in which short-term fluctuations in psychosocial distress directly parallel changes in coagulation. These speculations received support from our final exploratory analysis in which we found a mean overload-by-time interaction. However, it should be noted there are myriad ways to conceptualize caregiver distress, and overload represents one such strategy. Research over the past few decades has diversely operationalized caregiver stress to include patient factors (e.g., memory and behavior problems; functional impairment) and caregiver factors (e.g., perceived stress; burden) (43). Future research should examine whether other measures of stress are associated with t-PA over time.

Few participants completed all yearly assessments throughout the project period, and missing data has the potential for biasing parameter estimates and limiting generalizations from our results (44). This would be true if existing data for participants was not a random sample of their true growth trajectories. Although we do not believe our data are biased, this remains a possibility, and replication of our results is needed to strengthen the conclusions.

Although we included a review of systems to assess medical symptoms experienced by participants, there is a lack of empirical literature demonstrating its reliability and validity. This may have limited our ability to find an association between medical symptoms (or overall health) and t-PA. Future studies should utilize other measures of health, particularly those that assess severity of health symptoms (e.g., weighting symptoms based on severity).

Overall, the results of this study add to the emerging literature suggesting that chronic stresses, such as caring for a loved one with Alzheimer's disease, potentially contributes to both a hypercoagulable milieu and impaired fibrinolysis, both of which place individuals at greater risk for future cardiac events (15). Specifically, we demonstrated that the average rate of increase in t-PA antigen among caregivers was three times greater than that of noncaregivers over a 5-year period. These data provide a possible mechanistic explanation for how caregiving stress translates into an increased risk for CVD and mortality (7–9).


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
REFERENCES
 
Received for publication November 6, 2006; revision received July 23, 2007.

All authors declare no conflicts of interest. This research was supported by Grants AG15301 (Igor Grant) and AG23989 (Brent Mausbach) from the National Institute on Aging.

DOI:10.1097/PSY.0b013e318157d461


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 

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