October 12, 2005
ALS Association-Funded Researchers Publish Possible Biomarkers of ALS [Quick Summary: Certain molecules are either increased or decreased in the fluid surrounding the spinal cord and brain in ALS patients compared to controls that might prove useful in diagnosing ALS and in clinical trials of new ALS therapies.] Publishing in the September 29 online issue of the Journal of Neurochemistry, University of Pittsburgh researchers and collaborators funded by The ALS Association (ALSA) report on a set of molecules whose abundance is changed in patients with ALS as compared to controls. These potential biomarkers might serve to diagnose ALS earlier with more certainty and to allow better clinical trials of new therapies for the disease. “There is a critical need for biomarkers to diagnose ALS earlier and to allow improved clinical trials,” said Lucie Bruijn, Ph.D., ALSA vice president and science director. “These results are promising and bring us closer to identifying signatures specific for the disease.” A predictive panel of biomarkers would allow more rapid and accurate diagnosis for patients who often undergo months of tests and uncertainty before finding out whether they have ALS. “While continued studies are required to validate these findings, we are hopeful that biomarkers for ALS will also lead to new insights into the mechanisms of disease and help guide development of new drug therapies,” said Robert Bowser, Ph.D., Associate Professor at the University of Pittsburgh and lead investigator of the study. The scientists used cutting edge techniques to detect differences in molecules present in the fluid surrounding the spinal cord and brain (cerebrospinal fluid, abbreviated CSF). Methods now available make it possible to analyze very small amounts of fluid. By using charged surfaces of protein binding chips to separate CSF proteins and mass spectrometry to analyze proteins that bind to each chip surface, the investigators determined that certain molecules are decreased in CSF in the disease, and others increase. Almost all samples from ALS patients were from those who had sporadic disease, rather than inherited disease. People with sporadic ALS have no known genetic mutations. There is no way to predict who might develop sporadic ALS, nor are there available means to reliably diagnose ALS until the disease is quite advanced. Reliable biomarkers might change this picture. One of the molecules decreased in the CSF of ALS patients is cystatin C, which is secreted into the fluid, as is a protein called transthyretin. Increased amounts of a fragment of protein called neuroendocrine protein 7B2 were also found in the studies. The three proteins act within nerve cells to help make other proteins. The researchers consider that the changes simply reflect the loss of motor neurons with the disease. They did confirm that the spinal cord tissue of ALS patients does contain less of the two decreased molecules that are depleted in the CSF in ALS. Of course the researchers will look for any possible link of these proteins to ALS. They noted that transthyretin has shown protective effects on motor neurons in mice that have a mutation that is responsible for some inherited forms of ALS, according to findings by other investigators. No single molecule proved to be reliable enough on its own to accurately diagnose ALS. A set of markers will undoubtedly be required for any biomarker based diagnostic test, the investigators emphasized in their report. The researchers tested samples from only a hundred people examined at only two medical centers. So the investigators emphasize that larger numbers of samples need to be examined before any panel of biomarkers can be finalized as a reliable tool. Also the signature pattern of the biomarkers might change as the disease advances. Long term studies to follow ALS patients would help establish a reliable biomarker test for the disease, the researchers concluded. Bowser’s work is part of a consortium effort to find biomarkers for ALS (click here for more information). Investigators in the consortium include Merit Cudkowicz, M.D., Massachusetts General Hospital, Robert H. Brown, Jr., Ph.D., M.D., Massachusetts General Hospital; as well as Lisa Paige, Ph.D. and Rima Kaddurah-Daouk, Ph.D., of Metabolon, Inc. Support for this project came from Michael Zazlow's ZazAngels Fund. Click here for PubMed information