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. Our research over the last decade has described alterations of the hypothalamic-pituitary-adrenal (HPA) axis in posttraumatic stress disorder (PTSD). Specifically, in both Vietnam combat veterans and Holocaust survivors with PTSD, we have found reduced levels of basal cortisol and enhanced cortisol negative feedback inhibition in response to dexamethasone (DEX). However, Vietnam veterans show increased circadian rhythmicity whereas in elderly Holocaust survivors we have observed a smaller range of cortisol fluctuations over the diurnal cycle, similar to the dampening of the dynamic range seen in normal aging. Thus, these elderly subjects show some features typically associated with PTSD (low cortisol, enhanced suppression to DEX) and some features associated with aging (flattening of circadian rhythm). The current study is conceived to investigate the age associated changes of various neuroendocrine markers of PTSD and to evaluate the functional impact of those changes in aging ( age 50) PTSD patients. We will compare combat exposed and non-exposed subjects on symptomatology, baseline cognitive and memory performance, and various biological measures including 24-hour urinary cortisol, circadian salivary cortisol sampling, and plasma cortisol and lymphocyte glucocorticoid receptor levels before and after DEX (dexamethasone suppression test (DST)). In addition, for those medically eligible, and willing to participate, we will compare flat (MRI) and functional (PET) imaging data in aging PTSD patients for areas of interest with respect to the anatomic and functional correlates of HPA alterations and their associated (and perhaps consequent) cognitive impairments. The purpose of this study is to examine neuroendocrine, neuroanatomic, and cognitive measures in aging combat veterans with and without PTSD and/or MDD. This grant proposes to test the hypothesis that increased sensitivity of the glucocorticoid receptor underlies hippocampal atrophy and memory decline in PTSD, and in doing so will provide a systematic and comprehensive exploration of the glucocorticoid toxicity hypothesis in relation to hippocampal atrophy.
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