Test Could Improve Detection of Prion Disease in Humans
A highly sensitive post-mortem test could help scientists more accurately determine
if a person died of Creutzfeldt-Jakob disease (CJD), a human neurological disorder
caused by the same class of infectious proteins that trigger mad cow disease,
according to a new study supported in part by the National Institutes of Health (NIH).
The finding opens the possibility that such testing might be refined in the future so it can
be used to detect prion disease in living people and animals before the onset of symptoms.
The test, called conformation-dependent immunoassay (CDI), was originally developed to detect
various forms of disease-causing proteins called prions in cows, sheep, deer and other animals.
In the new study, researchers led by Jiri Safar, M.D., Bruce Miller, M.D., Michael Geschwind, M.D.,
Stephen DeArmond, M.D., and Nobel Laureate Stanley B. Prusiner, M.D., of the University of California,
San Francisco, found that CDI not only identifies prions in human brain tissue but is faster and far more precise
than the standard immunological detection methods, which only detect a small fraction of the infectious prions that
may be in the brain.
The finding appears in the March 1, 2005 issue of the Proceedings of the National Academy of Sciences, www.pnas.org.
Two components of the NIH, the National Institute of Neurological Disorders and Stroke (NINDS)* and the National
Institute on Aging (NIA), supported the study. Additional support was provided by the John Douglas French Foundation
for Alzheimer’s research, the McBean Foundation, and the Alzheimer’s Disease Research Center of California.
“The findings of this NIH-funded research are an important step forward for the detection of prions,” said
Michael Nunn, Ph.D., NINDS program director for prion research. “It has been very difficult to generate diagnostic
tests in this area and these results are a significant improvement for the diagnosis of CJD in living people.”
In the study, Prusiner and his colleagues extracted brain tissue from 28 people who had died of CJD. They tested
these samples using CDI, which uses highly specific antibodies that bind to all disease-causing prions in the brain.
They also used immunohistochemistry (IHC) to measure only the prion proteins that are resistant to an enzyme called
protease. Protease-resistant prions are abnormal and usually infectious, meaning they can cause CJD and other
neurodegenerative diseases. CDI detected abnormal prions in all of the sampled brain regions. In contrast,
the researchers found that IHC detected abnormal prions in less than 25 percent of the sampled brain regions.
The findings, according to the researchers, suggest that CDI could be used to establish or rule out the diagnosis
of CJD with greater accuracy than IHC, particularly when a small number of samples are available. Prusiner and
colleagues are exploring the possibility of using CDI in living tissue, like blood or muscle, to detect and
diagnose prion diseases, such as CJD or bovine spongiform encephalopathy (BSE, mad cow disease) while people
or animals are still alive.
“This research not only is an important advance for the detection and diagnosis of prion diseases, but,
with the identification of protease-sensitive infectious prions, will lead to a better understanding of the
underlying disease processes,” said Andrew Monjan, Ph.D., Chief of the NIA’s Neurobiology of Aging Branch.
Prusiner received the 1997 Nobel Prize in physiology or medicine for his discovery of prions. Unlike viruses,
bacteria, fungi, and parasites, prions contain no DNA or RNA. Instead, prions are an altered type of protein
normally found within cells in humans and other organisms. These abnormal prion proteins appear to convert other,
normal prions to an abnormal shape. Many scientists now believe this conversion process leads to several
dementing diseases in humans, including CJD. Similar diseases in animals include bovine spongiform
encephalopathy ("mad cow" disease) in cattle and scrapie in sheep. Abnormal, misfolded proteins contribute to
other age-related neurological diseases such as Alzheimer's and Parkinson's diseases. According to Prusiner
and his colleagues, CDI testing might eventually have a role in the diagnosis of other neurodegenerative diseases,
including Alzheimer’s and Parkinson’s, in which normally shaped proteins are structurally altered.
The NIA conducts and supports research on aging and age-related diseases,
including neurodegenerative diseases such
as Alzheimer’s disease and Parkinson’s disease. For more information on NIA’s
research programs visit its website at www.nia.nih.gov.
The National Institute of Neurological Disorders and Stroke (NINDS), also part of the NIH, conducts research
on neurological disorders and provides information to the public and to patients. For more information, please
visit the NINDS website at www.ninds.nih.gov.
* This project has been funded in whole or in part with Federal
funds from the National Institute of Neurological Disorders and Stroke, and
the National Heart, Lung, and Blood Institute of the National
Institutes of Health, under Contract No. N01-NS-0-2328.
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