The Importance of PET Imaging to Understanding Whole-Body Cortisol Metabolism in Alzheimer’s Disease

In a recent issue of the Journal of Alzheimer’s Disease, Villemagne et al. provide evidence of high regional brain occupancy of Xanamemtrademark in cognitively normal participants (CN) and mild-cognitive impairment (MCI)/mild Alzheimer’s disease (AD) patients, as determined by [¹¹C]TARACT positron emission tomography (PET) imaging of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) [1]. Caution is warranted before drawing steadfast conclusions based on the use of the proposed radioligand and the simplified tracer kinetic modeling employed in the current study. [¹¹C]TARACT PET with simplified tracer kinetic modeling has not been fully validated against the gold standard use of arterial blood sampling with metabolite correction, as has been explored in previous 11β– HSD1 PET radioligands [2]. Despite this, the current study provides interesting preliminary data that should be further examined prior to implementation in clinical trials.

The primary motivation of the PET study is to determine adequate dose requirements to achieve a desired brain occupancy. Given the flat dose responses above 5 mg (10–30 mg), the authors recommend doses of < 10 mg, for future clinical trials in AD and/or other conditions that may benefit from inhibition of 11β-HSD1. There is always concern that limiting cortisol metabolism through 11β-HSD1 inhibition may induce a compensatory adrenocorticotropic hormone response leading to elevated plasma cortisol levels; however, in a previous study with 10 mg of Xanamemtrademark, plasma levels remained unchanged, albeit in a younger cohort (< 60 years) compared to the current cohort (> 60 years) [3]. Changes in cortisol regeneration in multiple organs after long term inhibition therapy for AD remains to be fully understood in humans, particularly in those with comorbidities such as metabolic disease that may exacerbate cognitive symptoms of AD.

Excess cortisol is associated with more severe cognitive decline and more severe Alzheimer’s disease and related dementia (ADRD) phenotypes [4]. Whole-body regulation of cortisol is primarily maintained through the hypothalamic-pituitary-adrenal (HPA) axis and when dysregulated can lead to prolonged elevation of plasma cortisol. This prolonged elevation of plasma cortisol is thought to be neurotoxic leading to oxidative stress, neuronal loss, and ADRD. In addition to the regulation of plasma cortisol levels via the HPA axis, the intracellular enzyme 11β-HSD1, targeted for inhibition by Xanamemtrademark in this study, is responsible for the intracellular regeneration of inactive cortisone to active cortisol [5]. The regeneration of cortisol through 11β-HSD1 is driven by colocalization with hexose-6-phosphate dehydrogenase (H6PDH) in multiple tissues, such as brain, liver, and adipose [6]. It is of great importance to examine the effects of 11β-HSD1 inhibitors as AD-modifying therapies in larger trials; however, given the complex inter-organ physiology of 11β-HSD1 and cortisol metabolism, it is worth further examination into which patient phenotypes will benefit most from these therapies.

Several decades of research into the intracellular mechanisms of 11β-HSD1 have revealed its role in potently amplifying intracellular cortisol for binding at the glucocorticoid receptor with a plethora of downstream effects on cell signaling, immune function and energy metabolism [5, 7]. In preclinical models of aging rats or AD, such excess intracellular cortisol, regenerated by 11β-HSD1 in the brain, leads to cognitive defects and can be prevented by inhibition or knock-out models of 11β-HSD1 [8–12]. In one longitudinal study, men with higher urinary metabolites of cortisol at baseline, representative of increased whole-body 11β-HSD1 activity, had more significant brain atrophy and cognitive decline at follow-up [13], although this study was not designed to resolve which specific tissues were responsible for generating the excess cortisol. Recently, using stable isotope infusion of [9,11,12,12-²H₄]-cortisol (d4F) in mice with a model of whole-body H6PDH knock-out, regeneration of [9,12,12-²H₃]-cortisol (d3F) from [9,12,12-²H₃]-cortisone (d3E) was drastically reduced by 6-fold [14]. Cre-mediated disruption of only liver 11β-HSD1 led to a 36% reduction in liver cortisol regeneration but no change in brain or adipose tissue. Disruption of 11β-HSD1 in adipose tissue led to a 67% decrease in cortisol regeneration in adipose tissue, but more interestingly, a decrease in both liver and brain cortisol regeneration by 30%, as well. These results suggest that central 11β-HSD1 enzyme activity is also mediated by disruption of adipose tissue 11β-HSD1 activity to some extent.

Our group recently examined brain 11β-HSD1 enzyme levels using [¹⁸F]AS2471907 (11β-HSD1 enzyme antagonist) PET imaging and demonstrated a positive correlation with age, albeit in a younger cohort (24–54 years) then what would be typically be targeted for AD therapy [15]. This is in line with previous aged-mouse trajectories of 11β-HSD1 over the lifetime [16]. However, in the same cohort that we imaged, brain 11β-HSD1 enzyme levels, were negatively correlated with increasing body mass index [15]. This suggests that it is possible that an ADRD patient with comorbidities such as obesity or other metabolic diseases may have reduced brain 11β-HSD1 enzyme levels, although this remains to be studied. If this is true it is conceivable that targeting excess 11β-HSD1 activity in visceral adipose tissue, as well as brain, may be important in AD, as limiting visceral adipose tissue cortisol regeneration has been shown to limit brain cortisol regeneration, as well [14]. Of course, brain penetrant 11β-HSD1 inhibitors will by all appearances inhibit adipose tissue cortisol production to some extent, as they distribute to targets throughout the body. We are currently performing whole body PET imaging of 11β-HSD1 enzyme levels in preclinical models of obesity and individuals with obesity and fatty liver disease to understand changes in 11β-HSD1 enzyme levels during these diseases to assess what benefit inhibition of 11β-HSD1 may provide [17]. It remains important to understand the effects of targeting inhibition of 11β-HSD1 in the whole body, to assess long-term changes in 11β-HSD1 enzyme levels. PET imaging of radiolabeled 11β-HSD1 inhibitors allows the possibility of tracking 11β-HSD1 enzyme levels in response to therapy. Furthermore, if PET studies are combined with stable isotope tracer studies of cortisone and cortisol, 11β-HSD1 enzyme activity can be assessed to provide a comprehensive picture of cortisol metabolism in multiple organs.