Faculty Bibliography

Despite widespread use of antidepressants, major gaps remain in our knowledge of the effects of antidepressants on human performance. While most single-dose studies with normal subjects have suggested that the more sedating tricyclic antidepressants tend to produce impairment, the effects of antidepressant treatment in clinical populations have been less thoroughly examined, with both drug-induced impairment and improvement reported. This review suggests that factors such as age, diagnosis, drug plasma concentration, and length of treatment need to be explored to establish the effects of antidepressants on performance in clinical populations

The concentration of corticotropin-releasing factor-like immunoreactivity (CRF-LI) in the cerebrospinal fluid (CSF) of 15 probable Alzheimer's disease (AD) patients with mild to moderate dementia and 10 neurologically normal age-matched controls was examined. There were no significant alterations in the mean CSF CRF-LI concentration in AD compared to controls. However, in the AD group, CSF CRF-LI correlated significantly with the global neuropsychological impairment ratings, suggesting that greater cognitive impairment was associated with lower CSF CRF-LI concentrations. There was a significant reduction in the CSF concentration of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the AD patients, and there was a positive correlation between the concentration of CRF-LI and 5-HIAA in CSF. This latter finding suggests that serotoninergic neuronal systems may interact with CRF-containing neurons

The authors studied CSF gamma-aminobutyric acid (GABA) in 14 Alzheimer patients and nine age-matched normal subjects. The five normal subjects who were wives of the demented patients had higher CSF GABA concentrations than the four normal subjects without demented spouses

In contrast to the well established presynaptic cholinergic deficits which are associated with Alzheimer's Disease (AD), the functional status of the remaining muscarinic receptors has not received adequate attention. This paper examined the possibility that the presynaptic cholinergic deficits in AD may be accompanied by muscarinic supersensitivity. While the majority of QNB binding studies have failed to find an upregulation of muscarinic receptors in AD patients, most of those studies did not differentiate between presynaptic and postsynaptic receptors. In addition, receptor density and functional response are not necessarily correlated. To determine whether AD is accompanied by alterations in the functional status of central muscarinic receptors, we studied the biological responses to a muscarinic agonist in AD patients and controls. In this pilot study, AD patients demonstrated an increased arecoline-induced HVA response in the CSF. This finding is consistent with the hypothesis that AD is accompanied by muscarinic supersensitivity

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

Cerebrospinal fluid (CSF) from patients with Alzheimer's disease (AD) and controls was analyzed by one- and two-dimensional gel electrophoresis, electron microscopy, and fluorescence microscopy with thioflavin S staining. In CSF from patients with AD, abnormal proteins were found following two-dimensional gel electrophoresis and silver staining. In CSF samples from most of the AD patients studied, a highly argentophilic material was detected upon silver staining the stacking gel of the one-dimensional gels. Electron microscopy of material eluted from the stacking gel showed fibers of approximately 7-10 nm diameter, with some twisting; properties consistent with paired helical filaments or amyloid. Furthermore, material with the characteristics of amyloid (fiber diameter ranging from 4-10 nm) was found in the CSF sediment. The CSF from AD patients had significantly elevated numbers of yellow fluorescent particles following thioflavin S staining when compared with age-matched, other neurological disease controls. We did not see an increase in autofluorescence, indicating that thioflavin S staining is specific. Our data suggest that AD CSF contains plaque amyloid and possibly proteins from neurofibrillary tangles. The thioflavin S staining method appears to have potential for development as a diagnostic tool

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