Fourteen Three Three Protein

In the United States, approximately 1 in every 6,239 deaths are due to Creutzfeldt-Jakob disease (CJD) every year. This equates to approximately 400 to 500 cases per year. The main indications for testing for CJD are rapidly developing dementia and a range of neurological symptoms including unsteady gait, hallucinations, and sudden jerking movements. 

For many years, the only laboratory tests for prion disease were assays for 14-3-3 and total Tau proteins in cerebrospinal fluid (CSF). However, these are non-specific biomarkers of neuronal injury and their specificity for prion disease is relatively low. 

Many conditions besides CJD can cause these tests to be positive. Examples include Alzheimer's Disease, frontotemporal dementia, autoimmune encephalopathy, CNS infections, stroke, seizures, traumatic head injury, etc.).

The 14-3-3 proteins are a group of highly conserved proteins composed of several isoforms that are involved in the regulation of protein phosphorylation and mitogen actived protein kinase pathways. The beta, gamma and theta isoforms are found in tissues of the nervous system. 

Increased concentrations of 14-3-3 gamma proteins have been detected in the CSF of patients with various forms of Creutzfeldt-Jakob disease (CJD). However, not all patients with CJD had an increased concentration of 14-3-3 protein in CSF. The sensitivity is 68%.  

Subarachnoid hemorrhage, encephalitis, stroke with acute infarction, multi-infarct dementia, brain neoplasm, and paraenoplastic neurological disorders may cause false-positive results.

The reference range for 14-3-3 protein is 173-1999 AU/mL.

In 2015, The National Prion Disease Pathology Surveillance Center (NPDPSC) at Case Western Reserve introduced the second generation Real-Time Quaking Induced Conversion test (RT-QuIC) to aid in the diagnosis of prion disease from CSF samples. RT-QuIC is the only prion specific antemortem clinical laboratory test available for the diagnosis of prion disease aside from brain biopsy. RT-QuIC has a sensitivity of 90.3% for all forms of prion disease and a specificity of 98.5%.

NPDPSC performs RT-QuIC, total Tau, and 14-3-3 gamma assays on CSF submitted for the evaluation of CJD. The likelihood of CJD is based on the combined results of these three tests.  

References

Zerr I, et al. Updated clinical diagnostic criteria for sporadic Creutzfeldt Jakob disease, Brain 2009;132:2659–68.

https://case.edu/medicine/pathology/divisions/national-prion-disease-pathology-surveillance-center/clinical/csf-testing-prion-markers