Purpose in Life and Cerebral Infarcts in Community-Dwelling Older People
Background and Purpose—Purpose in life, the sense that life has meaning and direction, is associated with reduced risks of adverse health outcomes. However, it remains unknown whether purpose in life protects against the risk of cerebral infarcts among community-dwelling older people. We tested the hypothesis that greater purpose in life is associated with lower risk of cerebral infarcts.
Methods—Participants came from the Rush Memory and Aging Project. Each participant completed a standard measure of purpose in life. Uniform neuropathologic examination identified macroscopic infarcts and microinfarcts, blinded to clinical information. Association of purpose in life with cerebral infarcts was examined in ordinal logistic regression models using a semiquantitative outcome.
Results—Four hundred fifty-three participants were included in the analyses. The mean score on the measure of purpose was 3.5 (SD, 0.5; range, 2.1–5.0). Macroscopic infarcts were found in 154 (34.0%) people, and microinfarcts were found in 128 (28.3%) people. Greater purpose in life was associated with a lower odds of having more macroscopic infarcts (odds ratio, 0.535; 95% confidence interval, 0.346–0.826; P=0.005), but we did not find association with microinfarcts (odds ratio, 0.780; 95% confidence interval, 0.495–1.229; P=0.283). These results persisted after adjusting for vascular risk factors of body mass index, history of smoking, diabetes mellitus, and blood pressure, as well as measures of negative affect, physical activity, and clinical stroke. The association with macroscopic infarcts was driven by lacunar infarcts, and was independent of cerebral atherosclerosis and arteriolosclerosis.
Conclusions—Purpose in life may affect risk for cerebral infarcts, specifically macroscopic lacunar infarcts.
Purpose in life, a psychosocial construct, which involves having meaning and goal-directedness in life, is a key component of psychological well-being.1 Older people with a greater sense of purpose are less likely to develop adverse health outcomes, including mortality,2,3 decline in physical function,4 frailty,5 disability,6,7 Alzheimer’s disease (AD),8 and clinical stroke.9 The neurobiological basis underlying the beneficial effect of purpose in life is not well understood but may be related to other psychosocial factors that have been shown to influence cardiovascular disease risk.10,11 However, the relationship of purpose in life with cerebral infarct pathology is unknown. Clinical strokes are largely underreported in old age. Neuroimaging captures more infarcts but may miss those that are under 3 mm or microscopic.
In this study, using data from community-dwelling older people enrolled in the Rush Memory and Aging Project, we tested the hypothesis that greater purpose is associated with lower risk of cerebral infarcts. All participants completed a standard assessment of purpose in life, were followed over multiple years and underwent autopsy after death. Our primary analysis examined associations of purpose with infarcts (macroscopic versus microscopic), and we evaluated significant associations by further controlling for a series of potential confounding factors. We also examined the associations with specific subtypes of infarcts.
The Rush Memory and Aging Project is an ongoing clinical-pathological cohort study of aging and dementia.12 The study was approved by the Institutional Review Board of Rush University Medical Center. Each participant signed an informed consent and an Anatomic Gift Act, agreeing to annual clinical evaluations and organ donation at the time of death. Since October 1997, the Memory and Aging Project study has enrolled >1700 participants. By the time these analyses were performed, 719 participants had died, of which 554 (77.1%) had their autopsy results reviewed and approved by neuropathologists. We excluded participants who had incomplete purpose in life measure (n=50) or were demented at the purpose in life assessment (n=51). Primary analyses were performed on the remaining 453 participants (Table 1).
Purpose in Life
Assessment of purpose in life was performed annually using a modified 10-item measure derived from Ryff’s and Keyes’s scales of Psychological Well-being.1 During the assessment, participants rated their level of agreement with each item on a 5-point Likert scale. Ratings for negatively worded items were flipped, and scores at the item level were then averaged to obtain a composite score with a higher score indicating a greater sense of purpose in life, as reported previously.13,14 A valid score requires ≥8 items answered by the participants, and 99.3% of the participants in the analysis answered all 10 items. In the primary analysis, the first valid score of purpose was used to examine the association with cerebral infarcts. Longitudinal data were also used to assess the potential change in purpose in life over time.
Cerebral Infarct and Other Pathologies
Brains were removed, weighed, and 1 hemisphere was cut coronally into 1-cm slabs and fixed in 4% paraformaldehyde.15 Macroscopic cerebral infarcts (ie, infarcts visible to naked eyes) were identified using slabs or pictures from both the hemispheres, and confirmed by histological review.16 Blocks from ≥9 brain regions were cut into 6-μm sections, which were stained with hematoxylin/eosin and examined for microinfarcts using microscopy.17 We restricted our analysis to chronic infarcts. Lacunar infarcts were subcortical macroscopic infarcts that had all dimensions ≤10 mm, and nonlacunar infarcts had dimensions >10 mm. Each infarct measure was rated on a 3-level scale, including no infarct, 1 infarct, and multiple infarcts. Assessment of AD pathology and other cerebral vessel diseases are described in the online-only Data Supplement.
Clinical Stroke and Other Covariates
Details on clinical stroke diagnosis and assessment of other covariates are available in the online-only Data Supplement.
To test the association of purpose in life with risk of cerebral infarcts, we first fit an ordinal logistic regression model with 3-level measure of total macroscopic infarcts as the categorical outcome, and the scores of purpose in life as the predictor, adjusted for age at death, sex, and education. We repeated the model for microinfarcts. Both models estimate the odds ratios of the presence of infarct, as well as of multiple infarcts, for every 1 U increase in the score of purpose in life. Next, we performed a series of analyses to assess the robustness of significant associations (online-only Data Supplement). Finally, we explored whether the association differed by cortical versus subcortical infarcts using separate regression models. The score test18 assessed proportional odds assumptions, which were adequately met in all models. Analyses were performed using SAS/STAT software, version 9.3 (SAS Institute Inc, Cary, NC) and we used a nominal threshold of P<0.05 for statistical significance.
In 453 older people, 114 (25.3%) had clinical stroke. Nearly twice as many participants had macroscopic or micro infarcts at autopsy (n=216; 47.7%). Specifically, 76 (16.8%) had 1 macroscopic infarct, and 78 (17.2%) had ≥2 macroscopic infarcts; 81 (17.9%) had 1 microinfarct and 47 (10.4%) had ≥2 microinfarcts. Participants with macroscopic infarcts were more likely to have microinfarcts (P<0.001). Older age at death was associated with greater odds of both macroscopic (P=0.035) and microscopic (P=0.032) infarcts. We found no association of sex or years of education with either type of infarct. The mean score on the measure of purpose in life was 3.5 (SD, 0.5; range, 2.1–5.0). Comparing an individual with greater purpose (90th percentile) with one with less purpose (10th percentile), the score of our measure differed by ≈1 U. Figure shows that the level of purpose in life differs by macroscopic infarcts but not by microinfarcts.
Purpose in Life and Macroscopic Infarcts
In an ordinal logistic regression model adjusted for demographics, greater purpose in life was associated with lower odds of macroscopic infarcts (Table 2). Specifically, a 1-U increase of the score for purpose in life reduced the odds of having ≥1 macroscopic infarcts by ≈50% (odds ratio, 0.535; 95% confidence interval, 0.346–0.826; P=0.005). By contrast, we did not find an association of purpose with microinfarcts. We examined the potential sex difference in association of purpose with infarcts by adding a term for sex–purpose interaction; these were not significant suggesting no sex differences (Table I in the online-only Data Supplement). To account for the correlation between the 2 infarct outcomes, we reexamined simultaneously the associations of purpose in life with macroscopic and microinfarcts by fitting a bivariate Dale model. Results were unchanged (Table II in the online-only Data Supplement).
Next, by leveraging longitudinal data for purpose in life, we assessed change in purpose over time (online-only Data Supplement) and examined whether the association with infarcts was influenced by such change. On average, there was a small decline in purpose in life relative to baseline differences (annual rate of decline, −0.044; P <0.001). The association with infarcts persisted after adjustment for the individual-specific change in purpose in life (Table III in the online-only Data Supplement). These results support the relatively trait-like property of purpose in life. Separately, we explicitly examined the extent to which purpose in life measured many years versus just a few years before death differ by adding a model term for time from purpose assessment to death and its interaction with purpose. The interaction term was not significant, suggesting that the associations were not dependent on time between assessment and death (Table IV in the online-only Data Supplement).
We examined whether the relationship between purpose in life and macroscopic infarcts was affected by potential confounders (Table V in the online-only Data Supplement). First, because purpose in life reduces the adverse effect of AD pathology on change in cognition,13 we investigated whether the association of purpose with macroscopic infarcts is influenced by AD pathology. Burden of AD pathology did not differ by infarcts status, and greater purpose in life was still associated with lower odds for more macroscopic infarcts after controlling for the burden of AD pathology.
Second, because purpose in life has been associated with vascular risk factors,19 we repeated our model by including terms for body mass index, history of smoking, diabetes mellitus, and blood pressure. Higher systolic blood pressure was associated with greater odds for more macroscopic infarcts (P=0.015). However, the association of purpose in life and macroscopic infarcts persisted after controlling for these vascular risk factors.
Third, psychosocial risk factors are reported to be related to the risk of strokes or cerebral infarcts.20–23 Thus, we controlled the terms for depressive symptoms, harm avoidance, childhood adverse experiences, and loneliness and the association was not changed.
Fourth, purpose in life is associated with physical activity.24 Including the covariate for total daily activity, the association of purpose with macroscopic infarcts persisted. Finally, only a proportion of participants with macroscopic infarcts had a diagnosis of clinical stroke. We controlled for clinical stroke to examine whether the association of purpose in life with macroscopic infarcts is driven by those with clinical diagnosis. Notably, although clinical stroke was strongly associated with greater odds for macroscopic infarcts, the result on purpose in life was essentially unchanged.
Purpose in Life and Lacunar Infarcts
To further explore whether the association with macroscopic infarcts differs by the anatomic location, we fit separate logistic regression models for cortical and subcortical macroscopic infarcts. A greater purpose in life was associated with fewer subcortical macroscopic infarcts but not with cortical macroscopic infarcts (Table 3). Because subcortical macroscopic infarcts can be further categorized into lacunar and nonlacunar infarcts, we also tested the associations with these subtypes of subcortical infarcts. The association was significant only with respect to the lacunar infarcts (Table 4), particularly gray matter lacunar infarcts (Table VI in the online-only Data Supplement).
Finally, to assess whether the effect of purpose in life works through vessel diseases, we investigated the relationship with cerebral arteriolosclerosis and atherosclerosis. Purpose in life was not associated with the measure of arteriolosclerosis (P=0.619) or atherosclerosis (P=0.828). In a model adjusted for demographics and both the measures of arteriolosclerosis and atherosclerosis, the association of purpose in life and lacunar infarcts robustly retained (Table VII in the online-only Data Supplement).
We found that a greater sense of purpose in life is associated with ≈50% reduced likelihood of cerebral infarcts. The result was robust against the adjustment for several confounders. The association seems to be driven by lacunar infarcts, independent of cerebral large or small vessel disease.
A previous study shows that purpose in life is associated with a reduced risk of clinical strokes in a group of participants aged 53 to 105 years.9 We extend this finding in several ways. Although the earlier study reports that <4% of the participants had clinical stroke >4 years of follow-up, our data show that at autopsy >30% of our participants had macroscopic infarcts and >25% had microinfarcts. This difference suggests that purpose in life is protective for silent infarcts, as well as clinical stroke. Thus, the association persists after controlling for clinical stroke. Second, the earlier study focused only on the outcome of clinical stroke in general, we were able to examine the associations with more specific subtypes of infarcts. Interestingly, we found that the most robust association is with lacunar infarcts.
Reasons for the differential association of purpose with infarct subtypes are not clear. One potential mechanism would be through small vessel disease (or arteriolosclerosis), which is more commonly related to lacunar infarcts. Indeed, we confirm that more severe arteriolosclerosis is associated with more lacunar infarcts. However, purpose in life is not related to either arteriolosclerosis or atherosclerosis. Furthermore, the association persists after adjustment for burdens of arteriolosclerosis and atherosclerosis. This finding suggests that the association of purpose in life with cerebral infarct is probably independent of vessel disease.
More broadly, the neurobiological basis of the protective effect of purpose in life and other psychosocial constructs is complex and poorly understood. Our previous finding on purpose and AD pathology is consistent with the neural reserve theory, such that purpose is not directly related to AD pathology, instead older people with greater purpose tend to function better cognitively, whereas AD pathology accumulates in the brain. A recent study on neural correlates of purpose shows a positive association between purpose and insular cortex gray matter volume.25 Different from the finding on AD, in this study, we show a direct relationship between greater purpose and lower risk for infarct pathology. Thus, purpose in life may work through other pathways to influence health outcomes in old age.
There are 2 other possible explanations for the association of purpose in life with infarcts. First, purpose may reduce the risk of infarcts by promoting healthy lifestyles. Previous work suggests that purpose is associated with lower cardiovascular disease risk.19,26 However, the findings in our study persist after we adjusted for vascular risks of body mass index, history of smoking, diabetes mellitus, and blood pressure. Although purpose in life is correlated with physical activity, controlling for daily activity in our data did not attenuate our finding. Stress or stress-related factors may also play a role in the association of purpose with infarcts. One study found that the combination of social inhibition and negative affect increased risk for cardiovascular events and mortality in patients with coronary artery disease.27 However, our findings persist after the adjustment for measures of negative affect.
Second, purpose may directly be implicated in neuroendocrine function. Earlier studies show that psychological well-being is correlated with many biological markers, such as salivary cortisol level, epinephrine, and norepinephrine.28 Other potential mechanisms include inflammatory and potentially procoagulant and endothelial dysfunction markers, such as high sensitivity C-reactive protein, interleukin-6, soluble intercellular adhesion molecule, monocyte chemoattractant protein-1, interleukin-8, homocysteine, von Willebrand factor, E-selectin, P-selectin, and tumor necrosis factor-α.11,29 Further work is needed to address these potential mechanistic pathways.
Purpose in life is correlated with many other psychological constructs, including sense of coherence, resilience, and optimism.30 Importantly, purpose in life constitutes a distinct dimension of psychological well-being and is a potentially modifiable factor that promotes healthy aging. One study reported that dispositional optimism protects against stroke,31 and that purpose is associated with a lower risk even after controlling for optimism.9 These measures have not been collected in our cohort and we cannot directly examine their relationships with purpose.
This study has the following strengths. Purpose in life was documented in community-dwelling people without dementia. Participants were followed for >5 years and underwent neuropathologic examination after death with high rates of autopsy. Our finding on association of purpose with reduced risk of infarct pathology is robust against confounding variables. Limitations are also noted. Although people >80 years represent the fastest growing segment of the population; participants were older and had higher levels of education compared with the general population. Therefore, results may not generalize to other groups. Our finding that the association of purpose in life is primarily driven by lacunar infarcts requires replication from other studies.
We are grateful to all the participants of the Rush Memory and Aging Project. We also thank the staff at the Rush Alzheimer’s Disease Center for this work.
Sources of Funding
This study was supported by the National Institutes of Health grants: R01AG17917, R01AG24480, R01AG24871, R01AG33678, R01HL96944, and R01AG34374, and The Illinois Department of Public Health.
Dr Yu, Dr Boyle, Dr Wilson, and Dr Schneider received grant support from National Institutes of Health. Dr Levine received grant support from National Institutes of Health and Patient-Centered Outcomes Research Institute. Dr Schneider received consulting fees or sat on paid advisory boards for AVID radiopharmaceuticals, Eli Lilly Inc, and GE Healthcare; she is a monitoring editor of the Journal of Histochemistry and Cytochemistry and on the editorial board of International Journal of Clinical and Experimental Pathology. Dr Bennett serves on the editorial board of Neurology; he has received honoraria for nonindustry sponsored lectures; he served as a consultant to Danone, Inc, Wilmar Schwabe GmbH & Co, Eli Lilly, Inc, Schlesinger Associates, and Geson Lehrman Group. Dr Bennett received grant support from National Institutes of Health and research support from Zinfandel.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.114.008010/-/DC1.
- Received November 4, 2014.
- Revision received January 20, 2015.
- Accepted February 10, 2015.
- © 2015 American Heart Association, Inc.
- Boyle PA,
- Barnes LL,
- Buchman AS,
- Bennett DA.
- Collins AL,
- Goldman N,
- Rodríguez G.
- Emeny RT,
- Zierer A,
- Lacruz ME,
- Baumert J,
- Herder C,
- Gornitzka G,
- et al
- Schneider JA,
- Bienias JL,
- Wilson RS,
- Berry-Kravis E,
- Evans DA,
- Bennett DA.
- Arvanitakis Z,
- Leurgans SE,
- Barnes LL,
- Bennett DA,
- Schneider JA.
- 18.↵SAS Institute Inc. SAS/STAT® 13.2 User’s Guide. Cary, NC: SAS Institute Inc; 2014.
- Ryff CD,
- Singer BH,
- Dienberg Love G.
- Ostir GV,
- Markides KS,
- Peek MK,
- Goodwin JS.
- Dong JY,
- Zhang YH,
- Tong J,
- Qin LQ.
- Hooker SA,
- Masters KS.
- Lewis GJ,
- Kanai R,
- Rees G,
- Bates TC.
- Denollet J,
- Pedersen SS,
- Vrints CJ,
- Conraads VM.
- Wiseman S,
- Marlborough F,
- Doubal F,
- Webb DJ,
- Wardlaw J.
- Kim ES,
- Park N,
- Peterson C.