Substantial support

exists for both hypotheses, and they are not mutually exclusive. This report, does not resolve this issue; rather, we review evidence for several specific pathways by which depression may be linked to subsequent, cognitive decline and dementia and present, two related models that accommodate and reconcile Inhibitors,research,lifescience,medical many of the seemingly disparate research findings. One model is shown in Figure 1 and presents three interacting links which affect brain and cognitive reserve thereby moderating the relationship between underlying AD neuropatholgy and its expression as clinical dementia. In the sections that follow we discuss the evidence for each of the pathways and links. Figure 1. Proposed predominant mechanisms by Inhibitors,research,lifescience,medical which depression Neratinib manufacturer increases risk for Alzheimer’s dementia (AD). *The very recently postulated direct pathway

leading from hypercortisolemia or elevated glucocorticoids to AD neuropathology is represented with a dashed … Neurobiologie substrates mediating the depression-cognitive decline-dementia links Glucocorticoids contribute to hippocainpal atrophy and learning/episodic memory impairment Depression is associated with neuroendocrine changes similar to those observed in animal models of chronic stress, including abnormalities Inhibitors,research,lifescience,medical within the hypothalamicpituitary-adrenal (HPA) axis. Most notably, depressed subjects have been shown to exhibit, increased HPA central drive with elevated corticotrophin-releasing hormone (CRH) and vasopressin production by cells of the hypothalamic paraventricular Inhibitors,research,lifescience,medical nucleus (PVN); impaired negative feedback regulation due to decreased expression of corticosteroid receptors in the hypothalamus and pituitary as well as upstream CNS regulatory centers; and adrenal hypertrophy (reviewed in ref 25). The net effect of these changes in HPA function is chronic elevation Inhibitors,research,lifescience,medical of adrenal glucocorticoid production with impaired negative feedback

and abnormal homeostatic regulation. Such HPA dysregulation is clinically detectable (via dexamethasone nonsuppression or elevated 24-hour urinary Cortisol) in about, half of patients with major depression.25-26 HPA dysregulation may be more common among older depressed individuals, as suggested by the finding of a significant correlation between age and post-dexamethasone Cortisol levels in individuals with late-life depression.27 Adrenal glucocorticoid/cortisol regulates HPA activity through both direct, oxyclozanide negative feedback at the pituitary and hypothalamus and indirect, mechanisms involving higher central nervous system (CNS) centers. The human hippocampus, for example, contains large numbers of corticosteroid receptors and plays a critical role in downregulating CRH release via a multisynaptic pathway terminating in y-aminobutyric acid (GABA)-ergic output to the paraventricular nucleus (reviewed in ref 28). At.