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. Author manuscript; available in PMC: 2021 Aug 1.
Published in final edited form as: Mol Imaging Biol. 2020 Aug;22(4):1124–1131. doi: 10.1007/s11307-020-01490-z

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

Jason Bini 1, Shivani Bhatt 2, Ansel T Hillmer 1,2, Jean-Dominique Gallezot 1, Nabeel Nabulsi 1, Richard Pracitto 1, David Labaree 1, Michael Kapinos 1, Jim Ropchan 1, David Matuskey 1,2,3, Robert S Sherwin 4, Ania M Jastreboff 4,5, Richard E Carson 1, Kelly Cosgrove 1,2, Yiyun Huang 1
PMCID: PMC7351613  NIHMSID: NIHMS1572029  PMID: 32133575

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 (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±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 – 0.63xBMI + 0.27xAge, 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.

INTRODUCTION

The prevalence of obesity in the United States is nearly 40%, predisposing a large portion of the population to metabolic diseases.[1] Cortisol, a glucocorticoid steroid stress hormone, is primarily responsible for stimulating gluconeogenesis in the liver and promoting adipocyte differentiation and maturation. Plasma cortisol diffuses into the central nervous system [2], and is also activated intracellularly from cortisone in neurons and glial cells[3]. Prolonged exposure to excess levels of cortisol, as seen in Cushing’s syndrome, leads to visceral adiposity, insulin resistance, hyperglycemia, and memory dysfunction.[4, 5] In addition to association with obesogenic phenotypes, prolonged exposure to excess levels of cortisol has been linked to cognitive impairments, and more severe Alzheimer’s disease phenotypes.[6–14] Unlike Cushing’s syndrome, where high plasma cortisol leads to obesogenic phenotypes, plasma cortisol is reported to be normal or lower in individuals with obesity compared to lean individuals, likely due to higher excretion of cortisol in obese individuals.[3, 15, 16] This finding has led to the hypothesis that if excess cortisol is quickly excreted from peripheral sources (adrenals, liver, adipose tissue) in obese individuals, deleterious effects on the brain may occur from cortisol that is generated intracellularly in neurons and glial cells to different degrees within different brain regions.[3, 14, 17]

The intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive cortisone to active cortisol in key metabolic tissues, and the amount of 11β-HSD1 and its activity affect tissue-specific levels of cortisol; yet the levels of 11β-HSD1 in these tissues, including the brain, has not been directly quantified in vivo. In mice, age-related increases in 11β-HSD1 mRNA levels in the cortex and hippocampus were assayed by in vitro immunohistochemistry, and found to be associated with impaired memory.[14, 18] In humans, liver and adipose tissue 11β-HSD1 levels have previously been estimated through indirect methods using stable isotope labeling of cortisol and its metabolites, measured either locally (e.g., hepatic vein) or via urinary steroid metabolites.[15, 19] Until recently, there was no tool for direct in vivo measurement of 11β-HSD1 enzyme levels throughout the body, and more importantly, directly in the brain. We have developed and characterized two 11β-HSD1 inhibitor radioligands, 11C-AS2471907 [20, 21] and its 18F-labeled counterpart 18F-AS2471907 [22, 23], for in vivo imaging of 11β-HSD1 using positron emission tomography (PET). As discussed previously [22, 23], 11C-AS2471907 and 18F-AS2471907 is the same molecule labeled with different radioisotopes. Radiosynthesis of 11C-AS2471907 had low radiochemical yield. Availability of three fluorines in the AS2471907 molecule allowed the development of 18F AS2471907, which can be produced in high radiochemical yield.[22] The pharmacokinetic and binding properties of these two radioligands have been demonstrated to be very similar in humans.[21, 23] Both radioligands have high specific binding to the 11β-HSD1 enzyme in the brain and are suitable for quantitative measurement of 11β-HSD1 availability in humans. In the current study, we retrospectively analyzed PET scans of 11C-AS2471907 and 18F-AS2471907 in individuals with a range of body mass index (BMI, from lean to obese) and ages to examine the effects of body weight and age on brain 11β-HSD1 levels. We hypothesized that with increasing BMI and age, both associated with higher intracellular exposure to cortisol, we would find higher 11β-HSD1 enzyme levels indicative of higher intracellular brain cortisol production.

MATERIALS AND METHODS

In this study, we retrospectively analyzed PET scans with 11C-AS2471907 [21] or 18F-AS2471907 [23] in twenty-eight otherwise healthy individuals (23M/5F): 10 lean (BMI: 18 to 24.9 kg/m2) (mean±SD BMI 23.0±1.4 kg/m2), 13 overweight (BMI: 25 to 29.9 kg/m2) (mean BMI 27.6±1.3 kg/m2) and 5 obese (BMI: >30 kg/m2) (mean BMI 31.1±0.8 kg/m2) (Table 1). All subjects did not have a history of psychiatric disorders or substance abuse. Other exclusion criteria were current or past serious medical or neurological illness (e.g., history of head injury with loss of consciousness), current pregnancy (as documented by pregnancy testing at screening and on the day of the PET scan), lactating, or contraindications to magnetic resonance imaging (MRI). Subject eligibility was confirmed by medical and psychiatric histories, physical examination, neurological and mental status exam, routine laboratory tests and electrocardiogram. Individuals were also grouped into age ranges by decade to further examine the age effect: 20–30 years old (n=10), 30–40 years old (n=10), 40–50 years old (n=6) and 50–60 years old (n=2). The study was approved by the Yale University Human Investigation Committee, MRI Safety Committee, and Radiation Safety Committees. All subjects signed a written informed consent.

Table 1.

Participant demographics, and injected dose and mass for each radioligand (11C and 18F) with respect to each group (lean, overweight and obese)

n Age (y) BMI (kg/m2) Radiolgiand Injected Dose (MBq) Injected Mass Og/kg)
Lean 10(2) 32.7±8.8 23.0±l.4 11C, n=4 245±139 0.04±0.04
18F n=6 96±9 0.01±0.00
Overweight 13(2) 37.0±9.0 27.6±1.3* 11C, n=9 250±137 0.03±0.04
18F n=4 84±22 0.02±0.01
Obese 5 38.1±5.8 31.1±0.8+ 11C, n=5 239±145 0.04±0.04
18F n=1 101 0.01
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Number in parentheses is number of female individuals in each group. Significant differences:

*-

overweight vs. lean,

+-

obese vs. lean. No statistically significant differences seen with age, injected dose or injected mass between groups.

Each subject underwent PET imaging after injection of 11C-AS2471907 (n=17) or 18FAS2471907 (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. All subjects had an arterial line to permit blood sampling for plasma activity measurement and metabolite analysis, as described previously [21–23]. Subjects were scanned for 2 (11C-AS2471907) or 3 hours (18F-AS2471907) on the high-resolution research tomograph (HRRT) PET scanner (Siemens Healthcare) (resolution of 2.5–3.0mm FWHM). PET images were reconstructed with scatter and attenuation correction using the ordered subset-expectation maximization algorithm (OSEM, 2 iterations, 30 subsets). Each subject underwent one Magnetic Resonance (MR) scan as previously described [24] for anatomical localization of brain regions to analyze the PET data.

Fourteen regions of interest (ROIs) were selected from the Anatomical Automatic Labeling (AAL) template for SPM2 [25]: centrum semiovale, amygdala, caudate, putamen, thalamus, hippocampus, hypothalamus, cerebellum, cingulate, insula, frontal cortex, occipital cortex, parietal cortex and temporal cortex. The ROIs were applied to the PET data to generate regional time-activity curves (TACs) using each subject’s MR image to co-register the template and the PET data.[24] Volume of distribution (VT, mL/cm3), the ratio of radioligand concentration in tissue to that in plasma at equilibrium, [26] was estimated for each ROI using the multilinear analysis-1 (MA1) method with t*=30 min and tmax=120 min for 11C-AS2471907 or tmax=180 min for 18F-AS2471907 using the metabolite-corrected arterial plasma radioactivity concentration over time as input function.[21, 23, 27] Mean whole brain VT value was calculated by averaging the values in all ROIs. Data are presented as mean ± standard deviation unless otherwise specified. A generalized linear model, with VT as the response variable, was constructed using BMI, age, BMI × age interaction, radioligand (18F- vs. 11C-AS2471907), and time of scan as between-subject predictive factors (Minitab 18, Minitab, Inc). Given that there were only five female individuals in the study and we would be unable to assess sex differences, we repeated the linear regression model with the male-only cohort to provide an exploratory analysis that our initial correlation was not driven by any sex effect. Pearson’s correlations were performed where noted. Exploratory post hoc analyses of group means and regional brain analyses using t test were performed and were not corrected for multiple comparisons.

RESULTS

No significant differences were seen between lean, overweight, or obese groups with respect to injected activity dose or injected mass of the radiotracers (Table 1). Age was higher in the overweight and obese groups, but was not statistically different (p=0.27 and p=0.24, respectively, compared to lean individuals). Age range was similar between cohorts (Lean: 24–49 years; Overweight: Age 27–51 years; Obese: Age 32–45 years).

Correlation of BMI and age with brain VT

The MA1 model provided good fitting of all ROI TACs for the duration of the PET scan and reliable estimates of regional brain VT values. In the linear regression model, the F-statistic determined that time of scan, radioligand and the interaction term (BMI × age; Pearson’s R2=0.08, p=0.14) were found not to be significant based on the F-statistic and did not improve model parsimony, thus these terms were excluded for subsequent analysis. A linear regression model analysis of VT value with BMI and age was highly significant (VT = 15.23 – 0.63*BMI + 0.27*Age, p=0.001). Both coefficients of the linear regression were significant (BMI: β= −0.63, p=0.003; Age: β= 0.27, p=0.001).

Effect of BMI on whole-brain and region-specific group differences

When plotting age-adjusted mean whole brain VT value and BMI for all individuals, higher BMI was significantly correlated with lower mean whole brain VT value (Figure 1) (Pearson’s correlation R= −0.57, p=0.003). The age-adjusted mean whole brain VT in lean individuals was 10.7±0.9 mL/cm3 (Mean±SEM), and significantly lower in both overweight (7.1±0.9 mL/cm3; p=0.01) and obese individuals (5.3±1.3 mL/cm3; p=0.01) (Figure 2). Exploratory region-specific analyses revealed that mean VT in the thalamus were significantly lower in both overweight (10.9±1.8 mL/cm3; p=0.02) and obese (7.4±1.3 mL/cm3; p<0.01) versus lean individuals (17.2±1.9 mL/cm3) (Figure 3). Mean VT values in several additional regions were significantly lower in obese compared to lean individuals, including the caudate (2.8±0.5 vs. 4.8±0.6 mL/cm3; p=0.03), hypothalamus (3.3±0.5 vs. 8.0±1.9 mL/cm3; p=0.04), parietal lobe (8.6±1.1 vs. 14.1±1.7 mL/cm3; p=0.02), and putamen (7.0±1.1 vs. 11.0±1.1 mL/cm3; p=0.03).

Figure 1.

Figure 1

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Pearson’s correlation of age-adjusted mean brain volume of distribution and body mass index for all individuals (n=28).

Figure 2.

Figure 2

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Mean±SEM of group age-adjusted mean whole brain distribution volumes between lean, overweight and obese individuals.

Figure 3.

Figure 3

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Mean±SEM of individual brain regional distribution volumes. Individual brain regions were not age-adjusted. Significant differences: *- overweight vs. lean, +- obese vs. lean.

Effect of Age on whole-brain and region-specific group differences

When plotting BMI-adjusted VT values and age, greater age was significantly correlated with increased mean whole brain VT value (of 2.7 mL/cm3 per decade) (Figure 4) (Pearson’s correlation R= 0.61, p=0.001). Mean BMI-adjusted whole brain VT value was 6.0±0.6 mL/cm3 (Mean±SEM) in individuals 20 230 years old (n=10) and was higher in each subsequent age group: 8.1±0.8 mL/cm3 in the 30 – 40 years old group (n=10) (p=0.06 vs. 20–30 y), 8.9±1.2 mL/cm3 in the 40 – 50 years old group (n=6) (p=0.06 vs. 20–30 y), and 15.8±6.8 mL/cm3 in the 50–60 years old group (n=2) (Figure 5). Region-specific analyses revealed a similar trend of higher VT value with each successive decade in age in larger cortical regions (Figure 6); however, none of the age group differences by decade for mean whole brain or regional VT estimates were statistically significant.

Figure 4.

Figure 4

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Pearson’s correlation of BMI-adjusted mean brain volume of distribution and age for all individuals (n=28).

Figure 5.

Figure 5

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Mean±SEM of group BMI-adjusted distribution volumes grouped by range of age by decade.

Figure 6.

Figure 6

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Mean±SEM of individual brain regional distribution volumes grouped by range of age by decade. Individual brain regions were not BMI-adjusted.

Effect of Sex

To indirectly assess sex differences, the model was analyzed with only the data from male subjects. The linear regression model of VT with BMI and age remained significant (VT = 14.93 – 0.50*BMI + 0.16*Age, p=0.007) and the coefficients of the linear regression using only male individuals were still significant (BMI: β= −0.50, p=0.008; Age: β= 0.17, p=0.02). When plotting age-corrected VT and BMI values for male individuals, higher BMI was significantly correlated with lower mean whole brain VT (Pearson’s correlation R= −0.57, p=0.008). When plotting BMI-corrected VT values and age for male individuals, higher age was significantly correlated with higher mean whole brain VT values (Pearson’s correlation R= 0.51, p=0.02).

DISCUSSION

In the current study, we performed a retrospective analysis by combining data from PET imaging with both 11C- and 18F-AS2471907, inhibitor radioligands which bind to the cortisol regulating enzyme 11β-HSD1. The range of BMI (21–32 kg/m2) and age (24–54 years) allowed for the investigation of weight and age effects on radioligand binding to 11β-HSD1. In vivo PET estimates of 11β-HSD1 radioligand VT demonstrated a significant correlation whereby lower 11β-HSD1 levels in the brain were associated with higher BMI (obesity). In addition, higher 11β-HSD1 levels in the brain were significantly associated with advancing age.

Lower 11β-HSD1 radioligand binding in the brain correlating with greater BMI was counter to our original hypothesis, although, however, we can suggest a possible explanation for this result. Using indirect methods of measuring steroid metabolites in urine and/or blood, 11β-HSD1 levels have been reported to be lower [15, 16, 19, 28, 29] in hepatic tissue in individuals with obesity, the largest source of the 11β-HSD1 enzyme. In addition, in non-alcoholic fatty liver disease (NALFD), for which obesity is typically a risk factor and co-morbidity, early stage disease (hepatic steatosis) was found to be associated with a reduction in 11β-HSD1 levels while progression to non-alcoholic steato-hepatitis was associated with an increase in 11β-HSD1 levels.[30] With this in mind, it is possible that lower 11β-HSD1 levels in the brain with greater BMI may suggest a protective mechanism against increased cortisol production and brain exposure. The five inidividuals with obesity in this study only had BMIs ranging from 30 to 32 kg/m2 (Class I obesity), which does not allow examination of more severe obesity (Class II: 35 to 39.9 kg/m2 and Class III: >40 kg/m2].

Increases in 11β-HSD1 levels in the brain with aging have been well documented in rodent models.[14, 31–35] Increased exposure to cortisol, demonstrated by increased urine metabolites of cortisol used to infer 11β-HSD1 enzyme levels, has also demonstrated age-associated increases in humans.[6, 7, 9, 10, 12–14] However, direct in vivo measurement of brain 11β-HSD1 levels has not previously been possible. Our study is the first to directly assess 11β-HSD1 levels in vivo, in the human brain, and the results suggest a correlation of higher 11β-HSD1 levels with increasing age. The lack of significant differences in any age cohort may reflect the low number of individuals >50 years old (n=2). Excess plasma cortisol has previously been demonstrated to be predictive of cognitive decline but both cohorts were older (mean age ~70 years).[36, 37]

Increases in body weight, particularly increased visceral fat mass, have been associated with normal aging.[38]. Our positive correlation of age with respect to mean whole brain VT values could represent the normal effects of age-associated increase in 11β-HSD1. However, when VT values are corrected for age-associated effects, the overriding effect of an obesity associated decrease is demonstrated. The increased systemic (adipose tissue) generation of cortisol associated with increased BMI may cause chronic central glucocorticoid receptor (GR) activation leading to a protective downregulation of central 11β-HSD1 levels at moderately low obesity (Class I). Cortisol excretion is higher in obesity suggesting higher levels of cortisol at some point prior to excretion but the sources of whole-body cortisol production and sites of protective downregulation remain to be fully understood. It is possible to hypothesize a subsequent overloading and dysregulation of this brain 11β-HSD1 feedback system at higher BMIs (Class II to III) may then result in a subsequent increase in 11β-HSD1, which was demonstrated in the liver in NALFD.[30] It is also possible given dynamic changes in multiple organs (brain, liver and adipose tissue) that blood cortisol levels could appear to remain unchanged while the sources of cortisol production within each organ may be significantly increasing and decreasing during obesity. We are currently performing whole-body PET imaging studies with the 18F-AS2471907 radioligand to examine multiple organ changes in lean and obese individuals.

The extent to which 11C- and 18F-AS2471907 are sensitive to dynamic changes in cortisol activation via the HPA axis and the presence of non-active cortisone, which have similar affinities for the 11β-HSD1 enzyme,[3] remains to be explored. It is possible that increased plasma cortisone and/or cortisol is directly competing with our radioligands for binding to 11β-HSD1, as they may passively diffuse into the CNS.[2] However, when indirectly examining this by including the time of day for the PET scan in the linear regression analysis, which ranged from 9:40 to 15:51, no effect on VT measurements was seen. This may indirectly suggest that circulating cortisol levels, which can be nearly twice as high in the morning compared to that in the afternoon, did not have an effect on VT estimates. Indeed, in our previous study, no relationship between peripheral cortisol levels and VT estimates was found.[23] Exogenous challenges to the hypothalamus-pituitary-adrenal (HPA) axis, such as dexamethasone suppression, may be used to determine whether exogenous suppression of cortisol production has an effect on VT estimates. However, there is evidence that exogenous dexamethasone and insulin act directly on 11β-HSD1 activity and mRNA expression in adipose tissue of rats,[39] which may complicate the interpretation in vivo. Ex vivo and in vitro studies in brain tissue are needed to examine competitive binding of cortisone and cortisol, and dynamic changes due to exogenous challenges (e.g., dexamethasone and/or insulin), and to confirm their effects on 11β-HSD1 mRNA and protein levels.

Several limitations of the current study should be noted. All healthy controls were from the 11C-AS2471907 study, while all trauma-exposed controls were from the 18F-AS2471907 study. There were no group differences in VT when dividing the groups by radioligand or type of controls (p=0.29); however, it is not possible to parse individual influences of these factors. The combination of radioligands with different radioisotopes on the same structure may have confounding effects due to differences in biodistribution and metabolism of the radioligands, although full kinetic modeling with metabolite-corrected arterial radioactivity input function should accout for any differences in peripheral kinetics. It is unclear if trauma-exposed and non-exposed controls may differ in their radioligand binding. Finally, sex effects on plasma cortisol levels have been demonstrated previously.[40] However, our current cohort of study subjects could not be used to determine the possible sex effects because it contained only five females. In addition, a recent study demonstrated up to 1.6% gray matter volume loss in centrally obese individuals compared to lean individuals.[41] We did not apply partial volume correction to the current dataset but future studies may warrant exploration of these effects on our PET measurements.

Future studies will include more female individuals, a greater number of individuals with class II and III obesity and insulin-resistance, and exploration into the possible influence of plasma cortisone and/or cortisol levels and other circulating glucocorticoids in individuals who are lean, overweight and obese at various ages that may influence radioligand binding. Previously, higher systemic 11β-HSD1 activity was found to be predictive of progressive brain atrophy and cognitive decline after a follow-up of 6 years.[10] However, 11β-HSD1 activity was measured through urine metabolites which are unable to distinguish central or peripheral sources of cortisol and its metabolites. Similar longitudinal studies using our PET radioligand to directly measure in vivo brain 11β-HSD1 levels will help to clarify findings from these previous studies. In addition, whole-body PET imaging may allow the characterization of 11β-HSD1 levels in the liver, adipose and muscle tissues, in addition to brain, for a more complete analysis of cortisol regeneration in obesity and the potential impact on cognitive decline and neurological diseases where obesity may increase disease severity.[11]

CONCLUSION

In conclusion, in vivo PET imaging using 11β-HSD1 radioligands demonstrated, for the first time, a correlation of higher BMI (obesity) with lower levels of the enzyme 11β-HSD1 in the brain, and correlation of increased brain 11β-HSD1 levels with advancing age.

FUNDING AND DISCLOSURE

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

Footnotes

Publisher's Disclaimer: This Author Accepted Manuscript is a PDF file of a an unedited peer-reviewed manuscript that has been accepted for publication but has not been copyedited or corrected. The official version of record that is published in the journal is kept up to date and so may therefore differ from this version.

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.

REFERENCES

  • 1.Centers for Disease Control and Prevention. Overweight and Obesity. https://www.cdc.gov/obesity/index.html
  • 2.Mason BL, Pariante CM, Jamel S, Thomas SA (2010) Central Nervous System (CNS) delivery of glucocorticoids is fine-tuned by saturable transporters at the blood-CNS barriers and nonbarrier regions. Endocrinology 151:5294–5305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Chapman K, Holmes M, Seckl J (2013) 11 -Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action. Physiol Rev 93:1139–1206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Chanson P, Salenave S (2010) Metabolic syndrome in Cushing’s syndrome. Neuroendocrinology 92:96–101. [DOI] [PubMed] [Google Scholar]
  • 5.Starkman MN, Gebarski SS, Berent S, Schteingart DE (1992) Hippocampal formation volume, memory dysfunction, and cortisol levels in patients with Cushing’s syndrome. Biol Psychiatry 32:756–765. [DOI] [PubMed] [Google Scholar]
  • 6.Holmes MC, Seckl JR (2006) The role of 11β-hydroxysteroid dehydrogenases in the brain. Mol Cell Endocrinol 248:9–14. [DOI] [PubMed] [Google Scholar]
  • 7.Wyrwoll CS, Holmes MC, Seckl JR (2011) 11β-Hydroxysteroid dehydrogenases and the brain: From zero to hero, a decade of progress. Front Neuroendocrinol 32:265–286. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Yarchoan M, Arnold SE (2014) Repurposing Diabetes Drugs for Brain Insulin Resistance in Alzheimer Disease. Diabetes 63:2253–2261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Sandeep TC, Yau JLW, MacLullich AMJ, et al. (2004) 11Beta-hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics. Proc Natl Acad Sci USA 101:6734–6739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.MacLullich AMJ, Ferguson KJ, Reid LM, et al. (2012) 11β-Hydroxysteroid Dehydrogenase Type 1, Brain Atrophy and Cognitive Decline. Neurobiol Aging 33:207.e1–207.e8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Alford S, Patel D, Perakakis N, Mantzoros CS (2018) Obesity as a risk factor for Alzheimer’s disease: weighing the evidence. Obes Rev 19:269–280. [DOI] [PubMed] [Google Scholar]
  • 12.Meaney MJ, O’Donnell D, Rowe W, et al. (1995) Individual differences in hypothalamic-pituitary-adrenal activity in later life and hippocampal aging. Exp Gerontol 30:229–251 [DOI] [PubMed] [Google Scholar]
  • 13.Csernansky JG, Dong H, Fagan AM, et al. (2006) Plasma cortisol and progression of dementia in subjects with alzheimer-type dementia. Am J Psychiatry 163:2164–2169 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Yau JLW, Seckl JR (2012) Local amplification of glucocorticoids in the aging brain and impaired spatial memory. 4:1–15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Stewart PM, Boulton A, Kumar S, et al. (1999) Cortisol metabolism in human obesity: impaired cortisone-->cortisol conversion in subjects with central adiposity. J Clin Endocrinol Metab 84:1022–1027. [DOI] [PubMed] [Google Scholar]
  • 16.Rask E (2001) Tissue-specific dysregulation of cortisol metabolism in human obesity. J Clin Endocrinol Metab 86:1418–1421. [DOI] [PubMed] [Google Scholar]
  • 17.Morgan S a, McCabe EL, Gathercole LL, et al. (2014) 11β-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess. Proc Natl Acad Sci U S A 111:E2482–91. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Holmes MC, Carter RN, Noble J, et al. (2010) 11β-Hydroxysteroid Dehydrogenase Type 1 Expression Is Increased in the Aged Mouse Hippocampus and Parietal Cortex and Causes Memory Impairments. 30:6916–6920. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Andrew R, Smith K, Jones GC, Walker BR (2002) Distinguishing the Activities of 11β-Hydroxysteroid. J Clin Endocrinol Metab 87:277–285 [DOI] [PubMed] [Google Scholar]
  • 20.Iwashita A, Fushiki H, Fujita Y, et al. (2016) Discovery of a novel radioligand [11C] AS2471907 for PET imaging of the brain 11β-HSD1. J Nucl Med 57:1050 [Google Scholar]
  • 21.Gallezot J-D, Nabulsi N, Henry S, et al. (2019) Imaging the enzyme 11β-hydroxysteroid dehydrogenase type 1 with positron emission tomography: evaluation of the novel radiotracer 11C-AS2471907 in human brain. J Nucl Med 60:1140–1146. [DOI] [PubMed] [Google Scholar]
  • 22.Baum E, Zhang W, Li S, et al. (2019) A novel 18F-labeled radioligand for positron emission tomography imaging of 11β-hydroxysteroid dehydrogenase (11β-HSD1): synthesis and preliminary evaluation in nonhuman primates. ACS Chem Neurosci 10:2450–2458. [DOI] [PubMed] [Google Scholar]
  • 23.Bhatt S, Nabulsi NB, Li S, et al. (2019) First in-human PET study and kinetic evaluation of [18 F]AS2471907 for imaging 11β-hydroxysteroid dehydrogenase type 1. J Cereb Blood Flow Metab 271678X19838633. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Naganawa M, Waterhouse RN, Nabulsi N, et al. (2016) First-in-human assessment of the novel PDE2A PET radiotracer 18F-PF-05270430. J Nucl Med 57:1388–1395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Tzourio-Mazoyer N, Landeau B, Papathanassiou D, et al. (2002) Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage 15:273–289. [DOI] [PubMed] [Google Scholar]
  • 26.Innis RB, Cunningham VJ, Delforge J, et al. (2007) Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab 27:1533–1539. [DOI] [PubMed] [Google Scholar]
  • 27.Ichise M, Toyama H, Innis RB, Carson RE (2002) Strategies to improve neuroreceptor parameter estimation by linear regression analysis. J Cereb Blood Flow Metab 22:1271–1281. [DOI] [PubMed] [Google Scholar]
  • 28.Rask E, Walker BR, Söderberg S, et al. (2002) Tissue-specific changes in peripheral cortisol metabolism in obese women: increased adipose 11beta-hydroxysteroid dehydrogenase type 1 activity. J Clin Endocrinol Metab 87:3330–6. [DOI] [PubMed] [Google Scholar]
  • 29.Valsamakis G, Anwar a, Tomlinson JW, et al. (2004) 11Beta-Hydroxysteroid Dehydrogenase Type 1 Activity in Lean and Obese Males With Type 2 Diabetes Mellitus. J Clin Endocrinol Metab 89:4755–4761. [DOI] [PubMed] [Google Scholar]
  • 30.Ahmed A, Rabbitt E, Brady T, et al. (2012) A Switch in Hepatic Cortisol Metabolism across the Spectrum of Non Alcoholic Fatty Liver Disease. PLoS One 7:e29531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Caughey S, Harris AP, Seckl JR, et al. (2017) Forebrain-specific transgene rescue of 11β-HSD1 associates with impaired spatial memory and reduced hippocampal brain-derived neurotrophic factor mRNA levels in aged 11B-HSD1 deficient mice. J Neuroendocrinol 29:1–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Sooy K, Webster SP, Noble J, et al. (2010) Partial deficiency or short-term inhibition of 11B-dydroxysteroid dehydrogenase type 1 improves cognitive function in aging mice. J Neurosci 30:13867–13872. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Yau JLW, Mcnair KM, Noble J, et al. (2007) Enhanced hippocampal long-term potentiation and spatial learning in aged 11β-hydroxysteroid dehydrogenase type 1 knock out mice. J Neurosci 27:10487–10496. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Sooy K, Noble J, Mcbride A, et al. (2015) Cognitive and disease-modifying effects of 11β-hydroxysteroid dehydrogenase type 1 inhibition in male Tg2576 mice, a model of Alzheimer’s disease. Endocrinology 156:4592–4603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Yau JL, Noble J, Kenyon CJ, et al. (2001) Lack of tissue glucocorticoid reactivation in 11beta -hydroxysteroid dehydrogenase type 1 knockout mice ameliorates age-related learning impairments. Proc Natl Acad Sci U S A 98:4716–4721. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Lupien S, Lecours AR, Lussier I, et al. (1994) Basal cortisol levels and cognitive deficits in human aging. J Neurosci 14:2893–903 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Huang CW, Lui CC, Chang WN, et al. (2009) Elevated basal cortisol level predicts lower hippocampal volume and cognitive decline in Alzheimer’s disease. J Clin Neurosci 16:1283–1286. [DOI] [PubMed] [Google Scholar]
  • 38.Beaufrère B, Morio B (2000) Fat and protein redistribution with aging: Metabolic considerations. Eur J Clin Nutr 54:S48–S53. [DOI] [PubMed] [Google Scholar]
  • 39.Balachandran A, Guan H, Sellan M, et al. (2008) Insulin and dexamethasone dynamically regulate adipocyte 11β-hydroxysteroid dehydrogenase type 1. Endocrinology 149:4069–4079. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Van Cauter E, Leproult R, Kupfer D (2014) Effects of Gender and Age on the Levels Rhythmicity. J Clin Endocrinol Metab 81:2468–2473 [DOI] [PubMed] [Google Scholar]
  • 41.Hamer M, Batty GD (2019) Association of body mass index and waist-to-hip ratio with sbrain structure: UK Biobank study. Neurology 92:e594–e600. [DOI] [PMC free article] [PubMed] [Google Scholar]

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