Body Mass Index and Age Effects on Brain 11β-Hydroxysteroid Dehydrogenase Type 1: a Positron Emission Tomography Study

Context Cortisol, a glucocorticoid steroid stress hormone, is primarily responsible for stimulating gluconeogenesis in the liver and promoting adipocyte differentiation and maturation. Prolonged excess cortisol leads to visceral adiposity, insulin resistance, hyperglycemia, memory dysfunction, cognitive impairment, and more severe Alzheimer's disease phenotypes. The intracellular enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) catalyzes the conversion of inactive cortisone to active cortisol; yet the amount of 11 beta-HSD1 in the brain has not been quantified directlyin vivo. Objective We analyzed positron emission tomography (PET) scans with an 11 beta-HSD1 inhibitor radioligand in twenty-eight individuals (23 M/5F): 10 lean, 13 overweight, and 5 obese individuals. Each individual underwent PET imaging on the high-resolution research tomograph PET scanner after injection of(11)C-AS2471907 (n = 17) or(18)F-AS2471907 (n = 11). Injected activity and mass doses were 246 +/- 130 MBq and 0.036 +/- 0.039 mu g, respectively, for(11)C-AS2471907, and 92 +/- 15 MBq and 0.001 +/- 0.001 mu g for(18)F-AS2471907. Correlations of mean whole brain and regional distribution volume (V-T) with body mass index (BMI) and age were performed with a linear regression model. Results Significant correlations of whole brain meanV(T)with BMI and age (V-T = 15.23-0.63 x BMI + 0.27 x Age,p = 0.001) were revealed. Age-adjusted mean whole brainV(T)values were significantly lower in obese individuals.Post hocregion specific analyses revealed significantly reduced meanV(T)values in the thalamus (leanvs.overweight and leanvs.obese individuals). Caudate, hypothalamus, parietal lobe, and putamen also showed lowerV(T)value in obesevs.lean individuals. A significant age-associated increase of 2.7 mL/cm(3)per decade was seen in BMI-corrected mean whole brainV(T)values. Conclusions In vivoPET imaging demonstrated, for the first time, correlation of higher BMI (obesity) with lower levels of the enzyme 11 beta-HSD1 in the brain and correlation of increased 11 beta-HSD1 levels in the brain with advancing age.