For release: Wednesday, September 25, 1996
A protein widely distributed in tissues throughout the body, with the highest concentration in the brain, has been shown to be a specific marker in the spinal fluid of humans and animals infected with transmissible spongiform encephalopathies, scientists say. This discovery paves the way for the development of an improved test for the diagnosis of Creutzfeldt-Jakob disease in humans and encephalopathies in animals. The test could enable precise identification of disease in British cattle presently targeted for slaughter because of suspected infection with bovine spongiform encephalopathy, known as Mad Cow disease.
Investigators at the National Institute of Neurological Disorders and Stroke (NINDS) in Bethesda, Maryland, and the California Institute of Technology in Pasadena used a simple method to accurately isolate a protein marker called 14-3-3 in the cerebrospinal fluid (CSF) of both humans and animals. Complete study results appear in the September 26, 1996 issue of the New England Journal of Medicine.*
Transmissible spongiform encephalopathies (TSEs) are degenerative diseases characterized by acute, progressive dementia and abnormal limb movements. Death follows within 4-6 months. In addition to Creutzfeldt-Jakob disease (CJD), other TSEs include kuru in humans and scrapie in sheep.
"We hope this will be the first step to producing a commercially available test that will detect TSEs in humans and animals," said NINDS Director Zach W. Hall, Ph.D. "Such a test would be enormously useful in helping to find sound solutions to the current crisis."
In the recently published study, the scientists detected the 14-3-3 protein in spinal fluid from 96 percent of patients with CJD. The test showed false positives in four percent of patients with other dementing disorders. However, the false positive rate fell to only one percent if patients with recent brain injury were excluded. Investigators also found the protein present in six of nine cattle and fifteen of fifteen chimpanzees infected experimentally with TSE. In addition, the 14-3-3 protein was detected in five of six sheep naturally infected with scrapie. Investigators theorize that as a result of TSE, nerve cells die in the brain and the normal 14-3-3 protein within neurons may leak into surrounding CSF, explaining its presence in the spinal fluid.
"Any test arising from our work would be best applied to patients already suspected of having CJD, for example, those with rapid onset dementia," said Clarence J. Gibbs, Jr., Ph.D., Acting Chief of the NINDS Laboratory of Central Nervous System Studies and one of the study's authors. "A finding of 14-3-3 in the cerebrospinal fluid of such a patient would strongly suggest a diagnosis of CJD and would rule out other dementing diseases such as Alzheimer's disease."
CJD has a worldwide incidence of 1-2 cases per million per year. It is even rarer -- 5 cases per billion -- in those under 45 years of age. Currently, diagnosis of CJD relies on detection of the characteristic pathology of the disease -- sponge-like holes in brain tissues taken during pre- or post- mortem brain biopsies or during full autopsy. These procedures often miss the site of injury, impairing diagnosis of the disease. Pre-mortem biopsies also can be dangerous for patients since they involve brain surgery.
Public interest in TSEs remains high following the April 1996 revelation that 10 Britons developed a neuropathologically distinct variant of CJD, allegedly from eating beef infected with bovine spongiform encephalopathy (BSE). The resulting calamity shut down the $6.5 billion British beef industry and caused much panic to spread throughout Europe.
"A more accurate diagnosis reduces the risk of accidental transmission of CJD, BSE, or scrapie," said study co-author Michael G. Harrington, M.B., Ch.B., F.R.C.P. (UK), of the California Institute of Technology. "More accurate diagnosis of BSE can allow a more selective culling of affected animals."
BSE has been found in British cattle for 15 years, peaking at 37,000 cases in 1992. In the late 1980s, the British government introduced several measures aimed at controlling the epidemic, including a ban on the practice of using cattle feed containing brains, spinal cord, spleen, thymus, intestines, and other organs in which the infectious agent is found. The ban, along with voluntary compliance and monitoring, caused the incidence of BSE to fall sharply. New cases still occur, although at a much lower rate (fewer than 300 per week). The British government has ordered the destruction of all cattle over 30 months of age, representing the eldest of Britain's 11 million cattle. They are the most likely to have originally been exposed to BSE from contaminated feed products. As many as 4.5 million cattle have been condemned to slaughter at a rate of 15,000 cattle per week over the next 5-6 years and at a cost of $700 million. Since the outbreak of the BSE epidemic, more than 170,000 cattle with the disease have been killed.
The agent responsible for TSEs has fueled intense discussion in scientific circles. The leading theory at this time, first hypothesized by Stanley B. Prusiner, M.D., at the University of California at San Francisco, holds that the culprit is a prion, a biologically active and infectious protein that accumulates in the brain, causing destruction. Other scientists believe a virus, bacteria, or other conventional microorganism is behind the infection.
"Our discovery says nothing of what the causative agent is, nor does it tell us anything more about transmission or the possibility that these diseases can jump from one species to another," said Dr. Gibbs. "What it does is open up a new way of identifying these disorders in humans and animals."
The NINDS, one of the National Institutes of Health located in Bethesda, Maryland, is the nation's leading supporter of research on the brain and nervous system and a lead agency for the Congressionally designated Decade of the Brain.
*Hsich, Gary; Kenney, Kimbra; Gibbs, Jr., Clarence J.; Lee, Kelvin H.; Harrington, Michael G. "The 14-3-3 Brain Protein in Cerebrospinal Fluid as a Marker for Transmissible Spongiform Encephalopathies." New England Journal of Medicine, Vol. 335, No. 13, (pp. 924-930).
Originally prepared by Stephanie Clipper, Margo Warren, and Natalie Larsen, NINDS Office of Communications and Public Liaison.