Published on: August 21, 2015
by Kay Jackson for MedPage Today:
In older, community-dwelling, dementia-free adults, evening and morning cortisol levels may be differentially associated with volume reductions in gray and white matter and cognitive functioning, according to a population-based study.
In more than 4,000 participants, the mean morning cortisol level was 20 nmol/L and the median (10th-90th percentile) evening cortisol level was 2.3 nmol/L (0.9-6.9). Evening cortisol was associated with smaller total brain volume (highest versus lowest tertile -16.0 mL, 95% CI -19.7 to -12.2 mL) adjusted for age, sex, education, intracranial volume, smoking, steroid use, white matter lesions, and brain infarcts on MRI, reported Lenore J. Launer, PhD, from the National Institute on Aging in Bethesda, Md., and colleagues.
All regional brain volumes, with the exception of the striatum, were significantly smaller in the highest tertile of evening cortisol compared to the lowest tertile, they wrote in Neurology.
Understanding these differential associations may aid in developing strategies to reduce the effects of hypothalamic-pituitary-adrenal (HPA) axis dysfunction on late-life cognitive impairment, they stated.
“We found that higher levels of salivary evening cortisol were associated with smaller volume in multiple brain regions, significantly more in gray than in white matter, as well as with poorer cognitive performance in multiple domains,” Launer’s group wrote. This finding is consistent with the diffuse and widespread volume reductions in gray and white matter, they added.
However, morning cortisol levels painted a very different picture as they were “associated with slightly larger volumes in several white matter regions and were more selectively associated with better processing speed and executive functioning,” the authors wrote.
“But the reason for the differences between early and evening cortisol levels are not clear,” Launer cautioned.
“It is possible that changes in the brain due to other factors also led to changes in cortisol levels,” Launer told MedPage Today. “Since this was a cross-sectional study, designed to look at associations, temporality cannot be inferred.”
She noted that evening cortisol is thought to reflect basal or resting levels, while morning cortisol levels are thought to reflect acute stress from awakening. In addition, “gray matter and white matter differ in rates of atrophy and density of receptors.”
Prospective studies that integrate measures of chronic stress, HPA axis activity, and brain volumes are needed to determine the direction of association, she emphasized.
Data was take from the Reykjavik Study, which began in 1967, and included men and women born between 1907 and 1935 who lived in Reykjavik. From 2002 to 2006, 5,764 persons, randomly chosen from this study, were included in the AGES-Reykjavik Study, which set out to investigate the contribution of genetic and environmental factors to clinical and subclinical disease in older people.
Assessments included questionnaires, clinical examinations, venipuncture, cognitive testing, and MRI of the brain.
The analysis ultimately examined 4,244 persons without dementia (age 76) and 58% were women. All had undergone assessment of cognitive functioning, and over a period of 24 hours, saliva was collected at home 45 minutes after awakening and 30 minutes after eating at night.
Linear regression analysis was used to estimate the cross-sectional relationship among cortisol levels (in tertiles), brain volumes and cognitive functioning, adjusting for covariates, the investigators explained.
Results from multilevel models showed that gray matter was significantly (P<0.001) more affected by higher evening cortisol levels than was white matter.
Similarly, reduced cognitive functioning across all domains was also associated with higher evening cortisol.
While higher levels of morning cortisol were associated with slightly greater normal white matter volume, better processing speed and executive functioning, they were not associated with gray matter volume or with memory performance, they stated. Results of the multilevel models showed that white matter was significantly (P=0.0008) more affected than gray matter by morning cortisol.
These results did not change substantially, even with the exclusion of participants who used steroids, had mild cognitive impairment, or a lifetime diagnosis of major depressive disorder.
Until now, most investigations into the relationship between hippocampal volume and HPA axis activity have been carried out in younger adults, Launer explained. And while some studies have reported more atrophy of the hippocampus in the presence of higher cortisol, others have reported no association.
In older individuals, the largest study thus far has reported that increased evening cortisol levels and increased awakening levels after dexamethasone were associated with reduced volume of the hippocampus. On the other hand, the cortisol awakening response was not associated with reduced hippocampal volume.
“Although we did not have data on awakening levels after dexamethasone, our findings are consistent with that study but also extend those findings, because we report more widespread gray matter involvement,” she said. “Moreover, we observed differential gray and normal white matter involvement, where higher evening cortisol levels were more strongly associated with gray than white matter volume reduction, and higher morning cortisol levels were associated with larger white but not gray matter volumes.”
Also, with increasing age, the prevalence of dementia, including Alzheimer’s disease,increases exponentially, the authors noted.
Depressive symptoms are also common and may persist over years, frequently comorbid with cognitive impairment and dementia.
While prospective studies have suggested that depression may play a role in increasing risk of dementia, the relationship between depression and Alzheimer’s remains unclear.
“Several studies have found structural brain abnormalities to be associated with late-life depression, including hippocampal volume reduction,” Launer said. “Also, it has often been hypothesized that persistently high cortisol levels, often observed in depression, have neurotoxic effects on the hippocampus.”
A study limitation was that cortisol was assessed during a single day.
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