Choline is a precursor of several essential compounds in the brain, including the neurotransmitter acetylcholine and the membrane phospholipids phosphatidylcholine and sphingomyelin. Choline, itself, is not synthesized in brain in substantial qualities, and animal studies suggest that brain choline is primarily obtained from the diet. The development and application of an in vivo magnetic resonance spectroscopy (MRS) provides the capability to study the specific uptake and metabolism of choline in human brain during life. Using proton MRS we have performed the first studies showing that in adult humans, as in animals, choline- containing compounds in brain increase as blood levels rise following ingestion of choline. In addition, we have observed that choline uptake from blood to brain is reduced to very low levels in most healthy adults over age 60. Preliminary studies further suggest that this process begins in middle age, by which time there is wide interindividual variation in brain choline uptake, with some individuals showing both low uptake and reduced performance on cognitive tasks. An inability to transport choline efficiently into brain may lead to a deficiency of choline-containing compounds in brain and may be a factor underlying the loss of neurons, and cholinergic neurons in particular, commonly seen with age. To better understand the causes and consequences of this age-related decrease in brain choline uptake, we propose the following experiments: (1) Determining whether there is a relationship between brain choline uptake and measures of (a) cognitive performance and mood (b) mass and neuronal density and (c) catabolism of choline-containing membrane phospholipids; (b) determining whether there is an association between brain choline uptake and late life onset of two illnesses associated with cholinergic dysfunction, depression or dementia; and (3) obtaining evidences as to the mechanism underlying age-related reduction in brain choline uptake, specifically whether reduced net uptake with age is due to decreased transport of choline across the blood-brain barrier or decreased phosphorylation, and consequent trapping, of choline in brain. The results of these studies taken together will further define the degree and functional significance of a major physiologic changes associated with aging and psychiatric illness. In addition, the proposed experiments represent a unusual opportunity to study an age-related decline in function in adult humans which may be addressable by nutritional or pharmacologic means.

R01MH057520

1998-04-10

2004-01-31