Bonnie M. Davis

RS 86 in the treatment of alzheimer's disease: Cognitive and biological effects

Twelve patients who met Research Diagnostic Criteria for Alzheimers disease (AD) completed a double-blind crossover study comparing oral RS 86, a long-acting and specific muscarinic agonist, with placebo. Cognitive and noncognitive effects were assessed with the Alzheimers Disease Assessment Scale (ADAS). RS 86 was found to improve ADAS test scores consistently (both cognitive and noncognitive subscales) in seven patients, with a clinically obvious improvement in only two patients. RS 86 produced a significant increase in peak nocturnal cortisol levels, and this increase correlated with improvement on ADAS testing. Similarly, there was a 38% increase in amplitude of the P300 evoked potential with RS 86. The biological findings suggest that RS 86 was effective only to the extent that it enhanced central cholinergic activity.

Clinical studies of the cholinergic deficit in Alzheimer's disease. I. Neurochemical and neuroendocrine studies.

Autopsy studies indicating that cholinergic neurons are selectively lost in patients with Alzheimers disease (AD) and senile dementia of the Alzheimer type (SDAT) suggest that peripheral markers for central cholinergic activity would be useful in diagnosis. The present studies found that cerebrospinal fluid (CSF) concentrations of acetylcholine (ACh) correlated with the degree of cognitive impairment (r = .70) in a sample of carefully diagnosed patients with AD/SDAT, but metabolites of other neurotransmitters were not related to cognitive state; this suggests that CSF ACh may be a valid measure of cholinergic degeneration. cortisol and growth hormone were measured in plasma samples drawn from patients and controls every 30 minutes from 2100 to 1100 hours the next day. Mean plasma cortisol concentrations were higher in patients with AD/SDAT than in controls and correlated inversely with CSF methoxy‐hydroxyphenylglycol (MHPG) (r = .61) and positively with degree of cognitive impairment (r = +.53); as anticholinergic drugs suppress cortisol this finding indicates that cortisol dysregulation may be a marker for abnormalities in other neurotransmitter systems, particularly the noradrenergic system. Growth hormone secretion was not different in patients and controls but was positively correlated with CSF MHPG (r = + .63).

CSF Somatostatin in alzheimer's disease, depressed patients, and control subjects ☆

The widespread use of the NINCDS criteria for Alzheimer’s disease (McKhann et al. 1984) has substantially improved diagnostic accuracy; however, the degree of misdiagnosis is still in the range of lo%-20% (Barclay et al. 1986). Thus, continuing investigations seek a readily accessible antemortem marker of Alzheimer’s disease. A logical point of initiation in a search for an antemortem biological marker is with the neurochemical changes that have been consistently reported in postmortem examinations of Alzheimer’s brains. Although a number of neurotransmitters have been reported to be decreased in some subgroups of Alzheimer’s patients, the most consistent abnormalities appear to involve acetylcholine (Perry 1987) and the neuropeptide somatostatin (Rossor et al. 1980; Davies and Terry 198 1). Cerebrospinal fluid (CSF) concentrations of somatostatin have been reported to be reduced

Effects of cholinergic stimulation on pituitary hormone release

Abstract Physostigmine was infused into human volunteers to assess the effect of central cholinergic stimulation on memory and on neuroendocrine function. Methscopolamine bromide, a peripheral anticholinergic agent, was given simultaneously. The lower dose of physostigmine (1.0 mg) produced no change in AVP, cortisol, melatonin, GH or LH in those subjects without unpleasant cholinergic side effects. Larger doses of physostigmine usually produced nausea, and were associated with marked elevations of AVP, cortisol and prolactin, but no change in GH, LH or melatonin. Thus, cholinergic agents easily induce a stress response, but the GH component of this response can be suppressed by peripheral cholinergic blockade.

Clinical studies of the cholinergic deficit in Alzheimer's disease. II. Psychopharmacologic studies.

Two studies investigated the ability of physostigmine, given both intravenously and orally, to reduce symptoms of Alzheimers disease. Intravenous physostigmine significantly and reliably enhanced memory in 13 of 16 patients tested, but the dose producing the improvement varied among patients. Oral physostigmine decreased overall symptom severity in a reliable way in seven of 12 patients tested. The extent of improvement was correlated with the increase in mean cortisol secretion produced by physostigmine, suggesting that the drug improved behavior and cognition only to the extent that it had a specific central cholinomimetic effect. There was no significant association between response to physostigmine and results of a dexamethasone suppression test and physostigmine had no effect on growth hormone secretion.

Effects of propantheline bromide on basal growth hormone, cortisol and prolactin levels

Propantheline bromide, a peripheral anticholinergic drug with muscarinic and nicotinic blocking properties, was given by mouth to normal young men. Propantheline (45 mg) significantly lowered basal growth hormone concentrations at 0800 hr, 12 hr after administration. Propantheline (30 mg) tended (p = 0.08) to lower growth hormone concentrations at 1200 hr, 16 hr after administration. Cortisol and prolactin levels were not changed 12, 16 and 20 hr after propantheline (30 mg) nor 12 hr after propantheline (45 mg).

Gamma-hydroxybutyrate in the treatment of schizophrenia

Gamma-Hydroxybutyrate (GHB) inhibits firing of dopaminergic neurons and is thus potentially useful in the treatment of schizophrenia. GHB was administered to 10 schizophrenics concurrently with low-dose fluphenazine in a 6-week double-blind crossover study. No antipsychotic efficacy of GHB was noted. GHB had little if any effect on plasma prolactin levels after a single administration and caused few side effects. Trials with higher doses of GHB may be warranted.

Neuroendocrine dysfunction in Alzheimer's disease: results following TRH stimulation

Several neuroendocrine abnormalities, including abnormal responses to thyrotropin-releasing hormone (TRH), have been reported in patients with Alzheimers disease (AD). Some (e.g., Sunderland et al 1985; Thomas et al 1987.) but not all (e.g., El Sobky et al 1986; Molchan et al 1991; Peabody et al 1986) studies have found diminished thyroid-stimulating hormone (TSH) responses to TRH in AD patients. Prolactin (PgL) responses to TRH have been found to be elevated (El Sobky et al 1986; Peabody et al 1986), diminished (Newhouse et al 1986), or unchanged (Franceshi et al 1988; Thomas et al 1987) in AD. Growth hormone (GH) responses have been found to be increased (Thomas et al 1987) or unchanged (Peabody et al 1986). Cortisol responses to TRH have not been studied by elevations in basal corUsol (Davis et a11986), blunted cortisol circadian rhythms (Raskind et al 1982), and escape from dexamethasone suppression (Greenwald et al 1986) have been

Human and Animal Studies With Cholinergic Agents: How Clinically Exploitable is the Cholinergic Deficiency in Alzheimer’s Disease

Studies of brain neurotransmitter systems in patients with a diagnosis of Alzheimer’s Disease (AD) repeatedly demonstrated a deficit in the cholinergic system (Davies and Maloney, 1976) suggesting that a rational treatment approach would be the pharmacologic enhancement of cholinergic activity. Pharmacologic strategies employed in this attempt included: increasing Acetylcholine (ACh) synthesis by precursor loading; limiting ACh breakdown by inhibiting Acetylcholine Esterase (AChE); administration of direct receptor agonists; a combination of two pharmacologic strategies. This paper reviews animal and clinical data that attempt central cholinergic augmentation.