This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Elevated levels of the hormone cortisol are found in older patients with Alzheimer's Disease and in Major Depressive Disorder. Animal studies show that high levels of cortisol affect the hippocampus, the part of the brain involved in memory and learning. Patients with Cushing's Syndrome (CS) have highly elevated cortisol levels for months or years and develop symptoms such as abnormal mood, sex drive, learning and memory. The studies we propose will advance knowledge about the effect of elevated cortisol on the brain in humans. Animal studies also show that a toxic effect of cortisol on the hippocampus is the likely mechanism by which elevated steroids produce these symptoms. We will use magnetic resonance imaging (MRI) of the brain together with specific neuropsychological tests (NPT) to investigate such a mechanism on patients with CS. We will examine, prior to treatment, the volume of the hippocampus (HFV) in CS patients, and compare it to matched healthy research volunteers. We will then examine the association between the severity of cortisol elevation, NPT impairment and HFV. Other brain regions will be used as comparisons to examine the specificity of the association. Since cortisol levels normalize after treatment, we will study if these changes are reversible. For this purpose, we will repeat NPT and MRI 12 and 24 months following treatment. In addition to CS, these studies will help understand the impact of steroid hormones on the brain of patients with a wide variety of illnesses requiring long-term steroid treatment and other conditions in which steroid hormones are secreted abnormal
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