Mild autonomous cortisol secretion and brain function: cognitive, structural, and functional correlates

Mild autonomous cortisol secretion (MACS) is increasingly recognized as a condition associated with subtle cognitive, functional, and clinical alterations, despite the absence of overt hypercortisolism. Its impact on brain function, sleep quality, and mood, however, remains incompletely understood.

The aim of this observational, cross-sectional study was to investigate cognitive performance, sleep quality, mood, and structural and functional brain alterations in patients with MACS compared with those with non-functioning adrenal tumors (NFAT).

Forty-eight patients with adrenal incidentalomas were enrolled, including 28 patients with MACS and 20 with NFAT, all without clinical signs of overt hypercortisolism at study entry.

Participants had a confirmed failure to suppress cortisol on 1 mg of dexamethasone and underwent comprehensive neuropsychological testing, sleep quality assessment (PSQI), mood evaluation (BDI-II), and brain magnetic resonance imaging (MRI) including structural imaging, voxel-based morphometry, and resting-state functional MRI (fMRI).

Compared with patients with NFAT, those with MACS exhibited slightly lower Mini-Mental State Examination (MMSE) scores and poorer delayed verbal recall, both negatively correlated with serum cortisol levels. Patients with MACS also showed significantly poorer sleep quality, with MACS status and female sex emerging as independent predictors. No group differences were observed in depressive symptoms. Resting-state fMRI revealed altered hippocampal connectivity in MACS, with reduced connectivity with the caudate nucleus and increased connectivity with mesial occipital regions. Voxel-based morphometry showed no structural differences between groups.

Even mild, clinically silent cortisol excess can be associated with subtle cognitive alterations, impaired sleep, and early functional connectivity changes, despite preserved brain morphology. Longitudinal studies are needed to determine whether these alterations progress over time and whether they improve with targeted treatment.