Test Code (รหัสการทดสอบ):
090-81-2025
Order Name (ชื่อการทดสอบ):
Creutzfeldt-Jakob Disease (CJD) Evaluation, CSF **
Clinical Information (ข้อมูลทางคลินิก):
This evaluation is intended for use in patients with suspected Creutzfeldt-Jakob disease (CJD) and other human prion diseases. CJD is a rare and fatal neurodegenerative disorder that predominantly affects the brain and is caused by misfolded prion proteins (PrP[Sc]). CJD accounts for more than 90% of human prion diseases. Initial symptom onset is heterogenous but commonly includes rapidly progressive dementia, cerebellar ataxia, and myoclonus. The timeline of symptom progression and the pattern of symptom evolution can be divergent across patients and CJD subtypes, making an accurate diagnosis based on clinical presentation alone challenging. The inclusion of biomarkers with high diagnostic accuracy has improved the differentiation of CJD and related prion diseases from treatable neurological conditions with overlapping phenotypes. The real-time quaking-induced conversion (RT-QuIC) assay in cerebrospinal fluid (CSF) has been established to have strong clinical utility for early and accurate diagnosis of CJD through numerous independent studies. Furthermore, the robustness and reproducibility of the RT-QuIC assay for CJD across laboratories has been demonstrated through international ring trials. The clinical sensitivity and specificity of second-generation RT-QuIC assays in CSF have been consistently reported to be greater than or equal to 92% and greater than or equal to 99%, respectively. Despite the high diagnostic accuracy of the assay, RT-QuIC results should be interpreted in the appropriate clinical context along with other clinical and paraclinical findings. A definitive diagnosis of sporadic prion disease can be established only through neuropathological assessment of brain tissue.
Unexpectedly negative RT-QuIC test results should prompt careful consideration of the differential diagnosis. If there is high suspicion of prion disease, repeat RT-QuIC testing may be warranted. A small subset of cases initially negative by RT-QuIC may become positive as the disease progresses. However, RT-QuIC may be persistently negative in a small proportion of patients with definitive prion disease. False-negative RT-QuIC results are most often encountered in cases of genetic prion disease (eg, fatal familial insomnia and Gerstmann-Straussler-Scheinker disease) and in atypical sporadic prion disease subtypes (eg, MM2 cortical subtype) that have slower indolent disease progression. Other CSF biomarkers have been utilized to support the diagnosis of CJD, including 14-3-3, total Tau measurement, and the ratio of total Tau to phosphorylated Tau at threonine 181. Recent studies have indicated that the Tau ratio (total Tau to pT181-Tau or vice versa) has a very high diagnostic accuracy, which exceeds that provided by total Tau or 14-3-3 enzyme-linked immunosorbent assays (ELISA). In a cohort of probable/definite CJD cases and controls tested utilizing the Roche Total-Tau and p-Tau (threonine 181) Elecsys assays, the optimized cut-off value for total Tau (>393 ng/L) had a clinical sensitivity and specificity of 92.3% and 88.3% for CJD, respectively; and the optimized cut-off value for the total Tau to p-Tau ratio (>18) has a clinical sensitivity and specificity of 97.4% and 95.9% for CJD, respectively.
Importantly, total Tau or total Tau to p-Tau ratios utilize assay-dependent cut-off values, and cut-off values from one assay are not transferable to different assay platforms.
The National Prion Disease Pathology Surveillance Center (NPDPSC) coordinates autopsies and neuropathologic examinations on suspected prion disease cases. More information about services available at the NPDPSC may be found at https://case.edu/medicine/pathology/divisions/prion-center.
Reference Value (ค่าอ้างอิง):
RT-QuIC PRION, CSF: Negative
t-TAU/p-TAU: < or =18
TOTAL TAU: < or =393 pg/mL
Interpretation (การแปลผล):
A positive real-time quaking-induced conversion (RT-QuIC) is supportive of prion disease and, in the correct clinical context, fulfills the Centers of Disease Control and Prevention diagnostic criteria of probable prion disease.(1)
An elevated total Tau/p-Tau (threonine 181) ratio (>18) increases the likelihood of prion disease but can be seen in patients with rapidly progressive dementia due to other causes, including autoimmune encephalitis, central nervous system malignancy, seizure disorder, stroke, and other neurodegenerative diseases.
Negative results do not exclude the possibility of prion disease.
RT-QuIC = Real-time quaking-induced conversion
CAUTIONS
These test results should be interpreted in the appropriate clinical context along with other clinical and paraclinical findings. Only through neuropathological assessment of brain tissue can a definitive diagnosis of sporadic prion disease be established.
Some molecular subtypes of prion protein have been reported to have lower detectability by real-time quaking-induced conversion (RT-QuIC) assays.
Even small quantities of blood in cerebrospinal fluid (CSF) can result in false-negative RT-QuIC results.
The presence of fluorescent substances may interfere with testing and prevent an accurate interpretation of the RT-QuIC assay.
Careful consideration of the differential diagnosis is advised when RT-QuIC test results are unexpectedly negative. Repeat testing with RT-QuIC may be warranted if there is high suspicion of prion disease. A small subset of initially negative cases by RT-QuIC may become positive as the disease progresses. However, a small proportion of patients with definitive prion disease may be persistently negative by RT-QuIC. False-negative RT-QuIC results are most often encountered in cases of genetic prion disease, such as fatal familial insomnia and Gerstmann-Straussler-Scheinker disease, and in atypical sporadic prion disease subtypes that have slower indolent disease progression.
In rare cases, some individuals can develop antibodies to mouse or other animal antibodies (often referred to as human anti-mouse antibodies [HAMA] or heterophile antibodies), which may cause interference in some immunoassays. The presence of antibodies to streptavidin or ruthenium can also rarely occur and may interfere in this assay. Caution should be used in interpretation of results, and the laboratory should be alerted if the result does not correlate with the clinical presentation.
Clinical Reference (เอกสารอ้างอิง):
1. Centers for Disease Control and Prevention (CDC), National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Division of High-Consequence Pathogens and Pathology (DHCPP). Diagnostic criteria: CDC’s diagnostic criteria for Creutzfeldt-Jakob disease (CJD), 2018. CDC; Updated October 18, 2021. Accessed January 15, 2024. Available at www.cdc.gov/prions/cjd/diagnostic-criteria.html
2. Hermann P, Appleby B, Brandel JP, et al. Biomarkers and diagnostic guidelines for sporadic Creutzfeldt-Jakob disease. Lancet Neurol. 2021;20(3):235-246
3. Rhoads DD, Wrona A, Foutz A, et al. Diagnosis of prion diseases by RT-QuIC results in improved surveillance. Neurology. 2020;95(8):e1017-e1026
4. Hamlin C, Puoti G, Berri S, et al. A comparison of tau and 14-3-3 protein in the diagnosis of Creutzfeldt-Jakob disease. Neurology. 2012;79(6):547-552
5. Shir D, Lazar EB, Graff-Radford J, et al. Analysis of clinical features, diagnostic tests, and biomarkers in patients with suspected Creutzfeldt-Jakob disease, 2014-2021. JAMA Netw Open. 2022;5(8):e2225098
6. Skillback T, Rosen C, Asztely F, Mattsson N, Blennow K, Zetterberg H. Diagnostic performance of cerebrospinal fluid total tau and phosphorylated tau in Creutzfeldt-Jakob disease: results from the Swedish Mortality Registry. JAMA Neurol. 2014;71(4):476-483
7. Hermann P, Haller P, Goebel S, et al. Total and phosphorylated cerebrospinal fluid Tau in the differential diagnosis of sporadic Creutzfeldt-Jakob disease and rapidly progressive Alzheimer's disease. Viruses. 2022;14(2):276