Morning Cortisol Levels and Cognitive Abilities in People With Type 2 Diabetes: The Edinburgh Type 2 Diabetes Study

OBJECTIVE

People with type 2 diabetes are at increased risk of cognitive impairment but the mechanism is uncertain. Elevated glucocorticoid levels in rodents and humans are associated with cognitive impairment. We aimed to determine whether fasting cortisol levels are associated with cognitive ability and estimated lifetime cognitive change in an elderly population with type 2 diabetes.

RESEARCH DESIGN AND METHODS

This was a cross-sectional study of 1,066 men and women aged 60–75 years with type 2 diabetes, living in Lothian, Scotland (the Edinburgh Type 2 Diabetes Study). Cognitive abilities in memory, nonverbal reasoning, information processing speed, executive function, and mental flexibility were tested, and a general cognitive ability factor, g, was derived. Prior intelligence was estimated from vocabulary testing, and adjustment for scores on this test was used to estimate lifetime cognitive change. Relationships between fasting morning plasma cortisol levels and cognitive ability and estimated cognitive change were tested. Models were adjusted for potential confounding and/or mediating variables including metabolic and cardiovascular variables.

RESULTS

In age-adjusted analyses, higher fasting cortisol levels were not associated with current g or with performance in individual cognitive domains. However, higher fasting cortisol levels were associated with greater estimated cognitive decline in g and in tests of working memory and processing speed, independent of mood, education, metabolic variables, and cardiovascular disease (P < 0.05).

CONCLUSIONS

High morning cortisol levels in elderly people with type 2 diabetes are associated with estimated age-related cognitive change. Strategies targeted at lowering cortisol action may be useful in ameliorating cognitive decline in individuals with type 2 diabetes.Type 2 diabetes is associated with cognitive impairments, including deficits in processing speed, executive function and declarative memory, and with structural changes in the brain including reductions in hippocampal and amygdalar volumes, which are key areas influencing learning and long-term memory (1,2). Hyperglycemia, cerebral microvascular disease, and recurrent severe hypoglycemic episodes have all been implicated as potential causative factors of cognitive decline (3) but are unlikely to explain the entire effect of diabetes on cognition.Increasing evidence supports a link between elevated plasma glucocorticoids and cognitive dysfunction. Exogenous glucocorticoid administration and elevated endogenous glucocorticoids (as occurs in Cushing''s syndrome) are associated with cognitive impairment in animals and humans. More subtle alterations in hypothalamic-pituitary-adrenal (HPA) axis function have also been linked with cognitive function, with higher plasma cortisol levels at 0900 h being associated with poorer age-related cognitive ability in a small group of elderly, healthy male volunteers (4). Conversely, manipulations that reduce plasma glucocorticoid concentrations or their effects on target tissues can attenuate cognitive decline with ageing in rodents (5,6). Elevated glucocorticoid levels have widespread effects within the central nervous system, including deleterious effects on the structure and function of the hippocampus, a key locus for cognitive function, which also highly expresses glucocorticoid receptors (7,8).Several studies have demonstrated that people with type 2 diabetes have activation of the HPA axis, manifested by elevated basal plasma cortisol levels (9,10), higher late-night salivary cortisol levels (11), elevated ACTH levels (12), increased cortisol levels following overnight dexamethasone suppression (13,14), and impaired habituation of cortisol levels to repeated stress (15). These findings are consistent with a central dysregulation of the HPA axis in type 2 diabetes. The elevated plasma cortisol levels are associated with metabolic abnormalities in diabetes (16) and with complications of diabetes, including retinopathy, neuropathy, and nephropathy (17).Investigators have started to explore whether altered HPA axis activity contributes to cognitive impairment in diabetes. Impaired central negative feedback control of the HPA axis, as indicated by higher cortisol levels after 1.5 mg dexamethasone administration, was related to declarative memory impairments, possibly reflecting hippocampal dysfunction, in 30 individuals with type 2 diabetes compared with age-, sex-, and education-matched control subjects (18). However, the association between cortisol and cognitive function disappeared after adjustment for glycemic control (A1C). The same investigators reported similarly impaired HPA axis feedback control in association with verbal declarative memory deficits in 41 subjects with type 2 diabetes (1). In the latter study, the subjects with type 2 diabetes also had reduced hippocampal and prefrontal volumes, but there were no significant associations between the cortisol measurements and magnetic resonance image findings (1).Despite these findings from animal and human studies, information from large-scale epidemiological studies of representative populations is lacking, which could confirm or refute an association between circulating plasma cortisol levels and age-related cognitive impairment. We therefore examined the relationship between fasting cortisol and both late-life cognitive ability and estimated lifetime cognitive change in a large, representative study population of people with type 2 diabetes (the Edinburgh Type 2 Diabetes Study [ET2DS]). The ET2DS has the advantage over many previous epidemiological studies of having detailed cognitive testing in a range of cognitive domains and very extensive phenotyping for potential confounding or mediating factors.