The impact of glucocorticoids on brain structures can be expected to vary not only with age and disease selleck Crizotinib status, but also with individual genetic and environmentallyimparted selleckbio differences influencing hippocampal volume and connectivity, HPA reactivity, and other neurobiologie factors.39,51 Besides the possibility of persistent synapse or neuron loss induced directly by prolonged hypercortisolemia, glucocorticoid-related derangement of hippocampal Inhibitors,research,lifescience,medical physiology, as described above, may increase vulnerability to damage through other pathophysiologic mechanisms. This latter effect may become clinically relevant

in older persons with co-occurring neuronal insults such as accumulating AD pathology or cerebrovascular Inhibitors,research,lifescience,medical disease, promoting synapse or neuron loss through a synergistic relationship with these factors. The loss of hippocampal volume and memory function observed in some elders with late -life depression suggests the possibility that depression may be a predispositional risk

factor for AD in particular. Indeed, lower hippocampal volumes independently predict subsequent AD in groups of MCI and cognitively normal elderly subjects.52 Likewise, deficits Inhibitors,research,lifescience,medical in verbal learning and memory, similar to those described in cuthymic patients with history of major depression,30 also predict AD (eg, ref 53). While a primary causal role for depression in AD pathogenesis seems unlikely, depression-associated hypercortisolemia leading to decline in hippocampal size, connectivity and cognitive function may represent one of multiple links between depression

and dementia as described below (also see Figure 1). Biologic relationships between depression and Alzheimer’s Inhibitors,research,lifescience,medical disease The association between depression and dementia suggested by epidemiologic data10,11 may be partially explained by one or more direct, mechanistic links between late-life depression-related processes and ADspecific neuropathology (focal and diffuse Inhibitors,research,lifescience,medical cortical neuronal loss, P-amyloid plaques, and neurofibrillary tangles). Emerging evidence from neuroimaging studies, postmortem neuropathology analyses, and animal models provides support, for such links. Some structural GSK-3 magnetic resonance imaging (MRI) studies find that hippocampal atrophy is more strongly associated with late-onset than early-onset depression, suggesting that early AD-related pathophysiology could generate both hippocampal atrophy and depressive symptoms in some elderly persons.54,55 In addition, one of these studies failed to find a significant correlation between hippocampal volume and Cortisol level among elders with depression. Furthermore, the late-life depression subjects showed persistent memory and cognitive impairment at 6-month follow-up despite effective treatment of mood symptoms and normalization of Cortisol levels.