However, the long-term efficacy of this agent still needs to be evaluated. Neuroendocrine impairment Impairment, in the hypothalamic-pituitary-adrenal (HPA) axis activity is another physiological mechanism proposed to underlie the development of AD.103-106 Hypercortisolemia and
reduced negative feedback inhibition of Cortisol secretion are noted concomitants of AD.107-110 However, investigations of the relationship between dementia severity and Cortisol Inhibitors,research,lifescience,medical levels have yielded mixed findings. While some investigations observe a relationship between dementia severity and/or progression,111-115 others do not observe this relationship between HPA dysfunction and either severity or disease progression in AD.116-118 However, variations in age of onset and stage of illness may impact the relationship between hypercortisolemia and disease progression. Moreover, the nature of the relationship between Cortisol and cognitive decline in AD may be more difficult to assess Inhibitors,research,lifescience,medical as the disease progresses. As many suggest, the degenerative process of hippocampa! damage in AD patients may, with time, reduce the responsivity of this area to elevations in glucocorticoids. Thus, many investigators argue that impairments in neuro-endocrine function observed in AD reflect, rather than cause the neuronal degeneration in this
illness. However, the observations Inhibitors,research,lifescience,medical of a negative impact of elevated Cortisol levels on Selleckchem 17-AAG cognition in normal aging have led others to consider therapeutic approaches to AD based upon this pathophysiological mechanism. Currently, a clinical trial of AD patients, utilizing the glucocorticoid antagonist, mifepristone, is Inhibitors,research,lifescience,medical in progress. Cerebrovascular and cardiovascular impairments While cerebrovascular deficiencies arc typically associated with vascular dementia, an increasing body of evidence suggests that vascular factors may also contribute to the development, of AD.119 Many recent studies have found Inhibitors,research,lifescience,medical arterial hypertension to be associated with cognitive impairment120-123 and increased risk of AD has also
been observed in individuals with higher systolic-diastolic blood pressure values.124 Hofman et al125 observed patients with AD to be affected by more pronounced arteriosclerotic carotid lesions, and atrial fibrillation was found to be more strongly associated with AD (with cerebrovascular disease) than with vascular dementia. Some investigators have argued that vascular Bumetanide factors such as arterial hypertension may have a direct role in the pathogenesis of AD by increasing the production of β-amyloid. Animal studies have found ischemia to result in increased β-amyloid production in the hippocampus.126 Moreover, the observation of increased concentrations of senile plaques in the brains of hypertensive, nondemented patients further implicates the role of ischemia.127 Investigators have started to consider the use of antihypertensive agents as a potential.