26 June 2003. Soon after the World Health Organization bestowed its approval on the protein 14-3-3 as an important diagnostic marker for sporadic Creutzfeldt-Jakob disease (sCJD), reports began to come in that its sensitivity and specificity might not be all that was advertised. Serving as an example of the woes and complexities that beset the search for reliable diagnostic tests for neurodegenerative diseases overall, a report in the current Archives of Neurology echoes this suspicion, finding that the test only identified 53 percent of sporadic CJD cases referred to a major U.S. medical center.
The family of 14-3-3 proteins, found in all mammalian cells, play normal roles in modulating signal transduction. They have been implicated in responses to stress, cell cycle control, and apoptosis. There are even hints that they might play a role in regulating the abnormal aggregation of proteins in neurodegenerative disease (see ARF related news story).
In approving elevated 14-3-3 levels as a CJD marker, the WHO was acting on studies that had indicated 14-3-3 had over 90 percent sensitivity and specificity for cases of sporadic CJD. However, subsequent studies have pointed out that many other disorders, ranging from encephalitis to stroke, result in elevated CSF 14-3-3, suggesting that the protein is a nonspecific marker for different sorts of neuronal injury. The sensitivity of the test has also been called into question.
The authors of the present study, led by Michael Geschwind of the University of California, San Francisco, used only pathology-proved cases of sCJD and included results from seven different laboratories. They acknowledge that their finding of low sensitivity could be the result of a lack of uniform laboratory standards for the test in the United States; the studies that found higher sensitivity for the test were conducted in centralized laboratories in Europe. Geschwind and colleagues argue that if inaccurate U.S. tests are the problem, then the test should not be used as a diagnostic marker in this country, as the chances of a false negative are too great. Even so, they are not convinced that the laboratory tests were inaccurate. They write that the 14-3-3 test does not deserve the prominence placed on it by the WHO guidelines, which suggested it could substitute for an electroencephalogram. In an accompanying editorial, Allen Aksamit of the Mayo Clinic in Rochester, Minnesota, agrees with these conclusions, but argues that patient selection and laboratory and methodologic differences may have skewed the results of the study somewhat. He suggests that 14-3-3 is still a valuable adjunct test.-Hakon Heimer.
Geschwind MD, Martindale J, Miller D, DeArmond SJ, Uyehara Lock J, Gaskin D, Kramer JH, Barbaro NM, Miller BL. Challenging the clinical utility of the 14 3 3 protein for the diagnosis of sporadic Creutzfeldt Jakob disease. Arch Neurol. 2003 Jun;60(6):813 6. Abstract
Aksamit AJ. Cerebrospinal fluid 14-3-3 protein: Variability of sporadic Creutzfeldt-Jakob disease, laboratory standards, and quantitation. Arch Neurol. 2003 Jun;60(6):803-4. Abstract
See also FerlLab.