Proton MR spectroscopy monitors neural progenitor cells in human brain

Researchers have discovered a unique biomarker for neural progenitor and stem cells detectable with 3T proton MR spectroscopy. It noninvasively establishes the presence of the cells and their decreasing prominence with age in the brains of children, adolescents, and adult humans.

Principal investigator Dr. Mirjana Maletic-Savatic and colleagues at the State University of New York at Stony Brook, Cold Spring Harbor Laboratory, and Brookhaven National Laboratory identified the presence of neural stem and progenitor cells (NPCs) by following an MR spectrum with a profile featuring a prominent peak at the frequency of 1.28 ppm that is unique to those cells.

The biomarker was further validated using bromodeoxyuridine (BrdU) to label dividing cells in both ex vivo and in vivo mouse experiments. Neurogenesis was stimulated by electroconvulsive shock.

The 1.28 ppm biomarker most likely represents a mixture of lipids that includes saturated fatty acids and monounsaturated fatty acids, according to the authors. The precise relationship of the lipid mixture with neurogenesis has not yet been established.

The study was published in the Nov. 9 issue of Science (2007;318:980-985).

"The implications are huge if reproduced independently," said Jeff W.M. Bulte, Ph.D., director of the Institute for Cell Engineering at Johns Hopkins University School of Medicine. "It looks like they have a peak that is fairly specific. I think this will generate a lot of interest."

Bulte, who was not involved in the study, anticipates a rush of animal studies to explore the potential of the new biomarker for a wide range of questions - and possible drug therapies - in neurology and psychiatry, particularly depression and bipolar disorder.

The researchers have already made significant progress in human studies. Following the initial discovery and verification, Maletic-Savatic and her team demonstrated for the first time in vivo an age-related decrease in neurogenesis in the hippocampus of normal individuals from preadolescence to adulthood.

Proton MRS was performed at 3T on three preadolescents (ages eight to 10), three adolescents (ages 14 to 16), and five adults (ages 30 to 35) to record any age-related changes in the density of endogenous NPCs in the hippocampus.

Maletic-Savatic found that declines in amplitude at 1.28 ppm correlated with the increasing age of the subjects.

For the preadolescents, the 1.28 ppm mean peak area was 50 x 10^-6 (±4 x 10^-6). For the adolescents, the mean peak area was 26 x 10^-6 (±3 x 10^-6), and for the adults, it was 4 x 10^-6 (±14 x 10^-6). All the differences were highly statistically significant.

"These are the first data from the living human brain that indicate a decrease in NPCs during brain development from childhood to adulthood," the authors wrote.

The decrease in neurogenesis in humans was greater than expectations based on the results of animal studies, Maletic-Savatic said in an interview with Diagnostic Imaging. The effect of the decrease on the aging human brain is unknown.

Maletic-Savatic said her work complements findings published earlier this year by Dr. Scott A. Small and colleagues at the Columbia University College of Physicians and Surgeons who reported another noninvasive in vivo correlate of neurogenesis - MRI measurements of cerebral blood volume (Proc Natl Acad Sci USA 104, 5638-5643).

Small's correlate, which was applies to both rodents and humans, represents neural cell differentiation and integration.

"These are the two sides of the pathway," Maletic-Savatic said.

She is collaborating with Small and other researchers on studies to explore the role of NPCs in depression.

The study in Science follows a 2006 report by Bulte and others, in which they reported using proton NMR spectroscopy to identify the major low-molecular-weight metabolites in murine embryonic stem cells and their neural stem cell derivatives - potential markers to study the effects of differentiation on cell metabolism (Magn Reson Med 2006;56:666-670).

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