11β-hydroxysteroid dehydrogenase type 1, brain atrophy and cognitive decline.
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.
MacLullich
Alasdair M J
AM
Endocrinology, University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, Scotland, UK. a.maclullich@ed.ac.uk
Ferguson
Karen J
KJ
Reid
Louise M
LM
Deary
Ian J
IJ
Starr
John M
JM
Wardlaw
Joanna M
JM
Walker
Brian R
BR
Andrew
Ruth
R
Seckl
Jonathan R
JR
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000368:Aged; D000375:Aging / Q000473:pathology* / Q000523:psychology*; D001284:Atrophy; D001921:Brain / Q000473:pathology*; D003071:Cognition; D003072:Cognition Disorders / Q000209:etiology* / Q000628:therapy; D003348:Cortisone / Q000378:metabolism; D003430:Cross-Sectional Studies; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D058990:Molecular Targeted Therapy
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D003348:Cortisone; D006854:Hydrocortisone