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

Neurobiol Aging. 2012 Jan;33(1):207.e1-8. doi: 10.1016/j.neurobiolaging.2010.09.010. Epub 2010 Oct 18.

Abstract

Excess cortisol levels are linked with brain atrophy and cognitive decline in older people. 11β-hydroxysteroid dehydrogenase type 1 (11β-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 11β-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 11β-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 11β-HSD1 activity and progressive brain atrophy and cognitive decline suggests 11β-HSD1 inhibition as a plausible therapy for brain aging.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / physiology*
  • Aged
  • Aging / pathology*
  • Aging / psychology*
  • Atrophy
  • Brain / pathology*
  • Cognition Disorders / etiology*
  • Cognition Disorders / therapy
  • Cognition*
  • Cortisone / metabolism
  • Cross-Sectional Studies
  • Humans
  • Hydrocortisone / metabolism*
  • Longitudinal Studies
  • Magnetic Resonance Imaging
  • Male
  • Molecular Targeted Therapy

Substances

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1
  • Cortisone
  • Hydrocortisone