Loss of the cortisol response to naltrexone in Alzheimer's disease.

The administration of a single dose of the opiate antagonist naltrexone (NT) was accompanied by significant elevations in plasma cortisol in normal elderly subjects; in contrast, the cortisol response to NT was absent in individuals of comparable age with Alzheimer's disease (AD). The differential effect of AD on the cortisol response was not accompanied by a significant group difference in plasma prolactin in response to NT administration. Furthermore, this differential cortisol response to NT was not associated with any evident differences in age, sex ratio, plasma levels of naltrexone or its major metabolite beta-naltrexol, or with differences in measures of nonspecific stress, such as plasma free MHPG, pulse, or blood pressure, between the two groups. The absence of the well-characterized cortisol response to NT in AD, together with other reports of abnormal responses to other pharmacological challenges, suggests that neuroendocrine abnormalities might be an important concomitant and possibly a central contributor to the pathophysiology of Alzheimer's disease.

Chelation therapy. Unproved modality in the treatment of Alzheimer-type dementia.

Despite a dramatic increase in the understanding of the neuropathologic and neurochemical alterations accompanying Alzheimer's disease, by far the largest cause of progressive and incapacitating cognitive dysfunction in the elderly, physicians have as yet no pharmacologic agent that can be prescribed safely either to arrest or reverse this decline. This lack of effective therapeutic agents is contributing to the use by an increasing number of health professionals, including physicians and concerned families, of unproved, costly, and potentially dangerous modalities, such as chelation therapy. The purpose of this paper is to describe some individuals with Alzheimer-type dementia who have undergone chelation therapy.

Prospective strategies for cholinergic interventions in Alzheimer's disease.

The cholinergic hypothesis of memory dysfunction has guided most of the recent proposals for treating the primary symptoms of AD. The efficacy of these treatments has been severely limited. This review examines two major lines of evidence which suggest that the cholinergic hypothesis may have to be expanded and revised. The cholinergic hypothesis focuses on pre-synaptic defects. It assumes cholinoceptive neurons would function normally with adequate stimulation. Evidence is not sufficient to support this assumption. In addition, dissociations have been demonstrated between muscarinic receptor number and functional response of cholinoceptive neurons. Various measures are proposed to investigate the functional integrity of muscarinic receptors in AD patients. AD often has been characterized as a disorder produced by generalized cholinergic hypoactivity. Evidence for cortisol hypersecretion, abnormal dexamethasone suppression, and the occurrence of depressive symptoms, motoric dysfunction and sleep abnormalities in AD patients is more consistent with regional cholinergic hyperactivity than generalized hypoactivity. Resolution of these discrepancies could shed new light on the pathophysiology and treatment strategies for AD. Cholinoceptive neurons could be hypersensitive, subsensitive or have unaltered responsivity. These options would have very different treatment implications. New developments in outcome assessment which are capable of discriminating varieties of differential response to treatment can spur treatment development and improve quality of care for patients with complex disorders such as AD.

Evaluating the effects of drugs on behavior and quality of life: an alternative strategy for clinical trials.

Conventional clinical trials involve tests of hypotheses with statistics computed from values of dependent variables alone. An alternative is to test hypotheses with statistics computed from benefit/harm scores that measure longitudinal associations between dose and values of the dependent variables. The proposed standardized measure of benefit/harm quantifies the strength of evidence that a patient did either better or worse while on treatment. A benefit/harm score, particularly when obtained from a randomized, N-of-1 trial, indicates a beneficial or harmful treatment effect for the individual. Benefit/harm scores from samples of patients are evaluated with standard statistical tests, with or without group comparisons, to make inferences about populations. The proposed alternative strategy can yield within-patient indicators of treatment effect that are more reliable, valid, comprehensive, and detailed. This, in turn, could help make many population-based clinical trials more informative, cost-effective, and clinically useful for participants.

Equivalence of five forms of the Selective Reminding Test in young and elderly subjects.

This study evaluated the equivalence of five forms of the Selective Reminding Test, a widely used measure of verbal learning, 45 normal young and 45 normal elderly subjects were randomly administered three of the five test forms on three separate sessions. The five forms generally correlated well with one another and were of comparable difficulty, suggesting adequate test equivalence. Four of the five forms were particularly well matched.

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.