Elevated levels of the hormone cortisol are found in the aged patients with Alzheimer's Disease and in Major Depressive Disorder. Evidence is accumulating from animal studies that cognition and specific brain structures are negatively affected by high levels of cortisol. The studies we propose will advance knowledge about the role of elevated cortisol as a mechanism contributing to cognitive dysfunction in humans. Patients with Cushing's Disease (CD) generate highly elevated cortisol levels and develop a syndrome of abnormal mood, libido and cognition. Patients are exposed to high levels of this natural steroid for months to years. Since cortisol levels normalize after treatment, reversibility can also be studied. Animal studies indicate toxicity to the hippocampus is a likely mechanism by which elevated glucocorticoids lead to cognitive dysfunction. We will use magnetic resonance imaging (MRI) of the brain together with specific neuropsychological tests (NPT) to investigate such a mechanism in patients with CD. We will examine, prior to treatment, hippocampal formation volume (HFV) in CD patients, and compare to matched normal controls. We will examine the association between severity of cortisol elevation, NPT impairment and HFV. Other brain regions will be used as comparisons to examine the specificity of the association. We will repeat NPT and MRI one and two years following treatment of CD to determine if changes in cognition and HFV are at least partially reversible. These studies also have relevance to understanding the impact of steroid hormones on the brain in patients with a wide variety of illnesses requiring long term administration of similar steroids.
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