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

Abstract

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 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive cortisone to active cortisol; yet the amount of 11β-HSD1 in the brain has not been quantified directly in vivo. We analyzed positron emission tomography (PET) scans with an 11β-HSD1 inhibitor radioligand in twenty-eight individuals (23M/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 11C-AS2471907 (n= 17) or 18F-AS2471907 (n= 11). Injected activity and mass doses were 246 ± 130MBq and 0.036 ± 0.039μg, respectively, for 11C-AS2471907, and 92 ± 15MBq and 0.001 ± 0.001μg for 18F-AS2471907. Correlations of mean whole brain and regional distribution volume (VT) with body mass index (BMI) and age were performed with a linear regression model. Significant correlations of whole brain mean VT with BMI and age (VT = 15.23-0.63 × BMI + 0.27 × Age, p = 0.001) were revealed. Age-adjusted mean whole brain VT values were significantly lower in obese individuals. Post hoc region specific analyses revealed significantly reduced mean VT values in the thalamus (lean vs. overweight and lean vs. obese individuals). Caudate, hypothalamus, parietal lobe, and putamen also showed lower VT value in obese vs. lean individuals. A significant age-associated increase of 2.7mL/cm3 per decade was seen in BMI-corrected mean whole brain VT values. In vivo PET imaging demonstrated, for the first time, correlation of higher BMI (obesity) with lower levels of the enzyme 11β-HSD1 in the brain and correlation of increased 11β-HSD1 levels in the brain with advancing age.