HPA axis responsivity to dexamethasone and cognitive impairment in dementia

Gurevich, David; Siegel, B.V.; Dumlao, Manuel; Perl, Eliezer; Chaitin, Pamela; Bagne, Curtis A.; Oxenkrug, Gregory F.

doi:10.1016/0278-5846(90)90018-c

Cited by 33 publications

(19 citation statements)

References 28 publications

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“…A role for paraventricular CRH neurons in this pro cess was proposed since hippocampal lesions lead to hyperactive CRH neurons in rats [66]. Furthermore, the degree of HPA axis hyperactivity has been reported to correlate with the severity of the hippocampal atrophy and cognitive impairment in AD patients [67,68]. If this glucocorticoid cascade were a prominent mechanism in humans, one would expect considerable damage in the hippocampus of depressed patients since in these patients the HPA axis seems to be extremely activated.…”

Section: Discussionmentioning

confidence: 99%

Increased Numbers of Corticotropin-Releasing Hormone Expressing Neurons in the Hypothalamic Paraventricular Nucleus of Depressed Patients

et al. 1994

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The hypothalamo-pituitary-adrenal (HPA) axis is known to be activated in depressed patients. Although direct evidence is lacking, this activation is hypothesized to be due to hyperactivity of corticotropin-releasing hormone (CRH) neurons of the hypothalamic paraventricular nucleus (PVN). Recent immunocytochemical studies in experimental animals and in humans showed that the number of CRH-expressing neurons correlated with the activity of these neurons. In addition, colocalization of AVP in CRH neurons has been shown to be an index for the secretory activity. Therefore, we estimated the total number of CRH-immunoreactive neurons and their fraction showing colocalization with AVP in the PVN of 10 control subjects and of 6 depressed patients who were diagnosed to be suffering from a major depression or a bipolar disorder. The mean total number of CRH-expressing neurons of the 6 depressed patients was four times higher, and the number of CRH neurons co-expressing AVP was almost three times higher than those in the control group. We also determined the two activity parameters of CRH neurons in the PVN of 2 subjects with a depressive organic mood syndrome or a depressive disorder not otherwise specified. In these two ‘non-major depressed’ subjects, the activity parameters of CRH neurons were comparable to those of control subjects. Our observations strongly support the hypothesis that CRH neurons in the PVN are hyperactivated in major depressed patients. This hyperactivity might be causally related to at least part of the symptomatology of depression.

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Section: Discussionmentioning

confidence: 99%

Increased Numbers of Corticotropin-Releasing Hormone Expressing Neurons in the Hypothalamic Paraventricular Nucleus of Depressed Patients

et al. 1994

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“…In normal aging and dementia a defect of the glucocorticoid sensitivity in tissues and in peripheral immune cells has been demonstrated [24][25][26][27][28] and this defect has been associated with the generalized glucocorticoid hypothesis of brain aging and neurodegeneration [29][30][31]. The evidence of a decreased peripheral sensitivity to glucocorticoids in SDAT can also contribute to put forward a hypothesis that cortisol might be unable to counterbalance the overactivity in NK cytotoxic function during exposure to cytokines, so inducing the persistence of excitatory stimuli.…”

Section: Introductionmentioning

confidence: 99%

Decreased Immunosuppressive Effect of Cortisol on Natural Killer Cytotoxic Activity in Senile Dementia of the Alzheimer Type

Solerte

Cerutti

Severgnini

et al. 1998

Dement Geriatr Cogn Disord

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Former studies have indicated alterations of the cytotoxic activity of natural killer (NK) cells in senile dementia of the Alzheimer type (SDAT). These changes may be related to the increased reactivity of NK cells with cytokines, even if an impairment of the immunosuppressive effect of glucocorticoids cannot be excluded. In the present study we have demonstrated a lower immunosuppressive effect of cortisol on NK cytolytic function in patients with SDAT than in healthy elders and in patients with dementia of multi-infarct origin (MID). This suppression is completely lacking when cortisol is employed at low concentrations (10^–7 M) and is significantly reduced after incubation at physiological (10^–6 M; p < 0.001) and supraphysiological concentrations (10^–5 M; p < 0.001). The addition of IL-2 (50 and 100 IU/ml/cells) significantly antagonizes the effects of cortisol in SDAT, whereas the cortisol-dependent immunosuppression is partially maintained in healthy elders and in patients with MID. Our data indicate that the defect of the immunosuppressive effect of cortisol may play a role in NK dysregulation in SDAT, contributing to the cytokine-mediated NK overactivity in this disease.

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Results The massive neuroendocrine response observed consisted of an initial phase with concomitantly increased levels of ACTH and cortisol and a second phase with de-I nfection, trauma, or mental stress results in an increase in levels of cortisol.

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mentioning

confidence: 99%

“…Methods The secretion of corticotropin (adrenocorticotropic hormone [ACTH]) and cortisol was studied in 23 patients by determinations at hours 4,6,8,10, and 14 and days 1, 3, 5, and 7 after onset of symptoms. Acute confusional state (DSM-III-R criteria), extent of lesion (volumetry of computed tomographic scans), and neurological and functional outcome (Scandinavian Stroke Scale, Barthel Index scores) were assessed.…”

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confidence: 99%

Pattern of activation of the hypothalamic-pituitary-adrenal axis in acute stroke. Relation to acute confusional state, extent of brain damage, and clinical outcome.

Faßbender

Schmidt

Mößner

et al. 1994

Stroke

209

128

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Background and Purpose The aim of this study was to characterize the response of the hypothalamic-pituitary-adrenal system in the first hours of ischemic stroke and to relate its extent to the occurrence of acute confusional state, volume of brain damage, and clinical outcome.Methods The secretion of corticotropin (adrenocorticotropic hormone [ACTH]) and cortisol was studied in 23 patients by determinations at hours 4,6,8,10, and 14 and days 1, 3, 5, and 7 after onset of symptoms. Acute confusional state (DSM-III-R criteria), extent of lesion (volumetry of computed tomographic scans), and neurological and functional outcome (Scandinavian Stroke Scale, Barthel Index scores) were assessed.Results The massive neuroendocrine response observed consisted of an initial phase with concomitantly increased levels of ACTH and cortisol and a second phase with de-I nfection, trauma, or mental stress results in an increase in levels of cortisol. 1 Increased concentrations of cortisol and a failure of the normal suppression of cortisol levels by dexamethasone have also been observed in acute stroke. 24A number of studies have demonstrated the neurotoxicity of cortisol, 58 suggesting that strong activation of the hypothalamic-pituitary-adrenal (HPA) axis may be an aggravating factor in acute cerebral ischemia. Increased plasma and urinary cortisol levels after stroke have been found to be associated with a high mortality rate and poor functional outcome. 239 Moreover, hypercortisolism in reaction to various types of stress has recently been related to acute confusional state, 1013 which is a common symptom in acute stroke, 1416 and hypercortisolemia has been reported mainly in disoriented stroke patients. 4 However, the response of the HPA system in the important hyperacute phase of ischemic stroke has not yet been characterized. In this study the levels of these Received November 12,1993; final revision received February 3, 1994; accepted February 18, 1994. From the Department of Neurology (K.F., R.M., M.D., M.H.) and the Institute of Clinical Chemistry (R.S.), University of Heidelberg, Klinikum Mannheim (Germany).Correspondence to K. Fassbender, MD, Department of Neurology, University of Heidelberg, Theodor-Kutzer-Ufer, 68135 Mannheim, FRG. creased levels of ACTH while high concentrations of cortisol persisted. Initial levels of ACTH but not cortisol were significantly increased in patients with acute confusional state and significantly correlated with volume of brain lesion and neurological and functional outcome.Conclusions An early and persisting activation of the hypothalamic-pituitary-adrenal axis was observed in relation to severity of disease. Its characteristic biphasic pattern suggests an initial central stimulation of release of ACTH followed by feedback suppression concomitant with an increased susceptibility of the adrenal gland. Because these hormones are known to exacerbate hypoxic injury to neurons, their massive release in hyperacute stroke may increase the extent of brain damage. (Stroke. 1994;25:1105-11...

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HPA axis responsivity to dexamethasone and cognitive impairment in dementia

Cited by 33 publications

References 28 publications

Increased Numbers of Corticotropin-Releasing Hormone Expressing Neurons in the Hypothalamic Paraventricular Nucleus of Depressed Patients

Increased Numbers of Corticotropin-Releasing Hormone Expressing Neurons in the Hypothalamic Paraventricular Nucleus of Depressed Patients

Decreased Immunosuppressive Effect of Cortisol on Natural Killer Cytotoxic Activity in Senile Dementia of the Alzheimer Type

Pattern of activation of the hypothalamic-pituitary-adrenal axis in acute stroke. Relation to acute confusional state, extent of brain damage, and clinical outcome.

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