The 14-3-3 brain protein in cerebrospinal fluid as a marker for transmissible spongiform encephalopathies.
BACKGROUND
There is no practical and reliable premortem test for Creutzfeldt-Jakob disease and the related transmissible spongiform encephalopathies. Two proteins, designated 130 and 131, which have been detected in low concentrations in cerebrospinal fluid from patients with Creutzfeldt-Jakob disease, appear to be sensitive and specific markers for the disease. Attempts to identify these proteins, however, have been unsuccessful. We hypothesized that they may be present in the normal brain.


METHODS
We detected proteins 130 and 131 in normal human brain, partially sequenced their amino acids, and found that they matched the brain protein known as 14-3-3. We then developed a simple, rapid immunoassay for this protein and tested it in cerebrospinal fluid samples from 71 humans and 30 animals with spongiform encephalopathies and in control samples from 186 humans and 94 animals.


RESULTS
The immunoassay detected the 14-3-3 protein in cerebrospinal fluid from 68 of the 71 patients with Creutzfeldt-Jakob disease (96 percent, 95 percent confidence interval, 92 to 99 percent). Among 94 patients with other dementias, the specificity was 96 percent. If one excludes the three patients with dementia who had strokes within one month before testing, the specificity was 99 percent. The test was positive in 12 of 24 patients with viral encephalitis. In animals the sensitivity of the assay was 87 percent and the specificity was 99 percent.


CONCLUSIONS
In patients with dementia, a positive immunoassay for the 14-3-3 brain protein in cerebrospinal fluid strongly supports a diagnosis of Creutzfeldt-Jakob disease. This finding, however, does not support the use of the test in patients without clinically evident dementia.
Hsich
G
G
Laboratory of Central Nervous System Studies, National Institutes of Health, Bethesda, MD 20892-4122, USA.
Kenney
K
K
Gibbs
C J
CJ
Lee
K H
KH
Harrington
M G
MG
D048948:14-3-3 Proteins; D000595:Amino Acid Sequence; D000818:Animals; D015415:Biomarkers / Q000134:cerebrospinal fluid; D002556:Cerebrospinal Fluid Proteins / Q000032:analysis* / Q000737:chemistry; D007562:Creutzfeldt-Jakob Syndrome / Q000134:cerebrospinal fluid / Q000175:diagnosis*; D003704:Dementia / Q000134:cerebrospinal fluid / Q000175:diagnosis; D015180:Electrophoresis, Gel, Two-Dimensional; D006801:Humans; D007118:Immunoassay / Q000379:methods; D008969:Molecular Sequence Data; D017096:Prion Diseases / Q000134:cerebrospinal fluid / Q000175:diagnosis; D011506:Proteins / Q000032:analysis* / Q000737:chemistry; D012680:Sensitivity and Specificity; D014446:Tyrosine 3-Monooxygenase
D048948:14-3-3 Proteins; D015415:Biomarkers; D002556:Cerebrospinal Fluid Proteins; D011506:Proteins; D014446:Tyrosine 3-Monooxygenase