Plasma Cortisol and Progression of Dementia in Subjects With Alzheimer-Type Dementia

Abstract

Objective-Previous studies of subjects with dementia of the Alzheimer type (DAT) have reported correlations between increases in activity of the hypothalamic-pituitary-adrenal (HPA) axis and hippocampal degeneration. In this study, we sought to determine whether increases in plasma cortisol, a marker of HPA activity, were associated with clinical and cognitive measures of the rate of disease progression in DAT subjects.Method-Thirty-three subjects with very mild and mild DAT and 21 nondemented comparison subjects were assessed annually for up to 4 years using the Clinical Dementia Rating scale and a battery of neuropsychological tests. Plasma was obtained at 8AM on a single day and assayed for cortisol. Rates of change over time in the clinical and cognitive measures were derived from growth curve models.Results-In the DAT subjects, but not in the nondemented comparison subjects, higher plasma cortisol levels were correlated with more rapidly increasing symptoms of dementia and more rapidly decreasing performance on neuropsychological tests associated with temporal lobe function. Similar correlations were not observed between higher plasma cortisol levels and clinical and cognitive assessments obtained at the single assessment closest in time to the plasma collection.Conclusions-Higher HPA activity, as reflected by increased plasma cortisol levels, is associated with more rapid disease progression in DAT subjects.

Subchronic Glucocorticoid Receptor Inhibition Rescues Early Episodic Memory and Synaptic Plasticity Deficits in a Mouse Model of Alzheimer’s Disease

“…As described in other preclinical and clinical studies (Csernansky et al, 2006;Hebda-Bauer et al, 2013;Nasman et al, 1995;Rasmuson et al, 2001), we report an altered circadian rhythm of the HPA axis early in our mouse model. Whether this results from a dysregulation of the pulsatile ultradian pattern of CORT secretion is however yet to be demonstrated.…”

“…GR has a low affinity for CORT and is thus believed to be a key player under elevated CORT levels, although a role of MR cannot be excluded. Both AD patients and AD mouse models display a dysregulated HPA axis, marked by a mild hypercortisolemia that is apparent early during the pathology (Csernansky et al, 2006;Elgh et al, 2006;Hebda-Bauer et al, 2013;Nasman et al, 1995;Rasmuson et al, 2001;Weiner et al, 1997). Increased CORT levels are sufficient to exacerbate Ab deposits, and a recent study suggested that antagonism of GR could prevent this effect (Baglietto-Vargas et al, 2013).…”

Acute Inhibition of 11β-Hydroxysteroid Dehydrogenase Type-1 Improves Memory in Rodent Models of Cognition

“…As stress and/or excessive glucocorticoid activity are linked with the exacerbation of AD symptoms (Wilson et al, 2005;Csernansky et al, 2006), loss of hippocampal mass (Lupien et al, 1998), and reduced neurogenesis in rodents (Tanapat et al, 2001;Ambrogini et al, 2002), inhibition of HSD1 may also slow disease progress. Additional studies in models of AD, such as APP-overexpressing mice, may offer further evidence of the potential for HSD1 inhibitors to act as both symptomatic and disease-modifying agents.…”

“…Abnormally high levels of glucocorticoids are correlated with memory impairment in some patients with AD (Pomara et al, 2003) and depression (Bremmer et al, 2007). Increased glucocorticoid activity is also associated with greater hippocampal atrophy and memory impairment in the elderly (Lupien et al, 1998) and more rapid AD disease progression (Csernansky et al, 2006). Systemic administration of glucocorticoids increases ␤-amyloid formation and tau accumulation in transgenic AD mice (Green et al, 2006) and reduces neurogenesis in rats (Ambrogini et al, 2002).…”

Temporal control of glucocorticoid neurodynamics and its relevance for brain homeostasis, neuropathology and glucocorticoid-based therapeutics

“…Similar discrepancies have been observed in a number of other conditions, like multiple sclerosis and neurodegenerative disorders. For example, increased plasma cortisol levels have been associated with more rapid disease progression in subjects with Alzheimer-type dementia (AD) (Csernansky et al, 2006). In contrast, a large post-mortem neuropathological examination of individuals receiving systemic GCs for various medical reasons revealed at least 50% less histological markers of AD pathology compared to non-treated subjects (Beeri et al, 2012).…”