The psychopathology of Alzheimer's disease includes cognitive impairment and other behavioral disturbances. Increased activity of the hypothalamic pituitary adrenal (HPA) axis is a psychoneuroendocrine phenomenon of potential pathophysiologic relevance to the psychopathology of this disorder. This proposal will evaluate the HPA axis in Alzheimer's disease and human aging. The overall hypothesis is that increased HPA axis responsivity in Alzheimer's disease and aging results from decreased sensitivity of inhibitory feedback by cortisol at a central nervous system (CNS) level. Preclinical studies suggest a CNS mechanism for increased HPA axis responsivity in old animals. Because glucocorticoids appear toxic to hippocampal neurons, increased HPA axis activity represents a potential contributory mechanism for the CNS neuronal loss which underlies the psychopathology of Alzheimer's disease and aging. The proposed experiments measure the responsiveness of each level of the HPA axis in subjects with Alzheimer's disease and normal elderly and young subjects, while standardizing plasma cortisol concentrations across subject groups. Special Aim 1 will address adrenal cortex sensitivity to exogenous adrenocorticotropic hormone (ACTH) in the subject groups. Endogenous ACTH will be suppressed by dexamethasone and then the effect of exogenous ACTH infusion on plasma cortisol will be measured.
Specific Aim 2 addresses the sensitivity of the anterior pituitary to exogenous corticotropin releasing hormone (CRH). Endogenous cortisol production will be suppressed by metyrapone and then the response of plasma ACTH, beta endorphin (BE), and three graded doses of exogenous cortisol administered as two-hour infusions.
Specific Aim 3 will compare HPA axis responsivity at a CNS level among subject groups by measuring plasma ACTH and BE responses to methoxamine and physostigmine. To determine if increased HPA axis responsivity in AD and aging is due to reduced sensitivity to cortisol inhibitory feedback at a CNS level, subjects will be given metyrapone and HPA responses to either methoxamine or physostigmine will be measured during 3 graded doses of infused cortisol. These studies will provide data relevant to the psychoneuroendocrine physiology of Alzheimer's disease and human aging and potentially suggest directions for therapeutic interventions.
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