Neurocognitive Dysfunction in Adrenal Cortisol Insufficiency

/ABSTRACT Adrenal cortisol insufficiency (ACI), a rare disease that disrupts metabolic regulation, results in high risk for morbidity and mortality due to circulatory, musculoskeletal, immunological, cognitive, and behavioral derangements. Guideline-recommended treatment regimens with oral hydrocortisone do not accurately replicate the cortisol circadian rhythm or account for the cortisol ultradian rhythm, exposing patients to periods of cortisol excess or deficiency between hydrocortisone doses and in the early morning. Thus, although hydrocortisone treatment alleviates many manifestations of ACI, neurohormonal equilibrium of the hypothalamus-pituitary-adrenal axis remains disrupted, with patients reporting poor quality of life, “brain fog,” forgetfulness, being overwhelmed, mood changes, and cognitive dysfunction despite hydrocortisone treatment. These often debilitating life-long symptoms are unaddressed in management guidelines and often overlooked in the clinic. Cortisol is strongly linked to brain function, and cortisol excess was shown to adversely affect the hippocampus and cognition. However, the effect of cortisol deficiency on the brain and its resultant effect on neurocognitive function are poorly studied. Furthermore, ACI caused by direct adrenal damage (primary ACI, PACI) and ACI caused by damage to the pituitary (secondary ACI, SACI) are distinct subtypes of ACI that differ in their etiology, hormone profile, and comorbidities. However, the differential influence of cortisol dysregulation on neurocognitive function in these two disease subtypes is unclear. We will conduct a small, short- term, proof-of-concept study to address these knowledge gaps. We will define neurocognitive function profiles in PACI and SACI compared to controls using the NIH Toolbox Cognitive Battery and collect subjective patient- reported outcomes data from validated NIH PROMIS, quality of life, and other surveys. Our novel study will rigorously compare neurocognitive function in PACI and SACI. Our results will improve understanding of neurocognitive dysfunction in these ACI subtypes and serve as an evidence base for larger, hypothesis-driven clinicals trials that define the benefit of integrating neurocognitive testing into routine patient management. We will then be in a position to offer a clinically meaningful approach to addressing neurocognitive dysfunction in PACI and SACI. Project Number: 1R21AG091290-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Anat Ben-Shlomo | Institution: CEDARS-SINAI MEDICAL CENTER, LOS ANGELES, CA | Award Amount: $419,321 | Activity Code: R21 | Study Section: Behavioral Neuroendocrinology, Neuroimmunology, Rhythms, and Sleep Study Section [BNRS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11233117