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11β-hydroxysteroid dehydrogenase type 1, brain atrophy and cognitive decline

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    Rights statement: © MacLullich, A. M. J., Ferguson, K. J., Reid, L. M., Deary, I. J., Starr, J., Wardlaw, J. M., Walker, B. R., Andrew, R., & Seckl, J. R. (2012). 11β-hydroxysteroid dehydrogenase type 1, brain atrophy and cognitive decline. Neurobiology of Aging, 33(1), 207.e1–207.e8. 10.1016/j.neurobiolaging.2010.09.010

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http://www.sciencedirect.com/science/article/pii/S0197458010003854
Original languageEnglish
Pages (from-to)207.e1–207.e8
Number of pages8
JournalNeurobiology of Aging
Volume33
Issue number1
DOIs
Publication statusPublished - Jan 2012

Abstract

Excess cortisol levels are linked with brain atrophy and cognitive decline in older people. 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) potently amplifies intracellular glucocorticoid action by converting inert cortisone to active cortisol, but any causal importance in brain aging is unexplored. We tested the hypotheses that higher systemic 11 beta-HSD1 activity predicts brain atrophy and cognitive decline in older men.

In a longitudinal study of 41 men (65-70 years old at baseline) we measured baseline systemic 11 beta-HSD1 activity, the urinary 5alpha- and 5beta-tetrahydrocortisol to tetrahydrocortisone ratio (ratio of tetrahydrometabolites of cortisol (THFs)/ratio of tetrahydrometabolites of cortisol (THE)), and assessed change in brain atrophy, white matter lesions and cognitive function over 6 years.

Baseline THFs/THE correlated negatively with baseline hippocampal volumes (left: r = -0.37; right: r = -0.34; p < 0.05) and positively with ventricular volumes (r = 0.43, p = 0.006) and periventricular white matter lesions (rho = 0.31, p = 0.047). Importantly, baseline THFs/THE but not cortisol predicted increase in ventricular volumes (r = 0.33, p = 0.037) and decline in processing speed (r = -0.55, p = 0.0002) over 6 years.

The predictive link between systemic 11 beta-HSD1 activity and progressive brain atrophy and cognitive decline suggests 11 beta-HSD1 inhibition as a plausible therapy for brain aging.

    Research areas

  • Cognition, Glucocorticoids, Cortisol, Cerebral atrophy, White matter lesions, Dementia, Aging

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