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

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Abstract

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 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.

Objective

We analyzed positron emission tomography (PET) scans with an 11β-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 11C-AS2471907 (n = 17) or 18F-AS2471907 (n = 11). Injected activity and mass doses were 246 ± 130 MBq and 0.036 ± 0.039 μg, respectively, for 11C-AS2471907, and 92 ± 15 MBq and 0.001 ± 0.001 μg 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.

Results

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 2.7 mL/cm3 per decade was seen in BMI-corrected mean whole brain VT values.

Conclusions

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.

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Data Availability

The datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

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Funding

This work was funded by a NARSAD Independent Investigator Award (KC), the VA National Center for PTSD (KC), NIH DRC P30DK045735 (AMJ), and NIH NIDDK K01DK118005 (JB).

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Authors and Affiliations

  1. Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA

    Jason Bini, Ansel T. Hillmer, Jean-Dominique Gallezot, Nabeel Nabulsi, Richard Pracitto, David Labaree, Michael Kapinos, Jim Ropchan, David Matuskey, Richard E. Carson, Kelly Cosgrove & Yiyun Huang

  2. Yale University PET Center, 801 Howard Ave, PO Box 208048, New Haven, CT, 06520-8048, USA

    Jason Bini

  3. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    Shivani Bhatt, Ansel T. Hillmer, David Matuskey & Kelly Cosgrove

  4. Department of Neurology, Yale University School of Medicine, New Haven, CT, USA

    David Matuskey

  5. Department of Internal Medicine, Endocrinology, Yale University School of Medicine, New Haven, CT, USA

    Robert S. Sherwin & Ania M. Jastreboff

  6. Department of Pediatrics, Pediatric Endocrinology, Yale University School of Medicine, New Haven, CT, USA

    Ania M. Jastreboff

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  1. Jason Bini
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Corresponding author

Correspondence to Jason Bini.

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Conflict of Interest

AMJ consults for Novo Nordisk, Medtronic Diabetes, and Rhythm Pharmaceuticals. All other authors have nothing to disclose.

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Bini, J., Bhatt, S., Hillmer, A.T. et al. Body Mass Index and Age Effects on Brain 11β-Hydroxysteroid Dehydrogenase Type 1: a Positron Emission Tomography Study. Mol Imaging Biol 22, 1124–1131 (2020). https://doi.org/10.1007/s11307-020-01490-z

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