HPA axis responsivity to dexamethasone and cognitive impairment in dementia.

1. Animal and human studies suggest a possible relationship between dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and cognitive impairment. 2. In animals, prolonged exposure to high plasma cortisol levels causes irreversible hippocampal damage. 3. Abnormal cortisol plasma levels in response to dexamethasone challenge have been frequently observed in dementia of Alzheimer's type (DAT) patients. 4. The authors studied the relationship of responsivity of the HPA axis to cognitive impairment in 34 DAT patients drug free for at least 10 days. A decrease in HPA axis responsivity significantly correlated with greater cognitive impairment.

The relationship between cognitive impairment plasma cortisol levels and HPA responsibility to dexamethasone in dementia.

Previous studies show an association between increased plasma cortisol levels and aging, a process which is also associated with some deterioration of cognition. Animal studies demonstrated damage to pyramidal cells in the hippocampus, secondary to increased cortisol secretion. Conditions in which high cortisol plasma levels are encountered suggest an association between elevated cortisol levels and cognitive impairment. 34 patients drug free for at least 10 days, were challenged by 0.5mg dexamethasone. Pre- and post-challenge cortisol plasma levels were determined by RIA. Cognitive functioning was assessed by the GDS (34 subjects) and later also by the MMSE (17 subjects). Mean GDS score was 5.2 +/- 1.1 (Mean +/- SD) and mean MMSE score was 11.3 +/- 5.8. Mean preDEX and postDEX cortisol plasma levels were 17.03 +/- 6.67 micrograms/dl and 9.95 +/- 6.70 micrograms/dl respectively. Grouping patients by severity of dysfunction, we found that the more severely impaired patients had significantly higher postDEX cortisol levels 7.04 +/- 6.25 vs 12.87 +/- 5.96 (t = -2.7 P less than 0.009 for the GDS scale and 5.74 +/- 6.1 vs 13.82 +/- 6.32, (t = 02.63 P less than 0.019 for the MMSE scale) but no significant difference for preDEX cortisol levels. The Index of HPA Responsivity, defined as: (PreDEX Cortisol-PostDEX Cortisol)/Pre DEX Cortisol+PostDEX Cortisol), was significantly lower for the more impaired patients indicating a less responsive HPA axis in those patients. Pearson correlation between the Index vs the GDS and MMSE scores was -0.43 (F = 7.11, P less than 0.012, n = 34) and 0.49 (F = 4.89, P less than 0.043, n = 17) respectively. Age did not seem to play an important role in this sample. These findings support a relationship between plasma cortisol levels and cognitive impairment. The Index of Responsivity, a dynamic measure of the system, is suggested for future studies.

A prostaglandin theory of neuroleptic malignant syndrome.

A subgroup of patients with schizophrenia or other psychoses may have an increased PGE receptor sensitivity in the brain, which may be due to low levels of PGE. Some of these patients may develop a severe dopaminergic blockade when given neuroleptics which stimulate PGE synthesis. This may lead to the symptoms of neuroleptic malignant syndrome. Calcium channel blockers inhibit the prostaglandin output caused by norepinephrine and these agents may prove useful in the treatment of neuroleptic malignant syndrome.