Effects of acute tryptophan depletion on cognitive function in Alzheimer's disease and in the healthy elderly.

BACKGROUND: The cholinergic system is profoundly impaired in senile dementia of Alzheimer type (SDAT) and replacement therapy produces only modest clinical benefits. The serotonergic system is also impaired and may contribute both to cognitive and non-cognitive symptoms in SDAT. To investigate this further we assessed the effects of lowering brain serotonin using the technique of acute tryptophan depletion on cognitive function in patients with SDAT and in age matched control subjects. METHOD: Sixteen patients with probable SDAT and 17 healthy elderly subjects received two amino acid drinks in a within subject, double-blind, placebo-controlled, counterbalanced, crossover design. One of the drinks was nutritionally balanced and contained tryptophan (placebo), the other was identical but contained no tryptophan. A battery of detailed neuropsychological tests was performed between 4 and 6 h after the drink. Mood rating scales and other ratings of behavioural and emotional symptoms were also performed on both occasions. RESULTS: Acute tryptophan depletion resulted in impairment on tasks of working memory in both groups. There was no group specific effect. Female SDAT subjects performed better on a task of pattern recognition during acute tryptophan depletion compared with placebo. There were no changes in behavioural symptoms during acute tryptophan depletion in either group. CONCLUSION: Compromised serotonergic function may be an important contributor to cognitive decline in SDAT and in ageing. Strategies targeting specific 5HT receptors may be helpful in SDAT.

Cognitive deficit induced by acute tryptophan depletion in patients with Alzheimer's disease.

OBJECTIVE: The study assessed the effects on global cognitive function and mood of a reduction of brain serotonin by means of acute tryptophan depletion in 16 patients with dementia of the Alzheimer type and in 16 cognitively intact comparison subjects. METHOD: In a double-blind, crossover design, subjects received a tryptophan-free amino acid drink to induce acute tryptophan depletion and, on a separate occasion, a placebo drink containing a balanced mixture of amino acids. On each occasion, ratings of depressed mood were made at baseline and 4 and 7 hours later, and the Modified Mini-Mental State was administered at baseline and 4 hours later. RESULTS: Patients with dementia of the Alzheimer type had a significantly lower mean score on the Modified Mini-Mental State after acute tryptophan depletion than after receiving placebo. The comparison group showed no difference in mean score on the Modified Mini-Mental State after acute tryptophan depletion and after receiving placebo. No significant changes in mood were found in either group. CONCLUSIONS: Acute tryptophan depletion significantly impaired cognitive function in patients with dementia of the Alzheimer type. Compromised serotonergic function, in combination with cholinergic deficit, may make an important contribution to cognitive decline in dementia of the Alzheimer type.

5-Hydroxytryptamine receptor function in humans is reduced by acute administration of hydrocortisone.

5-Hydroxytryptamine1A (5-HT1A) receptors have been shown to be suppressed by corticosteroid hormones in a variety of animal experimental paradigms. It has been suggested that this effect may be central to the pathophysiology of severe clinical depressive illness, a condition in which 5-HT1A receptor function is reduced and corticosteroid hormones are elevated. We report the effects of acute administration of hydrocortisone in normal volunteers on a neuroendocrine model of 5-HT1A receptor function. Fifteen healthy male volunteers took part in a random order, double blind, placebo controlled study, in which 100 mg hydrocortisone or placebo was administered 11 h before infusion of L-tryptophan (L-TRP). Pre-treatment with hydrocortisone significantly reduced the growth hormone (GH), but not the prolactin (PRL) response to the infusion. These data are consistent with the view that acute administration of corticosteroid hormones significantly impairs 5-HT1A receptor mediated function in healthy human volunteers and are in line with animal studies of the effects of corticosteroid hormones on 5-HT1A receptors. We propose that this finding is relevant to the pathophysiological processes which cause severe depressive illness.