Large Neutral Amino Acid Changes and Delirium in Febrile Elderly Medical Patients

A hypothesized but unexplored mechanism for delirium in older persons is that changes in plasma large neutral amino acid (LNAA) concentrations alter brain serotonin levels, result in neurotoxicity, or both. Therefore we performed a prospective study of 21 acutely febrile long-term-care residents to study the relationship between LNAA changes and delirium. Plasma LNAA concentrations were evaluated during illness and 1 month later. Delirium was diagnosed by using the Confusion Assessment Method. Other data included age, body mass index, cognitive impairment, comorbidity, gender, maximum temperature, and medication use. Seven subjects (33%) were delirious during febrile illness. Although the phenylalanine (PHE)/LNAA ratio was higher during illness in both delirious and nondelirious groups, a two-sample t test demonstrated that delirium was associated with a higher illness PHE/LNAA ratio ( p 5 .03). The amount of change in PHE/LNAA from illness to recovery was not different between the delirious and nondelirious groups. Tryptophan/LNAA was not associated with delirium during illness or at recovery. These findings identify another potentially fruitful area of investigation for the prevention and treatment of delirium in older persons. ELIRIUM may be the most common, and perhaps the most important, complication of illness in older persons. Although epidemiologic studies have identified important risk factors associated with the occurrence of delirium, such as advanced age, cognitive impairment, and illness severity, knowledge regarding the pathophysiology of this difficult problem is lacking (1). One hypothesis is that changes in large neutral amino acids (LNAAs), which are precursors of several neurotransmitters that are involved in arousal, attention, and cognition, may play a role in delirium (2). All LNAAs (isoleucine, leucine, methionine, phenylalanine, tryptophan, tyrosine, and valine) enter the brain by using the same saturable carrier, in competition with each other. As the concentration of one LNAA increases, central nervous system entry of other LNAAs decline (3). For example, brain concentrations of serotonin may increase if the relative blood concentration of tryptophan (TRP) increases. Alternatively, serotonin concentrations may decrease if other LNAA concentrations are increased relative to TRP. Phenylalanine (PHE) has the additional interesting property of possible conversion to neurotoxic metabolites (4) and competes with TRP for entry into the brain and subsequent metabolism. This study tests the hypothesis that alterations in plasma LNAA concentrations, particularly the PHE/LNAA and TRP/LNAA ratios, are associated with delirium in febrile elderly patients.