Urinary cortisol excretion as a predictor of incident cognitive impairment
Introduction
Age-related declines in cognitive function are common, but there is substantial variability in the patterns and rates of cognitive decline in older adults, with rapid declines exerting an enormous toll on quality of life and cost of care for many older adults and their families. Therefore, there is considerable interest in the identification of predictors of rapid cognitive decline, and in the development of interventions to prevent it. An elevated circulating level of cortisol is one factor that has been implicated in the pathogenesis of cognitive impairments, because of the detrimental effects of glucocorticoids on hippocampal neurons [21], [32]. In cross-sectional studies in older adults with normal levels of cortisol (i.e., levels that do not meet clinical criteria for hypercortisolemia), high normal levels are associated with poorer cognitive performance and even dementia [5], [8], [11], [18], [19], [20], [23]. However, a causal relationship cannot be inferred from these cross-sectional studies; prospective studies are needed that demonstrate a link between cortisol levels measured at baseline and subsequent longitudinal decline in cognitive functioning. Unfortunately, there is a relative paucity of such prospective, longitudinal studies, and they are either small [16], [17], [35] or restricted to one gender [12], [35], or they examined concurrent changes in cortisol levels and cognitive function [16], [17], [33]. One moderately sized, prospective study of the association between cortisol levels at baseline and longitudinal change in cognitive functioning in older adults (N = 169) found no association between early morning serum cortisol levels measured at baseline and cognitive decline over the following 1.9 years [13].
This lack of association may, at least partially, be the result of blunting of the circadian cortisol rhythm in older adults with aging and cognitive impairment [8]. An acute rise in cortisol level (as with awakening in the morning and in response to acute stressors) has protective and adaptive effects in the short term; it increases the ability to concentrate, to think fast and creatively, and to interpret and store new information [28], and is cognitively enhancing [1], [6]. Chronically elevated cortisol levels, on the other hand, have been linked with hippocampal damage and cerebral atrophy [30], [31]. Hence, it is probably more important to study the effects of increases in resting levels of cortisol than in peak morning cortisol levels. Overnight urine cortisol excretion is a reliable, integrated measure of resting adrenal cortex activity; cross-sectional associations have been documented between elevated urinary cortisol excretion and cognitive impairment [19], [33]. In a prospective cohort study of 70–79-year-old adults who were high-functioning at baseline, we reported an independent association between 2.5-year increase in the level of overnight urinary cortisol and concurrent decrement in performance on memory tests; however, there was an interaction with gender: the association was seen only in women and not in men [33].
Memory impairment is often the first clinically evident step in the development of overt dementia [4], [10], [22], [27], and global cognitive deficits have also been reported in cross-sectional association with elevated levels of cortisol [5], [8], [19], [23], as have radiological changes (such as cortical atrophy) that are considered pathognomonic for dementia [11], [18]. Accordingly, our objective in this study was to examine the association between urine cortisol at baseline and longitudinal decline over a longer term (7 years) in more global cognitive functioning, as assessed by the short portable mental status questionnaire (SPMSQ), in a cohort of previously high-functioning older adults.
Section snippets
Study sample
Participants were from the MacArthur Study of Successful Aging, a longitudinal study of relatively high-functioning women and men, aged 70–79 years [2]. More than 4000 non-institutionalized 70–79-year-old men and women from three communities (Durham, NC, East Boston, MA, and New Haven, CT) were screened on the basis of four criteria of physical functioning and two criteria of cognitive functioning, to identify those in the top functioning tertile. The screening criteria were: (1) no
Results
Of the 756 participants who had urine cortisol levels measured at baseline (1988), 161 (21%) had died by 1995 and 65 others (8.6%) did not get SPMSQ testing in 1995. Because eight of these 226 participants without SPMSQ test results in 1995 had demonstrable cognitive decline (they scored less than 6 on the SPMSQ in 1991), they were included in the study sample. Thus, our study sample was composed of 538 individuals who had urine cortisol measurements at baseline and either SPMSQ testing in 1995
Discussion
Our objective was to examine the association between overnight urinary cortisol excretion, a measure of resting basal cortisol levels, and the risk, over 7 years of follow up, of decline in performance on the SPMSQ, in a cohort of previously high-functioning older adults. Because every participant scored 6 or better on the SPMSQ at baseline, as it was one of the selection criteria, a decline in the SPMSQ score is an indicator of incident cognitive impairment in this cohort. We found that
Acknowledgements
Work on this article was supported by NIH/NIA Mentored Clinical Scientist Development Award 1K12AG01004, a VA Career Development Award, NIA grants AG-17056 and AG-17265, and by the MacArthur Research Network on Successful Aging and the MacArthur Research Network on SES and Health through grants from the John D. and Catherine T. MacArthur Foundation.
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