Cortisol Reduces Hippocampal Glucose Metabolism in Normal Elderly, but Not in Alzheimer’s Disease*

Abstract

Glucocorticoids are known to play a role in the regulation of peripheral glucose mobilization and metabolism. Although several animal studies have shown that hippocampal glucose metabolism is reduced acutely and chronically by the action of corticosterone and that excess glucocorticoids are harmful to hippocampal neurons, little is known about the central effects of glucocorticoids in the human. In this study we examined the brain glucose utilization (CMRglu) response to hydrocortisone (cortisol) in seven normal elderly and eight Alzheimer's disease (AD) patients. On 2 separate days, immediately after the administration of a bolus of either 35 mg hydrocortisone or placebo, we administered 2-deoxy-2-[18F]fluoro-D-glucose. After a 35-min radiotracer uptake period, positron emission tomography (PET) images were collected. PET CMRglu images were analyzed using two methods: an image transformation that allowed analyses across cases on a voxel by voxel basis, and an anatomically based region of interest method that used coregistered magnetic resonance imaging scans. Both image analysis methods yielded similar results, identifying relative to placebo, a specific hippocampal CMRglu reduction in response to the hydrocortisone challenge that was restricted to the normal group. The region of interest technique showed CMRglu reductions of 16% and 12% in the right and left hippocampi, respectively. Blood collected during the PET scans showed, for the normal group, a rise in plasma glucose levels, starting approximately 25 min after hydrocortisone administration. The AD group did not show this effect. Baseline cortisol was elevated in the AD group, but the clearance of hydrocortisone was not different between the groups. In conclusion, these data show that among normal individuals in the presence of a pharmacological dose of cortisol, the glucose utilization of the hippocampus is specifically reduced, and serum glucose levels increase. Based in part on other studies, we offer the interpretation that glucocorticoid-mediated regulation of glucose transport is altered in AD, and this may underlie both the hippocampal insensitivity to cortisol and the failure in these patients to mount a peripheral glucose response. As our findings could reflect an altered state of the AD patients, we interpret our results as preliminary with respect to evidence for metabolic abnormalities in AD. The results suggest the continued study of the hydrocortisone challenge as a test of hippocampal responsivity.

11β-Hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics

“…The human CNS, including the hippocampus, highly expresses corticosteroid receptors (7), and glucocorticoids alter cognitive performance in humans, effects amplified by age (66)(67)(68)(69). Here, we found carbenoxolone-induced cognitive improvements in groups of healthy and diabetic older people.…”

Regulation of Glucose Homeostasis by Glucocorticoids

“…GC inhibit the expression of glucose transporter 1 (GLUT1) that results in a decreased glucose uptake into leukemia cells [128]. GC also suppress glucose uptake and oxidation in certain regions of brain, such as the hypothalamus and hippocampus [129–131]. The exact mechanisms of these GC effects on these cell types are mostly unclear.…”

Basal Hypothalamo-Pituitary-Adrenal Axis Activity and Corticotropin Feedback in Young and Older Men: Relationships to Magnetic Resonance Imaging-Derived Hippocampus and Cingulate Gyrus Volumes

“…Also, a failure to suppress cortisol secretion after DEX administration has been associated with atrophy of the hippocampus in patients with Alzheimer’s disease [28]. More recently, we have shown that the administration of a cortisol bolus selectively reduces hippocampal glucose utilization [29], thereby demonstrating in the human that an acute cortisol elevation affects the hippocampus directly.…”